Risperidone Versus Other Atypical PDF

Risperidone versus other atypical antipsychotics for
schizophrenia (Review)
Komossa K, Rummel-Kluge C, Schwarz S, Schmid F, Hunger H, Kissling W, Leucht S
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2013, Issue 1
http://www.thecochranelibrary.com
Risperidone versus other atypical antipsychotics for schizophrenia (Review)

Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Analysis 1.1. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 1 Global state: 1a. No clinically significant
response (as defined by the original studies). . . . . . . . . . . . . . . . . . . . . . . . 157
Analysis 1.2. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 2 Global state: 1b. No clinically important
change (as defined by the original studies). . . . . . . . . . . . . . . . . . . . . . . . . 158
Analysis 1.3. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 3 Global state: 1c. Relapse - medium term
(as defined by the original studies). . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Analysis 1.4. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 4 Leaving the study early. . . . . 160
Analysis 1.5. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 5 Mental state: 1a. General - no clinically
important change - medium term (less than 50% PANSS total reduction). . . . . . . . . . . . . . 161
Analysis 1.6. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 6 Mental state: 1b. General - no clinically
important change - short term (less than 20% PANSS total reduction). . . . . . . . . . . . . . . 161
Analysis 1.7. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 7 Mental state: 1c. General - no clinically
important change - medium term (less than 50% BPRS total reduction). . . . . . . . . . . . . . 162
Analysis 1.8. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 8 Mental state: 1d. General - no clinically
important change - short term (less than 40% BPRS total reduction). . . . . . . . . . . . . . . 162
Analysis 1.9. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 9 Mental state: 1e. General - average
endpoint score - (PANSS total, high = poor). . . . . . . . . . . . . . . . . . . . . . . . 163
Analysis 1.10. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 10 Mental state: 1f. General - average
endpoint score - BPRS total score (high = poor). . . . . . . . . . . . . . . . . . . . . . . 164
Analysis 1.11. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 11 Mental state: 2a. Positive symptoms -
average endpoint score - (PANSS positive, high = poor). . . . . . . . . . . . . . . . . . . . 165
Analysis 1.12. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 12 Mental state: 2b. Positive symptoms -
average endpoint score - short term (BPRS positive, high = poor). . . . . . . . . . . . . . . . . 166
Analysis 1.13. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 13 Mental state: 3a. Negative symptoms
- average endpoint score (PANSS negative, high = poor). . . . . . . . . . . . . . . . . . . . 167
Analysis 1.14. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 14 Mental state: 3b. Negative symptoms
- average endpoint scale (SANS total, high = poor). . . . . . . . . . . . . . . . . . . . . . 168
Analysis 1.15. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 15 General functioning: General 1a. No
clinically important change - medium term (less than 50% SOFAS total score reduction). . . . . . . . 168
Analysis 1.16. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 16 General functioning: General 1b.
average endpoint score - (SOFAS total score, high = poor). . . . . . . . . . . . . . . . . . . 169
Analysis 1.17. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 17 Adverse effects: 1. General - at least
one adverse effect. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Analysis 1.18. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 18 Adverse effects: 2. Death. . . 171
Analysis 1.19. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 19 Adverse effects: 3a. Cardiac effects -
QTc prolongation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
Risperidone versus other atypical antipsychotics for schizophrenia (Review) i
Analysis 1.20. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 20 Adverse effects: 4a. Central nervous
system - sedation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
Analysis 1.21. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 21 Adverse effects: 4b. Central nervous
system - seizures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Analysis 1.22. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 22 Adverse effects: 5a. Extrapyramidal
effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Analysis 1.23. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 23 Adverse effects: 5b Extrapyramidal
effects - scale measured. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
Analysis 1.24. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 24 Adverse effects: 6. Prolactin associated
side effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Analysis 1.25. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 25 Adverse effects: 8a. Metabolic effects
- weight gain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
Analysis 1.26. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 26 Adverse effects: 8b Metabolic effects -
weight gain - change from baseline in kg. . . . . . . . . . . . . . . . . . . . . . . . . 179
Analysis 2.1. Comparison 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term, Outcome 1 Global state: 1a.
No clinically significant response (as defined by the original studies). . . . . . . . . . . . . . . . 179
Analysis 2.2. Comparison 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term, Outcome 2 Global state: 1b.
No clinically important change (as defined by the original studies). . . . . . . . . . . . . . . . 180
Analysis 2.3. Comparison 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term, Outcome 3 Leaving the study
early. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Analysis 2.4. Comparison 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term, Outcome 4 Mental state: 1a.
General - average endpoint score (PANSS total, high = poor). . . . . . . . . . . . . . . . . . 182
Analysis 2.5. Comparison 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term, Outcome 5 Mental state: 2.
Positive symptoms average endpoint score (PANSS positive, high = poor). . . . . . . . . . . . . . 182
Analysis 2.6. Comparison 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term, Outcome 6 Mental state: 3.
Negative symptoms - average endpoint score - (PANSS negative, high = poor). . . . . . . . . . . . 183
Analysis 2.7. Comparison 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term, Outcome 7 Adverse effects: 1.
General - at least one adverse effect. . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Analysis 2.8. Comparison 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term, Outcome 8 Adverse effects: 2a.
Cardiac effects - QTc prolongation. . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Analysis 2.9. Comparison 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term, Outcome 9 Adverse effects: 2b.
Cardiac effects - QTc abnormalities - change from baseline in ms. . . . . . . . . . . . . . . . . 184
Analysis 2.10. Comparison 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term, Outcome 10 Adverse effects:
3a. Extrapyramidal effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
3b. Extrapyramidal effects - scale measured. . . . . . . . . . . . . . . . . . . . . . . . 186
4a. Prolactin associated side effects. . . . . . . . . . . . . . . . . . . . . . . . . . . 187
4b. Prolactin - change from baseline in ng/ml. . . . . . . . . . . . . . . . . . . . . . . . 188
5a. Metabolic effects - cholesterol - change from baseline in mg/dl. . . . . . . . . . . . . . . . 189
5b. Metabolic effects - glucose - change from baseline in mg/dl. . . . . . . . . . . . . . . . . . 189
5c. Metabolic effects - weight gain of 7% or more of total body weight. . . . . . . . . . . . . . . 190
5d. Metabolic effects - weight gain - change from baseline in kg. . . . . . . . . . . . . . . . . 190
Analysis 3.1. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 1 Global state: 1a. No clinically significant
Analysis 3.2. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 2 Global state: 1b. No clinically important
change - short term (as defined by the original studies). . . . . . . . . . . . . . . . . . . . 192
Analysis 3.3. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 3 Leaving the study early. . . . . . 193
Risperidone versus other atypical antipsychotics for schizophrenia (Review) ii
Analysis 3.4. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 4 Mental state: 1a.General - no clinically
important change - short term (less than 20 % PANSS total reduction). . . . . . . . . . . . . . . 194
Analysis 3.5. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 5 Mental state: 1b. General - no clinically
important change - short term (as defined by the original studies). . . . . . . . . . . . . . . . . 195
Analysis 3.6. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 6 Mental State: 1c. General - no clinically
important change - long term (less than 40% BPRS reduction). . . . . . . . . . . . . . . . . 195
Analysis 3.7. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 7 Mental State: 1d. General - no clinically
important change - short term (less than 20% BPRS reduction). . . . . . . . . . . . . . . . . 196
Analysis 3.8. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 8 Mental state: 1e. General - average
endpoint score (PANSS total, high = poor). . . . . . . . . . . . . . . . . . . . . . . . 197
Analysis 3.9. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 9 Mental state: 1f. General - average endpoint
score (BPRS total, high = poor). . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
Analysis 3.10. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 10 Mental state: 2a. Positive symptoms -
average endpoint score (PANSS positive, high = poor). . . . . . . . . . . . . . . . . . . . . 199
Analysis 3.11. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 11 Mental state: 2b. Positive symptoms -
Analysis 3.12. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 12 Mental state: 3a. Negative symptoms -
average endpoint score (PANSS negative, high = poor). . . . . . . . . . . . . . . . . . . . 201
Analysis 3.13. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 13 Mental state: 3b. Negative symptoms -
average endpoint score - short term (SANS total, high = poor). . . . . . . . . . . . . . . . . . 202
Analysis 3.14. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 14 General functioning: 1a. General -
average endpoint score - short term (GAF total, high = poor). . . . . . . . . . . . . . . . . . 202
Analysis 3.15. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 15 General functioning: 1b. Social
functioning - average endpoint score - short term (SFS, high = poor). . . . . . . . . . . . . . . . 203
Analysis 3.16. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 16 Cognitive functioning: 1a. Global - no
clinically important change in global neurocognitive score - medium term (less than 1/2 SD). . . . . . . 203
Analysis 3.17. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 17 Cognitive functioning: 1b. Global -
average endpoint score - medium term - (global neurocognitive score, high = poor). . . . . . . . . . . 204
Analysis 3.18. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 18 Adverse effects: 1. General - at least one
adverse effect. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
Analysis 3.19. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 19 Adverse effects: 2. Death. . . . 205
Analysis 3.20. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 20 Adverse effects: 3. Cardiac effects. 206
Analysis 3.21. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 21 Adverse effects: 4a. Central nervous
system - sedation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Analysis 3.22. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 22 Adverse effects: 4b. Central nervous
system - seizures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
Analysis 3.23. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 23 Adverse effects: 5a. Extrapyramidal
effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Analysis 3.24. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 24 Adverse effects: 5b. Extrapyramidal
symptoms - scale measured. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Analysis 3.25. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 25 Adverse effects: 6. Haematological -
white blood cells - significant low white blood cell count (as def. by the original studies). . . . . . . . . 212
Analysis 3.26. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 26 Adverse effects: 7a. Prolactin associated
side effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Analysis 3.27. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 27 Adverse effects: 7b. Prolactin associated
side effects - change from baseline in ng/ml. . . . . . . . . . . . . . . . . . . . . . . . 214
Analysis 3.28. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 28 Adverse effects: 3a. Metabolic -
cholesterol - change from baseline in mg/dl. . . . . . . . . . . . . . . . . . . . . . . . 215
Analysis 3.29. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 29 Adverse effects: 3b. Metabolic - glucose
- change from baseline in mg/dl. . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Analysis 3.30. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 30 Adverse effects: 3c. Metabolic - weight
gain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
Risperidone versus other atypical antipsychotics for schizophrenia (Review) iii

Analysis 3.31. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 31 Adverse effects: 3d. Metabolic - weight
gain - change from baseline in kg. . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Analysis 4.1. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 1 Global state: 1a. No clinically significant
Analysis 4.2. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 2 Global state: 1b. No clinically important
Analysis 4.3. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 3 Global state: 1c. Relapse (as defined by
the original studies). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Analysis 4.4. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 4 Leaving the study early. . . . . 221
Analysis 4.5. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 5 Mental state: 1a. General - no clinically
important change (less than 50% PANSS total score reduction). . . . . . . . . . . . . . . . . 223
Analysis 4.6. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 6 Mental state: 1b. General - no clinically
important change - short term (less than 20% PANSS total score reduction). . . . . . . . . . . . . 224
Analysis 4.7. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 7 Mental state: 1c. General - average
Analysis 4.8. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 8 Mental state: 1d. General - average
endpoint score (BPRS total score, high = poor). . . . . . . . . . . . . . . . . . . . . . . 226
Analysis 4.9. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 9 Mental state: 2a. Positive symptoms - no
clinically important change - short term (less than 50% PANSS positive subscore reduction). . . . . . . 227
Analysis 4.10. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 10 Mental state: 2b. Positive symptoms -
average endpoint score (PANSS positive, high = poor). . . . . . . . . . . . . . . . . . . . . 228
Analysis 4.11. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 11 Mental state: 3a. Negative symptoms -
Analysis 4.12. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 12 Mental state: 3b. Negative symptoms
- average endpoint score - long term (SANS total, high = poor). . . . . . . . . . . . . . . . . 230
Analysis 4.13. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 13 Quality of life: General - average
endpoint score - long term (QLS total score, high = poor). . . . . . . . . . . . . . . . . . . 230
Analysis 4.14. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 14 Cognitive functioning: 1a.General -
no clinically important change - medium term (less than SD in Global Neurocognitive Score improved). . 231
Analysis 4.15. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 15 Cognitive functioning: 1b. General -
average endpoint score - medium term (global neurocognitive score, high = poor). . . . . . . . . . . 231
Analysis 4.16. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 16 Cognitive functioning: 1c. General -
average endpoint score - long term (neurocognitive composite score, high = poor). . . . . . . . . . . 232
Analysis 4.17. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 17 Service use - number of patients
rehospitalised. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Analysis 4.18. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 18 Adverse effects: 1. General - at least
Analysis 4.19. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 19 Adverse effects: 2. Death. . . 235
Analysis 4.20. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 20 Adverse effects: 3a. Cardiac effects. 236
Analysis 4.21. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 21 Adverse effects: 3b. Cardiac effects -
QTc abnormalities - change from baseline in ms. . . . . . . . . . . . . . . . . . . . . . 237
Analysis 4.22. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 22 Adverse effects: 4a. Central nervous
system - sedation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Analysis 4.23. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 23 Adverse effects: 4b. Central nervous
system - seizures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
Analysis 4.24. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 24 Adverse effects: 5a. Extrapyramidal
effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
Analysis 4.25. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 25 Adverse effects: 5b. Extrapyramidal
Analysis 4.26. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 26 Adverse effects: 6. Haematological:
white blood cells - significant low white blood cell count (as def. by the original studies). . . . . . . . . 245
Analysis 4.27. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 27 Adverse effects: 7a. Prolactin associated
side effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
Risperidone versus other atypical antipsychotics for schizophrenia (Review) iv
Analysis 4.28. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 28 Adverse effects: 7b. Prolactin - change
from baseline in ng/ml. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
Analysis 4.29. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 29 Adverse effects: 8a. Metabolic -
cholesterol - significant cholesterol increase. . . . . . . . . . . . . . . . . . . . . . . . 250
Analysis 4.30. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 30 Adverse effects: 8b. Metabolic -
Analysis 4.31. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 31 Adverse effects: 8c. Metabolic - glucose
- abnormally high fasting glucose value. . . . . . . . . . . . . . . . . . . . . . . . . . 252
Analysis 4.32. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 32 Adverse effects: 8d. Metabolic -
glucose - change from baseline in mg/dl. . . . . . . . . . . . . . . . . . . . . . . . . 253
Analysis 4.33. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 33 Adverse effects: 8e. Metabolic - weight
gain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
Analysis 4.34. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 34 Adverse effects: 8f. Metabolic - weight
Analysis 5.1. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 1 Global state: 1a. No clinically significant
response (as def. by the original studies). . . . . . . . . . . . . . . . . . . . . . . . . . 256
Analysis 5.2. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 2 Global state: 1b. No clinically important
Analysis 5.3. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 3 Leaving the study early. . . . . 258
Analysis 5.4. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 4 Mental state: 1a General - no clinically
important change - short term (less than 30% PANSS total score reduction). . . . . . . . . . . . . 259
Analysis 5.5. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 5 Mental state: 1b. General - no clinicallly
important change - short term (less than 20% BPRS total score reduction). . . . . . . . . . . . . 260
Analysis 5.6. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 6 Mental state: 1c. General - average
endpoint score (PANSS total score, high = poor). . . . . . . . . . . . . . . . . . . . . . 261
Analysis 5.7. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 7 Mental state: 1d. General - average
endpoint score - short term (BPRS total score, high = poor). . . . . . . . . . . . . . . . . . . 262
Analysis 5.8. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 8 Mental state: 2a. Positive symptoms - no
clinically important change - short term (less than 40% PANSS positive reduction). . . . . . . . . . 262
Analysis 5.9. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 9 Mental state: 2b. Positive symptoms -
average endpoint score - (PANSS positive subscore, high = poor). . . . . . . . . . . . . . . . . 263
Analysis 5.10. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 10 Mental state: 2c. Positive symptoms -
average endpoint score - short term (BPRS positive subscore, high = poor). . . . . . . . . . . . . . 264
Analysis 5.11. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 11 Mental state: 3a. Negative symptoms -
no clinicallly important change - short term (less than 40% PANSS negative reduction). . . . . . . . . 264
Analysis 5.12. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 12 Mental state: 3b. Negative symptoms -
average endpoint score - (PANSS negative subscore, high = poor). . . . . . . . . . . . . . . . . 265
Analysis 5.13. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 13 Mental state: 3c. Negative symptoms -
average endpoint score - short term (BPRS negative subscore, high = poor). . . . . . . . . . . . . 266
Analysis 5.14. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 14 Quality of life: General - average
endpoint score - short term (QLS total score, high = poor). . . . . . . . . . . . . . . . . . . 266
Analysis 5.15. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 15 Service use: Number of participants
rehospitalised. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
Analysis 5.16. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 16 Adverse effects: 1. General - at least
Analysis 5.17. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 17 Adverse effects: 2. Death. . . . 269
Analysis 5.18. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 18 Adverse effects: 3a. Cardiac effects -
Analysis 5.19. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 19 Adverse effects: 3b. Cardiac effects -
Analysis 5.20. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 20 Adverse effects: 4. Central nervous
system - sedation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
Risperidone versus other atypical antipsychotics for schizophrenia (Review) v

Analysis 5.21. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 21 Adverse effects: 5a. Extrapyramidal
effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
Analysis 5.22. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 22 Adverse effects: 5b. Extrapyramidal
Analysis 5.23. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 23 Adverse effects: 6. Haematological:
Important decline in white blood cells. . . . . . . . . . . . . . . . . . . . . . . . . . 275
Analysis 5.24. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 24 Adverse effects: 7a. Prolactin associated
side effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Analysis 5.25. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 25 Adverse effects: 7b. Prolactin - change
from baseline in mg/dl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
Analysis 5.26. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 26 Adverse effects: 8a. Metabolic -
cholesterol - significant cholesterol increase. . . . . . . . . . . . . . . . . . . . . . . . 279
Analysis 5.27. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 27 Adverse effects: 8b. Metabolic -
Analysis 5.28. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 28 Adverse effects: 8c. Metabolic - glucose
- abnormally high fasting glucose value. . . . . . . . . . . . . . . . . . . . . . . . . . 281
Analysis 5.29. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 29 Adverse effects: 8d. Metabolic - glucose
- change from baseline in mg/dl. . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
Analysis 5.30. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 30 Adverse effects: 8e. Metabolic - weight
gain of 7% or more of total body weight. . . . . . . . . . . . . . . . . . . . . . . . . 283
Analysis 5.31. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 31 Adverse effects: 8f. Metabolic - weight
Analysis 6.1. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 1 Global state - 1a. No
clinically significant response (as defined by the original studies). . . . . . . . . . . . . . . . . 285
Analysis 6.2. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 2 Global state - 1b. No
clinically important change (as defined by the original studies). . . . . . . . . . . . . . . . . . 285
Analysis 6.3. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 3 Leaving the study
early. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
Analysis 6.4. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 4 Mental state: 1a.
General - no clinically important change (less than 50% PANSS total score reduction). . . . . . . . . 287
Analysis 6.5. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 5 Mental state: 1b.
General - average endpoint score (PANSS total, high = poor). . . . . . . . . . . . . . . . . . 287
Analysis 6.6. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 6 Mental state: 2.
Positive symptoms - average endpoint score (PANSS positive, high = poor). . . . . . . . . . . . . 288
Analysis 6.7. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 7 Mental state: 3.
Negative symptoms - average endpoint score (PANSS negative, high = poor). . . . . . . . . . . . . 288
Analysis 6.8. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 8 General functioning:
General - average endpoint score - (GAF total, high = poor). . . . . . . . . . . . . . . . . . . 289
Analysis 6.9. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 9 Adverse effects: 1.
General - at least one adverse effect. . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Death - suicide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
Analysis 6.11. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 11 Adverse effects:
3a. Cardiac effects - QTc prolongation. . . . . . . . . . . . . . . . . . . . . . . . . . 290
3b. Cardiac effects - QTc abnormalities - change from baseline in ms. . . . . . . . . . . . . . . 291
Central nervous system - sedation. . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
5a. Extrapyramidal effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
5b. Extrapyramidal symptom scales. . . . . . . . . . . . . . . . . . . . . . . . . . . 293
Risperidone versus other atypical antipsychotics for schizophrenia (Review) vi

Prolactin associated side effects - sexual dysfunction. . . . . . . . . . . . . . . . . . . . . 294
7a. Metabolic - cholesterol - change from baseline in mg/dl. . . . . . . . . . . . . . . . . . . 295
7b. Metabolic - glucose - change from baseline in mg/dl. . . . . . . . . . . . . . . . . . . . 295
7c. Metabolic - weight gain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
7d. Metabolic - weight gain - change from baseline in kg. . . . . . . . . . . . . . . . . . . . 296
Analysis 7.1. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 1 Global state: 1a. No clinically significant
Analysis 7.2. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 2 Global state: 1b. No clinically important
change - short term (as defined by the original studies). . . . . . . . . . . . . . . . . . . . 297
Analysis 7.3. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 3 Leaving the study early. . . . . 298
Analysis 7.4. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 4 Mental state: 1a. General - no clinically
important change - short term (less than 50% PANSS total reduction). . . . . . . . . . . . . . . 299
Analysis 7.5. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 5 Mental state: 1b. General - average
Analysis 7.6. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 6 Mental state: 1c. General - avergae
endpoint score - short term (BPRS total, high = poor). . . . . . . . . . . . . . . . . . . . . 301
Analysis 7.7. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 7 Mental state: 2a. Positive symptoms -
average endpoint score - medium term (PANSS positive, high = poor). . . . . . . . . . . . . . . 301
Analysis 7.8. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 8 Mental State: 2b. Positive symptoms -
Analysis 7.9. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 9 Mental state: 3. Negative symptoms -
Analysis 7.10. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 10 Service use: Number of patients
rehospitalised. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
Analysis 7.11. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 11 Adverse effects: 1. General - at least
Analysis 7.12. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 12 Adverse effects: 2. Death. . . 306
Analysis 7.13. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 13 Adverse effects: 3a. Cardiac effects -
Analysis 7.14. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 14 Adverse effects: 3b. Cardiac effects -
Analysis 7.15. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 15 Adverse effects: 4. Central nervous
system - sedation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
Analysis 7.16. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 16 Adverse effects: 5a. Extrapyramidal
effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Analysis 7.17. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 17 Adverse effects: 5b. Extrapyramidal
symptoms - scale measured. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
Analysis 7.18. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 18 Adverse effects: 6a. Prolactin
associated side effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Analysis 7.19. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 19 Adverse effects: 6b. Prolactin - change
from baseline in ng/ml. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
Analysis 7.20. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 20 Adverse effects: 7a. Metabolic -
Analysis 7.21. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 21 Adverse effects: 7b. Metabolic -
glucose - change from baseline in mg/dl. . . . . . . . . . . . . . . . . . . . . . . . . 313
Analysis 7.22. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 22 Adverse effects: 7c. Metabolic -
weight gain of 7% or more of total body weight. . . . . . . . . . . . . . . . . . . . . . . 314
Risperidone versus other atypical antipsychotics for schizophrenia (Review) vii

Analysis 7.23. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 23 Adverse effects: 7d. Metabolic -
weight gain - change from baseline in kg. . . . . . . . . . . . . . . . . . . . . . . . . 314
Analysis 8.1. Comparison 8 RISPERIDONE versus CLOZAPINE - sensitivity analysis (skewed data included), Outcome
1 Mental state: 1. General - average endpoint score (BPRS total, high = poor). . . . . . . . . . . . 315
2 Mental state: 2. Positive symptoms - average endpoint score (PANSS positive, high = poor). . . . . . . 316
3 Mental state: 3. Negative symptoms - average endpoint score (PANSS negative, high = poor). . . . . . . 317
Analysis 9.1. Comparison 9 RISPERIDONE versus OLANZAPINE - sensitivity analysis (skewed data excluded), Outcome
1 Mental state: 1a. General - average endpoint score (PANSS total, high = poor). . . . . . . . . . . . 318
2 Mental state: 2. General - average endpoint score (BPRS total, high = poor). . . . . . . . . . . . 319
3 Mental state: 3. Positive symptoms - average endpoint score (PANSS positive, high = poor). . . . . . . 320
4 Adverse effects: 1. Extrapyramidal effects - scale measured. . . . . . . . . . . . . . . . . . . 321
5 Adverse effects: 2. Prolactin associated side effects - change from baseline in ng/ml. . . . . . . . . . 322
Analysis 10.1. Comparison 10 RISPERIDONE versus QUETIAPINE - sensitivity analysis (skewed data included),
Outcome 1 Mental state: 1. Positive symptoms - average endpoint score (PANSS positive, high = poor). . . . 323
Analysis 10.2. Comparison 10 RISPERIDONE versus QUETIAPINE - sensitivity analysis (skewed data included),
Outcome 2 Adverse effects: 1. Extrapyramidal effects - scale measured. . . . . . . . . . . . . . . 324
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 326
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
Risperidone versus other atypical antipsychotics for schizophrenia (Review) viii

[Intervention Review]
Risperidone versus other atypical antipsychotics for

schizophrenia
Katja Komossa1 , Christine Rummel-Kluge2 , Sandra Schwarz3 , Franziska Schmid3 , Heike Hunger3 , Werner Kissling3 , Stefan Leucht3
1
Klinik und Poliklinik fr Psychosomatische und Medizin und Psychotherapie, Technische Universitt Mnchen, Klinikum rechts der
Isar, Mnchen, Germany. 2 Klinik und Poliklinik fr Psychiatrie und Psychotherapie der Universitt Leipzig, 04103 Leipzig, Germany.
3 Klinik und Poliklinik fr Psychiatrie und Psychotherapie, Technische Universitt Mnchen Klinikum rechts der Isar, Mnchen,
Germany
Contact address: Katja Komossa, Klinik und Poliklinik fr Psychosomatische und Medizin und Psychotherapie, Technische Universitt
Mnchen, Klinikum rechts der Isar, Moehlstrasse 26, Mnchen, 81675, Germany. k.komossa@lrz.tu-muenchen.de.
Editorial group: Cochrane Schizophrenia Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2013.
Review content assessed as up-to-date: 21 May 2008.
Citation: Komossa K, Rummel-Kluge C, Schwarz S, Schmid F, Hunger H, Kissling W, Leucht S. Risperidone versus other
atypical antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD006626. DOI:
10.1002/14651858.CD006626.pub2.
ABSTRACT
Background
In many countries of the industrialised world second-generation (atypical) antipsychotics (SGAs) have become the first line drug
treatment for people with schizophrenia. The question as to whether and if so how much the effects of the various SGAs differ is a
matter of debate. In this review we examined how the efficacy and tolerability of risperidone differs from that of other SGAs.
Objectives
To evaluate the effects of risperidone compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like
psychosis.
Search methods
1. Electronic searching
We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CENTRAL,
CINAHL, EMBASE, MEDLINE and PsycINFO.
2. Reference searching
We inspected the references of all identified studies for more trials.
3. Personal contact
We contacted the first author of each included study for missing information.
4. Drug companies
We contacted the manufacturers of all atypical antipsychotics included for additional data.
Risperidone versus other atypical antipsychotics for schizophrenia (Review) 1
Selection criteria
We included all randomised, blinded trials comparing oral risperidone with oral forms of amisulpride, aripiprazole, clozapine, olanzapine,
quetiapine, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychosis.
Data collection and analysis
We extracted data independently. For dichotomous data we calculated risk ratio (RR) and their 95% confidence intervals (CI) on
an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where
appropriate. For continuous data, we calculated mean differences (MD), again based on a random-effects model.
Main results
The review currently includes 45 blinded RCTs with 7760 participants. The number of RCTs available for each comparison varied: four
studies compared risperidone with amisulpride, two with aripiprazole, 11 with clozapine, 23 with olanzapine, eleven with quetiapine,
two with sertindole, three with ziprasidone and none with zotepine. Attrition from these studies was high (46.9%), leaving the
interpretation of results problematic. Furthermore, 60% were industry sponsored, which can be a source of bias.
There were few significant differences in overall acceptability of treatment as measured by leaving the studies early. Risperidone was
slightly less acceptable than olanzapine, and slightly more acceptable than ziprasidone in this regard.
Risperidone improved the general mental state (PANSS total score) slightly less than olanzapine (15 RCTs, n = 2390, MD 1.94 CI
0.58 to 3.31), but slightly more than quetiapine (9 RCTs, n = 1953, MD -3.09 CI -5.16 to -1.01) and ziprasidone (3 RCTs, n =
1016, MD -3.91 CI -7.55 to -0.27). The comparisons with the other SGA drugs were equivocal. Risperidone was also less efficacious
than olanzapine and clozapine in terms of leaving the studies early due to inefficacy, but more efficacious than ziprasidone in the same
outcome.
Risperidone produced somewhat more extrapyramidal side effects than a number of other SGAs (use of antiparkinson medication
versus clozapine 6 RCTs, n = 304, RR 2.57 CI 1.47 to 4.48, NNH 6 CI 33 to 3; versus olanzapine 13 RCTs, n = 2599, RR 1.28 CI
1.06 to 1.55, NNH 17 CI 9 to 100; versus quetiapine 6 RCTs, n = 1715, RR 1.98 CI 1.16 to 3.39, NNH 20 CI 10 to 100; versus
ziprasidone 2 RCTs, n = 822, RR 1.42 CI 1.03 to 1.96, NNH not estimable; parkinsonism versus sertindole 1 RCT, n = 321, RR
4.11 CI 1.44 to 11.73, NNH 14 CI 100 to 8). Risperidone also increased prolactin levels clearly more than all comparators, except for
amisulpride and sertindole for which no data were available.
Other adverse events were less consistently reported, but risperidone may well produce more weight gain and/or associated metabolic
problems than amisulpride (weight gain: 3 RCTs, n = 585, MD 0.99 CI 0.37 to 1.61), aripiprazole (cholesterol increase: 1 RCT, n =
83, MD 22.30 CI 4.91 to 39.69) and ziprasidone (cholesterol increase 2 RCTs, n = 767, MD 8.58 CI 1.11 to 16.04) but less than
clozapine (weight gain 3 RCTs n = 373, MD -3.30 CI -5.65 to -0.95), olanzapine (weight gain 13 RCTs, n = 2116, MD -2.61 CI
-3.74 to -1.48), quetiapine (cholesterol increase: 5 RCTs, n = 1433, MD -8.49 CI -12. 23 to -4.75) and sertindole (weight gain: 2
RCTs, n = 328, MD -0.99 CI -1.86 to -0.12). It may be less sedating than clozapine and quetiapine, lengthen the QTc interval less
than sertindole (QTc change: 2 RCTs, n = 495, MD -18.60 CI -22.37 to 14.83), produce fewer seizures than clozapine (2 RCTs, n =
354, RR 0.22 CI 0.07 to 0.70, NNT 14 CI 8 to 33) and less sexual dysfunction in men than sertindole (2 RCTs, n = 437, RR 0.34
CI 0.16 to 0.76, NNT 13 CI 8 to 33).
Authors conclusions
Risperidone seems to produce somewhat more extrapyramidal side effects and clearly more prolactin increase than most other SGAs. It
may also differ from other compounds in efficacy and in the occurrence of other adverse effects such as weight gain, metabolic problems,
cardiac effects, sedation and seizures. Nevertheless, the large proportion of participants leaving studies early and incomplete reporting
of outcomes makes it difficult to draw firm conclusions. Further large trials, especially comparing risperidone with those other new
drugs for which only a few RCTs are available, are needed.
PLAIN LANGUAGE SUMMARY

Risperidone versus other atypical antipsychotics for schizophrenia
This review examines the effects of risperidone compared to other second-generation antipsychotic (SGA) drugs for schizophrenia.
We identified 45 relevant studies with 7760 participants comparing risperidone with amisulpride, aripiprazole, clozapine, olanzapine,
quetiapine, sertindole and ziprasidone. Comparisons of risperidone with zotepine are currently not available. Risperidone was somewhat
more successful than quetiapine and ziprasidone, but somewhat less successful than clozapine and olanzapine. The main disadvantage
of risperidone were more frequent movement disorders and more prolactin increase compared to most other SGA drugs.
BACKGROUND
functioning, negative symptoms, movement disorders, quality of
life and the treatment of refractory people with schizophrenia.
Description of the condition

Schizophrenia is usually a chronic and disabling psychiatric dis- How the intervention might work
order which afflicts approximately one per cent of the population
world-wide with little gender differences. The annual incidence Risperidone has high affinity to 5-HT2 and D2 receptors; it also
of schizophrenia averages 15 per 100,000, the point prevalence binds to a1 receptors and with lower affinity to H1 and a2 re-
averages approximately 4.5 per population of 1000, and the risk of ceptors. It was developed following the observation that a se-
developing the illness over ones lifetime averages 0.7%. (Tandon lective serotonin receptor blocker (ritanserin) produced a benefi-
2008). Its typical manifestations are positive symptoms such as cial effect when combined with conventional neuroleptics (Gupta
fixed, false beliefs (delusions) and perceptions without cause (hal- 1994; Curtis 1995). Risperidone is described to have no affinity
lucinations), negative symptoms such as apathy and lack of drive, to cholinergic receptors. Although being a potential D2 antago-
disorganisation of behaviour and thought, and catatonic symp- nist it causes less motor retardation and cataleptic symptoms than
toms such as mannerisms and bizarre posturing (Carpenter 1994). typical antipsychotics (Janssen-Cilag 2005).
The degree of suffering and disability is considerable, with 80%-
90% not working (Marvaha 2004) and up to 10% dying (Tsuang
1978). In the age group of 15-44 years, schizophrenia is among Why it is important to do this review
the top 10 leading causes of disease-related disability in the world
The debate as to how far the SGA improve these outcomes com-
(WHO 2001).
pared to conventional antipsychotics continues (Duggan 2005;
El-Sayeh 2006) and the results from recent studies are sobering
(Jones 2006; Lieberman 2005). Nevertheless, in some parts of the
Description of the intervention world, especially in the highly industrialised countries, SGA have
Conventional antipsychotic drugs such as chlorpromazine and become the mainstay of treatment. The SGAs also differ in terms
haloperidol have traditionally been used as first-line antipsychotics of their costs: while amisulpride and risperidone are already generic
for people with schizophrenia (Kane 1993). The reintroduction of in many countries in 2009, aripiprazole, olanzapine, quetiapine,
clozapine in the United States of America and a finding that cloza- sertindole and ziprasidone are still not. Therefore the question as
pine was more efficacious and associated with fewer movement to whether they differ from each other in their clinical effects be-
disorders than chlorpromazine (Kane 1988) has boosted the devel- comes increasingly important. In this review we aim to summarise
opment of so-called atypical or new (second) generation antipsy- evidence from randomised controlled trials that compared risperi-
chotics (SGA). There is no good definition of what an atypical or done with other SGAs.
SGA is, but they were initially said to differ from typical antipsy-
chotics in that they do not cause movement disorders (catalepsy)
in rats at clinically effective doses (Arnt 1998). The terms new or
second generation antipsychotics are not much better, because OBJECTIVES
clozapine is a very old drug. According to treatment guidelines
(APA 2004; Gaebel 2006) SGAs include drugs such as amisul- To review the effects of risperidone compared with other atypical
pride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone antipsychotics for people with schizophrenia and schizophrenia-
sertindole, ziprasidone and zotepine, although it is unclear whether like psychosis.
some old and cheap compounds such as sulpiride or perazine have
similar properties (Mller 2000). The SGAs raised major hopes of
superior effects in a number of areas such as compliance, cognitive METHODS
Criteria for considering studies for this review 2.1 No clinically important change in global state (as defined by
individual studies)
2.2 Relapse (as defined by the individual studies)
Types of studies 3. Mental state (with particular reference to the positive and
negative symptoms of schizophrenia)
We included randomised controlled trials (RCTs) which were at
3.1 No clinically important change in general mental state score
least single-blind (blind raters). Where a trial was described as
3.2 Average endpoint general mental state score
double-blind, but it was only implied that the study was ran-
3.3 Average change in general mental state score
domised, we included these trials in a sensitivity analysis. If there
3.4 No clinically important change in specific symptoms (positive
was no substantive difference within primary outcomes (see types
symptoms of schizophrenia, negative symptoms of schizophrenia)
of outcome measures) when these implied randomisation studies
3.5 Average endpoint specific symptom score
were added, then we included these in the final analysis. If there
3.6 Average change in specific symptom score
was a substantive difference, we only used clearly randomised tri-
4. General functioning
als and described the results of the sensitivity analysis in the text.
4.1 No clinically important change in general functioning
We excluded quasi-randomised studies, such as those allocating
4.2 Average endpoint general functioning score
by using alternate days of the week. In crossover studies, we only
4.3 Average change in general functioning score
included the first treatment phase prior to crossover.
5. Quality of life/satisfaction with treatment
We included randomised crossover studies, but only data up to the
5.1 No clinically important change in general quality of life
point of first crossover because of the instability of the problem
5.2 Average endpoint general quality of life score
behaviours and the likely carry-over effects of all treatments.
5.3 Average change in general quality of life score
6. Cognitive functioning
Types of participants 6.1 No clinically important change in overall cognitive function-
ing
We included people with schizophrenia and other types of
6.2 Average endpoint of overall cognitive functioning score
schizophrenia-like psychosis (e.g. schizophreniform and schizoaf-
6.3 Average change of overall cognitive functioning score
fective disorders), irrespective of the diagnostic criteria used. There
7. Service use
is no clear evidence that the schizophrenia-like psychoses are
7.1 Number of people hospitalised
caused by fundamentally different disease processes or require dif-
8. Adverse effects
ferent treatment approaches (Carpenter 1994).
8.1 Number of participants with at least one adverse effect
8.2 Clinically important specific adverse effects (cardiac effects,
Types of interventions death, movement disorders, prolactin increase and associated ef-
fects, sedation, seizures, weight gain, effects on white blood cell
1. Risperidone: any oral form of application, any dose
count)
2. Other atypical antipsychotic drugs: amisulpride, aripipra-
8.3 Average endpoint in specific adverse effects
zole, clozapine, olanzapine, quetiapine, sertindole, ziprasidone,
8.4 Average change in specific adverse effects
zotepine: any oral form of application, any dose.
Types of outcome measures

Search methods for identification of studies
We grouped outcomes into the short term (up to 12 weeks),
We applied no language restriction within the limitations of the
medium term (13-26 weeks) and long term (over 26 weeks).
search tools.
Primary outcomes
Global state: no clinically important response as defined by the Electronic searches
individual studies (e.g. global impression less than much improved We searched the Cochrane Schizophrenia Groups Specialised Reg-
or less than 50% reduction on a rating scale). ister (April 2007) using the phrase:
[((ziprasidon* AND (amisulprid* OR aripiprazol* OR clozapin*
OR olanzapin* OR quetiapin* OR sertindol* OR risperidon* OR
Secondary outcomes zotepin*)) in title, abstract or index terms of REFERENCE) or
1. Leaving the studies early (any reason, adverse events, inefficacy ((ziprasidon* AND (amisulprid* OR aripiprazol* OR clozapin*
of treatment) OR olanzapin* OR quetiapin* OR sertindol* OR risperidon * OR
2. Global state zotepin*)) in interventions of STUDY)]

This register is compiled by systematic searches of major databases, 2. Management
hand searches and conference proceedings (see Group Module). KK, CRK, SS, HH, FS and SL extracted the data onto standard
The Cochrane Schizophrenia Group Trials Register is maintained simple forms. Where possible, we entered data in such a way that
on Meerkat 1.5. This version of Meerkat stores references as stud- the area to the left of the line of no effect indicated a favourable
ies. When an individual reference is selected through a search, all outcome for risperidone.
references which have been identified as the same study are also
selected.
3. Rating scales
A wide range of instruments are available to measure outcomes
Searching other resources in mental health studies. These instruments vary in quality and
many are not validated, or are even ad hoc. It is accepted generally
that measuring instruments should have the properties of relia-
1. Reference searching
bility (the extent to which a test effectively measures anything at
all) and validity (the extent to which a test measures that which
We inspected the reference lists of all studies identified in the search it is supposed to measure) (Rust 1989). Unpublished scales are
for more trials. known to be subject to bias in trials of treatments for schizophre-
nia (Marshall 2000). Therefore we included continuous data from
rating scales only if the measuring instrument had been described
2. Personal contact in a peer-reviewed journal.
We contacted the first author of each included study for missing
information.
Assessment of risk of bias in included studies
Again working independently, KK and SL assessed risk of bias
3. Drug companies using the tool described in the Cochrane Handbook for Systematic
Reviews of Interventions (Higgins 2008). This tool encourages con-
We contacted the manufacturers of all atypical antipsychotics in-
sideration of how the sequence was generated, how allocation was
cluded for additional data.
concealed, the integrity of blinding at outcome, the completeness
of outcome data, selective reporting and other biases.
We assessed the risk of bias in each domain and overall and cate-
Data collection and analysis gorised them into:
A. Low risk of bias: plausible bias unlikely to seriously alter the
results (categorised as Yes in Risk of Bias table)
B. High risk of bias: plausible bias that seriously weakens confi-
Selection of studies dence in the results (categorised as No in Risk of Bias table)
KK, CRK and SL independently inspected all reports. We resolved C. Unclear risk of bias: plausible bias that raises some doubt about
any disagreement by discussion, and where there was still doubt, we the results (categorised as Unclear in Risk of Bias table)
acquired the full article for further inspection. Once we obtained We categorised trials with high risk of bias (defined as at least
the full articles, we independently decided whether the studies four out of seven domains) as No. Where allocation was clearly
met the review criteria. If disagreement could not be resolved by not concealed, we did not include these trials in the review. If the
discussion, we sought further information and added these trials initial raters disagreed, we made the final rating by consensus with
to the list of those awaiting assessment. the involvement of another member of the review group. Where
inadequate details of randomisation and other characteristics of
trials were provided, we contacted authors of the studies in order
Data extraction and management to obtain further information. We reported non-concurrence in
quality assessment.
1. Data extraction Measures of treatment effect

KK, CRK and SL independently extracted data from selected trials.
When disputes arose we attempted to resolve these by discussion.
When this was not possible and further information was necessary 1. Data types
to resolve the dilemma, we did not enter data and added the trial We assessed outcomes using continuous (for example changes on
to the list of those awaiting assessment. a behaviour scale), categorical (for example, one of three categories

on a behaviour scale, such as little change, moderate change or of the data also leads to a bias, because a considerable amount of
much change) or dichotomous (for example, either no impor- data may be lost leading to a selection bias. Therefore, we included
tant changes or important change in a persons behaviour) mea- all studies in the primary analysis. In a sensitivity analysis we ex-
sures. Currently The Cochrane Collaborations Review Manager cluded potentially skewed data applying the following rules.
(RevMan) software (RevMan 2008) does not support categorical
data so we were unable to analyse this. a) When a scale started from the finite number zero the standard
deviation, when multiplied by two, was less than the mean (as
otherwise the mean is unlikely to be an appropriate measure of
1.1 Dichotomous- yes/no- data the centre of the distribution, Altman 1996).
We carried out an intention-to-treat analysis. We counted every- b) If a scale started from a positive value (such as PANSS which can
one allocated to the intervention, whether they completed the fol- have values from 30 to 210), we modified the calculation described
low-up or not. We assumed that those who dropped out had no above to take the scale starting point into account. In these cases
change of their outcome. This rule is conservative concerning re- skew is present if 2SD>(S-Smin), where S is the mean score and
sponse to treatment, because it assumes that those discontinuing Smin is the minimum score.
the studies would not have responded. It is not conservative con- c) In large studies (as a cut-off we used 200 participants) skewed
cerning side effects, because it assumes that those discontinuing data pose less of a problem. In these cases we entered the data in
the studies would not have developed the side effect if they had a synthesis.
remained in the study, but we felt that assuming that all drop-outs d) The rules explained in a) and b) do not apply to change data.
would have developed side effects would overestimate the risk. The reason is that when continuous data are presented on a scale
Where possible, we made efforts to convert outcome measures to which includes a possibility of negative values, it is difficult to
dichotomous data. This can be done by identifying cut-off points tell whether data are non-normally distributed (skewed) or not.
on rating scales and dividing participants accordingly into clini- This is also the case for change data (endpoint minus baseline). In
cally improved or not clinically improved. It was generally as- the absence of individual patient data it is impossible to know if
sumed that if there had been a 50% reduction in a scale-derived data are skewed, though this is likely. After consulting the ALL-
score such as the Brief Psychiatric Rating Scale (BPRS, Overall STAT electronic statistics mailing list, we presented change data in
1962) or the Positive and Negative Syndrome Scale (PANSS, Kay RevMan Analyses in order to summarise available information. In
1986); this could be considered as a clinically significant response doing this, it was assumed either that data were not skewed or that
(Leucht 2005a; Leucht 2005b). If data based on these thresholds the analysis could cope with the unknown degree of skew. With-
were not available, we used the primary cut-off presented by the out individual patient data it is impossible to test this assumption.
original authors. We therefore included change data and did not apply a sensitivity
We calculated the risk ratio (RR) and its 95% confidence interval analysis.
(CI) based on the random-effects model, as this takes into account
any differences between studies even if there is no statistically sig-
nificant heterogeneity. It has been shown that RR is more intu- 2. Data synthesis
itive (Boissel 1999) than odds ratios (OR) and that OR tend to be For continuous outcomes we estimated a mean difference (MD)
interpreted as RR by clinicians (Deeks 2000). This misinterpreta- between groups. MDs were again based on the random-effects
tion then leads to an overestimate of the impression of the effect. model, as this takes into account any differences between studies
When the overall results were significant we calculated the num- even if there is no statistically significant heterogeneity. We com-
ber needed to treat (NNT) and the number- needed- to- harm bined both endpoint data and change data in the analysis, because
(NNH) as the inverse of the risk difference. there is no principal statistical reason why endpoint and change
data should measure different effects (Higgins 2008). When stan-
dard errors instead of standard deviations (SD) were presented, we
1.2 Continuous data converted the former to standard deviations. If both were missing
we estimated SDs from P values or used the average SD of the
other studies (Furukawa 2006).
1.2.1 Normal distribution of the data
The meta-analytic formulae applied by RevMan Analyses (the sta- Unit of analysis issues
tistical programme included in RevMan) require a normal distri-
bution of data (RevMan 2008). The software is robust towards
some skew, but to which degree of skewness meta-analytic calcula- 1. Cluster trials
tions can still be reliably carried out is unclear. Conversely, exclud- Studies increasingly employ cluster randomisation (such as ran-
ing all studies on the basis of estimates of the normal distribution domisation by clinician or practice) but analysis and pooling of

clustered data poses problems. Firstly, authors often fail to account completing them. However we addressed the drop-out problem
for intraclass correlation in clustered studies, leading to a unit in all parts of the review, including the abstract. For this purpose
of analysis error (Divine 1992) whereby P values are spuriously we calculated, presented and commented on frequency statistics
low, confidence intervals unduly narrow and statistical significance (overall rates of leaving the studies early in all studies and com-
overestimated. This causes type 1 errors (Bland 1997; Gulliford parators pooled and their ranges).
1999).
Where clustering was not accounted for in primary studies, we
presented the data in a table, with a (*) symbol to indicate the Assessment of heterogeneity
presence of a probable unit of analysis error. In subsequent ver-
sions of this review we will seek to contact first authors of studies
1. Clinical heterogeneity
to obtain intraclass correlation coefficients of their clustered data
and to adjust for this using accepted methods (Gulliford 1999). We considered all the included studies within any comparison to
Where clustering has been incorporated into the analysis of pri- judge for clinical heterogeneity.
mary studies, we will also present these data as if from a non-clus-
ter randomised study, but adjusted for the clustering effect.
2. Statistical
We have sought statistical advice and have been advised that the
binary data as presented in a report should be divided by a design
effect. This is calculated using the mean number of participants
2.1 Visual inspection
per cluster (m) and the intraclass correlation coefficient (ICC)
[Design effect = 1+(m-1)*ICC] (Donner 2002). If the ICC was We visually inspected graphs to investigate the possibility of sta-
not reported we assumed it to be 0.1 (Ukoumunne 1999). tistical heterogeneity.
If cluster studies had been appropriately analysed taking into ac-
count ICC and relevant data documented in the report, we syn-
2.2 Employing the I2 statistic
thesised these with other studies using the generic inverse variance
technique. We supplemented visual inspection using, primarily, the I2 statistic.
This provides an estimate of the percentage of variability due to
heterogeneity rather than chance alone. Where the I2 estimate was
2. Crossover trials greater than or equal to 50% we interpreted this as indicating the
A major concern of crossover trials is the carry-over effect. It occurs presence of considerable levels of heterogeneity (Higgins 2003).
if an effect (e.g. pharmacological, physiological or psychological) of
the treatment in the first phase is carried over to the second phase.
Assessment of reporting biases
As a consequence, on entry to the second phase the participants
can differ systematically from their initial state despite a wash- Reporting biases arise when the dissemination of research findings
out phase. For the same reason crossover trials are not appropriate is influenced by the nature and direction of results (Egger 1997).
if the condition of interest is unstable (Elbourne 2002). As both These are described in section 10.1 of the Cochrane Handbook for
effects are very likely in schizophrenia, we will only use data of the Systematic Reviews of Interventions (Higgins 2008). We are aware
first phase of crossover studies. that funnel plots may be useful in investigating small-study effects
but are of limited power to detect such effects when there are
few studies. We entered data from all identified and selected trials
3. Studies with multiple treatment groups into a funnel graph (trial effect versus trial size) in an attempt to
Where a study involved more than two treatment groups, if rele- investigate the likelihood of overt publication bias. We did not
vant, we presented the additional treatment groups in additional undertake a formal test for funnel-plot asymmetry.
relevant comparisons. We have not double counted data. Where
the additional treatment groups were not relevant, we have not
reproduced these data. Data synthesis
Where possible for both dichotomous and continuous data, we
used the random-effects model for data synthesis as this takes into
Dealing with missing data account any differences between studies even if there is no statis-
At some degree of loss of follow-up data must lose credibility (Xia tically significant heterogeneity. We understand that there is no
2007). Although high rates of premature discontinuation are a closed argument for preference for use of fixed or random-effects
major problem in this field, we feel that it is unclear which de- models. The random-effects method incorporates an assumption
gree of attrition leads to a high degree of bias. We, therefore, did that the different studies are estimating different, yet related, in-
not exclude trials on the basis of the percentage of participants tervention effects. This does seem true to us, however, random-

effects does put added weight onto the smaller of the studies - blind (blind raters). Eight studies were sponsored by pharmaceuti-
those trials that are most vulnerable to bias. cal companies producing risperidone; 19 studies were sponsored by
pharmaceutical companies producing the comparator substances
and 14 studies had a neutral sponsor. The sponsoring of four stud-
Subgroup analysis and investigation of heterogeneity ies remained unclear despite written requests.
If data are clearly heterogeneous we checked that data are correctly
extracted and entered and that we had made no unit of analysis
1. Length of studies
errors. If inconsistency was high and clear reasons explaining the
heterogeneity were found, we presented the data separately. If not, Thirty-one studies presented short-term (up to 12 weeks) data.
we commented on the heterogeneity of the data. Six studies fell into the medium-term category (13-26 weeks) and
eight trials fell in the long-term category (more than 26 weeks).
Sensitivity analysis
2. Setting
In sensitivity analyses we excluded studies with potentially skewed
Eighteen trials took place in both inpatient and outpatient settings;
data. A recent report showed that some of the comparisons of
12 used an inpatient design and three studies an outpatient setting.
atypical antipsychotics may have been biased by using inappropri-
The setting of 10 studies was not reported.
ate comparator doses (Heres 2006). We, therefore, also analysed
whether the exclusion of studies with inappropriate comparator
doses changed the results of the primary outcome and the general 3. Participants
mental state. All studies used operationalised diagnostic criteria, most frequently
the Diagnostic and Statistical Manual (DSM, APA 1994), usually
version IV, only Addington 2004, Daniel 1996 and Bondolfi 1998
used DSM-III). Svestka 2003 applied the International Classifica-
RESULTS tion of Diseases and Related Health Problems (ICD-10). Riedel
2005 diagnosed according to DSM-IV and ICD-10. Sikich 2004
applied DSM-IV as well as the Schedule for Affective Disorders
and Schizophrenia (K-SADS-P). Ren 2002, a study from China,
Description of studies
used the Chinese Classification of Mental Disorders Version 3
See: Characteristics of included studies; Characteristics of excluded (CCDM-3) and Zhou 2000 used Version 2 (CCDM-2) of the
studies; Characteristics of ongoing studies. same classification.
For substantive description of studies please see Characteristics of All studies included people with schizophrenia; 21 studies addi-
included studies and Characteristics of excluded studies tables. tionally included those with schizoaffective disorder (Addington
2004; Chan 2007; Conley 2001; Daniel 1996; Gureje 2003;
Heinrich 1994; Jeste 2003; Keefe 2006; McEvoy 2007; Mller
Results of the search 2005; McGurk 2005; Potkin 2003; Potkin 2006; Robinson
The search strategy yielded 3620 reports. We closely inspected 2005; Sikich 2004; Svestka 2003; Tran 1997; Van Nimwegen
330 reports. We excluded 241 studies, included 45 and designated 2006; Volavka 2002; Wang 2006; Wynn 2007) and seven stud-
seven as ongoing (Eli Lilly 2003; Eli Lilly 2006; Gafoor 2005; ies also included people with schizophreniform disorder (Gureje
Lieberman 2001; Ratna 2003; Reveley 2000; Sireling 2003). No 2003; McEvoy 2007; Mller 2005; Robinson 2005; Sikich 2004;
study is awaiting assessment . For further descriptions please see Tran 1997; Van Nimwegen 2006). Nevertheless, people with
below and the included, excluded and ongoing studies tables. schizophrenia clearly dominated the trials.
The 45 included studies provided data on seven comparisons: four Five studies randomised people with acute exacerbations (
studies compared risperidone with amisulpride, two with aripipra- Addington 2004; Chan 2007; Heinrich 1994; Potkin 2003;
zole, 11 with clozapine, 23 with olanzapine, 11 with quetiapine, Potkin 2006). McEvoy 2007, Robinson 2005 and Svestka 2003
two with sertindole and three with ziprasidone. We identified no examined those with a first episode of schizophrenia, and Purdon
RCTs comparing risperidone with zotepine. 2000 included only participants in the early phase of the illness.
Five studies restricted randomisation to chronic schizophrenia
(Breier 1999; Daniel 1996; Lieberman 2005; Sechter 2002; Stroup
Included studies 2006). Insufficient response or resistance to previous treatment
The 45 studies randomised approximately 7700 people with was an inclusion criterion in nine studies (Azorin 2001; Azorin
schizophrenia and schizophrenia-like disorders. All but six in- 2006; Bondolfi 1998; Conley 2005; Kane 2005; McEvoy 2006;
cluded studies were double blind; the remaining six were single McGurk 2005; Volavka 2002; Wahlbeck 2000), but the criteria

varied widely. One study examined people with postpsychotic de- 6.2 Response to treatment
pression (Dollfus 2005) and another one participants with pre-
The studies rarely reported the response cut off at least 50% reduc-
dominant negative symptoms (Riedel 2005).
tion (Addington 2004; Dollfus 2005; Gureje 2003; Sechter 2002;
In most studies participants were 18 years old or older. Two stud-
Tran 1997) of a scales baseline value that we considered clini-
ies randomised only patients aged 60 or older (Jeste 2003; Mller
cally meaningful. In contrast, Breier 1999 used at least 20% BPRS
2005). Another study examined childhood schizophrenia and in-
total score reduction from baseline, Conley 2001 and Wahlbeck
cluded only children and adolescents with ages between 8 and 19
2000 at least 20% PANSS total score reduction, and Potkin 2006
years (Sikich 2004).
and Zhong 2006a at least 30% PANSS total score reduction from
In Van Nimwegen 2006 all participants had a recent history of
baseline.
cannabis use in addition to schizophrenia.
Heinrich 1994 based its assessment of response on the Clinical
Global Impression Scale (CGI) and defined at least much im-
4.Study size
proved compared to baseline as a cutoff.
Other studies applied combined criteria: Chan 2007 and Potkin
Lieberman 2005 was the largest study (1460 participants) whereas 2003 used at least much improved on the CGI or at least 30%
Daniel 1996 and Wahlbeck 2000 included the smallest samples PANSS total score reduction from baseline; Conley 2005 and
with 20 participants each. Twelve studies had fewer than 50 par- Sikich 2004 at least minimally improved on the CGI and at
ticipants, 13 had 50 to 100 participants, 16 had 100 to 400 par- least 20% BPRS total reduction from baseline; McEvoy 2007 all
ticipants and two randomised more than 400 people. Two studies PANSS items mild or better and a CGI-severity scale of mildly ill
did not indicate the total number of randomised participants. or better; McGurk 2005 at least 20% improvement on the BPRS
psychosis cluster and no psychotic symptom rated worse than mild
and Robinson 2005 certain SADS-C+PD items mild or better and
5 Interventions
at least much improved on the CGI.
5.1 Risperidone
The trialists gave risperidone in a wide range of doses from 0.5 mg/ 6.3 Relapse
day to 12 mg/day (McGurk 2005 up to 16 mg/ per day). Three Only three studies (Dollfus 2005; Lieberman 2005; Stroup 2006)
studies used a fixed dose design. Seven studies did not report the provided data for relapse and used different definitions.
dose range.
5.2 Comparators 6.4 Service use

Seven other SGA drugs were used as comparators with the fol- A few studies reported the number of participants who had to be
lowing dose ranges: amisulpride (100 mg/day to 1000 mg/day), readmitted to the hospital.
aripiprazole (15 mg/day to 30 mg/day), clozapine (25 mg/day to
900 mg/day), quetiapine (50 mg/day to 800 mg/day), olanzapine
(2.5 mg/day to 40 mg/day), sertindole (12 mg/day to 24 mg/day),
and zisprasidone (40 mg/day to 160 mg/day). Eight studies in- 6.5 Outcome scales
cluded more than one comparator arms of interest therefore num- We have provided details below of scales that provided usable
ber of comparisons (56) is higher than number of included studies data. We have provided reasons for exclusion of data from other
(45). Some studies also included additional arms with the typical instruments under Outcomes in the Included studies section.
antipsychotic drugs haloperidol, perospirone or perphenazine as
comparators. These results were not considered in the current re-
view.
6.5.1 Global state scales

6. Outcomes
6.5.1.1 Clinical Global Impression Scale - CGI Scale (Guy 1976)
This is used to assess both severity of illness and clinical improve-
ment, by comparing the conditions of the person standardised
6.1 Leaving the study early against other people with the same diagnosis. A seven-point scor-
We evaluated the number of participants leaving the studies early ing system is usually used, with low scores showing decreased sever-
due to any reason, due to adverse events and due to lack of efficacy. ity and/or overall improvement.

6.5.2 Mental state scales The SWN is an instrument to measure the subtle subjective
6.5.2.1 Brief Psychiatric Rating Scale - BPRS (Overall 1962) changes, such as restrictions in emotionality, the clarity of think-
This is used to assess the severity of abnormal mental state. The ing and spontaneity, that are often referred as pharmacogenic de-
original scale has 16 items, but a revised 18-item scale is commonly pression or the neuroleptic induced deficit syndrome.
used. Each item is defined on a seven-point scale varying from
not present to extremely severe, scoring from 0-6 or 1-7. Scores
can range from 0-126, with high scores indicating more severe 6.5.5 Cognitive functioning scales
symptoms.
6.5.5.1 Global Neurocognitive Score (Volavka 2002)
6.5.2.2 Positive and Negative Syndrome Scale - PANSS (Kay
This score consists of 15 tests that assess the domains general
1986)
ability, learning and memory, attention, executive functions, and
This schizophrenia scale has 30 items, each of which can be defined
motor skills. Sixteen variables were selected from 12 tests. For each
on a seven-point scoring system varying from 1 - absent to 7 -
test variable, z-scores were computed. This global score was then
extreme. It can be divided into three sub-scales for measuring the
computed by averaging the z-scores of contributing variables. All
severity of general psychopathology, positive symptoms (PANSS-
z-scores were computed in a way that positive scores indicate better
P), and negative symptoms (PANSS-N). A low score indicates less
performance.
severity.
6.5.5.2 Neurocognitive Composite Score (Keefe 2006)
6.5.2.3 Scale for the Assessment of Negative Symptoms - SANS
The Neurocognitive Composite Score comprises individual cog-
(Andreasen 1983)
nitive domains (executive function, learning and memory, pro-
This six-point scale gives a global rating of the following negative
cessing speed, attention/vigilance, verbal working memory, ver-
symptoms: alogia, affective blunting, avolition-apathy, anhedonia-
bal fluency, motor function, and visuospatial ability) measured by
asociality and attention impairment. Higher scores indicate more
various tests that were transformed into a composite score.
symptoms.
6.5.5.3 PANSS cognitive subscore
6.5.2.4 Scale for the Assessment of Positive Symptoms - SAPS
This score has been derived from the Positive and Negative Syn-
(Andreasen 1984)
drome Scale - PANSS (Kay 1986).
This four-point scale gives a global rating of the following positive
symptoms: hallucinations, paranoia, disorganised behaviour and
disorganised thinking. Higher scores indicate more symptoms.
6.5.6 Adverse effects scales
6.5.6.1 Abnormal Involuntary Movement Scale - AIMS (Guy
1976)
6.5.3 General functioning scales
This has been used to assess tardive dyskinesia, a long-term, drug-
6.5.3.1 Social and Occupational Functioning Assessment Scale - induced movement disorder and short-term movement disorders
SOFAS (Goldman 1992) such as tremor.
The SOFAS focuses on the different levels of social and occupa- 6.5.6.2 Barnes Akathisia Scale - BAS (Barnes 1989)
tional functioning. Higher scores indicate a higher level of func- The scale comprises items rating the observable, restless move-
tioning. ments that characterise akathisia, a subjective awareness of restless-
6.5.3.2 Global Assessment of Functioning - GAF (APA 1994) ness, and any distress associated with the condition. These items
This is a rating scale for a patients overall capacity of psychosocial are rated from 0 - normal to 3 - severe. In addition, there is an
functioning scoring from 1-100. Higher scores indicate a higher item for rating global severity (from 0 - absent to 5 - severe). A
level of functioning. low score indicates low levels of akathisia.
6.5.6.3 Extrapyramidal Symptom Rating Scale - ESRS (
Chouinard 1980)
This consists of a questionnaire relating to parkinsonian symp-
6.5.4 Quality of life scales toms (nine items), a physicians examination for parkinsonism and
6.5.4.1 Quality of Life Scale - QLS (Carpenter 1984) dyskinetic movements (eight items), and a clinical global impres-
This semi-structured interview is administered and rated by sion of tardive dyskinesia. High scores indicate severe levels of
trained clinicians. It contains 21 items rated on a seven-point scale movement disorder.
based on the interviewers judgement of patient functioning. A to- 6.5.6.4 Hillside Akathisia Scale - HAS (Fleischhacker 1989)
tal QLS and four subscale scores are calculated, with higher scores The Hillside Akathisia Scale (HAS) is another rating scale to ex-
indicating less impairment. amine akathisia, a subjective awareness of restlessness, and any dis-
6.5.4.2 Subjective Well-being under Neuroleptics Scale - SWN tress associated with the condition. It has two subjective and three
(De Haan 2002) objective items for which anchored rating points are provided.

6.5.6.5 Simpson Angus Scale - SAS (Simpson 1970) Awaiting assessment
This 10-item scale, with a scoring system of 0-4 for each item, No studies are awaiting assessment.
measures drug-induced parkinsonism, a short-term drug-induced
movement disorder. A low score indicates low levels of parkinson-
ism. Ongoing studies
We identified six RCTs comparing risperidone with other atypical
antipsychotics which appear to be ongoing (Astra Zeneca 2002;
Eli Lilly 2006; Eli Lilly 2003; Lieberman 2001; Lundbeck 2002;
Excluded studies Reveley 2000). We have presented further details in the ongoing
studies table.
We excluded 241 studies for the following reasons: 22 studies
because they were not randomised; 186 because they were open-
label trials without any effort to blind medication; 17 because they
were pooled-analyses of several trials; 11 because they did not use
Risk of bias in included studies
appropriate interventions; and five because they did not present For details of risk of bias, please refer to risk of bias table (Figure
any usable data. 1, Figure 2)

Figure 1. Methodological quality summary: review authors judgements about each methodological quality
item for each included study

Figure 2. Methodological quality graph: review authors judgements about each methodological quality
item presented as percentages across all included studies
Allocation
death or laboratory values) was low, but there was a risk of bias for
All included studies were randomised, but only eight trials pro- subjective outcomes.
vided some details about the randomisation process (Chan 2007;
Gureje 2003; Purdon 2000; Ren 2002; Sikich 2004; Stroup 2006;
Wahlbeck 2000; Wynn 2007). Four studies (Gureje 2003; Purdon Incomplete outcome data
2000; Sikich 2004; Wahlbeck 2000) used a computer-generated The overall number of participants leaving the studies early was
randomisation procedure, and Ren 2002 described a process to high (46.9%), although the percentages in the different compar-
make participants draw a ball out of a box. For all the other stud- isons varied. Eight studies did not report on leaving the study
ies the information was so little that it remained unclear whether early (Breier 1999; Mori 2004; Mller 2005; Ren 2002; Svestka
there was a risk of bias. Details on allocation concealment were 2003; Van Nimwegen 2006; Wang 2006; Wynn 2007). Nearly all
not provided for any of the studies. the studies analysed their data on an intention-to-treat basis using
the last observation carried forward. This method of accounting
for missing data is imperfect, because it assumes that participants
would not have experienced a change of their condition if they
Blinding
had stayed in the trial. This assumption can obviously be wrong.
Of the included studies, 38 were double-blind. The remaining Conversely it is a positive aspect of the evidence base that most
seven trials were single-blind (Atmaca 2003; Conley 2005; Daniel studies indicated the specific reasons for leaving early.
1996; Robinson 2005; Sacchetti 2004; Wahlbeck 2000; Zhou
2000). Another 16 studies described using identical capsules for
blinding. No study examined whether blinding was effective. We Selective reporting
found that the side-effect profiles of the examined compounds In most studies the reporting of secondary or even primary out-
are quite different, which may have made blinding difficult. We come data was incomplete (Addington 2004; Bondolfi 1998;
therefore conclude that the risk of bias for objective outcomes (e.g. Conley 2005; Daniel 1996; Dollfus 2005; Heinrich 1994; Hwang
2003; McGurk 2005; Mori 2004; Mller 2005; Peuskens 1999; 1.1.2 Global state: no clinically important change
Potkin 2003; Potkin 2006; Purdon 2000; Ren 2002; Riedel 2005; Overall there was no significant difference (3 RCTs, n = 586, RR
Robinson 2005; Sacchetti 2004; Stroup 2006; Svestka 2003; Van 1.12 CI 0.82 to 1.53), but some heterogeneity (I2 54%). Again,
Nimwegen 2006; Volavka 2002; Wang 2006; Wynn 2007; Zhou when the outlier study (Hwang 2003) was excluded there was a
2000). Often only those adverse events that occurred in at least significant superiority of amisulpride (2 RCTs, n = 586, RR 1.28
5% or 10% of the participants, or that were of moderate or worse CI 1.04 to 1.56, NNH 10 CI 6 to 50) in the short (Peuskens
severity, or that were significantly different between groups were 1999) (1 RCT, n=228, RR 0.96 CI 0.50 to 1.85) and medium
reported (Azorin 2006; Bondolfi 1998; Chan 2007; Conley 2001; term (Sechter 2002) (1 RCT, n = 310, RR 1.27 CI 0.99 to 1.64).
Gureje 2003; Hwang 2003; Jeste 2003; Kane 2005; Keefe 2006;
McEvoy 2007; Peuskens 1999; Potkin 2003; Potkin 2006; Sechter
2002; Tran 1997; Zhong 2006). This procedure is problematic,
1.1.3 Global state: relapse - medium term
because rare, but potentially serious side effects may be missed.
Only five studies appeared to have a low risk of bias (Atmaca 2003; Only one study provided data for this outcome and did not reveal
Lieberman 2005; Purdon 2000; Sikich 2004; Wahlbeck 2000). a significant difference between amisulpride and risperidone (1
RCT, n = 173, RR 1.50 CI 0.94 to 2.39).
Other potential sources of bias

1.2 Leaving the study early
One study was free of other bias (McGurk 2005), but for all
others we felt that there was at least a possibility of risk of bias. There was no significant difference between groups. Of the partic-
The main reason was sponsoring of the pharmaceutical industry. ipants, 34% in the amisulpride group and 32% in the risperidone
Of the included studies, 60% were sponsored by pharmaceutical group left the studies early due to any reason (3 RCTs, n = 586,
companies, 18% by the manufacturers of risperidone and 42% by RR 1.02 CI 0.68 to 1.53); 11% in the amisulpride group and
the manufacturers of the comparator compounds. Pharmaceutical 12% in the risperidone group left the studies early due to adverse
companies have an inevitable conflict of interest which may well events (4 RCTs, n = 622, RR 0.93 CI 0.61 to 1.42); and 10 % in
lead to bias (Heres 2006; Leucht 2008). Other potential sources the amisulpride group compared to 7% in the risperidone group
of bias were missing wash-out phases (Lieberman 2005; McEvoy left the studies early due to lack of efficacy of treatment (3 RCTs,
2006; Mori 2004), low numbers of participants (Conley 2001; n = 586, RR 1.45 CI 0.83 to 2.53).
Sikich 2004; Wahlbeck 2000), baseline imbalance in duration of
illness (Conley 2005) and missing data on allowed dose ranges
(Ren 2002). 1.3 Mental state
Effects of interventions
1.3.1 General - no clinically important change - medium
term (less than 50% PANSS total score reduction)
Sechter 2002 showed a tendency in favour of amisulpride which
1. Comparison 1. Risperidone versus amisulpride
did not reach a conventional level of statistical significance (1 RCT,
Four included studies fell in this category. n = 310, RR 1.24 CI 1.00 to 1.53).
1.1 Global state 1.3.2 General - no clinically important change - short term
(less than 20% PANSS total score reduction)
In Hwang 2003 there was no significant difference between groups
1.1.1 No clinically significant response - as defined by the (1 RCT, n = 48, RR 0.69 CI 0.28 to 1.69).
original studies
The results of three studies were slightly heterogeneous (I2 54%).
The combined analysis did not indicate a difference (3 RCTs, n 1.3.3 General - no clinically important change - medium
= 586, RR 1.12 CI 0.83 to 1.50), but when the outlier study term (less than 50% BPRS total score reduction)
(Hwang 2003) was excluded there was a significant superiority of A single study (Sechter 2002) found a significant superiority of
amisulpride (2 RCTs, n = 538, RR 1.25 CI1.05 to 1.50, NNH 9 amisulpride (1 RCT, n = 310, RR 1.29 CI 1.02 to 1.62, NNH 8
CI 5 to 50). CI 4 to 100).

1.3.4 General - no clinically important change - short term 1.4 General functioning
(less than 40% BPRS total score reduction)
Peuskens 1999 found no significant difference (1 RCT, n = 228,
RR 1.29 CI 0.92 to 1.80). 1.4.1 General functioning - no clinically important change -
medium term (less than 50 % SOFAS total score reduction)
There was no significant difference (1 RCT, n = 310, MD 1.11
1.3.5 General - average score at endpoint - PANSS total CI 0.98 to 1.25).
There was no significant difference (2 RCTs, n = 291, MD -0.38
CI -5.33 to 4.57) in either the short (1 RCT, n = 47, MD -4.30
(-14.59 to 5.99) or the medium term (1 RCT, n = 244, MD 0.80 1.4.2 General functioning - average score at endpoint -
CI -4.5 to 6.45). SOFAS total score
There was no significant difference (2 RCTs, n = 291, MD 2.31
CI -1.28 to 5.90) in either the short (1 RCT, n = 47, MD 1.10 CI
1.3.6 General - average score at endpoint - BPRS total -7.03 to 9.23) or medium term (1 RCT, n = 244, MD 2.60 CI -
1.40 to 6.60).
CI -1.79 to 3.14) in either the short (2 RCTs, n = 275, MD 0.50
CI -4.54 to 5.53) or medium term (1 RCT, n = 244, MD 0.20 CI
-3.28 to 3.68). 1.5 Adverse effects
1.3.7 Positive symptoms - average score at endpoint - PANSS 1.5.1 General - at least one adverse effect
positive
There was no significant difference (4 RCTs, n = 622, RR 1.00 CI
There was no significant difference (3 RCTs, n = 519, MD 0.03 0.90 to 1.10).
CI -2.17 to 2.47) or medium term (1 RCT, n = 244, MD -0.30
CI -2.11 to 1.51).
1.5.2 Death
Only Sechter 2002 reported on death and did not find a significant
difference in terms of natural causes (1 RCT, n = 310, RR 0.32
1.3.8 Positive symptoms - average score at endpoint - BPRS CI 0.01 to 7.81) or suicide (1 RCT, n = 310, RR 0.48 CI 0.04 to
positive 5.25).
CI -0.89 to 1.89).
1.5.3 Cardiac effects - number of participants with QTc
prolongation
1.3.9 Negative symptoms - average score at endpoint - No participant had a prolongation of the QTc interval (2 RCTs,
PANSS negative n = 276, RR not estimable).
CI -1.72 to 2.92) or the medium term (1 RCT, n = 244, MD 1.20 1.5.4 Central nervous system - sedation
CI -0.21 to 2.61). There was no significant difference (1 RCT, n = 310, RR 1.44 CI
0.61 to 3.43).
1.3.10 Negative symptoms - average score at endpoint -

SANS total 1.5.5 Central nervous system - seizures
There was no significant difference (1 RCT, n = 224, MD 2.70 Only Sechter 2002 reported on this outcome. No participant had
CI -2.33 to 7.73). a seizure (1 RCT, n = 310, RR not estimable).

1.5.6 Extrapyramidal effects 2.1 Global state
There was no significant difference between risperidone and
amisulpride in the frequency of akathisia (3 RCTs, n = 586, RR
1.25 CI 0.90 to 1.74), extrapyramidal symptoms (1 RCT, n = 228, 2.1.1 Global state - no clinically significant response - as
RR 0.88 CI 0.60 to 1.30), hyperkinesia (2 RCTs, n = 538, RR defined by the original studies
0.75 CI 0.49 to 1.14), parkinsonism (2 RCTs, n = 538, RR 1.13 There was no significant difference (2 RCTs, n = 384, RR 0.88 CI
CI 0.66 to 1.95), rigor (2 RCTs, n = 276, RR 1.08 CI 0.27 to 0.62 to 1.24).
4.36), tremor (3 RCTs, n = 586, RR 1.46 CI 0.66 to 3.21) or use
of antiparkinson medication (3 RCTs, n = 586, RR 1.07 CI 0.72
to 1.57). 2.1.2 Global state - no clinically important change
0.62 to 1.24).
1.5.7 Extrapyramidal effects - scale measured
There was no significant difference in dyskinesia (AIMS: 2 RCTs,
n = 538, MD -0.08 CI -0.72 to 0.55) or extrapyramidal side effects 2.2 Leaving the study early
in general (SAS: 2 RCTs, n = 538, MD 0.03 CI -0.06 to 0.13).
There was no significant difference between groups. 35% of the
participants in the risperidone group and 34% of the participants
1.5.8 Prolactin associated side effects in the aripiprazole group left the studies early due to any reason
(2 RCTs, n = 384, RR 1.06 CI 0.79 to 1.41). There was also no
There was no significant difference in the frequency of amenorrhea significant difference in leaving the studies early due to adverse
(1 RCT, n = 310, RR 0.96 CI 0.06 to 15.24) and galactorrhea events (8% versus 10%; 2 RCTs, n = 384, RR 0.79 CI 0.39 to
(2 RCTs, n = 538, RR 0.74 CI 0.17 to 3.27). In men sexual 1.61), or in leaving the studies early due to inefficacy of treatment
dysfunction occurred more frequently in the risperidone group (6% versus 8%; 2 RCTs, n = 384, RR 0.89 CI 0.41 to 1.93).
than in the amisulpride group (2 RCTs, n = 538, RR 9.52 CI 1.22
to 74.44, NNH 33 CI 100 to 17).
2.3 Mental state
1.5.9 Metabolic - weight gain

More participants in the risperidone group than in the amisulpride 2.3.1 General - average endpoint score - PANSS total
group had a clinically important weight gain (2 RCTs, n = 538,
There was no significant difference (2 RCTs, n = 372, MD -1.50
RR 1.75 CI 1.07 to 2.87, NNH not estimable).
CI -5.96 to 2.96).
1.5.10 Metabolic - weight gain - mean change from baseline

in kg 2.3.2 Positive symptoms - average endpoint score - PANSS
positive
Risperidone was associated with more weight gain than amisul-
pride (3 RCTs, n = 585, MD 0.99 CI 0.37 to 1.61). There was no significant difference (2 RCTs, n = 372, MD -1.24
CI -2.74 to 0.26).
1.6 Publication bias

2.3.3 Negative symptoms - average endpoint score - PANSS
Due to small number of included studies (< 10 studies), we did
negative
not perform a funnel plot analysis.
CI -0.87 to 1.78).
1.7 Sensitivity analyses
The reasons for the preplanned sensitivity analyses did not apply
2.4 Adverse effects
and therefore we have not performed these.
2. Comparison 2. Risperidone versus aripiprazole - all 2.4.1 General - at least one adverse effect
data short term There was no significant difference (2 RCTs, n = 384, RR 1.02 CI
Two included studies fell in this category. 0.95 to 1.09).

2.4.2 Cardiac effects - number of participants with QTc 2.4.8 Metabolic - cholesterol - mean change from baseline in
prolongation mg/dl
There was no significant difference (1 RCT, n = 301, RR 14.21 Risperidone was associated with significantly more cholesterol in-
CI 0.74 to 272.45). crease than aripiprazole (1 RCT, n = 83, MD 22.30 CI 4.91 to
39.69).
2.4.3 Cardiac effects - mean change of QTc interval from 2.4.9 Metabolic - glucose - mean change from baseline in
baseline in ms mg/dl
There was no significant difference (2 RCTs, n = 383, MD 7.19 There was no significant difference (1 RCT, n = 83, MD -6.80 CI
CI 2.19 to 12.19). -19.70 to 6.10).
2.4.10 Metabolic - weight gain of 7% or more of total body

2.4.4 Extrapyramidal effects weight
There was no significant difference in akathisia (2 RCTs, n = 384, There was no significant difference (2 RCTs, n = 284, RR 1.30 CI
RR 1.56 CI 0.21 to 11.45). The results of the two included studies 0.55 to 3.07).
were heterogeneous, but neither one found a significant difference
between groups (Potkin 2003: n = 301, RR 0.71 CI 0.41 to 1.25
2.4.11 Metabolic - weight gain - mean change from baseline
and Chan 2007: n = 83, RR 5.76 CI 0.67 to 49.35). There was also
in kg
no significant difference in extrapyramidal symptoms (2 RCTs, n
= 384, RR 1.18 CI 0.68 to 2.06), parkinsonism (1 RCT, n = 301, There was no significant difference (2 RCTs, n = 383, MD 0.54
RR 0.14 CI 0.01 to 2.35) and use of antiparkinson medication (1 CI -0.15 to 1.24).
RCT, n = 83, RR 1.68 CI 0.89 to 3.17). More participants in the
risperidone group than in the amisulpride group had a dystonia
(1 RCT, n = 301, RR 7.14 CI 2.41 to 21.13, NNH 8 CI 20 to
5), while in the same study more participants in the aripiprazole Due to the small number of included studies, we have not per-
group suffered from tremor (1 RCT, n = 301, RR 0.21 CI 0.05 to formed a funnel plot analysis.
0.90, NNH 14 CI 8 to 50).
2.6 Sensitivity analysis

The reason for the preplanned sensitivity analyses did not apply
2.4.5 Extrapyramidal symptoms - scale measured and we have therefore not performed these.
n = 383, MD 0.25 CI -0.75 to 1.24), akathisia (BAS: 2 RCTs, n
= 388, MD 0.11 CI -0.11 to 0.49) or extrapyramidal side effects 3. Comparison 3. Risperidone versus clozapine
in general (SAS: 2 RCTs, n = 388, MD 0.70 CI -0.82 to 2.22). Eleven included studies fell in this category.
3.1 Global state

2.4.6 Prolactin associated side effects
In one study many more participants in the risperidone group than
in the aripiprazole group had elevated prolactin levels (1 RCT, n 3.1.1 Global state - no clinically significant response - as
= 301, RR 26.23 CI 12.64 to 54.46, NNH not estimable). defined by the original studies
There was no significant difference in the frequency of dysmen- There was no significant difference (6 RCTs, n = 575, RR 1.07 CI
orrhoea (1 RCT, n = 91, RR 0.32 CI 0.02 to 5.91). 0.98 to 1.16).
3.1.2 Global state - no clinically important change - short

2.4.7 Prolactin - mean change from baseline in ng/ml term - as defined by the original studies
Risperidone was associated with clearly more prolactin increase There was no significant difference (2 RCTs, n = 333, RR 1.07 CI
than aripiprazole (2 RCTs, n = 383, MD 54.71 CI 49.36 to 60.06). 0.88 to 1.30).

3.2 Leaving the study early 3.3.6 General - average score at endpoint - BPRS total
A similar number of participants in the risperidone group (35%) There was a trend in favour of clozapine which did not reach the
and the clozapine group (31%) left the studies early due to any conventional 5% level of statistical significance (4 RCTs, n = 364,
reason (8 RCTs, n = 675, RR 1.10 CI 0.86 to 1.41). Nevertheless, MD 3.07 CI -0.01 to 6.16). This was in contrast to long-term (1
fewer participants in the risperidone group (7%) than in the cloza- RCT, n = 52, MD -0.20 CI -4.12 to 3.72) and short-term data (3
pine group (12%) left the studies early due to adverse events (7 RCTs, n = 345, MD 4.90 CI 2.17 to 7.64).
RCTs, n = 647, RR 0.55 CI 0.31 to 0.98, NNH not estimable). In
contrast, more participants in the risperidone group (14%) than
in the clozapine group (5%) left the studies early due to inefficacy 3.3.7 Positive symptoms - average score at endpoint - PANSS
of treatment (7 RCTs, n = 647, RR 2.51 CI 1.43 to 4.40, NNH positive
not estimable). Data on this outcome showed a superiority of clozapine (6 RCTs, n
= 591, 1.26 CI 0.18 to 2.35), but when two studies with potentially
skewed data were excluded (Breier 1999; Ren 2002) the difference
3.3 Mental state was no longer statistically significant (4 RCTs, n = 442, MD 0.60,
CI -1.34 to 2.53).
3.3.1 General - no clinically important change - short term - 3.3.8 Positive symptoms - average score at endpoint - short
less than 20% PANSS total score reduction term - BPRS positive
There was no significant difference (2 RCTs, n = 106, RR 0.84 CI There was no significant difference (1 RCT, n = 29, RR 2.10 CI
0.50 to 1.42). -0.56 to 4.76).
3.3.2 General - no clinically important change - short term 3.3.9 Negative symptoms - average score at endpoint -
PANSS negative
(Kane 1988 criteria)
There was no significant difference (1 RCT, n = 273, RR 1.05 CI There was no significant difference, in the short (4 RCTs, n = 481,
0.85 to 1.29). MD -0.55 CI -2.80 to 1.71) or medium term (1 RCT, n = 81,
MD 1.40 CI -1.42 to 4.22), or overall (5 RCTs, n = 562, MD -
0.13 CI -1.96 to 1.71).
3.3.3 General - no clinically important change - long term -

less than 20% BPRS total score reduction 3.3.10 Negative symptoms - average score at endpoint - short
There was no significant difference (1 RCT, n = 29, RR 1.24 CI term - SANS total
0.78 to 1.98). There was no significant difference (2 RCTs, n = 69, MD -0.62
CI -3.74 to 2.51).
3.3.4 General - no clinically important change - short term -

less than 40% BPRS total score reduction 3.4 General functioning
There was no significant difference (1 RCT, n = 107, RR 1.05 CI

0.76 to 1.45).
3.4.1 General functioning - average score at endpoint - GAF
There was no significant difference (1 RCT, n = 19, MD 9.00 CI
3.3.5 General - average score at endpoint - PANSS total -0.44 to 18.44).
There was no significant difference, in the short term (4 RCTs, n

= 387, MD 0.75 CI -5.35 to 6.85) in the medium term (1 RCT,
3.4.2 General functioning - average endpoint - short term -
n = 81, MD 3.60 CI -6.12 to 13.32), or overall (5 RCTs, n = 468,
social functioning scale
RR 1.49 CI -3.44 to 6.42). The results were heterogeneous due to
the study by Azorin 2001 which showed a pronounced superiority There was no significant difference (1 RCT, n = 19, MD 47.00
of clozapine. Excluding this study did not change the results. CI 0.45 to 93.55, P = 0.05).

3.5 Cognitive functioning 3.6.6 Extrapyramidal effects
There was no significant difference in akathisia (1 RCT, n = 40,
RR 0.11 CI 0.01 to 1.94), akinesia (1 RCT, n = 86, RR 1.00
3.5.1 Cognitive functioning - medium term - no clinically CI 0.38 to 2.61), dystonia (1 RCT, n = 86, RR 2.00 CI 0.19 to
important change in global neurocognitive score (less than 21.24), extrapyramidal symptoms (2 RCTs, n = 333, RR 1.30 CI
1/2 SD) 0.44 to 3.85) and tremor (1 RCT, n = 40, RR 0.50 CI 0.18 to
1.40).
However, a single small study found more parkinsonism (1 RCT,
0.60 to 1.05).
n = 86, RR 0.63 CI 0.41 to 0.97, NNH 4 CI 2 to 33) in the
clozapine group. In contrast, the combination of six RCTs revealed
a consistently more frequent use of antiparkinson medication in
3.5.2 Cognitive functioning - average endpoint - medium the risperidone group (6 RCTs, n = 304, RR 2.57 CI 1.47 to 4.48,
term - global neurocognitive score NNH 6 CI 33 to 3).
-0.06 to 0.72).
There was no difference in extrapyramidal side effects according
3.6 Adverse effects to the Simpson-Angus Scale (2 RCTs, n = 69, MD 0.81 CI -0.10
to 1.73) nor the ESRS total score (1 RCT, n = 81, MD -0.30 CI
-1.91 to 1.31).
3.6.1 General - at least one adverse effect
0.51 to 1.42), but the results of two studies were heterogeneous 3.6.8 Haematological - white blood cells - low white blood
(Heinrich 1994: n = 60, RR 0.63 CI 0.42 to 0.96; Azorin 2001: cell count
n = 273, RR 1.06 CI 0.94 to 1.19). We did not identify obvious There was no significant difference (5 RCTs, n = 567, RR 1.69 CI
reasons for the heterogeneity. 0.51 to 5.58).
3.6.2 Death 3.6.9 Prolactin associated side effects

One study reported on death due to any reason and showed no There was no significant difference in the frequency of sexual dys-
significant difference between groups (1 RCT, n = 273, RR 1.02 function (1 RCT, n = 86, RR 2.00 CI 0.39 to 10.35).
CI 0.06 to 16.18).
3.6.10 Prolactin - change from baseline in ng/ml

3.6.3 Cardiac effects Risperidone was associated with a clearly higher increase of pro-
Cardiac effects were reported as preterminally negative t-wave lactin levels than clozapine (men and women: 1 RCT, n = 27, MD
(1 RCT, n = 60, RR 1.54 CI 0.07 to 36.11) and any significant 38.50 CI 23.30 to 53.70; men only: 1 RCT, n = 28, MD 20.00
cardiac effect (1 RCT, n = 86, RR not estimable), but there was CI 8.19 to 31.81).
not significant difference.
3.6.11 Metabolic - cholesterol - change from baseline in

3.6.4 Central nervous system - sedation mg/dl
There was a significant difference in favour of risperidone (5 RCTs, There was no significant difference .(1 RCT, n = 31, MD -7.10
n = 479, RR 0.53 CI 0.32 to 0.86, NNT 5 CI not estimable). CI -34.01 to 19.81).
3.6.5 Central nervous system - seizures 3.6.12 Metabolic - glucose - change from baseline in mg/dl
There was a significant difference in favour of risperidone (2 RCTs, There was no significant difference (1 RCT, n = 31, MD -1.70 CI
n = 354, RR 0.22 CI 0.07 to 0.70, NNT 14 CI 8 to 33). -12.04 to 8.64).

3.6.13 Metabolic - weight gain 4.1.2 Global state: no clinically important change (as defined
by the original studies)
There was no significant difference in weight gain of 10% or more
of total body weight (1 RCT, n = 81, RR 0.56 CI 0.18 to 1.76) There was no significant difference (5 RCTs, n = 975, RR 0.98 CI
or in weight gain reported as an adverse event (1 RCT, n = 86, 0.88 to 1.09) in short-term (3 RCTs, n = 589, RR 1.00 CI 0.87 to
RR 0.63 CI 0.32 to 1.22). 1.16), medium-term (1 RCT, n = 120, RR 0.83 CI 0.60 to 1.16)
or long-term data (1 RCT, n = 266, 0.98 CI 0.71 to 1.35).
3.6.14 Metabolic - weight gain - mean change from baseline 4.1.3 Global state: relapse (as defined by the original studies)
in kg There was no significant difference (2 RCTs, n = 211, RR 1.25
Clozapine was associated with significantly more weight gain than CI 0.57 to 2.71) in either short-term (1 RCT, n = 76, RR 0.75
risperidone (3 RCTs, n = 373, MD -3.30 CI -5.65 to -0.95). CI 0.25 to 2.25) or long-term data (1 RCT, n = 135, RR 1.70 CI
Although all three studies showed a consistent trend in favour of 0.79 to 3.67).
risperidone, the results were heterogeneous, with Atmaca 2003
revealing a particularly high difference (Azorin 2001: n = 270, 4.2 Leaving the study early
MD -2.20 CI -3.50 to -0.90; Volavka 2002: n = 77, MD -1.90
Significantly more participants in the risperidone group (56%)
CI -3.63 to -0.17; Atmaca 2003: n = 26, MD -5.98 CI -7.87 to -
than in the olanzapine group (48%) left the studies early due to
4.09).
any reason (15 RCTs, n = 2662, RR 1.14 CI 1.07 to 1.21, NNH
13 CI 9 to 25).
Leaving the studies early due to adverse events did not differ be-
3.7 Publication bias: tween groups (11% versus 12%, 13 RCTs, n = 2519, RR 0.96
CI 0.71 to 1.30). There was a trend that more participants in the
Due to the small number of included studies, we did not perform
risperidone group (15%) than in the olanzapine group (11%) left
a funnel plot analysis.
the studies early due to inefficacy of treatment, but the difference
did not reach a conventional level of significance (14 RCTs, n =
2668, RR 1.28 CI 1.02 to 1.60).
3.8 Investigation for heterogeneity and sensitivity analysis:
Excluding Breier 1999 (skewed data) from the outcome BPRS to- 4.3 Mental state
tal score did not change the overall result. Excluding Ren 2002
(skewed data) and Breier 1999 (skewed data) from the outcome
PANSS positive subscore, the advantage for clozapine was no 4.3.1 General - no clinically important change - (less than
longer significant (4 RCTs, n = 441, MD 0.60 CI -1.34 to 2.53). 50% PANSS total score reduction)
The exclusion of Ren 2002 (skewed data) from the outcome There was a significant difference in favour of olanzapine (3 RCTs,
PANSS negative subscore did not influence the result to any im- n = 472, RR 1.09 CI 1.00 to 1.18, NNH not estimable) in short-
portant extent. term (1 RCT, n = 71, RR 0.43 CI 0.04 to 4.57) and long-term
outcomes (2 RCTs, n = 401, RR 1.09 CI 1.00 to1.18).
4. Comparison 4. Risperidone versus olanzapine 4.3.2 General - no clinically important change - short term
Twenty-three studies fell into this category. (less than 20% PANSS total score reduction)
0.88 to 1.19).
4.1 Global state
4.3.3 General - average endpoint score - PANSS total
There was a significant difference in favour of olanzapine (15
RCTs, n = 2390, MD 1.94 CI 0.58 to 3.31), which was most
4.1.1 Global state - no clinically significant response - as
prominent in long-term (5 RCTs, n = 1431, MD 2.59 CI 0.20 to
defined by the original studies
4.98), short-term (7 RCTs, n = 728, MD 0.97 CI -1.10 to 3.05)
There was no significant difference (7 RCTs, n = 1376, RR 1.06 and medium-term outcomes (4 RCTs, n = 231, MD 4.11 CI -
CI 0.99 to 1.13). 0.71 to 8.93).

4.3.4 General - average endpoint score - BPRS total There was no significant difference (1 RCT, n = 80, RR 1.30 CI
There was no significant difference (3 RCTs, n = 428, MD 4.16 0.88 to 1.94).
CI 0.03 to 8.29) in either short-term (1 RCT, n = 35, MD 5.00
CI -5.74 to 15.74) or long-term outcomes (2 RCTs, n = 493, MD
4.5.2 Cognitive functioning - average score at endpoint -
4.28 CI -1.34 to 9.91).
medium term - mean global neurocognitive score
There was no significant difference (1 RCT, n = 52, MD 0.04 CI
4.3.5 Positive symptoms - no clinically important change - -0.31 to 0.39).
short term - less than 50% PANSS positive subscore
reduction
4.5.3 Cognitive functioning - average score at endpoint -
long term - neurocognitive composite score
0.93 to 1.04).
CI -0.11 to 0.13).
4.3.6 Positive symptoms - average endpoint score - PANSS
positive
4.6 Service use - number of patients rehospitalised
CI -0.09 to 1.02), but medium- (3 RCTs, n = 231, MD 1.58 CI There was no significant difference overall (3 RCTs, n = 965, RR
-0.03 to 3.20) and long-term data (5 RCTs, n = 810, MD 0.68 1.34 CI 0.96 to 1.86) or in the short (1 RCT, n = 76, RR 1.35
CI -0.04 to 1.40) almost indicated a benefit for the control group, CI 0.41 to 4.40), medium (1 RCT, n = 212, RR 1.38 CI 0.69 to
compared to short-term (5 RCTs, n = 661, MD -0.48 CI -1.53 to 2.78) or long term (1 RCT, n = 677, RR 1.32 CI 0.89 to 1.96).
0.57).
4.7 Adverse effects
negative
4.7.1 At least one adverse effect
CI -0.09 to 1.02). Long-term data (5 RCTs, n = 810, MD 0.81 There was no significant difference (11 RCTs, n = 2576, RR 0.96
CI 0.07 to 1.54) indicated a benefit for the control group, whereas CI 0.88 to 1.03).
short-term (5 RCTs, n = 661, MD 0.19 CI -0.85 to 1.22) and
medium-term data did not show a significant difference (3 RCTs,
4.7.2 Death
n = 231, MD 0.00 CI -1.58 to 1.59).
Tran 1997 reported on death due to any reason and found no
difference between groups (1 RCT, n = 339, RR 3.09 CI 0.13 to
4.3.8 Negative symptoms - average endpoint score - long 75.30).
term - SANS total Two studies examined death due to natural causes. Overall there
There was a significant superiority in favour of olanzapine (1 RCT, was no significant difference, but there was only one death which
n = 308, MD 1.40 CI 0.37 to 2.43). occurred in the olanzapine group (2 RCTs, n = 252, RR 0.34 CI
0.01 to 8.26).
Completed suicides and suicide attempts were reported by four
4.4 Quality of life - average endpoint score - long term - QLS and five studies, respectively. There was no significant difference
total in either outcome (suicide: 4 RCTs, n = 730, RR 3.11 CI 0.13 to
In two trials the quality of life of the participants in the olanzapine 75.59; suicide attempts: 5 RCTs, n = 1724, RR 1.15 CI 0.37 to
group was significantly better than that of those in the risperidone 3.54).
group (2 RCTs, n = 296, MD 5.10 CI 1.09 to 9.1).
4.7.3 Cardiac effects

4.5 Cognitive functioning Cardiac effects were reported as ECG abnormalities (2 RCTs, n =
415, RR 0.42 CI 0.08 to 2.30) and QTc prolongation (2 RCTs,
n = 853, RR 2.69 CI 0.12 to 60.00), without significant difference
4.5.1 Cognitive functioning - no clinically important change
between groups.
- medium term (less than half a standard deviation
The data on QTc prolongation were heterogeneous, possibly due
improvement in a global neurocognitive score)
to a difference in age groups, because Jeste 2003 included only

elderly participants with schizophrenia. Nevertheless, neither one subscore: 3 RCTs, n = 572, MD 0.24 CI -1.09 to 1.57. It should
of the two individual studies found a significant difference between be noted that some of these results were heterogeneous, but no
groups (Jeste 2003: n = 176, RR 0.77 CI 0.18 to 3.33; Lieberman clear reason for the heterogeneity could be identified.
2005: 1 RCT, n = 677, RR 14.78 CI 0.85 to 257.77).
4.7.9 Haematological - white blood cells - number of

4.7.4 Cardiac effects - mean change of QTc interval from participants with low white blood cell count
baseline in ms Overall there was no significant difference (3 RCTs, n = 484, RR
There was no significant difference (6 RCTs, n = 1518, MD 0.96 1.00 CI 0.09 to 10.59). The results of the three studies were het-
CI -2.74 to 4.67). erogeneous, but the single trials did not show significant differ-
ences between risperidone and olanzapine either (Tran 1997: n =
339, RR 0.15 CI 0.02 to 1.18; Volavka 2002: n = 80, RR 4.76
4.7.5 Central nervous system - sedation CI 0.24 to 96.16; and Gureje 2003: n = 65, RR 2.91 CI 0.12 to
There was no significant difference (11 RCTs, n = 2576, RR 0.93 68.95).
CI 0.84 to 1.04).
4.7.10 Prolactin associated side effects

4.7.6 Central nervous system - seizures Significantly more participants in the risperidone group suffered
There was no significant difference (4 RCTs, n = 671, RR 0.26 CI from amenorrhea (7 RCTs, n = 565, RR 1.50 CI 1.02 to 2.22,
0.03 to 2.35). NNH not estimable) and abnormal ejaculation (3 RCTs, n =
531, RR 4.34 CI 1.49 to 12.69, NNH not estimable). More par-
ticipants in the risperidone group had abnormally high prolactin
4.7.7 Extrapyramidal effects
levels, but this result did not reach conventional levels of statistical
There was no significant difference in the number of participants significance (3 RCTs, n = 477, RR 3.02 CI 0.99 to 9.23).
with akinesia (3 RCTs, n = 681, RR 1.21 CI 0.82 to 1.79), dysk- There were no significant differences in decreased libido (3 RCTs,
inesia (3 RCTs, n = 580, RR 1.02 CI 0.36 to 2.90), dystonia (3 n = 781, RR 2.48 CI 0.77 to 8.00), galactorrhea (7 RCTs, n = 547,
RCTs, n = 591, RR 1.79 CI 0.37 to 8.77), rigor (2 RCTs, n = RR 1.64 CI 0.79 to 3.39), gynaecomastia (5 RCTs, n = 1083, RR
141, RR 0.41 CI 0.06 to 2.70), tremor (5 RCTs, n = 973, RR 1.39 CI 0.70 to 2.77), impotence (3 RCTs, n = 531, RR 2.00 CI
0.87 CI 0.48 to 1.57) or extrapyramidal symptoms (4 RCTs, n = 0.68 to 5.89), orgasmic dysfunction (1 RCT, n = 377, RR 5.03
1104, RR 1.33 CI 0.83 to 2.13). The results of the latter outcome CI 0.24 to 104.00) and sexual dysfunction (7 RCTs, n = 1715,
were heterogeneous, possibly due to a single study in elderly par- RR 1.07 CI 0.90 to 1.28).
ticipants which showed an opposite trend compared to the other
studies (Jeste 2003). Excluding Jeste 2003 there was a significant
superiority of olanzapine (RR 1.54, CI 1.05 to 2.28, NNH 13 CI 4.7.11 Prolactin - mean change from baseline in ng/ml
8 to 33). Risperidone was associated with significantly more prolactin in-
Risperidone produced more akathisia (8 RCTs, n = 1988, RR 1.30 crease than olanzapine (men and women combined: 6 RCTs, n
CI 1.02 to 1.66, NNH not estimable) and parkinsonism (1 RCT, = 1291, MD 22.84 CI 17.69 to 27.98; men only: 2 RCTs, n =
n = 776, RR 1.65 CI 1.08 to 2.51, NNH not estimable), and it was 70, MD 19.91 CI 13.64 to 26.18; women only: 1 RCT, n = 71,
associated with more frequent use of antiparkinson medication MD 41.40 CI 29.64 to 53.16). There was some heterogeneity in
(13 RCTs, n = 2599, RR 1.28 CI 1.06 to 1.55, NNH 17 CI 9 to the degree of the difference, but all studies consistently favoured
100). olanzapine.
4.7.8 Extrapyramidal symptoms - scale measured 4.7.12 Metabolic - cholesterol - number of participants with
There was no significant difference in akathisia (BAS: 2 RCTs, n a cholesterol increase
= 353, MD 0.72 CI -0.36 to 1.81; ESRS akathisia subscore: 1 There was no significant difference (1 RCT, n = 266, RR 0.78 CI
RCT, n = 359, MD 0.00 CI -0.27 to 0.27), dyskinesia (AIMS: 0.44 to 1.38).
11 RCTs, n = 302, MD 0.03 CI -0.72 to 0.78; ESRS dyskinesia
subscore: 3 RCTs, n = 572, MD -0.08 CI -0.76 to 0.60), dystonia
(ESRS dystonia subscore: 1 RCT, n = 42, MD -0.09 CI -0.91 to 4.7.13 Metabolic - cholesterol - mean change from baseline
0.73), overall general extrapyramidal symptoms (ESRS total score: in mg/dl
4 RCTs, n = 682, MD 0.30 CI -0.35 to 0.94; SAS: 5 RCTs, n = 522, There was a significant difference favouring risperidone (7 RCTs,
MD 0.62 CI -0.08 to 1.33) or parkinsonism (ESRS parkinsonism n = 1391, MD -10.36 CI -14.43 to -6.28).

4.7.14 Metabolic - glucose - abnormally high fasting glucose Overall there was no significant difference. As the results were
value heterogeneous we present the single studies separately. Potkin 2006
There was no significant difference (3 RCTs, n = 670, RR 0.50 CI reported a significant difference in favour of risperidone (1 RCT,
0.22 to 1.16). n = 177, RR 0.79 CI 0.65 to 0.96), while Zhong 2006a (1 RCT, n
= 495, RR 1.00 CI 0.92 to 1.10), McEvoy 2007 (1 RCT, n = 103,
RR 0.85 CI 0.62 to 1.15) and Conley 2005 found no significant
4.7.15 Metabolic - glucose - change from baseline in mg/dl difference between groups (1 RCT, n = 25, RR not estimable).
There was a significant difference in favour of risperidone (7 RCTs,
n = 1201, MD -7.58 CI -11.23 to -3.93).
5.1.2 Global state - no clinically important change (as
defined by the original studies)
4.7.16 Metabolic - weight gain - number of participants with Short-term studies (3 RCTs, n = 1007, RR 0.86 CI 0.70 to 1.07)
weight gain and long-term studies (1 RCT, n = 267, RR 0.85 CI 0.62 to 1.15)
Significantly fewer participants in the risperidone group than in tended to favour risperidone, but the difference was not statistically
the olanzapine group suffered from weight gain (11 RCTs, n = significant.
2594, RR 0.55 CI 0.43 to 0.72, NNT 9 CI 7 to 14). There was
some heterogeneity due to a first episode study (McEvoy 2007)
5.2 Leaving the study early
which showed only a small difference between groups, but the
overall trend was very consistent in favour of risperidone. There was no significant difference in the number of participants
leaving the studies early due to any reason (risperidone 54%, que-
tiapine 57%, 10 RCTs, n = 2278, RR 0.94 CI 0.87 to 1.02) or
4.7.17 Metabolic - weight gain - mean change from baseline due to adverse events (9% versus 11%, 7 RCTs, n = 1851, RR
in kg 0.84 CI 0.56 to 1.27). Leaving early due to inefficacy showed an
Risperidone was associated with significantly less weight gain than almost significant superiority of risperidone (24% versus 19%, 7
olanzapine (3 RCTs, n = 2116, MD -2.61 CI -3.74 to -1.48). RCTs, n = 1851, RR 0.79 CI 0.62 to 1.01).
The results were heterogeneous, because Atmaca 2003 showed an
extreme superiority of risperidone. Excluding this study resolved
the heterogeneity and risperidones superiority prevailed (12 RCTs, 5.3 Mental state
n = 2090, MD -2.06 CI -2.74 to -1.37).

4.8 Publication bias less than 30% PANSS total score reduction from baseline
A funnel plot of the outcome PANSS total score (> 10 included There was no significant difference (2 RCTs, n = 982, RR 0.90
studies) did not suggest a significant publication bias. CI 0.71 to 1.15), but the results were heterogeneous. Potkin 2006
found a superiority of risperidone (n = 177, RR 0.79 CI 0.65 to
0.96), whereas Zhong 2006a found no difference between groups
4.9 Investigation for heterogeneity and sensitivity analysis (n = 495, RR 1.00 CI 0.92 to 1.10).
Excluding Mori 2004 (skewed data) from the outcome PANSS
positive score did not change the result. The exclusion of Sikich
2004 (skewed data) from the analysis of the BPRS total score did 5.3.2 General - no clinically important change - short term -
not have an important impact on this outcome. less than 20% BPRS total score reduction from baseline
0.66 to 1.60).
5. Comparison 5. Risperidone versus quetiapine
Eleven included studies fell in this category.
5.3.3 General - average score at endpoint - PANSS total
5.1 Global state
n = 1953, MD -3.09 CI -5.16 to -1.01), which was seen in long-
term data (2 RCTs, n = 743, MD -3.11 CI -5.82 to -0.40), but
not in medium-term (2 RCTs, n = 146, MD -6.27 CI -16.48 to
3.94) or short-term (5 RCTs, n = 1064, MD -2.44 CI -5.69 to
0.81) data.

5.3.4 General - average score at endpoint - short term - BPRS 5.5 Service use: number of participants rehospitalised
total There was a benefit in favour of risperidone in the overall analysis
There was no significant difference (1 RCT, n = 25, MD -1.68 CI (2 RCTs, n = 877, RR 0.75 CI 0.56 to 1.00), as well as in the
-11.69 to 8.33). medium (1 RCT, n = 199, RR 0.77 CI 0.42 1.41) and long term
(1 RCT, n = 681, RR 0.7 CI 0.53 1.03).
5.3.5 Positive symptoms - short term - less than 40% PANSS

positive subscore reduction from baseline 5.6 Adverse effects
0.9 to 1.12).
There was no significant difference (8 RCTs, n = 2226, RR 0.96
5.3.6 Positive symptoms - average endpoint score - PANSS CI 0.85 to 1.08).
positive
n = 1264, MD -1.82 CI -2.48 to -1.16), 5.6.2 Death
which was most prominent in short-term data (4 RCTs, n = 1037, There was no significant difference in the number of completed
MD -2.10 CI -3.19 to -1.00) as well as medium-term (2 RCTs, n suicides (3 RCTs, n = 1139, RR 0.71 CI 0.05 to 9.16) or in the
= 146, MD -2.15 CI -4.31 to 0.01) and long-term (1 RCT, n = number of suicide attempts (2 RCTs, n = 945, RR 2.30 CI 0.34
81, MD -1.30 CI -2.73 to 0.13) data. to 15.65).
5.3.7 Positive symptoms - average endpoint score - short 5.6.3 Cardiac effects - number of participants with QTc
term - BPRS positive prolongation
There was a significant difference in favour of risperidone (1 RCT, There was no significant difference between groups (2 RCTs, n =
n = 25, MD -1.10 CI -2.02 to -0.18). 1351, RR 1.15 CI 0.39 to 3.40).
5.3.8 Negative symptoms - average endpoint score - short 5.6.4 Cardiac effects - mean change of QTc interval from
term - less than 40% PANSS negative subscore reduction baseline in ms
from baseline There was no significant difference (3 RCTs, n = 940, MD -2.21
There was no significant difference (1 RCT, n = 673, RR 1.02 CI CI -9.48 to 5.05).
0.96 to 1.08).
5.6.5 Central nervous system - sedation

5.3.9 Negative symptoms - average endpoint score - PANSS There was a significant difference in favour of risperidone (8 RCTs,
negative n = 2226, RR 0.82 CI 0.69 to 0.97, NNT 20 CI 11 to 50).
There was no significant difference in the short (4 RCTs, n = 956,
MD -1.46 CI -4.11 to 1.19), medium (2 RCTs, n = 146, MD 1.3
CI -3.35 to 0.75) or long term (1 RCT, n = 81, MD 0.8 CI -2.27 5.6.6 Central nervous system - somnolence
to 0.61). There was a significant difference in favour of risperidone (1 RCT,
n = 309, RR 0.25 CI 0.09 to 0.75, NNT 13 CI 8 to 50).
5.3.10 Negative symptoms - average endpoint score - short

term - BPRS negative 5.6.7 Extrapyramidal effects - number of participants with
There was a significant difference favouring risperidone (1 RCT, extrapyramidal side effects
n = 25, MD -0.57 CI -0.97 to -0.17). There was no significant difference in akinesia (1 RCT, n = 267,
RR 1.10 CI 0.73 to 1.65) and rigor (1 RCT, n = 309, RR 2.24 CI
0.80 to 6.30). Nevertheless, risperidone produced more dystonias
5.4 Quality of life: average endpoint score - short term - QLS (1 RCT, n = 673, RR 18.16 CI 2.44 to 135.27, NNH 20 CI 33
total to 13) and more extrapyramidal symptoms (2 RCTs, n = 872, RR
There was no significant difference (1 RCT, n = 22, MD 0.5 CI - 1.69 CI 1.23 to 2.34, NNH 14 CI 33 to 8). More participants in
12.87 to 13.87). the risperidone group used antiparkinson medication at least once

(6 RCTs, n = 1715, RR 1.98 CI 1.16 to 3.39, NNH 20 CI 10 to 5.6.14 Metabolic - glucose - abnormally high fasting glucose
100). value
0.29 to 1.79).
5.6.8. Extrapyramidal symptoms - scale measured
Risperidone induced more extrapyramidal side effects than queti-
apine according to the Simpson-Angus Scale (5 RCTs, n = 1077, 5.6.15 Metabolic - glucose - mean change from baseline in
MD 0.59 CI 0.02 to 1.16). There was no significant difference in mg/dl
dyskinesia (AIMS, 2 RCTs, n = 958, MD 0.34 CI -0.08 to 0.75) There was no significant difference (5 RCTs, n = 1436, MD 0.04
and akathisia (BAS, 2 RCTs, n = 700, MD 0.73 CI -0.54 to 2.0). CI -2.83 to 2.92).
5.6.9 Haematological - white blood cell count - number of 5.7.16 Metabolic - weight gain - number of participants with
participants with low white blood cell count 7% or more gain of total body weight
There was no significant difference (1 RCT, n = 673, RR 0.34 CI There was no significant difference (7 RCTs, n = 1942, RR 1.03
0.01 to 8.23) CI 0.88 to 1.22).
5.6.10 Prolactin associated side effects 5.7.17 Metabolic - weight gain - mean change from baseline
Amenorrhea (4 RCTs, n = 359, RR 2.14 CI 1.26 to 3.64, NNH in kg
not estimable) and galactorrhea (5 RCTs, n = 478, RR 2.65 CI Overall there was no significant difference (7 RCTs, n = 1446,
1.19 to 5.91, NNH 25 CI 100 to 13) were more frequent in the MD -0.71 CI -2.47 to 1.04), but the data were highly heteroge-
risperidone group, while gynaecomastia (1 RCT, n = 78, RR 4.33 neous presumably due to one small outlier study (Atmaca 2003)
CI 1.34 to 14.02, NNH 4 CI 11 to 2) occurred more frequently that showed a dramatic advantage of risperidone. Nevertheless,
in the quetiapine group. There was no significant difference in the excluding this study did not change the overall result.
frequency of sexual dysfunction (6 RCTs, n = 2157, RR 1.24 CI
0.99 to 1.54) or dysmenorrhoea (1 RCT, n = 163, RR 2.23 CI
0.42 to 11.86). 5.8 Publication bias
The funnel plot of the outcome PANSS total score (> 10 included
studies) did not suggest a significant publication bias.
5.6.11 Prolactin - change from baseline in ng/ml
There was a significant and consistent difference in favour of que-
tiapine (6 RCTs, n = 1731, MD 35.28 CI 26.19 to 44.36). Only 5.9 Investigation for heterogeneity and sensitivity analysis
the amount of the difference varied, leading to significant hetero- Excluding Mori 2004 (skewed data) from the analysis of the
geneity (Lieberman 2005: n = 678, MD 24.70 CI -20.68 to 28.72; PANSS positive subscore did not change the overall result. When
McEvoy 2006: n = 24, MD 28.6 CI 14.18 to 43.02; Potkin 2006: Riedel 2005 was excluded from the analysis of the SAS score, que-
n = 309, MD 50.4 CI -40.56 to 60.24; Stroup 2006: n = 199, tiapine was no longer significantly superior in terms of general
MD 30.3 CI 23.50 to 37.10; Zhong 2006a: n = 440, MD 47.0 extrapyramidal side effects.
CI 41.03 to 52.97; McEvoy 2007: n = 81, MD 30.8 CI 23.50 to
38.10).
6. Comparison 6. Risperidone versus sertindole - all
data short term
5.6.12 Metabolic - cholesterol - number of participants with Two included studies fell in this category.
increased cholesterol
0.45 to 1.39). 6.1 Global state
5.6.13 Metabolic - cholesterol - mean change from baseline 6.1.1 Global state - no clinically significant response - as
in mg/dl defined by the original studies
Risperidone was associated with less cholesterol increase than que- There was no significant difference (1 RCT, n = 187, RR 1.14 CI
tiapine (5 RCTs, n = 1433, MD -8.49 CI -12.23 to 4.75). 0.92 to 1.40).

6.1.2 Global state - no clinically important change 6.4 Adverse effects
0.91 to 1.68).
6.2 Leaving the study early 0.90 to 1.05).
There were no significant differences between groups. 30% of the
participants in the risperidone group and 36% of those in the
6.4.2 Death
sertindole group left the study early due to any reason (2 RCTs,
n = 508, RR 0.81 CI 0.63 to 1.06). 7% of the participants in the There was no significant difference (1 RCT, n = 187, RR 3.30 CI
treatment group and 9% of those in the sertindole group left the 0.14 to 79.98).
studies due to adverse events (2 RCTs, n = 508, RR 0.73 CI 0.39
to 1.35). 10% and 14% of the participants in the risperidone and
6.4.3 Cardiac effects - number of participants with QTc
sertindole groups, respectively, left the studies early due to lack of
prolongation
efficacy (2 RCTs, n = 508, RR 0.76 CI 0.46 to 1.25).
Fewer participants in the risperidone group had a prolongation of
the QTc interval (2 RCTs, n = 508, RR 0.21 CI 0.08 to 0.51,
6.3 Mental state NNH not estimable).
6.4.4 Cardiac effects - mean change of QTc interval from

6.3.1 General - no clinically important change (less than
baseline in ms
50% PANSS total score reduction)
Risperidone was associated with less QTc change than sertindole
(2 RCTs, n = 495, MD -18.60 CI -22.37 to -14.83).
0.92 to 1.40).
6.4.5 Central nervous system - sedation

There was no significant difference (2 RCTs, n = 493, MD -1.98 CI
0.69 to 1.92).
-12.20 to 8.24), but the results were heterogeneous. One study in
treatment refractory participants showed a significant superiority
of risperidone (Kane 2005: n = 321, MD -6.94 CI -12.14 to - 6.4.6 Extrapyramidal effects
1.74), whereas another study without this criterion revealed no Risperidone produced more akathisia (1 RCT, n = 321, RR 2.24
significant difference (Azorin 2006: n = 172, MD 3.50 CI -3.42 CI 1.02 to 4.92, NNH not estimable) and more parkinsonism
to 10.42). (1 RCT, n = 321, RR 4.11 CI 1.44 to 11.73, NNH 14 CI 100
to 8) than sertindole. There was no significant difference in the
frequency extrapyramidal symptoms (1 RCT, n = 187, RR 1.53
6.3.3 Positive symptoms - average endpoint score - PANSS
CI 0.90 to 2.61) or tremor (1 RCT, n = 187, RR 0.66 CI 0.16 to
positive
2.69).
CI -1.35 to 2.95).
n = 477, MD 0.31 CI -0.25 to 0.86) and general EPS (SAS: 2
negative
RCTs, n = 500, MD 0.37 CI -0.61 to 1.35), but there was a
There was no significant difference (1 RCT, n = 172, MD 1.30 significant superiority of sertindole in akathisia (BAS: 2 RCTs, n
CI -0.53 to 3.13). = 500, MD 0.22 CI 0.03 to 0.41).
6.3.5 General functioning - average endpoint score - GAF 6.4.8 Prolactin associated effects - sexual dysfunction
total Overall, risperidone produced less sexual dysfunction than sertin-
There was no significant difference (1 RCT, n = 114, RR 2.90 CI dole (2 RCT, n = 437, RR 0.34 CI 0.16 to 0.76, NNT 13 CI 8
-2.61 to 8.41). to 33).

6.4.9 Metabolic - cholesterol - change from baseline in mg/dl 7.2 Leaving the study early
There was no significant difference (1 RCT, n = 176, MD 4.90 There were no significant differences. 58% of the participants in
CI -3.73 to 13.53). the risperidone group and 65% of those in the ziprasidone group
left the studies early due to any reason (3 RCTs, n = 1036, RR
0.90 CI 0.83 to 0.98). 9% of the risperidone group and 11% of
6.4.10 Metabolic - glucose - mean change from baseline in the ziprasidone group left the studies early due to adverse events (3
mg/dl RCTs, n = 1036, RR 0.82 CI 0.50 to 1.32). 20% of the risperidone
There was no significant difference (1 RCT, n = 176, MD 2.00 group and 23% of the ziprasidone group left the studies early due
CI -5.85 to 9.85). to lack of efficacy of treatment (3 RCTs, n = 1036, RR 0.88 CI
0.60 to 1.27).
6.4.11 Metabolic - weight gain - number of participants with

weight gain 7.3 Mental state
0.41 to 1.43).

6.4.12 Metabolic - weight gain - mean change from baseline less than 50% PANSS total reduction
in kg There was no significant difference (1 RCT, n = 296, RR 1.02 CI
Risperidone was associated with less weight gain than sertindole 0.93 to 1.12).
(2 RCTs, n = 328, MD -0.99 CI -1.86 to -0.12).

Due to the small number of included studies, a funnel plot analysis n = 1016, MD -3.91 CI -7.55 to -0.27), but the results were
was not meaningful. heterogeneous. The long-term study by Lieberman 2005 revealed
a significant difference (1 RCT, n = 516, MD -6.01 CI -10.03 to
-1.99), whereas a short-term study (Addington 2004: 1 RCT, n
6.6 Investigation for heterogeneity and sensitivity analysis = 296, MD -1.50 CI -3.16 to 0.16), and a medium-term study
The reason for the preplanned sensitivity analysis did not apply (Stroup 2006: 1 RCT, n = 204, MD -6.30 CI -12.77 to 0.17)
and we therefore have not performed this. revealed only a trend in favour of risperidone.
7. Comparison 7. Risperidone versus ziprasidone 7.3.3 General - average endpoint score - short term - BPRS
Three included studies fell in this category. total
There was no significant difference (1 RCT, n = 296, MD -0.70
CI -4.33 to 2.93).
7.1 Global state
7.3.4 Positive symptoms - average endpoint score - medium

term - PANSS positive
There was no significant difference (1 RCT, n = 296, RR 1.02 CI There was a significant difference in favour of risperidone (1 RCT,
0.93 to 1.12). n = 204, MD -2.50 CI -4.62 to -0.38).
7.1.2 Global state - no clinically important change - short 7.4.5 Positive symptoms - average endpoint score - medium
term - as defined by the original studies term - BPRS positive
There was no significant difference (1 RCT, n=296, RR 0.81 CI There was no significant difference (1 RCT, n = 296, MD-0.50
0.63 to 1.04). CI -1.15 to 0.15).

7.4.6 Negative symptoms - average endpoint score - PANSS 7.6.7 Extrapyramidal effects - scale measured
negative There were no significant differences in dykinesia (AIMS: 1 RCT,
There was no significant difference overall (2 RCTs, n = 500, MD n = 296, MD 0.21 CI 0.17 to 0.25) and akathisia (BAS: 1 RCT,
-0.04 CI -1.20 to 1.12), or in the short (1 RCT, n = 296, MD n = 296, MD 0.56 CI 0.51 to 0.61), but risperidone produced
0.00 CI -1.48 to 1.48) or medium term (1 RCT, n = 204, MD - more overall EPS than ziprasidone (SAS: 1 RCT, n = 296, MD
0.10 CI -1.98 to 1.78). 0.34 CI 0.26 to 0.42).
7.5 Service use - number of participants rehospitalised 7.6.8 Prolactin-associated side effects
There was no significant difference (2 RCTs, n = 777, RR 0.87 CI There was no significant difference in the frequency of abnormal
0.63 to 1.22). ejaculation (1 RCT, n = 215, RR 2.10 CI 0.65 to 6.75), amenor-
rhea (1 RCT, n = 81, RR 0.93 CI 0.20 to 4.33), decreased libido
(1 RCT, n = 296, RR 1.65 CI 0.70 to 3.86), erectile dysfunction
7.6 Adverse effects
(1 RCT, n = 215, RR 1.05 CI 0.38 to 2.88) and galactorrhea (2
RCTs, n = 159, RR 5.07 CI 0.61 to 42.45). Only orgastic dys-
function occurred more frequently in the risperidone group than
7.6.1 At least one adverse effect
in the ziprasidone group (2 RCTs, n = 516, RR 1.44 CI 1.03 to
There was no significant difference (3 RCTs, n = 1063, RR 1.07 2.02).
CI 0.98 to 1.17).
7.6.9 Prolactin - mean change from baseline in ng/ml

7.6.2 Death
Risperidone was associated with more prolactin increase than
There was no significant difference in the number of suicide at-
ziprasidone (2 RCTs, n = 767, MD 21.97 CI 16.60 to 27.34).
tempts (1 RCT, n = 526, RR 1.09 CI 0.10 to 11.89) or in the
number of completed suicides (1 RCT, n = 241, RR 0.66 CI 0.06
to 7.17) 7.6.10 Metabolic - cholesterol - change from baseline in
mg/dl
7.6.3 Cardiac effects - number of participants with QTc There was a significant difference in favour of ziprasidone (2 RCTs,
prolongation n = 767, MD 8.58 CI 1.11 to 16.04).
0.40 to 9.05). 7.6.11 Metabolic - glucose - mean change from baseline in
mg/dl
7.6.4 Cardiac effects - mean change of QTc interval from There was no significant difference (2 RCTs, n = 767, RR 4.94 CI
baseline in ms -1.91 to 11.80).
There was no significant difference (3 RCTs, n = 793, RR -2.24
CI -6.39 to 1.92).
7.6.12 Metabolic - weight gain of 7% or more of total body
weight
7.6.5 Central nervous system - sedation Three studies showed a significant difference in favour of ziprasi-
There was no significant difference (3 RCTs, n = 1063, RR 1.15 done (3 RCTs, n = 1063, RR 2.03 CI 1.35 to 3.06, NNH 14 CI
CI 0.83 to 1.59). 33 to 10).
7.6.6 Extrapyramidal effects 7.6.13 Metabolic - weight gain - change from baseline in kg
There was no significant difference in the frequency of akathisia Only one study reported on this outcome. It found no significant
(2 RCTs, n = 1063, RR 1.02 CI 0.55 to 1.89) and tremor (1 RCT, difference (1 RCT, n = 461, MD 1.10 CI -0.15 to 2.35).
n = 296, RR 0.95 CI 0.47 to 1.89), but risperidone produced
more extrapyramidal symptoms (1 RCT, n = 241, RR 3.16 CI
1.15 to 8.69, NNH 13 CI 100 to 7) and more participants in the 7.7 Publication bias
risperidone group used antiparkinson medication at least once (2 Due to the small number of included studies, a funnel plot analysis
RCTs, n = 822, RR 1.42 CI 1.03 to 1.96, NNH not estimable). was not meaningful.

7.8 Sensitivity analyses 2. Comparison 1. Risperidone versus amisulpride
The reasons for the preplanned sensitivity analysis did not apply
and we have therefore not performed this.
2.1 Leaving the studies early
There were no significant differences in the number of partici-
pants leaving the studies early due to any reason, due to adverse
events or due to inefficacy of treatment. These results suggest a
DISCUSSION similar overall acceptability, tolerability and efficacy of risperidone
and amisulpride. Nevertheless, four studies with 622 participants
do not provide a firm basis for such a conclusion. Furthermore,
although the overall rate of participants leaving the studies early
Summary of main results of 33.2% was lower than that of some other comparisons, it was
still considerable.
1. General
2.2 Efficacy outcomes (global state, overall and specific
In the last years the number of randomised risperidone trials has mental state)
dramatically increased. A previous Cochrane review comparing
There was no clear efficacy difference between risperidone and
risperidone with other SGA drugs included only nine RCTs (
amisulpride. There was a significant superiority of amisulpride in
Gilbody 2000). The current review includes 45 RCTs, although
terms of 50% BPRS reduction. However, this result was based
we had more stringent inclusion criteria and excluded open RCTs.
on only one trial and may have well occurred by chance alone,
Nevertheless, many problems that were identified by the previous
given the high number of statistical tests applied (Sechter 2002).
review have not been solved:
Furthermore, the same trial did not find any difference in the mean
The number of participants leaving schizophrenia trials prema-
values at endpoint of the BPRS.
turely remain high (Wahlbeck 2001). The overall attrition of 47%
in the included studies is a threat to the validity of the findings.
Adverse events were often only reported if they had a frequency of 2.3 General functioning
5%/10% or greater. This procedure results in underreporting of A single study using the SOFAS scale reported on social function-
rare but important adverse effects. We suggest to abandon the > ing and found no difference between risperidone and amisulpride.
5%/10% frequency rule for reporting of adverse effects and suggest Pragmatic studies that are conducted in situations that are more
that all adverse events should be reported instead, for example similar to routine care are needed to address this important out-
as online supplements that are nowadays made available by most come.
journals.
Most trials provided data on leaving the studies early and overall
efficacy. Outcomes that are possibly more important for daily life 2.4 Adverse effects
such as general functioning or satisfaction with treatment are rarely There were some data on extrapyramidal side effects, cardiac ef-
presented. Authors keep using different criteria for response to fects, prolactin associated side effects, sedation, seizures and death.
treatment making comparisons difficult, although validated sug- Besides the reporting on sexual dysfunction which indicated a ben-
gestions for the presentation of response to treatment are available efit for amisulpride, the only adverse event showing a significant
(Leucht 2005a; Leucht 2005b; Van Os 2006). difference was weight gain which was 1kg more in the risperidone
More than half of the 45 included trials were categorised as short- group. This difference was found in short- to medium-term stud-
term studies and only eight were long-term studies with a length ies. It may well be that the difference would be more pronounced
of more than 26 weeks. Schizophrenia is a chronic, often life-long in the long term, but longer studies are needed to verify this as-
disorder, making more long-term studies necessary. sumption. Nevertheless, if metabolic issues are a concern, amisul-
60% of the studies were sponsored by pharmaceutical companies pride may be a better choice than risperidone.
producing either risperidone or its comparator drugs, whereas only
31% of the studies had a neutral sponsor (the sponsor of the
remaining RCTs remained unclear). Due to the inevitable conflict 3. Comparison 2. Risperidone versus aripiprazole
of interest, industry sponsorship is a concern (Heres 2006).
Finally, most studies compared risperidone with clozapine, olan-
zapine and quetiapine. Fewer RCTs comparing risperidone with 3.1 Leaving the studies early
amisulpride, aripiprazole, sertindole and ziprasidone are available, Again, the number of participants leaving the two studies early was
and comparisons with zotepine are completely missing. considerable (34.4%). There was no significant difference between

both compounds, suggesting that their acceptability is similar, but 4.2 Efficacy outcomes (global state, overall and specific
two included studies - both sponsored by the manufacturers of mental state)
aripiprazole - are no firm basis for any conclusion. The only significant difference between risperidone and clozapine
was a superiority of the latter in terms of positive symptoms. Even
this difference was not robust, because when two studies with
3.2 Efficacy outcomes (global state, overall and specific possibly skewed data were excluded it was no longer statistically
mental state) significant.
There were no statistically significant differences in global state, This failure to find clozapine superior was surprising, because
general mental state, positive and negative symptoms. The cur- clozapine is generally considered to be the most efficacious an-
rently available small evidence base does thus not suggest a tipsychotic drug available. This superiority has recently been con-
difference in efficacy between both compounds. Nevertheless, firmed by the industry independent studies CATIE II (McEvoy
no evidence of effect does not mean evidence of no effect 2006) and CUtLASS (Lewis 2006) which could not be included
(Tarnow-Mordi 1999). here. The clozapine group of CATIE II was a non-blinded study
arm and CUtLASS compared clozapine with a number of second
generation antipsychotics as a group.
One reason for the failure to find a consistent superiority of cloza-
3.3 Adverse effects
pine may be that efficacy was addressed in different ways (e.g.
Limited data were available on extrapyramidal side effects, cardiac different scales or different definitions of response to treatment),
effects, cholesterol, glucose, prolactin increase, prolactin associated making a summation difficult. Indeed at most six out of 11 studies
side effects and weight gain. could be combined in a meta-analysis, and frequently the results
There was a significant benefit for aripiprazole in terms of dysto- were even based on only one RCT.
nia, QTc abnormalities, prolactin increase and cholesterol levels, Another possible explanation may be relatively low clozapine
whereas tremor was less frequent in the risperidone group. Over- doses. The mean doses in two pivotal studies demonstrating
all risperidone s tolerability profile may be somewhat worse than clozapines superiority to first-generation antipsychotic drugs were
that of aripiprazole, but these results are based on very limited 600mg/day (Kane 1988) and 523mg/day (Rosenheck 1997). A
data. Any conclusion would be premature. randomised, blinded dose finding study found that a clozap-
ine dose of 600mg/day was more efficacious than lower doses
(Simpson 1999). In contrast, of the 11 trials included in this review
4. Comparison 3. Risperidone versus clozapine only two studies had mean clozapine doses higher than 500mg/
day (Volavka 2002: 526mg/day; Azorin 2001: 642 mg/day), and
indeed the latter study found a superiority of clozapine. Several
trials limited the upper clozapine dose range to 400mg/day.
4.1 Leaving the studies early Nevertheless, a definitive, industry independent trial with suffi-
The 11 included studies showed a considerable overall attrition of cient clozapine doses is necessary to establish the relative efficacy
33.4%. Although this attrition was not as high as in some other of clozapine and risperidone.
comparisons of this review, it nevertheless limits the interpretation
of all results beyond the outcome of leaving the studies early.
4.3 General functioning
A similar number of participants in the risperidone and the cloza-
pine groups left the studies early due to any reason, suggesting a Only a very small study reported on general and social function-
comparable overall acceptability of both compounds. Neverthe- ing, but found no significant difference between groups. From a
less, there were significant differences in the reasons why partici- more global public health perspective, but also for people with
pants left the studies. schizophrenia, it may be more important to know whether a drug
Adverse events were a greater problem in the clozapine group. improves functioning in the community than whether it reduces
Clozapine is associated with a number of serious and partly dan- symptoms. It is therefore disappointing that so few data on these
gerous adverse effects such agranulocytosis, seizures, sedation or important outcomes were available.
weight gain (see 4.4 below), which may explain risperidones su-
periority in this regard.
Inefficacy of treatment led more frequently to leaving the studies 4.4 Adverse effects
early in the risperidone group. This suggests a certain efficacy Very few data on extrapyramidal side effects, cardiac effects, change
superiority of clozapine. Indeed, clozapine was associated with a in cholesterol level, death, prolactin increase and associated side
somewhat more pronounced reduction of positive symptoms than effects, sedation, seizures, and low white blood cell count were
risperidone, although the difference was not robust (see 4.2 below). available. At most five (sedation, white blood cell count) to six

(use of antiparkinson medication) out of 11 included studies could 5.2 Efficacy outcomes (global state, overall and specific
be combined in a meta-analysis. This may well reflect selective mental state)
reporting and limits the conclusions. Most data were available for the general mental state (PANSS
Nevertheless, risperidone was associated with clearly more use of total score, 15 RCTs) and positive and negative symptoms of
antiparkinson medication than clozapine. Use of antiparkinson schizophrenia (PANSS positive and negative subscore, 13 RCTs).
medication is a useful proxy measure of movement disorders. One Olanzapine was slightly superior in the improvement of the general
out of six people treated with risperidone instead of clozapine mental state, but not superior for specific symptoms of schizophre-
suffered from these very unpleasant adverse events which are well nia. The difference was numerically very small (two points differ-
visible and can therefore contribute to the stigma associated with ence on the PANSS total score) and of questionable clinical im-
schizophrenia. portance. Only three studies reported on responder rates defined
Risperidone also produced more prolactin increase than clozapine. as at least 50% reduction of the PANSS total score and found a
This result was based on only two RCTs, but prolactin increase is marginal but statistically significant difference in favour of olan-
a well-known adverse event of risperidone. The long-term conse- zapine (RR 1.09). A number needed to harm could not be calcu-
quences can be osteoporosis and sexual side effects, although the lated, because the risk difference was not significant. Most other
latter could not be demonstrated in this review, at least partly be- efficacy-related outcomes were based on very small numbers and
cause the individual studies presented so few data. showed equivocal results.
Conversely clozapine was associated with more seizures, sedation
and weight gain. One out of 14 participants treated with clozap-
ine instead of risperidone had a seizure. This is a considerable and 5.3 Quality of life
clinically important difference, because seizures are dangerous ad- The results suggested a better quality of life of participants treated
verse events. Clozapine is well known for its sedating effects. Many with olanzapine compared to risperidone. Since only two studies
people taking antipsychotic drugs do not like the sedation asso- provided data on this outcome, any recommendation for practice
ciated in varying degrees with these compounds, but sometimes would be premature.
sedation is only transient. The weight gain produced by clozapine
is a major concern, because in the long term it can lead to diabetes
and cardiovascular diseases such as myocardial infarction or stroke. 5.4 Cognitive functioning
It is reassuring that - despite the limited data available - the review
Only two studies compared the cognitive effects of risperidone and
was able to document some of the expected differences in toler-
olanzapine and found no significant difference between groups.
ability between risperidone and clozapine. Clinicians and people
with schizophrenia may use the results in their choice of drug.
5.5 Service use
5. Comparison 4. Risperidone versus olanzapine In three trials a similar number of participants in the risperidone
and olanzapine groups had to be rehospitalised. This lack of a dif-
ference suggests a similar efficacy of both compounds. Or possible
5.1 Leaving the studies early efficacy differences are so small that they do not translate in more
Risperidone and olanzapine have been compared in a relatively global outcomes such as rehospitalisation.
large number of 23 blinded RCTs and 3207 participants. Nev-
ertheless, the high overall rate of participants leaving the studies
early (52%) is a source of concern. The field must urgently find 5.6 Adverse effects
ways to decrease the amount of attrition in schizophrenia trials, The adverse effects that occurred in a statistically significantly dif-
because the typically high discontinuation rates make the validity ferent frequency can be grouped in three categories.
of the results questionable. Olanzapine was associated with more weight gain and associ-
Risperidone may be a somewhat less acceptable treatment than ated metabolic problems such as cholesterol and glucose increase.
olanzapine for people with schizophrenia, because more partici- Therefore, risperidone might be a more appropriate treatment for
pants in the risperidone group left the studies early due to any people at risk to develop a metabolic syndrome, overweight peo-
reason. In addition, more risperidone treated participants left the ple, individuals suffering from diabetes or those with high choles-
studies early due to inefficacy of treatment. This may reflect a terol levels.
somewhat better efficacy of olanzapine which is also supported by Risperidone produced some extrapyramidal side effects more fre-
a stronger improvement of the participants general mental state quently than olanzapine. Namely, the participants in the risperi-
(see below). Leaving the studies early due to adverse events showed done group used more antiparkinson medication and suffered
no difference between groups suggesting a similar overall tolera- more frequently from akathisia and parkinsonism. Although the
bility of risperidone and olanzapine. number needed to treat for use of antiparkinson medication was

relatively high (NNT 17), movement disorders are very unpleas- 20 participants treated with risperidone instead of quetiapine one
ant side effects and should be avoided. needed antiparkinson medication) extrapyramidal side effects are
Risperidone was also associated with clearly more prolactin in- very unpleasant adverse events which should be avoided. Prolactin
crease and related sexual dysfunctions such as abnormal ejacula- increase can lead to sexual side effects and indeed the frequency of
tion in men and amenorrhea in women. Clinicians and people amenorrhea and galactorrhea was approximately two times higher
with schizophrenia may consider these different tolerability pro- in the risperidone group.
files of both compounds in their drug choice. Conversely quetiapine was associated with more sedation and
cholesterol increase than risperidone. The long-term consequences
of the latter adverse event can be cardiovascular problems such as
6. Comparison 5. Risperidone versus quetiapine myocardial infarction or stroke.
These differences in the side effect profile and the slightly better
efficacy of risperidone may be weighed in drug choice.
6.1 Leaving the studies early
We included 11 studies with 3770 participants in this compari-
son. This could be a reasonable basis for the examination of the
relative effects of risperidone and quetiapine, but the overall dis- 7. Comparison 6. Risperidone versus sertindole
continuation rate was high (56.7%). Such high attrition limits the Again only two studies could be included in this comparison and
interpretation of any other results beyond the outcome leaving the one of the studies (Kane 2005) has to date only been published as
studies early. If more than 50% of the data must be estimated by a conference poster presenting limited information. This evidence
statistical modelling, the validity of the findings is called into ques- base is too limited to draw firm conclusions.
tion. Nevertheless, there was no clear difference in the number of
participants leaving the studies early due to any reason or due to
adverse events, suggesting a similar overall acceptability and toler-
ability of risperidone and quetiapine. Only the outcome leaving 7.1 Leaving the studies early
the studies early due to inefficacy tended to favour risperidone,
Although the number of participants leaving the studies early due
which is consistent with a certain efficacy superiority of risperi-
to any reason was considerable (33.7%), there was no significant
done (see 6.2 below).
difference between sertindole and risperidone, suggesting a similar
overall acceptability of treatment. Specific reasons for leaving the
6.2 Efficacy outcomes (global state, overall and specific studies early (adverse events, inefficacy of treatment) did not show
mental state) a difference between both compounds either.
The only statistically significant differences in efficacy were found
for the general mental state and positive symptoms. Risperidone
was more efficacious than quetiapine in these aspects of psy- 7.2 Efficacy outcomes (global state, overall and specific
chopathology. Nevertheless, the differences were small (e.g. only 3 mental state)
points on the PANSS total score). The clinical relevance of this dif-
ference is difficult to interpret. Unfortunately, dichotomous data There was no clear difference in efficacy based on CGI, PANSS
on response to treatment, which can be interpreted more intu- totals score, PANSS positive and negative subscore. Nevertheless,
itively, were rarely indicated. Only four studies (less than half of the results on the general mental state as measured by the PANSS
those available for the PANSS total score) showed a trend in favour total score were heterogeneous. One study suggested that in people
of risperidone in terms of no important improvement of the par- with treatment-resistant schizophrenia, risperidone may be some-
ticipants global state (P = 0.06) which did not reach the conven- what more efficacious (Kane 2005), while in the other study with-
tional 5% level of statistical significance. out this criterion, no difference was found (Azorin 2006). Any
interpretation is certainly limited by the small number of included
trials and participants. Replications are needed.
6.3 Adverse effects
Adverse effects were available for at least one adverse effect, cardiac
effects, cholesterol increase, changes in serum glucose, increase of
7.3 General functioning
prolactin level and associated side effects, death, extrapyramidal
side-effects, sedation, weight gain and white blood cell count. Only one short-term study provided data on general functioning
Among these, risperidone was worse than quetiapine in various and showed no difference between groups. We believe that long-
measures of extrapyramidal side effects and prolactin associated term, real world, pragmatic studies are needed to examine this
effects. Although the differences were not very large (e.g. among important outcome.

7.4 Adverse effects 8.3 Adverse effects
There were some data on extrapyramidal symptoms, cardiac ef- Ziprasidone was more tolerable than risperidone concerning a
fects, cholesterol, glucose, sedation, sexual dysfunction, suicide number of adverse events: certain extrapyramidal side effects, glu-
and weight gain. cose levels, cholesterol increase, prolactin increase, and weight
These limited data suggest that akathisia and parkinsonism may gain.
occur more frequently under treatment with risperidone than with In treatment decisions this better tolerability profile of ziprasidone
sertindole. However, relatively high risperidone dose ranges of 4- needs to be weighted with the somewhat lower efficacy, always
10 mg/day and 4-12 mg/day in the two included studies must be keeping in mind the small amount of available data.
taken into account. It is well known that the EPS risk of risperidone
is dose related and lower doses (e.g. 2-8mg/day) may produce
similar efficacy, but are better tolerated (Marder 1994). 9. Summary
Conversely cardiac effects (QTc prolongation), male sexual dys- The review currently includes 45 at least single blind studies and
function and weight change indicated a benefit for risperidone. 7760 participants. The number of RCTs available for each com-
These differences in tolerability may be considered in drug choice. parison varied: four studies compared risperidone with amisul-
Due to the known effects of sertindole on the QTc interval, the pride, two with aripiprazole, 11 with clozapine, 23 with olanza-
drug cannot be recommended for people with schizophrenia and pine, 11 with quetiapine, two with sertindole, three with ziprasi-
cardiac problems. The long-term consequences of weight gain such done and none with zotepine. Attrition from these studies was
as diabetes and cardiovascular disease can be dramatic. high (46.9%). This high attrition makes the interpretation of the
results problematic, because half of the results must be estimated
by statistical modelling. Furthermore, 60% were industry spon-
8. Comparison 7. Risperidone versus ziprasidone sored, which can be a source of bias.
Risperidone was slightly less acceptable than olanzapine, and
Data based on three studies were available for this comparison.
slightly more acceptable than ziprasidone in terms of leaving the
Similar to the comparisons with olanzapine and quetiapine, a very
studies early due to any reason. The results of all other comparisons
high overall attrition of 63.1% clearly limits the interpretation of
were equivocal. There were also only few differences in efficacy-
any findings beyond the outcome leaving the study early.
related outcome; risperidone may be somewhat more efficacious
than quetiapine and ziprasidone, but slightly less efficacious than
olanzapine and clozapine. Whether the differences are clinically
8.1 Leaving the studies early meaningful is difficult to say, because most studies reported the
As fewer participants in the risperidone group than in the ziprasi- mean scores of rating scales, whereas only a few reported more
done group left the studies prematurely, risperidone may be more intuitive data on response to treatment and used different defini-
acceptable for people with schizophrenia. As there were no signif- tions for this.
icant differences in specific reasons (adverse events of inefficacy It was the best documented tolerability difference of the review that
of treatment) for study discontinuation, the reason for this better risperidone produced somewhat more extrapyramidal side effects
acceptability is unclear. than a number of other SGA drugs (all except for amisulpride and
aripiprazole compared to which only a few RCTs were available).
Risperidone also increased prolactin levels clearly more than all
comparators, except for amisulpride and sertindole for which no
8.2 Efficacy outcomes (global state, overall and specific
data were available.
mental state)
Other differences in adverse effects were less well documented,
A statistically significant, but numerically small benefit (4 points but risperidone may well produce more weight gain and/or as-
difference on the PANSS total score) for risperidone was present sociated metabolic problems than amisulpride, aripiprazole and
in general mental state and in positive symptoms. Although the ziprasidone, but less than clozapine, olanzapine, quetiapine and
small number of included trials and the high drop-out rates limit sertindole. It may be less sedating than clozapine and quetiap-
the validity of this finding, risperidone maybe somewhat more ef- ine, lengthen the QTc interval less than sertindole, produce fewer
ficacious for the positive symptoms of schizophrenia than ziprasi- seizures than clozapine and less sexual dysfunction in men than
done. Whether the numerically small difference is clinically im- sertindole.
portant is again difficult to say. Unfortunately dichotomous data
on response to treatment which can be more intuitively under-
stood were only reported by a single study which did not find a
significant difference. It cannot be excluded that selective report-
Overall completeness and applicability of
ing played a role.
evidence

The amount of RCTs comparing risperidone with the other SGA Agreements and disagreements with other
drugs varied substantially. A high number of studies compared studies or reviews
risperidone with olanzapine with risperidone (N = 23). A reason-
Many new RCTs have compared risperidone with other SGA
able amount of trials comparing olanzapine with clozapine (N =
drugs since the publication of a previous Cochrane review on the
11) and quetiapine (N = 11) was available. In contrast, few trials
same topic (Gilbody 2000). Gilbody 2000 included only nine
compared olanzapine with amisulpride (N = 4), aripiprazole (N =
RCTs which compared risperidone with clozapine, olanzapine and
2), sertindole (N = 2) and ziprasidone (N = 3). We did not iden-
amisulpride. Due to this large difference in sample size the reviews
tify any RCT comparing risperidone with zotepine. Therefore the
are hardly comparable. Nevertheless, as in our review risperidone
evidence is incomplete.
was overall as acceptable as clozapine for people with schizophre-
Furthermore, it is also obvious that most of the studies reported on
nia (leaving the study early due to any reason), but slightly less
leaving the studies early due to any reason and overall symptoms
acceptable than olanzapine. Efficacy data tended to favour cloza-
of schizophrenia. All other outcomes were usually based on much
pine and olanzapine, but statistically significant effects were rare
smaller numbers. Very little information is available on general
which is not surprising, because even in the current much larger
functioning, satisfaction with care or cognition. These outcomes
review the differences were small. Risperidone also produced more
may be more important for people suffering from schizophrenia
extrapyramidal side effects but less weight gain than olanzapine,
than the improvement of symptoms. Only three included studies
while very few side effect data compared to clozapine were avail-
reported on service use, although such data would be crucial for
able. As in the current review there were no major differences
policy makers.
between risperidone and amisulpride and the evidence base has
Most of the included studies had tight inclusion criteria limiting
grown only slightly (from one to four RCTs).
external validity. Further effectiveness studies are needed.
Another more recent review specifically compared risperidone with
olanzapine (Jayaram 2006). Again, more participants in the risperi-
done group left the studies early due to any reason, but there were
no clear differences in the efficacy of both compounds. Risperi-
done produced more extrapyramidal side effects, but less weight
Quality of the evidence
gain and associated metabolic effects than olanzapine. Overall, we
A major threat for the quality of the evidence is the high overall believe that many findings of the previous reviews are compatible
attrition of 47% in the studies. It is questionable whether even a with the current report. Therefore, the evidence has become more
sophisticated statistical method can account for such a high per- robust, although still insufficient in quality, over time.
centage of participants leaving the studies before their end. Most
studies used the last observation carried forward method which is
based on the assumption that a participant leaving a study early
would not have changed if he had stayed in the study. This as-
sumption can obviously be wrong. AUTHORS CONCLUSIONS
All included studies were stated to be randomised and all but
seven studies were double-blind. The remaining seven trials de- Implications for practice
scribed blinded raters. Nevertheless, the randomisation and blind-
ing methods were rarely described. The study authors did also not
make attempts to verify whether blinding was successful. 1. For people with schizophrenia
The majority of the trials fell in the short-term category, which is
problematic in a chronic disease such as schizophrenia. All these People with schizophrenia need to know that risperidone differs in
factors limit the overall quality of the evidence. adverse effects from other SGA drugs. It seems to produce some-
what more movement disorders and clearly more prolactin increase
than most other SGA drugs. Its risk for weight gain and associated
metabolic problems was intermediate - less than clozapine, olanza-
pine, quetiapine and sertindole, but more than amisulpride, arip-
Potential biases in the review process iprazole and ziprasidone. Differences in efficacy were less clear, but
We are not aware of obvious flaws in our review process. Never- risperidone may be overall slightly less efficacious than olanzapine
theless, we admit that we present only a selection of outcomes. and clozapine, but slightly more efficacious than quetiapine and
Although these outcomes were defined a priori in the protocols ziprasidone.
and although we think that we made a meaningful selection, other
people may have different opinions and differences in other out-
comes may have been missed. 2. For clinicians

Attrition was very high (overall 47%). Almost half of the results different definitions for response to treatment, making a compar-
had to be estimated by statistical modelling which calls the valid- ison of the results difficult. Potentially important outcomes such
ity of the findings in question. It is also important to know that as satisfaction with care, functioning in the community or service
risperidone has been compared in many RCTs with olanzapine use are rarely examined. Simple descriptions of the randomisation
and in a reasonable amount of trials with clozapine and quetiap- or blinding methods are usually not presented. Strict adherence
ine, but few comparisons with the other SGA drugs are available. to the CONSORT statement (Moher 2001) would improve the
Differences in side effects should be considered in choice of drug. reporting and conduct of future trials.
Risperidone seems to produce somewhat more extrapyramidal side
effects, clearly more prolactin increase and intermediate weight
gain compared to other SGA drugs. 2. Specific
Comparisons of risperidone with most SGA drugs are currently
based on small numbers and no RCT which compares risperidone
3. For managers/policy makers to zotepine is available. These gaps need to be filled by future trials
(Table 1).
There is insufficient information to guide the decisions of man-
agers and policy makers. Service use was reported by only three of
45 included studies and the results were equivocal. The evidence
base is too limited for making any recommendation. Nevertheless,
in some countries risperidone is now available as a generic and ACKNOWLEDGEMENTS
could therefore be cheaper than other SGA drugs. We would like to thank all members of the Cochrane Schizophre-
nia Group for their editorial assistance. We also thank Simon
Implications for research Gilbody, Anne-Marie Bagnall, Lorna Duggan and Arja Tuunainen
for their work on a previous version of this review, and additionally
the following authors and pharmaceutical companies for providing
1. General additional information on their studies: D. Addington, R. Conley,
D. Daniel, S. Dollfus, H. Heinrich, T. Hwang, D. Jeste, J. Kane,
There is room for improvement in the conduct and reporting of R. Keefe, S. McGurk, K. Mori, Q. Ren, M. Riedel, N. Schooler,
RCTs for schizophrenia. Rating scale derived efficacy outcomes D. Sechter, J. Svestka, J. Volavka, K. Zhong, Astra Zeneca, Eli
dominate the trials and even in this regard authors keep using Lilly, Lundbeck, Pfizer and Sanofi Aventis.
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Zhong 2006 {published data only}
B, McEvoy JP, Cooper TB, Chakos M, Lieberman JA.
Zhong K, Harvey P, Brecher M, Sweitzer D. A randomized
Changes in glucose and cholesterol levels in patients with
double - blind study of quetiapine and risperidone in the
schizophrenia treated with typical or atypical antipsychotics.
treatment of schizophrenia. Schizophrenia Bulletin 2005;31:
American Journal of Psychiatry 2003;160(2):2906.
508.
Lindenmayer JP, Czobor P, Volavka J, Lieberman JA,
Zhong KX, Sweitzer DE, Hamer RM, Lieberman JA.
Citrome L, Sheitman B, McEvoy JP, Cooper TB, Chakos
Comparison of quetiapine and risperidone in the treatment
M. Effects of atypical antipsychotics on the syndromal
of schizophrenia: a randomized, double-blind, flexible-
profile in treatment-resistant schizophrenia. Journal of
dose, 8-week study. Journal of Clinical Psychiatry 2006;67
Clinical Psychiatry 2004;65(4):5516.
(7):1093103.
Volavka J, Czobor P, Cooper TB, Sheitman B, Lindenmayer
JP, Citrome L, McEvoy JP, Lieberman JA. Prolactin levels in Zhou 2000 {published data only}
schizophrenia and schizoaffective disorder patients treated Zhou Z, Shu Z, Yu Y. A control study of risperidone and
with clozapine, olanzapine, risperidone, or haloperidol. clozapine in the treatment of the negative symptoms of
Journal of Clinical Psychiatry 2004;65(1):5761. schizophrenia. Aerospace Medicine 2000;11:6971.
Volavka J, Czobor P, Nolan K, Sheitman B, Lindenmayer JP, References to studies excluded from this review
Citrome LMJP, Cooper TB, Lieberman JA. Overt aggression
and psychotic symptoms in patients with schizophrenia Akdede 2006 {published data only}
treated with clozapine, olanzapine, risperidone, or Akdede BB, Anil Yaciolu AE, Alptekin K, Turgut TI,
haloperidol. Journal of Clinical Psychopharmacology 2004;24 Tumuklu M, Yazici MK, Jayathilake K, Tunca Z, Gogus
(2):2258. A, Meltzer HY. A double-blind study of combination of

Volavka J, Czobor P, Sheitman B, Lindenmayer JP, clozapine with risperidone in patients with schizophrenia:
Citrome L, McEvoy JP, Cooper TB, Chakos M, Lieberman effects on cognition. Journal of Clinical Psychiatry 2006;67
JA. Clozapine, olanzapine, risperidone, and haloperidol (12):19129.
in the treatment of patients with chronic schizophrenia Almond 1999 {published data only}
and schizoaffective disorder. American Journal of Psychiatry
Almond S, ODonnell O, McKendrick J. The cost-analysis
2002;159(2):25562. of olanzapine compared with haloperidol and risperidone
in the treatment of schizophrenia in the UK. Journal of the
European College of Neuropsychopharmacology 1999;9:289.
Wahlbeck 2000 {published data only}

Wahlbeck K, Cheine M, Tuisku K, Ahokas A, Joffe G, Alvarez 2006 {published data only}
Rimon R. Risperidone versus clozapine in treatment-

Alvarez E, Ciudad A, Olivares JM, Bousono M, Gomez
resistant schizophrenia: a randomized pilot study. Progress JC. A randomized, 1-year follow-up study of olanzapine
in Neuropsychopharmacology and Biological Psychiatry 2000; and risperidone in the treatment of negative symptoms
24(6):91122. in outpatients with schizophrenia. Journal of Clinical
Wahlbeck K, Cheine M, Tuisku K, Ahokas A, Joffe G, Psychopharmacology 2006;26(3):23849.
Rimn R. Risperidone versus clozapine in treatment- Alvarez-Jimenez 2006 {published data only}
resistant schizophrenia: a randomized pilot study.
Alvarez-Jimenez M, Gonzalez-Blanch C, Vazquez-
International Journal of Neuropsychopharmacology 2000;3 Barquero JL, Perez-Iglesias R, Martinez-Garcia O,
(Suppl 1):122. Perez-Pardal T, Ramirez-Bonilla ML, Crespo-Facorro B.
Wahlbeck K, Cheine M, Tuisku K, Joffe G. Risperidone Attenuation of antipsychotic-induced weight gain with early
versus clozapine in treatment resistant schizophrenia: a behavioral intervention in drug-naive first-episode psychosis
randomised pilot trial. Schizophrenia Research 2000;41(1): patients: a randomized controlled trial. Journal of Clinical
197. Psychiatry 2006;67(8):125360.
Antonova 2005 {published data only} Bera 2001 {published data only}

Antonova E, Kumari V, Halari R, Zachariah E, Mehrotra
Bera RB. A comparison of patient satisfaction between
R, Kumar A, Sharma T. Superior cognitive efficacy of seroquel, olanzapine and risperidal. Schizophrenia Research
atypical antipsychotics olanzapine, risperidone, and 2001;49(1, 2):220.
quetiapine, as a group, relative to low doses of conventional Beuzen 2005 {published data only}
antipsychotics. Schizophrenia Bulletin 2005;31:474.
Beuzen J-N, Pans M, Modell S, Hagens P, McQuade R,
Apiquian 2003 {published data only} Iwamoto T, Carson W. Naturalistic study of aripiprazole

Apiquian R, Fresan A, Herrera K, Ulloa RE, Loyzaga treatment. Proceedings of the XIII World Congress of
C, De LaFuente-Sandoval C, Gutierrez D, Nicolini H. Psychiatry; 2005 Sept 10-15; Cairo, Egypt. 2005.
Minimum effective doses of haloperidol for the treatment Bitter 2004 {published data only}
of first psychotic episode: a comparative study with
Bitter I, Basson BR, Dossenbach MR. Antipsychotic
risperidone and olanzapine. International Journal of treatment and sexual functioning in first-time neuroleptic
Neuropsychopharmacology 2003;6(4):4038. treated schizophrenic patients. International Clinical
Psychopharmacology 2005;20:1921.
Aquila 2000 {published data only}

Aquila R, Weiden PJ, Kinon BJ, Milton DR, Zygmunt Boylan 2004 {published data only}
A, Swindle RW, Stauffer VL. Effectiveness of olanzapine

Boylan LS, Labovitz DL. Unbalanced statistical analysis
upon psychiatric and vocational rehabilitation outcomes. of combined divalproex and antipsychotic therapy for
Proceedings of the 153rd Annual Meeting of the American schizophrenia. Neuropyschopharmacology 2004;29(3):636.
Psychiatric Association; 2000 May 13-18; Chicago, Illinois, Briken 2002 {published data only}
USA. 2000.
Briken P, Nika E, Moritz S, Haasen C, Perro C, Yagdiran
Ascher-Svanum 2006 {published data only} O, Naber D, Krausz M. Effect of zotepine, olanzapine

Ascher-Svanum H, Zhu B, Faries D, Landbloom R, and risperidone on hostility in schizophrenic patients.
Swartz M, Swanson J. Time to discontinuation of atypical Schizophrenia Research 2002;57:3113.
versus typical antipsychotics in the naturalistic treatment of Byerly 2006 {published data only}
schizophrenia. BMC Psychiatry 2006;6(8):116.
Byerly MJ, Nakonezny P, Bugno R, Boles J. A randomized,
double-blind pilot trial of switching to quetiapine vs.
Bai 2003 {published data only}
Risperidone continuation in outpatients with risperidone-
Bai YM, Yu SC, Lin CC. Risperidone for severe tardive
associated sexual dysfunction. Proceedings of the 159th
dyskinesia: a 12-week randomized, double-blind, placebo-
Annual Meeting of the American Psychiatric Association;
controlled study. Journal of Clinical Psychiatry 2003;64:
2006 May 20-25, Toronto, Canada. 2006.
13428.
Cai 2000 {published data only}
Baloescu 2006 {published data only}
Cai C, Wan C, Cheng F. The controlled investigation of
Baloescu A, Vasile D, Gheorghe MD, Grigorescu G. Side
risperidone and clozapine in the treatment of schizophrenia.
effects of atypical antipsychotics - prediction factor for
Health Psychology Journal 2000;8(2):1524.
compliance. European College of Neuropsychopharmacology
2006;16(Suppl 4):403. Canas 2006 {published data only}

Canas F, Perez V, Tafalla M. Quetiapine and risperidone
Basson 2001 {published data only} in the treatment of schizophrenia: a short- and long-term,

Basson BR, Kinon BJ, Taylor CC, Szymanski KA, Gilmore non-randomized study. Proceedings of the 159th Annual
JA, Tollefson GD. Factors influencing acute weight change Meeting of the American Psychiatric Association; 2006 May
in patients with schizophrenia treated with olanzapine, 20-25, Toronto, Canada. 2006.
haloperidol, or risperidone. Journal of Clinical Psychiatry
Cao 2001 {published data only}
2001;62(4):2318.
Cao D, Xie S. Different effects of clozapine and risperidone
Beasley 2001 {published data only} on levels of blood glucose in patients with schizophrenia.

Beasley CM, Berg PH, Dananberg J, Kwong KC, Taylor Modern Rehabilitation 2001;5(12):1445.
CCM, Breier A. Treatment-emergent potential impaired Cao 2003 {published data only}
glucose tolerance and potential diabetes with olanzapine Cao W, Liu X-L, Wei H-Y. A comparative study of the
compared to other antipsychotic agents and placebo. therapeutic effects of clozapine and risperidone in the
Biological Psychiatry 2001;49(8):121. treatment of schizophrenia. Herald of Medicine 2003;22
Beasley 2003 {published data only} (10):67980.

Beasley CM, Sowell MO, Carlson C, Mukhopadhyay N, Cao 2005 {published data only}
Dananberg J, Henry R, Breier A, Cavazzoni P. Prospective Cao D, Xie S, Chen Q, Yuan Y, Fan Q. Comparison of the
evaluation of insulin sensitivity by the hyperinsulinemic, effects of chlorpromazine, risperidone and quetiapine on
euglycemic clamp in healthy volunteers treated with hypothalamic-pituary -gonodal axis and sexual function in
olanzapine, risperidone or placebo. Schizophrenia Research male patiens with schizophrenia. Chinese Journal of Clinical
2003;60(1):309. Rehabilitation 2005;9:1489.
Cha 2002 {published data only} Chou 1999 {published data only}
Cha A, Xu Y, Zhu XH. The curative effect comparison of Chou X, Chen Q, Li J. A clinical controlled study between
risperidone and clozapine to treat recurrent schizophrenia. risperidone and clozapine in the treatment of chronic
Chinese Medical Journal of Metallurgical Industry 2002;19 schizophrenia. Sichuan Mental Health 1999;12(4):2446.
(3):1434. Chowdhury 1999 {published data only}
Chaudhry 2006 {published data only}

Chowdhury AN, Mukherjee A, Ghosh K, Chowdhury

Chaudhry HR, Niaz S, Arshad N, Peracha F, Ayub A, S, Das Sen K. Horizon of a new hope: Recovery of
Mufti KA. Comparison of risperidone, olanzapine and schizophrenia in India. International Medical Journal 1999;
quetiapine in relation to body weight, serum blood glucose 6(3):1815.
and prolactin levels. Journal of the European College of Citrome 2004 {published data only}
Citrome L, Casey DE, Daniel DG, Wozniak P, Kochan
LD, Tracy KA. Adjunctive divalproex and hostility among
Chen 1999 {published data only}
patients with schizophrenia receiving olanzapine or
Chen ZA, Lan LM, Zhu PJ. Risperidone vs clozapine in
risperidone. Psychiatric Services 2004;55(3):2904.
treatment of schizophrenia. Chinese Journal of New Drugs
And Clinical Remedies 1999;18(5):27780. Ciudad 2004 {published data only}
Ciudad A, Alvarez E, Bousono M, Cuesta M, Gomez JC,
Chen 2002 {published data only} Olivares JM. Olanzapine versus risperidone: results of a
Chen L. A comparative stndy of EEg changes in patients one year randomized trial in outpatients with schizophrenia
treated by risperidone, chlorpromazine and clozpine. with prominent negative symptoms. Schizophrenia Research
Journal of Qiqihar Medical 2002;23(5):4856. 2004;67(1):1612.
Chen 2003 {published data only} Conley 1999 {published data only}
Chen C-Q. A study of risperidone and clozapine in

Conley J, Goldman RS, Bilder RM, Bates J, Reiter G,
treatment of first episode schizophrenia. HuaXia medicine Pappadopulos E, Robinson D, Alvir JMA, Liebrman J,
2003;27:5789. Schooler N. A comparison of the neurocognitive effects of
treatment with typical and atypical neuroleptics in first-
Chen 2004 {published data only} episode schizophrenia. Schizophrenia Research 1999;36(1-
Chen Y-H, Li Y-M, Li S. A study of risperidone with 3):128.
haloperidol and clozapine in treatment of positive symptom
Cornblatt 2002 {published data only}
schizophrenia. Suzhou University Journal of Medical Science
Cornblatt B, Kern RS, Carson WH, Stock E, Ali
2004;24:9127.
M, Ingenito G, Green MF. Neurocognitive effects of
Chen 2004a {published data only} aripiprazole versus olanzapine in patients with stable
Chen Q, Huang C-F. The influence of risperidone and psychosis. Schizophrenia Research 2002;53(3 Suppl 1):27.
clozapine in the quality of life of schizophrenia. Chinese Crespo-Facorro 2006 {published data only}
Journal of Clinical Rehabilitation 2004;8(18):36401.
Crespo-Facorro B, Perez-Iglesias R, Ramirez-Bonilla M,
Chen 2005 {published data only} Martinez-Garcia O, Llorca J, Vazquez-Barquero JL. A
Chen Q, Tang Y-L, Mao P-X, Cai Z-J. Effects of clozapine practical clinical trial comparing haloperidol, risperidone,
and risperidone on the glucose-regulating mechanism of and olanzapine for the acute treatment of first-episode
patients with schizophrenia. Chinese Journal of Clinical nonaffective psychosis. Journal of Clinical Psychiatry 2006;
Rehabilitation 2005;9(4):1168. 67(10):151121.
Cui 2002 {published data only}
Chen 2005a {published data only}
Cui B, Shen J, Tian H, Wang Y, Guo X. A comparative study
Chen B, Liu X, Zhang X. A study of risperidone
of the effects of risperidone, chlorpromazine and clozapine
combination with clozapine in the treatment of the
to patients with schizophrenia by the electrocardiograms.
schizophrenia. Heath Psychology Journal 2005;13(2):1167.
Tianjin Pharmacy 2002;14(3):545.
Chen 2005b {published data only} Czekalla 2001 {published data only}
Chen Q, Yuan Y, Fang Q. Characteristics of the sexual
Czekalla J, Beasley CM Jr, Dellva MA, Berg PH, Grundy
disturbance caused by chlorpromazine, risperidone, S. Analysis of the qtc interval during olanzapine treatment
quetiapine and olanzapine and their associations with the of patients with schizophrenia and related psychosis. Journal
changes of blood glucose and blood lipids in male patients of Clinical Psychiatry 2001;62(3):1918.
with schizophrenia. Chinese Clinical Rehabilitation 2005;9:
David 1999 {published data only}
634.
David SR, Meehan KM, Sutton VK, Taylor CC.
Cheng 2002 {published data only} Treatment of negative symptoms with olanzapine in
Cheng S-Z, Chi X-Z, Li Q-H, Jiang Y-Q. A study comparison with other novel antipsychotic agents. Journal
of risperidone and clozapine in treatment of resistant of the European College of Neuropsychopharmacology 1999;9:
schizophrenia. Heath Psychology Journal 2002;10(1):446. 292.
David 2000 {published data only} function and response to treatment in schizophrenia.

David SR, Taylor CC, Kinon BJ, Breier A. The effects Journal of the European College of Neuropsychopharmacology
of olanzapine, risperidone, and haloperidol on plasma 2006;16(Suppl 4):406.
prolactin levels in patients with schizophrenia. Clinical Estrella 1996 {published data only}
Therapeutics 2000;22(9):108596.
Estrella MH, Soria FL, Gonzalez CJC, Butron MAL,
De Haan 2002 {published data only} Torres JA, Escareo RR. Cost-effectiveness of clozapine vs

De Haan L, Beuk N, Hoogenboom B, Dingemans respiridona for treatment-resistant schizophrenic patients.
P, Linszen D. Obsessive-compulsive symptoms during Proceedings of the 10th World Congress of Psychiatry;
treatment with olanzapine and risperidone: a prospective 1996 Aug 23-28; Madrid, Spain. 1996.
study of 113 patients with recent-onset schizophrenia or Fan 2003 {published data only}
related disorders. Journal of Clinical Psychiatry 2002;63(2): Fan C, Leiying, Wang K. The effect of clozapine and
1047. risperidone on blood sugar of patients with schizophrenia.
Ding 2004 {published data only} Shandong Archives of Psychiatry 2003;16(3):1312.
Ding Y, An B, Li G. A comparative study of risperidone Feng 2004 {published data only}
and quetiapine in the treatment of schizophrenia and Feng Y-P. The influence of clozapine and risperidone on the
relationship between efficacy and the serum levels of IL-2, weight. Jounal of Clinical Psychiatry 2004;14:101.
SIL-2R. Shangdong Arch Psychiatry 2004;17:768.
Gan 1999 {published data only}
Ding 2005 {published data only} Gan JL. A control study of risperidone and clozapine in the
Ding Z, Yu Z, Xu G. Control studies of increase of blood freatment of first episode schizophrenia. Medical Journal of
sugar induced by neo-antipsychotics. Journal of Clinical Chinese Civil Administration 1999;11(1):61.
Psychosomatic Diseases 2005;11(4):30910.
Garca 2006 {published data only}
Dossenbach 2005 {published data only}
Garca MC, Vidal M, Ramos R. Sexual side effects of

Dossenbach M, Arango-Davila C, Ibarra HS, Landa E, antipsychoticcs and treatment adherence. Journal of the
Aguilar J, Caro O, Leadbetter J, Assuncao S. Response European College of Neuropsychopharmacology 2006;16
and relapse in patients With schizophrenia treated with (Suppl 4):378.
olanzapine, risperidone, quetiapine, or haloperidol: 12-
Ge 2004 {published data only}
month follow-up of the intercontinental schizophrenia
Ge Q, Xiong L, Liang X. A comparative study of risperidone,
outpatients health outcomes (IC-SOHO) study. Journal of
clozapine and haloperidol in the treatment of patients with
Clinical Psychiatry 2005;66(8):102130.
schizophrenia. Sichuan Mental Health 2004;17(2):7981.
Du 2003 {published data only}
Goldberg 2000 {published data only}
Du W-J, Yu J-L, Zheng H-B, Zhong X-Q, Ma C. The
Goldberg TE, Dodge M, Aloia M, Egan MF, Weinberger
influence of chlorpromazine, clozapine and risperidone
DR. Effects of neuroleptic medications on speech
on the cognitive function of schizophrenia. International
disorganization in schizophrenia: biasing associative
Medicine 2003;9:8688.
networks towards meaning. Psychological Medicine 2000;30
Du 2004 {published data only} (5):112330.
Du Z-H, Wu H-L. Comparison of chlorpromazine,
Guan 2005 {published data only}
clozapine and risperidone in the effect on indices of liver
Guan D-H, Song H-F. A control study of social function
function. Journal of Practical Medical Techniques 2004;11
improvement in schizophrenia patients with risperdal and
(6A):8856.
clozapine. Medical Journal of Chinese People Health 2005;17
Du 2004a {published data only} (9):5067.
Du Z-H. A study on the change of serum thyroxin treated
Guo 2001 {published data only}
with risperdal or clozapine. Journal of Practical Medical
Guo HR, Zhang SR, Sun FG. Clinical controlled study of
Techniques 2004;11(68):10201.
risperidone and clozapine in treatment of schizophrenia.
Du 2005 {published data only} Journal of Xinxiang Medical College 2001;18(3):1746.
Du Z, Wu H. Effects of clozapine and risperidone on the Guo 2003 {published data only}
glucose metabolism in schizophrenic patients. Qilu Journal Guo S, Lu L, Cheng W. Effect of clozapine and risperidone
of Medicall Aboratory Sciences 2005;16(1):89. on interleukin-2 on schizophrenia. Shanghai Archives of
Earnst 1999 {published data only} Psychiatry 2003;15(1):358.

Earnst KS, Taylor SF, Smet IC, Goldman RS, Tandon R, Hagger 1997 {published data only}
Berent S. The effects of typical antipsychotics, clozapine,
Hagger C, Mitchell D, Wise AL, Schulz SC. Effects of
and risperidone on neuropsychological test performance in oral ziprasidone and risperidone on cognitive functioning
schizophrenia. Schizophrenia Research 1999;40(3):2556. in patients with schizophrenia or schizoaffective disorder:
Ertugrul 2006 {published data only} Preliminary data. Proceedings of the 10th European College

Ertugrul A, Anil Yagcioglu AE, Woodward ND, of Neuropsychopharmacology Congress; 1997 Sep 13-17;
Jayathilake K, Meltzer HY. Genetic predictors of cognitive Vienna, Austria. 1997.
Han 2000 {published data only} Huber 2004 {published data only}
Han P. A study of risperidone and clozapine in treatment
Huber TJ, Borsutzky M, Schneider U, Emrich HM.
of resistant schizophrenia. Journal of Jining Medical College Psychotic disorders and gonadal function: evidence
2000;23(3):75. supporting the oestrogen hypothesis. Acta Psychiatrica
Han 2005 {published data only} Scandinavica 2004;109(4):26974.
Han Z-Y, Wang L-J, Wang J. Analysis of risperidone Janssen-Ortho 2006 {published data only}
clonazepam in treatment of positive symptom schizophrenia.
Janssen-Ortho Inc. Pragmatic randomised trial of
Ningxia Medical Journal 2005;27:6312. RISPERDAL CONSTA versus oral atypical
antipsychotics in poorly adherent subjects with
Harrigan 2004 {published data only}
schizophrenia in a routine care setting: UK Revised Protocol

Harrigan EP, Miceli JJ, Anziano R, Watsky E, Reeves KR,
V2. Unpublished report 2006.
Cutler NR, Sramek J, Shiovitz T, Middle M. A randomized
evaluation of the effects of six antipsychotic agents on QTC, Jones 2006 {published data only}
in the absence and presence of metabolic inhibition. Journal

Jones PB, Barnes TRE, Davies L, Dunn G, Lloyd H,
of Clinical Psychopharmacology 2004;24(1):629. Hayhurst KP, Murray RM, Markwick A, Lewis SW.
Randomized controlled trial of the effect on quality of
He 2005 {published data only} life of second- vs first-generation antipsychotic drugs in
He Y-Q, Ma S-H, Du J. A controlled study on hostility schizophrenia: Cost utility of the latest antipsychotic drugs
and side effects in clozapine and risperidone for treatment in schizophrenia study (CUtLASS 1). Archives of General
of patients with schizophrenia. Journal of Xinxiang Medical Psychiatry 2006;63(10):107987.
College 2005;22(2):11820.
Karow 2002 {published data only}
Heresco-Levy 2005 {published data only}
Karow A, Naber D. Subjective well-being and quality of life

Heresco-Levy U, Javitt DC, Ebstein R, Vass A, under atypical antipsychotic treatment. Psychopharmacology
Lichtenberg P, Bar GCS, Ermilov M. D-serine efficacy as 2002;162:310.
add-on pharmacotherapy to risperidone and olanzapine for
Keks 2006 {published data only}
treatment-refractory schizophrenia. Biological Psychiatry
Keks NA, Tonso M, Tabone K, McHugh M, Thomas
2005;57(6):57785.
R, Tune P, Gelman M. Clinical experience with atypical
Hou 2001 {published data only} antipsychotics in an acute inpatient unit: Focus on
Hou J, Xu G, Ma C. The effects of clozapine and risperidone quetiapine. International Journal of Psychiatry in Clinical
on serum prolactin levels of female schizophrenia. Journal Practice 2006;10(2):13841.
of Clinical Psychological Medicine 2001;11(1):13.
Kelemen 2006 {published data only}
Hrdlicka 2001 {published data only}
Kelemen O, Nagy O, Mttyssy A, Kiss I, Janka Z, Kri

Hrdlicka M, Rosillon D, Duchesne I. Czech results S. Do second-generation antipsychotics disrupt decision-
of the RODOS study: comparison of risperidone and making abilities in schizophrenia?. European College of
olanzapine from the point of view of efficacy, tolerability Neuropsychopharmacology 2006;16(Suppl 4):430.
and treatment costs [Ceske vysledky studie RODOS:
Kim 2004 {published data only}
Porovnani risperidonu a olanzapinu z hlediska ucinnosti,
Kim JG, Cho DH, Choi HK, Kim HJ, Cho JH, Kang SH,
snasenlivosti a nakladu lecby]. Ceska A Slovensk Psychiatrie
Lee SJ, Lee JG, Kim HT. The comparison of risperidone,
2001;97(7):3439. olanzapine and quetiapine in the treatment of chronic
Hu 2000 {published data only} schizophrenia and schizoaffective disorder. European College
Hu X-C, Tao R-F. A study of risperidone and clozapine of Neuropsychopharmacology 2004;14(Suppl 3):245.
in treatment of schizophrenia. Journal of Handan Medical Knegtering 2004 {published data only}
College 2000;13(2):91.
Knegtering R, Castelein S, Bous H, Van Der Linde
Hu 2005 {published data only} J, Bruggeman R, Kluiter H, Van Den Bosch RJ. A
Hu T-S. A study of risperidone in treatment of dominant randomized open-label study of the impact of quetiapine
positive symptoms in schizophrenia. Chinese Journal of versus risperidone on sexual functioning. Journal of Clinical
Behavioral Medical Science 2005;14(5):428. Psychopharmacology 2004;24(1):5661.
Huang 2000 {published data only} Koenigsberg 2000 {published data only}
Huang Y-H, Luo B-M. A study of risperidone and
Koenigsberg HW, Goodman M, Mitropoulou V, New
chlorpromazine clozapine. Health Psychology Journal 2000; AS, Siever LJ. Risperidone in the treatment of schizotypal
9:3212. personality. Proceedings of the 153rd Annual Meeting of
Huang 2001 {published data only} the American Psychiatric Association; 2000 May 13-18;
Huang Q-M, Li J, Zhu X-W, Mel Q-Y. A study of Chicago, Illinois, USA. 2000.
risperidone and clozapine in treatment of the behaviors in Kolff 2000 {published data only}
schizophrenia. Shanghai Archives of Psychiatry 2001;13(3):
Kolff M, Coenen A, Van Dis H, Duigemans P. Differential
1524. effects of antipsychotic drugs on clinical symptoms and
cognitive functions in the treatment of schizophrenia. Li 2005 {published data only}
European College of Neuropsychopharmacology 2000;10 Li G, Chen Q, Zhang Q. A comparison analysis on the
(Suppl 2):S59. efficacy of quetiapine and risperidone in cognitive function
Kong 2001 {published data only} of schizophrenia. Chinese Journal of Behavioral Medical
Kong Q-R, Yang R-X, Li S-C, Lu Z-S, Li J-Y, Chen X. Science 2005;14:10079.
A study of clozapine with risperidone and clozapine with Liang 2005 {published data only}
sulpiride in treatment of resistant schizophrenia. Archives of Liang Z-Y, Huang X-S. A study of risperidone and clozapine
General Psychiatry 2001;14:11920. in treatment of first episode schizophrenia. Medical Journal
of Chinese People Health 2005;17(9):50910.
Kores 2003 {published data only}

Kores Plesnicar B, Zalar B, Tomori M, Krajnc I. Liao 2004 {published data only}
Measurement of simple reaction time in antipsychotic Liao C, Yang H, Gao H. Effects of clozapine and
treatment of patients with schizophrenia. Wiener Klinische risperidone on blood routine examinations of patients with
Wochenschrift 2003;115(1-2):5862. schizophrenia. Journal of Clinical Psychosomatic Diseases
Lee 2005 {published data only} 2004;10(3):1567.

Lee JN, Yang BH, Nam CW. The influences of risperidone Lin 2005 {published data only}
and clozapine on body weight and glucose level in patients Lin Z, Li F, Yu Y, Zhong T. A controlled study of olanzapine
with chronic schizophrenia - comparison with haloperidol. and risperidone in the treatment of elderly patients with
European College of Neuropsychopharmacology 2005;15 schizophrenia. Hainan Medical Journal 2005;16(8):379.
(Suppl 3):457. Lipkovich 2005 {published data only}
Lee 2006 {published data only}
Lipkovich I, Baron D, Houston J, Ahl J, Rotelli M.

Lee C, Wu K-H, Habil H, Dyachkova Y, Lee P. Treatment Flexible-dose clinical trials: predictors and outcomes
with olanzapine, risperidone or typical antipsychotic drugs of antipsychotic dose adjustments. Journal of Clinical
in Asian patients with schizophrenia. Australian and New Psychopharmacology 2005;25(4):3816.
Zealand Journal of Psychiatry 2006;40(5):43745. Littrell 1999 {published data only}
Lei 2002 {published data only}
Littrell KH. Patients switched from depot antipsychotics
Lei X, Liang T, Zhang X. A controlled study on risperidone to oral risperidone or olanzapine: an open-label randomized
and clozapine in treatment of schizophrenia. China trial. Proceedings of the 152nd Annual Meeting of the
Pharmacist 2002;5(3):16971. American Psychiatric Association; 1999 May 15-20;
Lewis 2004 {published data only} Washington DC, USA. 1999.

Lewis SW, Davies L, Jones PB, Barnes TRE, Murray RM, Liu 1999 {published data only}
Kerwin R, Taylor D, Hayhurst KP, Lloyd H, Markwick Liu Q, Man C, Li X. A control study of risperidone
A. A randomised, controlled trial of new atypical drugs and colzapine to treating the positive symptoms of
versus clozapine in treatment-resistant schizophrenia. schizophrenia. Sichuan Mental Health 1999;12(2):98-9,
Schizophrenia Research 2004;67(1):67. 100.
Li 2000 {published data only} Liu 2001 {published data only}
Li X-X. A study of risperidone and clozapine in treatment of Liu Q, Li X. A comparative study on the efficacy of
chronic schizophrenia. He Nan Medical Information 2000; combining risperidone and clozapine in the treatment of
8:523. schizophrenia. Shandong Archives of Psychiatry 2001;14(1):
Li 2001 {published data only} 2830.
Li J, Dai X. A comparative study of rispredone and sulpride Liu 2003 {published data only}
in treating schizophrenia. Medical Journal of Chinese Civil Liu F, Dai M. The effects of risperidone and clozapine to
Administration 2001;13(3):1368. patients with schizophrenias life quality. Sichuan Mental
Li 2003 {published data only} Health 2003;16(4):2034.
Li T, Xue XM, Gong CF. A comparison study on the efficacy Liu 2003a {published data only}
of risperidone vs dozapine in cognition of schizophrenia. Liu Y, Li H, Wang H. Effect and related factors of
Medical Journal of Chinese People Health 2003;15(11): clozapine and risperidone on glucose-insulin homeostasis
6536. in schizophrenic patients. Shanghai Archives of Psychiatry
Li 2003a {published data only} 2003;15(4):25759.
Li X, Lao G. Comparison of efficacy and safety of seroquel Liu 2004 {published data only}
and risperidone in the treatment of schizophrenia. Chinese Liu TF, Yang JZ. Risperidone vs clozapine for treatment of
Journal of Behavioural Medical Science 2003;12:456. schizophrenia in 30 patients each. Chinese Journal of New
Li 2004 {published data only} Drugs and Clinical Remedies 2004;3(3):1479.
Li Z. A comparative study of clozapine and risperdone lead Liu 2004a {published data only}
to putting on weight. Heath Psychology Journal 2004;12(5): Liu J-B, Wu J. The influence of clozapine, risperidone and
3967. chlorpromazine on the Glu.TG.TC and the weight in the
first-episode schizophrenia. Chinese Journal of Nerval and Malla 2004 {published data only}
Mental Diseases 2004;30(4):2934.
Malla A, Norman R, Scholten D, Townsend L,
Liu 2004b {published data only} Manchanda R, Takhar J, Haricharan R. A comparison
Liu N-H, Zhang J-Y. A study of risperidone with of two novel antipsychotics in first episode non-affective
clonazepam in treatment of schizophrenia. Journal of Hai psychosis: one-year outcome on symptoms, motor side
Nan Medical College 2004;10:3945. effects and cognition. Psychiatry Research 2004;129:15969.
Liu 2004c {published data only} Malyarov 1999 {published data only}
Liu Y, Li H-F, Wang H-F, Wang K-X, Gao Z-S, Gu N- Malyarov S, Dzub G. Comparative assessment of the
F. Influence of clozapine and risperidone on body weight, positive and negative symptom dynamics in schizophrenic
leptin level and lipid metabolism in schizophrenic patients. patients treated with atypical antipsychotics or haloperidol.
Chinese Journal of New Drugs and Clinical Remedies 2004;9 European College of Neuropsychopharmacology 1999;9:296.
(23):57982.
Liu 2005 {published data only} Malykhin 2003 {published data only}
Liu K, Jiao Z-A. A study of the influence of clozapine and

Malykhin N. Comparative efficacy of risperidone,
risperidone on the weight in schizophrenia. Medical Journal clozapine and haloperidol in the treatment of schizoaffective
of Chinese Peoples Health 2005;17:5134. disorders with manic symptoms. European College of
Neuropsychopharmacology 2003;13(4):304.
Liu 2005a {published data only}
Liu G-F, Zhou J-S. The influence of risperidone and Mao 2000 {published data only}
clozapine in the quality of life of schizophrenia. Medical Mao Y, Da Z. Study of cost-effectiveness on risperidone vs
Journal of Chinese People Health 2005;17(6):28990. clozapine in the treatment of inpatients with schizophrenia.
Liu 2005c {published data only} Shanghai Archives of Psychiatry 2000;12(4):2113.
Liu Y. A comparative study of risperidone and clozapine in
Mazurek 2003 {published data only}
the treatment of refractory schizophrenia. Journal of Heze
Mazurek I, Loza B, Lecyk A. Atypical versus typical
Medical College 2005;17(1):134.
antipsychotic treatment prognosis based on veps and wcst
Loza 2005 {published data only} scores in paranoid schizophrenia. European College of

Loza B, Bartyzel M, Matysiewicz W, Mazurek I, Mosiolek Neuropsychopharmacology 2003;13(4):347.
A, Opielak G, Varghese S. Hyperprolactinemia during
schizophrenia treatment with atypical antipsychotics: Mei 2001 {published data only}
oral risperidone, depot risperidone, and oral olanzapine. Mei Q, Zhu X, Shen J. A comparative study of social
European College of Neuropsychopharmacology 2005;15 function in schizophrenic patients treated with risperidone
(Suppl 3):522. or clozapine. Journal of Clinical Psychological Medicine 2001;
11(2):835.
Lu 2002 {published data only}
Lu Y, Ren Q, Tian M. A comparison of cognitive function Meltzer 2002 {published data only}
in the first-onset schizophrenia treated with risperidone
Meltzer HY, Gilliam JH, Nasdahl C. Olanzapine
and clozapine. Shandong Archives of Psychiatry 2002;15(4): causes greater increases in serum lipids than risperidone.
2067. Proceedings of the 155th Annual Meeting of the American
Lu 2004 {published data only} Psychiatric Association; 2002 May 18-23; Philadelphia,
Lu L-X, Guo S-Q, Chen W, Li Q, Cheng J, Zhang H-Y, Shi Pennsylvania, USA. 2002.
T-Y, Shi Y. Effects of clozapine and risperidone on serum
Meltzer 2004 {published data only}
interleukin-2,-10,-18 in adolescent schizophrenia patients.
Meltzer HY, Arvanitis L, Bauer D, Rein W, Meta-
Journal of Applied Clinical Pediatrics 2004;19(11):9836.
Trial Study Group. Placebo-controlled evaluation of four
Lu 2005 {published data only} novel compounds for the treatment of schizophrenia and
Lu S, Zhang S-A, Ren Y. Comparative study on the schizoaffective disorder. American Journal of Psychiatry
psychopathology and the quality of life of schizophrenia 2004;161(6):97584.
treated with risperidone, clozapine and quetiapine. Journal
of Nursing Science 2005;20(3):579. Mintzer 2004 {published data only}

Mintzer JE, Mullen JA, Sweitzer DE. A comparison of
Ma 1999 {published data only}
Ma Q-M, Guan H-Y, Jiang L, Zhang Y-Y, Yi X-R, Guo J- extrapyramidal symptoms in older outpatients treated with
quetiapine or risperidone. Current Medical Research and
M, Sun S-G, Liu K-H, Gao S-Q, Wu H-R, Xu S-W. A
study of risperidone in treatment of chronic schizophrenia. Opinion 2004;20(9):148391.
Heath Psychology Journal 1999;7(3):2903. Mohr 2000 {published data only}
Mai 2005 {published data only}
Mohr E, Mendis T, Hildebrand K, De Deyn PP.
Mai G, Cai GH, Huang JM. Comparative Study on the Risperidone in the treatment of dopamine-induced
effect of aripiprazole and risperidone on schizophrenia. psychosis in Parkinsons disease: an open pilot study.
Chinese Journal of Rehabilitation 2005;20(3):1846. Movement Disorder 2000;15(6):12307.
Mu 2002 {published data only} Pan 2004 {published data only}
Mu Z-Q, Zong Y-S, Luo Y. A study of risperidone instead of Pan M, Zhang S, Zhao Z. A comparative study of
typical antipsychotics and clozapine in treatment of chronic domestic quetiapine and risperidone in the treatment of
schizophrenia. Health Psychology Journal 2002;10:2345. schizophrenia. Medical Journal of Chinese People Health
Mullen 2001 {published data only} 2004;16(10):5978.

Mullen J, Jibson MD, Sweitzer D. A comparison of the Pan 2004a {published data only}
relative safety, efficacy, and tolerability of quetiapine and Pan M, Zhang S-Q, Zhao Z. Influence of three antipsychotic
risperidone in outpatients with schizophrenia and other drugs on electrocardiogram in patients with schizophrenia.
psychotic disorders: the quetiapine experience with safety Journal of Xin Xiang Medical College 2004;21(5):4034.
and tolerability (QUEST) study. Clinical Therapeutics
Peng 2001 {published data only}
2001;23(11):183954.
Peng H, Kuang Y, Huang X. A control study of risperidone
Musil 2006 {published data only} in combination with clozapine in treating refractory

Musil RL, Spellmann I, Riedel M, Douhet A, Dehning S, schizophrenia. Journal of Modern Clinical Medical
Maino K, Zill P, Mller N, Mller HJ, Bondy B. SNAP- Bioengineering 2001;7(2):1002.
25 gene polymorphisms and weight gain in schizophrenic
Peng 2004 {published data only}
patients treated with atypical antipsychotics. European
Peng J-F, Xu Y-M, Wang Y-B. Effects of clozapine and
College of Neuropsychopharmacology 2006;16(Suppl 4):415.
risperidone on the serum prolactin levels and body weight
Naber 2001 {published data only} regulation. Journal of Clinical Psychological Medicine 2004;

Naber D, Moritz S, Lambert M, Pajonk F, Holzbach 14(5):2689.
R, Mass R, Andresen B. Improvement of schizophrenic
patients subjective well-being under atypical antipsychotic Perro 1999 {published data only}
drugs. Schizophrenia Research 2001;50:7988.

Perro C, Naber D, Lambert M, Moritz S, Krause M.
A prospective clinical comparative-study of four atypical
Naber 2002 {published data only}
antipsychotic agents in the treatment of schizophrenia.

Naber D, Karow A, Lambert M. Psychosocial outcomes in
Proceedings of the 11th World Congress of Psychiatry;
patients with schizophrenia: quality of life and reintegration.
1999 Aug 6-11; Hamburg, Germany. 1999; Vol. 2:13.
Current Opinion in Psychiatry 2002;15:316.
Peuskens 2004 {published data only}
Nan 2001 {published data only}
Peuskens J, Deberdt W, Van Brunt D, Hill A, Liu-
Nan Z, Wang J, Ji H. A controlled study of risperidone and
Seifert H, Csernansky J, Buckley P. Medication-specific
clozapine both influences congnitive function of patients
correlates of relapse risk in schizophrenia. European College
with schizophrenia. Sichuan Mental Health 2001;14(4):
of Neuropsychopharmacology 2004;14(Suppl 3):238.
198200.
Ni 2001 {published data only} Qi 2004a {published data only}
Ni J-L, Jiiang L-C, Hong X, Yang H, Zheng X-P. A study Qi F, Wang L, Zhen Y. Comparison of efficacy and
of clozapine and risperidone in treatment of schizophrenia. safety of quetiapine and risperidone in the treatment of
Heath Psychology Journal 2001;9(3):1812. schizophrenia. Shanghai Archives of Psychiatry 2004;16:
7880.
Nicholls 2003 {published data only}

Nicholls CJ, Hale AS, Freemantle N. Cost-effectiveness Qian 2004 {published data only}
of amisulpride compared with risperidone in patients with Qian D, Pan B, Yang G. Cost-effectiveness analysis of 3
schizophrenia... first published as: Journal of Medical kinds of therapeutic schemes for schizophrenia. Evaluation
Economics 2003;6:31-41. Journal of Drug Assessment 2003; and Analysis of Drug-use in Hospital of China 2004;4(2):
6(2):7989. 1101.
Opjordsmoen 2000 {published data only} Qin 2005 {published data only}

Opjordsmoen S, Brunsvik S, Melle I, Dahl A, Friis Qin Y, Kang W, Song L. A comparative study of risperidone
S, Haahr U, Hustoft K, Johannessen JO, Larsen TK, combining alprazolam and clozapine in the treatment of
McGlashan TH, Simonsen E, Vaglum P. A comparison patients with schizophrenia. Heath Psychology Journal 2005;
between novel and traditional antipsychotics as first-line 13(6):4445.
medication in early psychosis. Proceedings of the 2nd Rabinowitz 2005 {published data only}
International Conference on Early Psychosis; 2000 Mar 31
Rabinowitz J. Pattern mixture approach to comparing
- Apr 2; New York, New York, USA. 2000. outcomes - of benefit in guideline development. Proceedings
Ortega-Soto 1997 {published data only} of the 18th European College of Neuropsychopharmacology

Ortega-Soto H, Apiquian R, Ulloa RE, Salas M, Loyzaga Congress; 2005 October 22-26, Amsterdam, Netherlands.
C, Mendizabal A, Brunner E. Olanzapine vs risperidone. A 2005.
double blind trial in Mexican patients. Proceedings of the Ren 2000 {published data only}
Collegium Internationale Neuro-Psychopharmacologicum Ren J-J, Su J-L, Li B-Q. A study of risperidone and
Regional Meeting; 1997 Aug 21-23; Acapulco, Mexico. clozapine in treatment of resistant schizophrenia. Baotou
1997. Medical Journal 2000;35(2):67.
Ren 2004 {published data only} Sowell 2002 {published data only}
Ren K, Zhao X, Jiang X. Effects of risperidone and clozapine
Sowell M, Cavazzoni P, Roychowdhury SM, Breier
on life quality of schizophrenics. Journal of Clinical A. Antipsychotics and diabetes: lack of evidence
Psychosomatic Diseases 2004;10(1):34. for a causal relationship. International Journal of
Roerig 2004 {published data only}

Roerig JL, Mitchell JE, De Zwaan M, Crosby RD, Su 2004 {published data only}
Gosnell BA, Pederson K. A comparison of the effects Sun D, Jiang Q, Su S. Effect of risperidone and clozapine
of olanzapine and risperidone versus placebo on eating on blood fat in patients with schizophrenia. Journal of Hebei
behaviors and ghrelin plasma levels in normal human Medical College for Continuing Education 2004;21, 2:89.
subjects. Proceedings of the Thematic Conference of the Su 2005 {published data only}
World Psychiatric Association on Treatments in Psychiatry:
Su K-P, Wu P-L, Pariante CM. A crossover study on
An Update; 2004 Nov 10-13; Florence, Italy. 2004. lipid and weight changes associated with olanzapine and
Ryu 2006 {published data only} risperidone. Psychopharmacology 2005;183(3):3836.

Ryu SH, Jang WS, Cho EY, Kim SK, Lee DS, Hong Sun 2000 {published data only}
KS. Association of leptin gene polymorphism with Sun T. A controlled study comparing risperidone and
antipsychotic drug-induced weight gain. European College clozapine in the treatment of schizophrenia. Health
of Neuropsychopharmacology 2006;16(Suppl 4):419. Psychology Journal 2000;8(3):2901.
Sajatovic 2002 {published data only} Sun 2001 {published data only}

Sajatovic M, Mullen JA, Sweitzer D. Efficacy of quetiapine Sun Q-Z, Liang J-S, Yu G-H, Huang X. A study of
and risperidone against depressive symptoms in outpatients risperidone and clozapine in treatment of negative
with psychotic disorders. Proceedings of the 155th Annual symptoms of resistant schizophrenia. Journal of Qiqihar
Meeting of the American Psychiatric Association; 2002 May Medical 2001;22(11):12478.
18-23; Philadelphia, Pennsylvania, USA. 2002. Swanson 2006 {published data only}
Shao 1999 {published data only}

Swanson JW, Swartz MS, Van Dorn RA. Effectiveness of
Shao Y-Q. The extrapyramidal side effects of risperidone. atypical antipsychotics for substance abuse in schizophrenia
Journal of Southeast China National Defense Medicinal patients. Proceedings of the 159th Annual Meeting of
Science 1999;1(1):2829. the American Psychiatric Association; 2006 May 20-25,
Toronto, Canada. 2006.
Sheng 2003 {published data only}
Sheng Y, Liu T, Li Y. A comparison study of the blood sugar Tandon 2006 {published data only}
in the treatment of schizophrenic patients with risperidone,

Tandon R, Marcus RN, Stock EG, Riera LC, Kostic D,
clozapine and chlorpromazine. Qilu Journal of Medicall Pans M, McQuade RD, Nyilas M, Iwamoto T, Crandall
Aboratory Sciences 2003;14(1):112. DT. A prospective, multicenter, randomized, parallel-group,
open-label study of aripiprazole in the management of
Sheng 2005 {published data only} patients with schizophrenia or schizoaffective disorder in
Sheng Y. Effects of clozapine and risperidone on serum general psychiatric practice: Broad Effectiveness Trial With
interleukin-2 and interleukin-6 of patients with first episode Aripiprazole (BETA). Schizophrenia Research 2006;84(1):
schizophrenia. Qilu Journal of Medical Laboratory Sciences 7789.
2005;16(5):145.
Tang 2002 {published data only}
Shi 2000 {published data only} Tang M, Wang H, Huang J. Influences of treating
Shi F, Cheng X, Zhang Y. Controlled study of risperidone schizophrenics with risperidone and clozapine on the quality
and clozapine in the treatment of schizophrenia. Shanghai of life of their spouses and parents. Nervous Diseases and
Archives of Psychiatry 2000;12(1):279. Mental Hygiene 2002;2(2):679.
Shi 2001 {published data only} Tang 2002a {published data only}
Shi X-H. A study of risperidone and clozapine in treatment Tang M, Zhao G, Wang H. Comparison of quality of life of
of schizophrenia. Medical Journal of Communications 2001; family with schizophrenic outpatients. Nervous Disease and
15(6):6523. Mental Hygiene 2002;2:679.
Shi 2004 {published data only} Tian 2005 {published data only}
Shi T, Zhang R, Guo X. Influences of risperidone and Tian R-F. A study of risperidone and clozapine in
clozapine on plasma levels of cytokine in first-episode treatment of schizophrenia in children. Journal of Clinical
schizophrenics. Chinese Journal of Nervous and Mental Psychosomatic Diseases 2005;11(3):261.
Diseases 2004;30(5):33941. Tong 2005 {published data only}
Simpson 2004 {published data only} Tong S-N, Gan H-Q, Liu Y-Y. A study of clozapine

Simpson GM, Fayek M, Weiden PJ, Murray S, Warrington and risperidone influencing on IQ and memory in
L, Loebel A. Ziprasidone: long-term post-switch efficacy in schizophrenia. Chinese Journal of Behavioral Medical Science
schizophrenia. World Psychiatry 2004;3(S1):220. 2005;14(7):634.
Tunis 2006 {published data only} Wang 2005b {published data only}

Tunis SL, Faries DE, Nyhuis AW, Kinon BJ, Ascher- Wang X, Yang J, Guo H. Clinical study of quetiapine and
Svanum H, Aquila R. Cost-effectiveness of olanzapine risperidone in the treatment of schizophrenia. Journal of
as first-line treatment for schizophrenia: results from a Clinical Psychosomatic Diseases 2005;11(2):1189.
randomized, open-label, 1-year trial. Value in Health 2006;
Weickert 2003 {published data only}
9(2):7789.
Weickert TW, Goldberg TE, Marenco S, Bigelow LB,
Van Bruggen 2003 {published data only} Egan MF, Weinberger DR. Comparison of cognitive
Van Bruggen J, Tijssen J, Dingemans P, Gersons B, Linszen performances during a placebo period and an atypical
D. Symptom response and side-effects of olanzapine and antipsychotic treatment period in schizophrenia: critical
risperidone in young adults with recent onset schizophrenia. examination of confounds. Neuropyschopharmacology 2003;
International Clinical Psychopharmacology 2003;18(6): 28(8):1491500.
3416.
Weng 1998 {published data only}
Vaughan 2000 {published data only} Weng Y. A controlled trial of risperidone versus clozapine

Vaughan K, McConaghy N, Wolf C, Myhr C, Black in the treatment of schizophrenia. Journal of Clinical
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care, medication compliance, behavioural disturbance
and readmission. Australian and New Zealand Journal of Wolf 2002 {published data only}
Psychiatry 2000;34(5):8018.

Wolf K, Wolf K, Mass R, Kiefer F, Wiedemann K, Naber
D. Improvement of facial expression of emotions (fee) of
Wang 2000a {published data only}
schizophrenic patients under olanzapine versus risperidone.
Wang M, Liu L. A controlled study on seroquel and
A prospective facial-emg study. Proceedings of the 12th
risperidone in the treatment of schizophrenic patients.
World Congress of Psychiatry; 2002 Aug 24-29; Yokohama,
Journal of Clinical Psychology in Medical Settings 2000;10, 4:
Japan. 2002.
2001.
Wang 2001 {published data only} Wolf 2005 {published data only}
Wang J, Nan Z, Bai J. The relationship of schizophrenic

Wolf K, Mass R, Kiefer F, Eckert K, Stritzky AV, Haasen
cognitive function impairment with positive and negative C, Wiedemann K, Naber D. The influence of olanzapine
symptoms. Journal of Clinical Psychology in Medical Settings versus risperidone on facial expression of emotions in
2001;11:3467. schizophrenia-preliminary results of a facial electromyogram
study. Journal of Clinical Psychopharmacology 2005;25(3):
Wang 2002 {published data only}
27881.
Wang G, Chen Z, Wang H. Comparative study on quality of
life of schizophrenics treated with risperidone or clozapine. Wu 2001 {published data only}
Chinese Mental Health Journal 2002;16(3):2002. Wu T, Li Y, Li M. Efficacy of low dosage risperidone in the
treatment of first episode schizophrenia. Journal of Clinical
Wang 2002a {published data only}
Psychology in Medical Settings 2001;11:1524.
Wang R, Geng Y, Pan D. A comparative trial on the
efficacy of risperidone and clozapine in treatment-resistant Wu 2002 {published data only}
schizophrenia. Shandong Archives of Psychiatry 2002;15(4): Wu L. A control study of risperidone and clozapine
2212. combination for the treatment of refractory schizophrenia.
Wang 2003 {published data only} Health Psychology Journal 2002;10(2):1357.
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and clozapine on life quality of schizophrenia. Shandong Wu J-F, Li Z-G. A study of risperidone and clozapine in
Archires of Psychiatry 2003;16(3):14950. treatment of schizophrenia. Medical Journal of Chinese
Wang 2003a {published data only} People Health 2004;16(4):2134.
Wang J-J. A study of risperidone and clozapine with Wu 2006 {published data only}
sulpiride in treatment of schizophrenia. Shandong Archires
Wu R-R, Zhao J-P, Liu Z-N, Zhai J-G, Guo X-F, Guo W-
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Wang 2005 {published data only} glucose-insulin homeostasis and lipid metabolism in first-
Wang C-H, Li Y, Ma J-D, Wang L-H, Pan M, Mu J-L. episode schizophrenia. Psychopharmacology 2006;186(4):
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clozapine. Chinese Journal of Nervous and Mental Diseases
Wyszogrodzka-Kucharska A, Rabe-Jablonska J. Vitamin
2005;31(4):26771. D deficiency and impaired parathormone metabolism
Wang 2005a {published data only} as a risk factor of low bone mineral density in patients
Wang S-Y, Liu Z, Bian J, Xu J-G. The influence of with diagnosis of schizophrenia treated with second
risperidone in the quality of life in schizophrenia. Nervous generation antipsychotics. Journal of the European College of
Diseases and Mental Hygiene 2005;5(2):1534. Neuropsychopharmacology 2006;16(Suppl 4):373.
Xiao 2003 {published data only} schizophrenic patients. Journal of The Fourth Military
Xiao X-M, Song X-C, Jiang H-Y. A study of risperidone and Medical University 2004;25(14):13235.
clozapine in treatment of schizophrenia. Journal of Clinical
Ye 2005 {published data only}
Psychology Medicine 2003;21:33.
Ye S-C, Zhang W-Y, Zhang Y-M. Observation of
Xie 2005 {published data only} developments of the level of serum prolactin of first-episode
Xie B-Q, Wang Z-M, Han Q-L. A control study of schizophrenia patients during the treatment. Medical
risperidone and clozapine in the treatment the chronic Journal of Chinese People Health 2005;17(6):2678.
schizophrenia. Shandong Archives of Psychiatry 2005;18(2):
Ye 2005a {published data only}
767.
Ye X, Xia X. A comparative study between aripiprazole
Xin 2001 {published data only} and risperidone in treatment of first-onset schizophrenia.
Xin X, Du B, Zeng Z. A controlled clinical study Medical Journal of National Defending Forces in Southwest
of risperidone and low dose of clozapine in treating China 2005;15(6):6167.
schizophrenia. Herald of Medicine 2001;20(8):5012.
Yin 2002 {published data only}
Xu 2001 {published data only} Yin Y, Son L. The impact of clozapine and risperidone on
Xu C, Tang J, Zhang X. The effect of risperidone and QTc. Shanghai Archives of Psychiatry 2002;14(3):1545.
clozapine treatment on serum interleukin 8, interleukin
15 in schizophrenis. Medical Journal of Chinese Civil Yin 2004 {published data only}
Administration 2001;13(3):1325. Yin H-R, Fang Y-M, Huang R-H, Yang X-Q. A study of
risperidone and clozapine in treatment of schizophrenia.
Xu 2005 {published data only}
China Medical Engineering 2004;12(3):878.
Xu X, Zhang X, Zhaao C, Dai X. Comparison of efficacy
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schizophrenia. Journal of Clinical Medicine in Practice 2005; Yu G-H, Huang X. A study of risperidone and clozapine
9:201. in treatment of resistant patients of schizophrenia. Chinese
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Yagdiran O, Krausz M. Depressive symptoms under Yu 2002 {published data only}
atypical neuroleptic treatment in schizophrenia. Nervenarzt Yu G, Ding G, Li X. An economic burden comparison
2000;71(Suppl 1):1356. of typical and atypical antipsychotic therapies for
Yamashita 2005 {published data only} schizophrenia. Chinese Journal of Psychiatry 2002;35(3):

Yamashita H, Mori K, Nagao M, Okamoto Y, Morinobu 1779.
S, Yamawaki S. Influence of aging on the improvement of Yu 2005 {published data only}
subjective sleep quality by atypical antipsychotic drugs in Yu D-S, Xu J, Sun D-H, Zeng Y-Y, Gao X-N, Jiang X-J.
patients with schizophrenia: comparison of middle-aged A comparative study of clozapine vs risperidone on body
and older adults. American Journal of Geriatric Psychiatry posture balance. Chinese Journal of New Drugs and Clinical
2005;13(5):37784. Remedies 2005;24(2):1258.
Yan 2002 {published data only} Yue 2004 {published data only}
Yan M, Wu B-Q. A study of risperidone and clozapine Yue Y, Song L, Xu Y. A comparative study on risperidone in
in treatment of chronic schizophrenia. Journal of Chinese the two-year treatment of schizophrenia. Shanghai Archives
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Yang 1998 {published data only} Zelaschi 2006 {published data only}
Yang Z, Xu H, Song Y. A controlled study of efficacy of
Zelaschi Sr NM, Rodriguez Sr JL, Gaitan Sr S, Palacios
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Sichuan Mental Health 1998;11(3):151-2, 159. follow-up study of patients with chronic schizophrenia.
Yang 2003 {published data only} Proceedings of the 159th Annual Meeting of the American
Yang X, Mei Q. A comparison of olanzapine and risperidone Psychiatric Association; 2006 May 20-25, Toronto, Canada.
in the treatment of first episode schizophrenia. Shanghai 2006.
Archives of Psychiatry 2003;15:3389. Zeng 2002 {published data only}
Yang 2004 {published data only} Zeng Y, Fang Q, Gao X. The 4th day serum prolactin level
Yang X-N, Mei Q-Y. A study of risperidone with clonazepam predicting the effective dose taking risperidone or clozapine.
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2004;25:274. Zhan 2002 {published data only}
Yang 2004a {published data only} Zhan L-Y. Analysis of risperidone and clozapine in
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Zhang 1999 {published data only} Zhong 2006a {published data only}
Zhang B-S, Liu B-Q, Shang F-Z, Song C-A, Huang C-B, Zhong Z-Y, Tao J, Wang X-L, Wu X-L, Zhang J-B. Effect of
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Zhang 2000 {published data only} Zhou 2005 {published data only}
Zhang C. A controlled study comparing risperidone and Zhou B, Tang Y, Zhu L. Effects of risperidone vs clozapine
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Zhang 2002 {published data only} Zhu 1999 {published data only}
Zhang Q. A comparison of cognitive function in the first- Zhu X, Mei Q. A controlled study comparing drug
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Journal of Qiqihar Medical 2002;23(8):8523. schizophrenia. Journal of Clinical Psychological Medicine
1999;9(3):1512.
Zhang 2002a {published data only}
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Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Addington 2004
Methods Allocation: random, no further details.

Blindness: double, no further details.
Duration: 8 weeks.
Design: parallel.
Location: multicentre.
Participants Diagnosis: (DSM-III-R) schizophrenia (n = 260) or schizoaffective disorder (n = 36),

acute exacerbation, PANSS total score of 60 or more.
N = 296.
Age: 18-64 years.
Sex: 215 M, 81 F.
History: duration not reported, age at onset mean risperidone = 24.6 years, mean ziprasi-
done = 25.2 years.
Setting: not reported.
Interventions 1. Risperidone: flexible dose, allowed dose range: 6-10 mg/day, mean dose = 7.4 mg/
day. N = 147.
2. Ziprasidone: flexible dose, allowed dose range: 80-160 mg/day, mean dose = 114.2
mg/day. N = 149
Outcomes Leaving the study early: any reason, adverse events, inefficacy.
Global State: CGI.
Mental State: PANSS total score, PANSS derived BPRS, BPRS positive subscore, PANSS
negative subscore, depression MADRS.
General functioning: GAF.
Adverse effects: open interviews, EPS (akathisia, tremor, use of antiparkinson medication,
AIMS, BAS, SAS), cardiac effects (ECG),
prolactin-associated side effects, sedation, weight gain, laboratory (urine, blood chem-
istry)
Unable to use:
GAF total score (no usable data).
QTc abnormalities in ms (no usable data).
Notes
Risk of bias
Bias Authors judgement Support for judgement
Adequate sequence generation? Unclear risk Random, no further details.
Allocation concealment? Unclear risk No further details.

Addington 2004 (Continued)
Blinding? Unclear risk Double, no further details. Whether blind-

subjective outcomes ing was successful has not been examined,
but the compounds differ quite substan-
tially in side effects. This can be a problem
for blinding
Blinding? Low risk Objective outcomes such as laboratory

objective outcomes measures or death are unlikely to have been
much affected by problems of blinding
Incomplete outcome data addressed? High risk The overall attrition was rather high (33.
All outcomes 3%). The LOCF method was used to ac-
count for people leaving the study early. It
assumes that a participant who discontin-
ued the study would not have had a change
of his condition if he had remained in the
study. This assumption can obviously be
wrong. Data on study completers were also
available. It is unclear whether this led to
bias
Free of selective reporting? High risk Reporting on secondary outcomes was in-
complete.
Free of other bias? High risk The study was sponsored by the manufac-
turer of ziprasidone.
Atmaca 2003

Blindness: single, rater-blinded.
Duration: 6 weeks.
Design: parallel.
Location: single centre.
Participants Diagnosis: (DSM-IV) schizophrenia.

N=56.
Sex: 24 M, 29 F (3 not reported)
Age: 19-46 years (mean clozapine = 31.3 years, mean olanzapine = 29.6 years, mean
quetiapine = 30.1 years, mean risperidone = 27.9 years, mean control group = 32.1 years)
.
History: duration ill mean clozapine = 6.6 years, mean olanzapine = 6.3 years, mean
quetiapine = 5.9 years, mean risperidone = 5.6, age at onset: not reported
Interventions 1. Clozapine: flexible dose. Allowed dose range: not reported. Mean dose: 207.1 mg/
day. N = 14.
2. Olanzapine: flexible dose. Allowed dose range: not reported. Mean dose: 15.7 mg/
day. N = 14.

Atmaca 2003 (Continued)
3. Quetiapine: flexible dose. Allowed dose range: not reported. Mean dose: 535.7 mg/
day. N = 14.
4. Risperidone: flexible dose. Allowed dose range: not reported. Mean dose: 6.7 mg/day.
N = 14
Outcomes Leaving the study early: any reason.

Mental state: PANSS total score.
Adverse effects: EPS (use of antiparkinson medication), weight gain (BMI), laboratory
(serum leptin, triglyceride levels)
Notes
Risk of bias
Blinding? Unclear risk Single, rater-blind. Whether blinding was

subjective outcomes successful has not been examined, but the
compounds differ quite substantially in
side effects. This can be a problem for
blinding

Incomplete outcome data addressed? Low risk Three subjects in the control groups left
All outcomes the study early (5.4%). Reason for drop-
out were not assessed, only completer data
were presented. But due to the very low rate
we do not think that there was a risk of bias
Free of selective reporting? Low risk Probably free of bias. The study focused on
serum leptin and triglyceride levels which
were adequately described
Free of other bias? Unclear risk Data on the allowed dose range have
not been presented. Furthermore, the pre-
study treatment was quite heterogeneous as
19 participants had never taken any psy-
chotropic drugs while most other partici-
pants had a long history of previous treat-
ment

Azorin 2001

Duration: 12 weeks.
Design: parallel.
Location: multicenter.
Participants Diagnosis: (DSM-IV) schizophrenia disorganised (n = 46), catatonic (n = 4), paranoid

(n = 140), residual (n = 15) or undifferentiated (n = 51) of intent to treat population,
poor previous treatment response, CGI of 4 or more, BPRS of 45 or more.
N = 273.
Sex: 182 M, 74 F (of intent-to-treat population, n = 256).
Age: 18-65 years (mean clozapine = 37.8, mean risperidone = 39.5) (of intent-to-treat
population).
History: duration ill mean clozapine = 13.0 years, mean risperidone = 15.5 years (of
intent-to-treat population), age at onset: not reported.
Setting: in- and outpatient.
Interventions 1. Clozapine: flexible dose. Allowed dose range: 200-900 mg/day. Mean dose: 642 mg/
day. N = 138.
2. Risperidone: flexible dose. Allowed dose range: 2-15 mg/day. Mean dose: 9 mg/day.
N = 135
Global State: CGI.
Mental State: PANSS total score, BPRS total score, PANSS positive subscore, PANSS
negative subscore, Calgary depression scale, psychotic depression scale, psychotic anxiety
scale.
Adverse effects: open interviews, death, EPS,
sedation, seizures, constipation, hypotension, sialorrhoea, tachycardia, agitation, anxiety,
insomnia, nausea, headache, fatigue, fever, weight gain, laboratory (white blood cell
count)
Notes
Risk of bias

for blinding

Azorin 2001 (Continued)

Incomplete outcome data addressed? Unclear risk The overall attrition was moderate (26.7%)
All outcomes . The LOCF method was used to account
for people leaving the study early. It as-
sumes that a participant who discontinued
the study would not have had a change of
his condition if he had remained in the
wrong. It is unclear whether this led to bias
Free of selective reporting? High risk Only those adverse events that occurred
in at least 5% of the participants were re-
ported. This procedure can miss rare, but
important adverse events
turer of clozapine.
Azorin 2006

Blindness: double, identical capsules.
Duration: 12 weeks.
Design: parallel.
Participants Diagnosis: schizophrenia (DSM-IV).

N = 187.
Sex: 113 M, 73 F (intent-to-treat group).
Age: 18-65 years (mean ~ 36 years).
History: duration ill unclear, age at onset unclear, at least moderately ill on CGI-S.
Setting: inpatient and outpatient.
Interventions 1. Sertindole: flexible dose (permitted range 12-24 mg/day, mean 16.2). N = 98
2. Risperidone: flexible dose (permitted range 4-10 mg/day, mean 6.6). N = 89
Outcomes Leaving study early: any reason, adverse effects, inefficacy.

Global state: CGI.
Mental state: PANSS (total, positive, negative sub-score).
Functioning: GAF.
Attitude: Drug attitude inventory.
Adverse effect/event: at least one adverse effect, QTc prolongation, death, extrapyramidal
side effects (tremor, AIMS, BAS, SAS), prolactin associated effects (amenorrhoea, sexual
dysfunction), sedation, weight change

Azorin 2006 (Continued)
Notes
Risk of bias
Blinding? Unclear risk Double, identical capsules. Whether blind-

but both compounds differ quite substan-
for blinding

much affected by lack of blinding
Incomplete outcome data addressed? High risk Data on reasons for leaving the study
All outcomes early were available, but total number was
considerably high (35.8%). The LOCF
method was used to account for people
leaving the study early. It assumes that
a participant who discontinued the study
would not have had a change of his condi-
tion if he had remained in the study. This
assumption can obviously be wrong
Free of other bias? High risk The study was industry sponsored by the
manufacturer of sertindole
Bondolfi 1998

Duration: 8 weeks.
Design: parallel.
Location: multicenter.

Bondolfi 1998 (Continued)
Participants Diagnosis: (DSM-III-R) chronic schizophrenia, non-responders or intolerance, PANSS

between 60 and 120.
N = 86.
Sex: 61 M, 25 F.
Age: 18-65 years (mean = 37.3).
History: age at first hospitalisation mean clozapine = 25.0, mean risperidone = 26.0, age
at onset mean clozapine = 23.5, mean risperidone = 22.4.
Setting: inpatient.
Interventions 1. Clozapine: flexible dose. Allowed dose range: 150-400 mg/day. Mean dose: 291.2 mg/
day. N = 43.
2. Risperidone: flexible dose. Allowed dose range: 3-10 mg/day. Mean dose: 6.4 mg/day.
N = 43
Mental State: PANSS total score, PANSS positive subscore, PANSS negative subscore).
Adverse effects: cardiac effects, EPS (akinesia, dystonia, parkinsonism, use of antiparkin-
son medication), prolactin associated side effects (sexual dysfunction), sedation, failing
memory, concentration difficulties, nausea, weight gain, laboratory (hematology)
Unable to use:
Change of weight in kg (no usable data).
Notes
Risk of bias

for blinding


Bondolfi 1998 (Continued)

wrong
Free of selective reporting? High risk Secondary outcomes were not fully re-
ported. For treatment emergent adverse
events there was an incidence of at lest 5%
occurrence for being reported
turer of risperidone.
Breier 1999

Duration: 6 weeks.
Design: parallel.
Location: not reported.
Participants Diagnosis: (DSM-IV) chronic schizophrenia, BPRS (positive subscale) of 8 or more,

SANS of 20 or more.
N = 29.
Sex: 19 M, 10 F.
Age: 18-55 years (mean clozapine = 37.7, mean risperidone = 32.4).
History: duration ill mean clozapine = 13.9 years, mean risperidone = 11.1 years, age at
onset mean clozapine = 23.7, mean risperidone = 21.3.
day. N = 14.
N = 15
Outcomes Mental State: BPRS total score, BPRS positive subscore, SANS.
Adverse effects: EPS (use of antiparkinson medication, Simpson Angus Scale), laboratory
(prolactin)
Notes
Risk of bias

Breier 1999 (Continued)

for blinding

Incomplete outcome data addressed? High risk Data on subjects leaving the study early
All outcomes were not available.
Free of selective reporting? High risk Exclusion of 5 participants after randomi-

sation, incomplete information
Free of other bias? Unclear risk One of the authors is an employee of a phar-
maceutical company producing olanzapine
Canive 2000

Duration: 16 weeks (first 8 weeks observed).
Design: crossover.
Participants Diagnosis: schizophrenia.

N = 8.
Sex: not reported.
Age: not reported.
History: duration ill not reported, age at onset not reported.
Interventions 1. Olanzapine: fixed/flexible dose: not reported.

Allowed dose range: not reported. Mean dose: not reported. N = not reported.
2. Risperidone: fixed/flexible dose: not reported.
Allowed dose range: not reported. Mean dose: not reported. N = not reported
Outcomes Global State: CGI.

Mental State: PANSS total score, PANSS positive subscore, PANSS negative subscore
depression Calgary depression scale
Unable to use:
CGI (no usable data).
Mental State (no usable data).
Notes

Canive 2000 (Continued)
Risk of bias

for blinding

Incomplete outcome data addressed? High risk Data on leaving the study early were not
All outcomes available.
Free of selective reporting? High risk Data were only presented as a poster, data
on primary outcomes were missing
turer of olanzapine.
Chan 2007
Methods Allocation: random, permuted block randomisation stratified by centre.

Duration: 4 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia (n = 80) or schizoaffective disorder (n = 3), acute

relapse. PANSS total score of 60 or more.
N = 83.
Age: 18-65 years (mean aripiprazole = 35.2 years, mean risperidone = 35.1 years).
Sex: 45 M, 38 F.
History: duration illness not reported, age at onset not reported.
Setting: inpatient.
Interventions 1. Aripiprazole: fixed dose: 15 mg/day. N = 49.

2. Risperidone: fixed dose: 6 mg/day. N = 34.

Chan 2007 (Continued)
Global state: CGI.
Mental state: PANSS total score, PANSS positive subscore, PANSS negative subscore.
Adverse effects: at least one adverse effect, cardiac effects (QTc), extrapyramidal side
effects (use of antiparkinson medication, extrapyramidal symptoms, AIMS, BAS, SAS),
cholesterol increase, glucose elevation, prolactin increase, weight
Notes
Risk of bias
Adequate sequence generation? Unclear risk Random, permuted block randomisation

stratified by centre.

for blinding

Incomplete outcome data addressed? Unclear risk Total number of participants leaving the
All outcomes study early was possibly acceptable (25%)
.
The LOCF method was used to account
Free of selective reporting? High risk Only adverse events with an incidence of
at least 5% in any treatment group were
reported, therefore important side effects
may have been missed by this procedure
Free of other bias? High risk The study was industry sponsored by the
manufacturer of aripiprazole

Conley 2001
Methods Allocation: random, stratified by site.

Duration: 8 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia (n = 325) paranoid (n = 213) or schizoaffective

disorder (n = 52), PANSS between 60 and 120.
N = 377.
Sex: 274 M, 103 F.
Age: 18-64 years (mean = 40.0 years).
History: duration ill mean olanzapine = 15.4 years, mean risperidone = 16.5 years, age
at onset mean olanzapine = 23.6 years, mean risperidone = 24.5 years.
Interventions 1. Olanzapine: flexible dose. Allowed dose range: 5-20 mg/day. Mean dose: 13.1 mg/
day. N = 189.
N = 188
Global State: CGI.
Mental State: PANSS total score, PANSS positive subscore, PANSS negative subscore.
Adverse effects: open interviews, cardiac effects (ECG), death (suicide attempt), EPS (use
of antiparkinson medication, ESRS), prolactin associated side effects (abnormal ejacu-
lation, amenorrhea, decreased libido, galactorrhea, gynecomastia, impotence, orgastic
dysfunction, sexual dysfunction) depression, insomnia, dry mouth, agitation, rhinitis,
dizziness, anxiety, vision abnormalities, sedation, weight gain, laboratory (liver enzymes,
lipids)
Notes
Risk of bias

for blinding


Conley 2001 (Continued)
in a study with moderate attrition
Free of selective reporting? High risk Only those adverse events that occurred in
at least 10% of the participants were re-
turer of risperidone. The total number of
participants was very low (n = 13), which
may limit the validity of results
Conley 2005

Duration: 12 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia, treatment resistance, persistent positive psychotic

symptoms, BPRS total score of 35 or more plus CGI score of 4 or more.
N = 38.
Sex: 30 M, 8 F.
Age: 18-65 years (mean fluphenazine = 44.2 years, mean quetiapine = 43.7 years, mean
risperidone = 46.3 years).
Setting: inpatient.
Interventions 1. Fluphenazine: flexible dose. Allowed dose range: 10-15 mg/day. Mean dose: 13.2 mg/
day. N = 13.
2. Quetiapine: flexible dose. Allowed dose range: 300-500 mg/day, Mean dose: 463.6
mg/day. N = 12.
N = 13
Global State: CGI.
Mental State: BPRS total score, BPRS positive subscore, BPRS negative subscore.
Cognitive functioning: Neuropsychological testing.

Conley 2005 (Continued)
Quality of life: QLS.

Adverse effects: open interviews, EPS (use of antiparkinson medication, SAS), prolactin
increase, sexual dysfunction, sedation, weight gain, laboratory (thyroidal hormones)
Unable to use:
Prolactin increase: no useable data.
Sexual dysfunction: no useable data.
Notes
Risk of bias

for blinding

Incomplete outcome data addressed? High risk The drop-out rate was considerable (36%)
All outcomes . The analysis was based on the intention-
to-treat sample and a mixed effects model.
It is unclear whether any statistical method
can account for higher drop-out rates
Free of selective reporting? High risk Not all of the predefined adverse effects
were assessed.
Free of other bias? Unclear risk There was a slight baseline imbalance in
terms of mean age and previous numbers of
hospitalizations (14 in the risperidone and
9.7 in the quetiapine group)

Daniel 1996

Duration: 12 weeks (6 weeks observed).
Design: crossover.
Participants Diagnosis: (DSM-III-R) chronic schizophrenia (n = 16) or schizoaffective disorder (n =

4).
N = 20.
Sex: 7 M, 13 F.
History: duration ill n.i., age at onset mean = 22.7 years.
Setting: outpatient.
day. N = 10.
N = 10
Global state: CGI-S.
Cognitive functioning: Wechsler memory scale.
Adverse effects: insomnia, malaise, nausea, vomiting, diarrhoea, anorexia, depressed
mood, agitation, weight gain
Unable to use:
Weight gain: no useable data.
Notes
Risk of bias

blinding

Incomplete outcome data addressed? Unclear risk The overall attrition was moderate (15%).
All outcomes Further details were not provided

Daniel 1996 (Continued)
Free of selective reporting? High risk Outcomes were reported incompletely. Six
weeks interim data before crossover were
hardly reported. The study was only pub-
lished as an abstract
Dollfus 2005

Duration: 8 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia with post-psychotic depression, PANSS positive

subscore of 28 or less and MADRS score of 16 or more.
N = 76.
Sex: 53 M, 23 F.
Age: 18-65 years (mean olanzapine = 39 years, mean risperidone = 39.6 years).
History: duration ill mean olanzapine = 13.7 years, mean risperidone = 13.1 years, age
at onset not reported.
Interventions 1. Olanzapine: flexible dose. Allowed dose range: 5-15 mg/day. Mean dose: not reported.
N = 36.
2. Risperidone: flexible dose. Allowed dose range: 4-8 mg/day. Mean dose: not reported.
N = 40
Outcomes Global state: relapse.

Mental State: PANSS total score, PANSS positive subscore, PANSS negative subscore,
depression MADRS.
Service use: number of participants rehospitalised.
Adverse effects: open interviews, cardiac effects (ECG), death (natural causes, suicide)
, EPS (akathisia, akinesia, dystonia, parkinsonism, rigor, tremor, use of antiparkinson
medication, continuous: ESRS total score), prolactin associated side effects (abnormally
high prolactin value, amenorrhea, sexual dysfunction), sedation, seizures, weight gain.
Weight (change from baseline in kg).
Unable to use:
White blood cell count (no usable data).
Notes
Risk of bias

Dollfus 2005 (Continued)

for blinding

Incomplete outcome data addressed? High risk Data on leaving the study early were
All outcomes not published separately for each group,
the overall attrition was moderate (25%).
(Data on both treatment attrition were pro-
vided from contact of the author)
Free of selective reporting? High risk Data on efficacy outcomes were incom-
pletely reported.
Dolnak 2001

Duration: 8 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia.

N = 40.
Sex: not reported.
Age: 18-65 years.

Allowed dose range: not reported. Mean dose: not reported. N = 20.
2. Risperidone:
fixed/flexible dose: not reported. Allowed dose range: not reported. Mean dose: not
reported. N = 20

Dolnak 2001 (Continued)
Outcomes General functioning: scale of functioning.
Notes
Risk of bias

for blinding

Incomplete outcome data addressed? High risk No data on leaving the study early available.
All outcomes
Free of selective reporting? Unclear risk Insufficient data.
Free of other bias? Unclear risk Insufficient data.
Gureje 2003
Methods Allocation: random, computer-generated randomisation.

Blindness: double, double-dummy design.
Duration: 30 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia, schizoaffective disorder or schizophreniform dis-

order, BPRS total score of 36 or more.
N = 65.
Sex: 38 M, 27 F.
Age: 18 years or more (mean olanzapine = 35.6 years, mean risperidone = 34.8 years).
day. N = 32.

Gureje 2003 (Continued)
N = 33
Outcomes Leaving the study early: any reason, inefficacy.

Global state: CGI-S.
negative subscore.
Quality of life: QLS, SF-36.
Adverse effects: open interviews, death (suicide attempt), cardiac effects (ECG), EPS
(akathisia, dyskinesia, parkinsonism, rigor, tremor, use of antiparkinson medication),
prolactin associated side effects (abnormal ejaculation, decreased libido, gynaecomastia,
impotence), sedation, weight change,
laboratory (glucose, leukopenia).
Unable to use:
Cardiac effects (no data).
Notes
Risk of bias
Adequate sequence generation? Low risk Random, computer-generated randomisa-

tion.
Blinding? Unclear risk Double, double-dummy design. Whether

subjective outcomes blinding was successful has not been exam-
ined, but the compounds differ quite sub-
stantially in side effects. This can be a prob-
lem for blinding

Incomplete outcome data addressed? High risk The overall attrition was high (55.4%). The
All outcomes LOCF method was used to account for
people leaving the study early. It assumes
that a participant who discontinued the
study would not have had a change of his
condition if he had remained in the study.
This assumption can obviously be wrong

Gureje 2003 (Continued)
Heinrich 1994

Duration: 4 weeks.
Design: parallel.
Location: single-centre.
Participants Diagnosis: acute schizophrenia, disorganised (n = 1), catatonic (n = 1), paranoid (n =

47), unspecified (n = 2) type. Schizoaffective psychosis schizodominant type (n = 8).
N = 59.
Sex: 31 M, 28 F.
Age: 19-65 years.
Interventions 1. Clozapine: fixed dose: 400 mg/day. N = 20.

Global State: CGI.
General Mental State: BPRS total score.
Adverse effects: open interviews, cardiac effects (preterminal negative T-wave), EEG,
EPS (extrapyramidal symptoms, use of antiparkinson medication, Simpson-Angus Scale)
, sedation, vital signs, laboratory (agranulocytosis)
Unable to use:
White blood cell count: agranulocytosis (no data).
Notes BPRS subscores available.
Risk of bias

for blinding

Heinrich 1994 (Continued)

Free of selective reporting? High risk Acutely ill subjects were included but data
on the reduction of positive symptoms were
not available. Secondary outcome data in
terms of adverse effects were reported in-
completely
Free of other bias? Unclear risk Fixed doses of 4mg/day and 8mg/day of
risperidone were compared with a fixed
dose of 400mg of clozapine, for a fixed
dose regimen it might be difficult to decide
which doses are appropriate
Hwang 2003

Duration: 6 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia disorganised (n = 9), paranoid (n = 22) or undif-

ferentiated (n = 16) (of intent-to-treat population).
N = 48.
Age: 18-65 years (mean amisulpride = 36.3 years, mean risperidone = 34.1 years).
Sex: 20 M, 27 F (of intent-to-treat population).
Setting: not described.
History: duration ill mean amisulpride = 13.3 years, mean risperidone = 13.4 years, age
at onset not reported
Interventions 1. Amisulpride: flexible dose. Allowed dose range: 400-800 mg/day. Mean dose: 630
mg/day. N = 23.
N = 25

Hwang 2003 (Continued)
Global State: CGI.
Mental State: PANSS total, BPRS total, PANSS positive subscore, PANSS negative
subscore.
General Functioning: SOFAS total score.
Adverse effects: open interviews, cardiac effects (QTc interval of > 500 ms), EPS
(akathisia, rigor, tremor, use of antiparkinson medication), weight, laboratory (hematol-
ogy, blood chemistry, urinanalysis)
Unable to use:
ESRS: no data.
Leukopenia: no data.
Notes
Risk of bias

but both compounds differ in side effects.
This may be a problem for blinding

Incomplete outcome data addressed? Low risk The rate of participants leaving the study
All outcomes early was below 10% and data on reasons
for drop-out were available. The data were
analysed on an intent-to-treat basis with the
LOCF method. This method is not perfect,
but due to the very low attrition the risk of
bias was low
Free of selective reporting? High risk Data on the extrapyramidal symptom scale
have not been presented. Only those ad-
verse events that occurred in at least 5% of
the participants were reported. This proce-
dure can miss rare, but important adverse
events
turer of amisulpride.

Jeste 2003

Duration: 8 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia (n = 149) or schizoaffective disorder (n = 26),

PANSS between 50 and 120.
N = 176.
Age: 60 years or more (mean olanzapine = 71.4 years, mean risperidone = 70.9 years)
(of intent-to-treat population).
History: duration ill mean = 36.5 years, age at onset mean olanzapine = 33.4 years, mean
risperidone = 36.0 years (of intent-to-treat population).
day. N = 89.
N = 87
Global State: CGI.
Adverse effects: open interviews, cardiac effects (ECG), death (natural causes, suicide)
EPS (akinesia, dystonia, extrapyramidal symptoms, parkinsonism, tremor, use of an-
tiparkinson medication, ESRS), sedation, seizures, weight change, laboratory (choles-
terol, glucose, prolactin)
Notes
Risk of bias

for blinding


Jeste 2003 (Continued)
Incomplete outcome data addressed? Unclear risk Number of participants leaving the study
All outcomes early was moderate (23.9%). The LOCF
method was used to account for people
leaving the study early. It assumes that
a participant who discontinued the study
would not have had a change of his condi-
tion if he had remained in the study. This
assumption can obviously be wrong. It is
unclear whether this led to bias
turer of risperidone. The mean age of in-
cluded subjects was about 71 years. Prob-
ably due to this reason the upper dose
range limit of risperidone was rather low
(3mg/day), compared to that of olanzapine
(20mg/day)
Kane 2005

Duration: 12 weeks.
Design: parallel.
Setting: not specified.
Participants Diagnosis: schizophrenia (DMS-IV).

N = 321.
Sex: 250 M, 71 F.
Age: 18-55 years (mean ~ 39).
History: duration ill not specified, mean age at onset ~ 22 years, treatment resistance,
>
PANSS total score = 60
Interventions 1. Sertindole: flexible dose (permitted range 12-24 mg/day, mean 18.1). N = 216.
2. Risperidone: flexible dose (permitted range 6-12 mg/day, mean 9). N = 105
Outcomes Leaving study early: any reason, adverse events, inefficacy.

Mental state: PANSS total score.
Adverse effects/event: at least one adverse effect, QTc prolongation, cholesterol, ex-
trapyramidal effects (akathisia, parkinsonism, AIMS, BAS, SAS), glucose, sexual dys-
function, sedation, weight

Kane 2005 (Continued)
Notes
Risk of bias

subjective outcomes ing was successful has not been examined.
Both compounds differ substantially in side
effects which can be a problem for blinding

Incomplete outcome data addressed? High risk Data on reason for drop-out were available
All outcomes but total numbers was considerably high
(32.4%). The LOCF method was used to
account for people leaving the study early.
It assumes that a participant who discontin-
wrong
turer of sertindole.
Keefe 2006

Duration: 52 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia or schizoaffective disorder.

N = 414.
Sex: 282 M, 132 F.

Keefe 2006 (Continued)
Age: 18-55 years (mean = 39 years).

Interventions 1. Haloperidol: flexible dose. Allowed dose range: 2-19 mg/day. Mean dose: 8.2 mg/day.
N = 97.
2. Olanzapine: flexible dose. Allowed dose range: 5-20 mg/day. Mean dose: 12.3 mg/
day. N = 159.
N = 158
Global State: relapse.
depression (MADRS), anxiety (Hamilton anxiety scale).
Cognitive Functioning: Neurocognitive Composite Score.
Adverse effects: open interviews, EPS (akathisia, tremor, use of antiparkinson medica-
tion, AIMS, BAS, SAS), sedation, weight change, laboratory (cholesterol, prolactin, uri-
nanalysis)
Notes
Risk of bias

for blinding


Keefe 2006 (Continued)
Lieberman 2005

Duration: 78 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia, previously more than one schizophrenic episode,
responder.
N = 1493.
Sex: 1080 M, 380 F.
History: duration not reported, age at onset not reported.
Interventions 1. Olanzapine: flexible dose, allowed dose range: 7.5-30 mg/day, mean dose=20.1 mg/
day. N = 336.
2. Perphenazine: flexible dose, allowed dose range: 8-32 mg/day, mean dose=20.8 mg/
day. N = 261.
3. Quetiapine: flexible dose, allowed dose range: 200-800 mg/day, mean dose=543.4
mg/day. N = 337.
4. Risperidone: flexible dose, allowed dose range: 1.5-6.0 mg/day, mean dose=3.9 mg/
day. N = 341.
5. Ziprasidone: flexible dose, allowed dose range: 40-160 mg/day, mean dose=112.8 mg/
day. N = 185
Global State: CGI-S.
Mental State: PANSS total score.
Service use: number of patients re-hospitalised.
Death: suicide attempt.
Adverse effects: open interviews, EPS (use of antiparkinson medication, akathisia), car-
diac effects (ECG), prolactin-associated side effects, sedation, weight gain, laboratory
(prolactin, lipids, glucose)
Unable to use:
Withdrawal due to extrapyramidal effects (no usable data).
Notes Note: 33 patients were excluded before analysis.

Lieberman 2005 (Continued)
Risk of bias

for blinding

Incomplete outcome data addressed? High risk The overall attrition was high (75%), and
All outcomes it is unclear whether any statistical method
can account for such a high drop-out rate.
Efficacy outcomes were evaluated based on
mixed effects model analysis
Free of selective reporting? Low risk There was no evidence for selective report-
ing.
Free of other bias? Unclear risk Dose ranges were quite different, the up-
per dose range of olanzapine was 30 mg
whereas risperidone could only be titrated
up to 6mg /day. There was no wash-out pe-
riod. An overlap in the administration of
formerly given antipsychotics was permit-
ted for the first four weeks after randomi-
sation. Allocation to ziprasidone treatment
was not possible from the start of the study
due to the later availability of ziprasidone
McEvoy 2006

Duration: 52 weeks (26 weeks observed, because of small group sizes).
Design: parallel.

McEvoy 2006 (Continued)
Participants Diagnosis: (DSM-IV) schizophrenia, inadequate efficacy in previous study, clozapine

treatment (n = 49) was open-label.
N = 99 (observed N = 50).
Sex: 80 M, 19 F.
History: duration ill, age at onset: not reported.
Interventions 1. Olanzapine: flexible dose. Allowed dose range: 7.5-30 mg/day. Mean dose: 23.4 mg/
day. N = 19.
2. Quetiapine: flexible dose. Allowed dose range: 200-800 mg/day. Mean dose: 642.9
mg/day. N = 15.
3. Risperidone: flexible dose. Allowed dose range: 1.5-6 mg/day. Mean dose: 4.8 mg/
day. N = 16
Global state: CGI.
Adverse effects: open interviews, amenorrhoea, galactorrhoea, sexual dysfunction, seda-
tion, laboratory (lipids, glucose, prolactin, haemoglobin A1C level), weight gain
Unable to use:
Global state CGI: no data.
Notes
Risk of bias

for blinding

Incomplete outcome data addressed? High risk The overall attrition was high (74%). It is
All outcomes doubtful that the validity was not affected
by this high rate

Free of selective reporting? High risk Due to small numbers and the very high
attrition only data on 26 weeks treatment
(rather than 52 weeks) were presented
Free of other bias? Unclear risk Dose ranges were quite different, the up-
per dose range of olanzapine was 30 mg
whereas risperidone could only be titrated
up to 6mg /day. Patients had a history of
former inefficacy to one of the medications.
It was excluded that the same medication
could be given again but still this might im-
plicate a risk of bias due to baseline imbal-
ance in terms of former treatment. There
was no wash-out period
McEvoy 2007

Duration: 52 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia (n = 231), schizophreniform disorder (n = 115) or

schizoaffective disorder (n = 54), first episode, psychotic symptoms for 1 month to 5
years, PANSS psychosis and CGI-S score of 4 or more.
N = 400.
Sex: 292 M, 108 F.
History: duration ill mean = 1.08 years, age at onset 23.5 years.
day. N = 133.
2. Quetiapine: flexible dose. Allowed dose range: 100-800 mg/day. Mean dose: 506 mg/
day. N = 134.
day. N = 133
Global State: CGI.
Mental State: PANSS total, PANSS positive subscore, PANSS negative subscore, depres-
sion Calgary depression scale.
Adverse effects: open interviews, death (suicide attempt, suicide, EPS (akathisia, akine-
sia, use of antiparkinson medication, laboratory (cholesterol, fasting glucose, prolactin)
, prolactin associated side effects (amenorrhoea, galactorrhoea, gynaecomastia, sexual
dysfunction), sedation, insomnia, dry mouth, orthostatic faintness, constipation, sial-
orrhoea, skin rash, gynaecomastia, urinary hesitancy, incontinence, weight gain (BMI,

waist circumference)
Notes
Risk of bias

for blinding

Incomplete outcome data addressed? High risk The attrition was high (70.3.%). The pri-
All outcomes mary analysis was based on a mixed ef-
fect model, secondary approaches used the
last-observation-carried forward approach
or included only study completers. Never-
theless, it is unclear whether any statistical
method can account for such a high attri-
tion
Free of selective reporting? High risk Adverse events were presented only in case
of moderate or worse severity
turer of quetiapine.
McGurk 2005

Blindness: double, double-dummy protocol.
Duration: 29 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia (n = 93) or schizoaffective disorder (n = 14), treat-

ment resistance, moderate severity score on BPRS or SANS.
N = 107.

McGurk 2005 (Continued)
Sex: 84 M, 23 F.
Age: 18-60 years (mean = 42 years).
History: duration ill n.i., age at onset mean clozapine = 23 years, mean risperidone = 22
years.
day.
N = 53.
N = 54
Global state: CGI.
General Mental State: BPRS total score, SANS.
Cognitive functioning: Spatial working memory performance, social skill and problem
solving assessment.
Adverse effects: TESS, laboratory (hematology).
Unable to use:
SANS (modified version).
Notes
Risk of bias
Blinding? Unclear risk Double, double-dummy protocol.

subjective outcomes Whether blinding was successful has not
been examined, but the compounds differ
quite substantially in side effects. This can
be a problem for blinding

Incomplete outcome data addressed? High risk The overall attrition was high 63.9%. The
All outcomes analysis was based on mixed effect mod-
els, but it is unclear whether any statistical
method can account for such a high drop-
out rate

McGurk 2005 (Continued)
Free of selective reporting? High risk Outcome reporting was

incomplete. Quote: ...adverse events data
have been reported elsewhere (unpublished
study of N.R. Schooler et al.)
Free of other bias? Low risk Review authors did not find other sources
of bias. Probably yes
Mori 2004

Duration: 8 weeks (last 4 weeks observed).
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia disorganised (n = 23), paranoid (n = 10), undiffer-

entiated (n = 34). N = 77.
Sex: 39 M, 38 F.
History: duration ill mean = 34.51 years, age at onset: not reported.
Setting: inpatient.
day. N = 20.
2. Perospirone: flexible dose. Allowed dose range: 4-48 mg/day. Mean dose: 37.3 mg/
day. N = 18.
3. Quetiapine: flexible dose. Allowed dose range: 50-750 mg/day. Mean dose: 432.5 mg/
day. N = 20.
4. Risperidone: flexible dose. Allowed dose range: 1-12 mg/day. Mean dose: 7.37 mg/
day. N = 19
Outcomes Mental State: PANSS total score, PANSS positive subscore, PANSS negative subscore.
Cognitive functioning: digit span distractibility test.
Notes
Risk of bias

Mori 2004 (Continued)

for blinding

Incomplete outcome data addressed? High risk There was no data on attrition available.
All outcomes
Free of selective reporting? High risk Adverse events were not reported. Numbers
on use of antiparkinson medication have
not been presented
Free of other bias? High risk There was no wash-out period. The previ-
ous antipsychotic treatment was gradually
tapered over 4 weeks. Thus, during a pe-
riod of 4 weeks the participants were on
two drugs
Mller 2005

Duration: 6 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia, schizophreniform disorder, schizoaffective disor-

der, delusional disorder or shared psychotic disorder.
N = 36.
Age: 65 years or more.
Sex: not described.
Location: not described.
Setting: not described.
History: duration ill, age at onset: not described.
Excluded: conditions such as: not described.
Interventions 1. Amisulpride: flexible dose. Allowed dose range: 100-400 mg/day. Mean dose: n.i. N
= 24
2. Risperidone: flexible dose. Allowed dose range: 1-4 mg/day. Mean dose: n.i. N = 12
Outcomes Leaving the study early: adverse events.

Cognitive functioning: MMSE.
Adverse effects: open interviews.
Unable to use:
Mental state, PANSS total score, BPRS total score: no usable data.
Cardiac effects (QTc), laboratory tests: no data.

Mller 2005 (Continued)
Notes
Risk of bias


Incomplete outcome data addressed? High risk Numbers of participants leaving the study
All outcomes early were only reported for the category
due to adverse effects. The statistical
method used to account for incomplete
data was not described
Free of selective reporting? High risk The study is only available as an abstract.
The data for primary outcomes were either
not available or only available in percentage
change without a standard deviation
turer of amisulpride. Whether there was a
baseline imbalance could not be judged due
to insufficient data
Peuskens 1999

Duration: 8 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia disorganised, paranoid or undifferentiated, BPRS

of 36 or more. N = 228.
Age: 18-65 years (mean amisulpride = 36 years, mean risperidone = 37 years).
Sex: 137 M, 91 F.

Peuskens 1999 (Continued)
History: duration ill mean amisulpride = 7.9 years, mean risperidone = 10.2 years, age
at onset n.i
Interventions 1. Amisulpride: fixed dose: 800 mg/day. N = 115.

Global State: CGI.
Mental State: BPRS total score, PANSS positive subscore, BPRS positive subscore,
PANSS negative subscore.
General functioning: SOFAS.
Adverse effects: open interviews, cardiac effects (arrhythmia, ECG, QTc interval of >
500 ms), EPS
(akathisia, extrapyramidal symptoms, hyperkinesia, parkinsonism, rigor, tremor, use of
antiparkinson medication, AIMS, SAS), prolactin associated side effects, weight
Unable to use:
General Functioning - SOFAS: no data.
Notes Individual BPRS factors are also available.
Risk of bias

but both compounds in side effects. This
may be a problem for blinding

Incomplete outcome data addressed? High risk The rate of leaving the study early was
All outcomes moderate (30.3%). The statistical analysis
was based on a last-observation-carried-for-
ward method to account for people leav-
ing the study early. It assumes that a par-
ticipant who discontinued the study would
not have had a change of his condition if he
had remained in the study. This assump-
tion can obviously be wrong

Peuskens 1999 (Continued)
Free of selective reporting? High risk Data on general functioning (secondary

outcome) were not available. Only those
adverse events that occurred in at least 5%
of the participants were reported. This pro-
cedure can miss rare, but important adverse
events
Potkin 2003

Duration: 4 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia (n = 289) or schizoaffective disorder (n = 115),

hospitalised due to an acute relapse, response to previous antipsychotic treatment other
than clozapine, PANSS of 60 or more.
N = 404.
Sex: 283 M, 121 F.
History: duration illness not reported, age at onset not reported.
Setting: inpatient.
Interventions 1. Aripiprazole: fixed dose: 20 mg/day. N = 101.

2. Aripiprazole: fixed dose: 30 mg/day. N = 101.
Global state: CGI.
Mental state: PANSS total score, PANSS positive subscore, PANSS negative subscore.
Adverse effects: At least one adverse effect, cardiac effects (ECG, QTc prolongation,
QTc abnormalities in ms), extrapyramidal side effects (akathisia, dystonia, parkinson-
ism, rigor, tremor, AIMS, BAS, SAS), prolactin-associated side effects (dysmenorrhoea,
increase of prolactin level above 23 ng/ml, change from baseline in ng/ml), sedation,
weight gain
Notes Note: There is a placebo group (n = 103), which is not relevant for this review
Risk of bias

Potkin 2003 (Continued)

for blinding

much affected by lack of blinding
Incomplete outcome data addressed? High risk The overall drop-out rate was high (36.
All outcomes 9%). The LOCF method was used to ac-
count for people leaving the study early. It
assumes that a participant who discontin-
wrong
Free of selective reporting? High risk For efficacy outcomes standard deviations
or standard errors had not been indicated
which had to be back calculated from P val-
ues. Only adverse events with an incidence
of more than 5% were reported. This pro-
cedure may have missed important adverse
events
Free of other bias? Unclear risk The study was sponsored by the manu-
facturer of aripiprazole. The study used a
fixed-dose regimen. It is difficult to say
whether the chosen doses were appropriate
Potkin 2006
Methods Allocation:random, no further details.

Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia (n = 341) disorganised, paranoid or undifferentiated

or schizoaffective disorder (n = 30) plus (n = 11), CGI-S of 5 or more, recent exacerbation.
N = 382.
Sex: 251 M, 131 F.

Setting: inpatient.
Interventions 1. Quetiapine: flexible dose. Allowed dose range: 50-800 mg/day. Mean dose: 523.8 mg/
day (after 2 weeks). (579.5 mg/day, after 6 weeks). N = 156.
2. Risperidone: flexible dose. Allowed dose range: 1-6 mg/day. Mean dose: 4.32 mg/day
(after 2 weeks). (4.7 mg/day, after 6 weeks). N = 153

Global State: CGI.
Depression Hamilton Rating Scale for Depression, Readiness for Discharge Question-
naire.
Satisfaction of treatment: Study Medication Satisfaction.
Adverse effects: open interviews, death (natural cause), cardiac effects (ECG), EPS
(akathisia, rigor, AIMS, BAS, SAS), prolactin associated side effects (amenorrhoea, de-
creased libido), sedation, headache , insomnia, constipation, laboratory (prolactin)
Unable to use:
BAS: no data.
Cardiac effects - QTc-prolongation: no data.
Notes There was a placebo group (n = 73).
Risk of bias
Allocation concealment? Low risk Quote: were assigned using a centralised

interactive voice response system. Probably
done

for blinding

Incomplete outcome data addressed? Low risk The overall attrition was rather low (12%)


wrong. Nevertheless, due to the overall low
attrition it is unlikely that the results have
been affected
Free of selective reporting? High risk Data on some adverse effects were not avail-
able. Only those adverse events that oc-
curred in at least 10% of the participants
were reported. This procedure can miss
rare, but important adverse events
Purdon 2000

Duration: 54 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia, in early phase.

N = 65.
Sex: 46 M, 19 F.
Age: 18-65 years (mean haloperidol = 28.83 years, mean olanzapine = 26.01 years, mean
risperidone = 31.77 years).
History: duration ill mean haloperidol = 2.45 years, mean olanzapine = 2.79 years, mean
risperidone = 2.67 years, age at onset mean haloperidol = 24.25 years, mean olanzapine
= 23.37 years, mean risperidone = 28.86 years.
Interventions 1. Haloperidol: flexible dose. Allowed dose range: 5-20 mg/day. Mean dose: 9.70 mg/
day. N = 23.
day. N = 21.
day. N = 21
Mental state: PANSS positive subscore, PANSS negative subscore.
Cognitive functioning: Cognitive test battery (finger tapping, digit span, Peabody picture
vocabulary test, trailmaking test).
Adverse effects: EPS (use of antiparkinson medication, ESRS)
Unable to use:
Cognitive Functioning (no overall score).
Notes

Purdon 2000 (Continued)
Risk of bias

tion.

for blinding

Free of selective reporting? Low risk The study focused on neuropsychological

changes, but data for efficacy and some
side effects were also presented. Probably
no bias
Ren 2002
Methods Allocation:random, ball drawing out of box.

Blindness: double.
Duration: 12 weeks.
Design: parallel.
Participants Diagnosis: schizophrenia (CCMD-3).

N:120.
Sex: not reported.
Age mean: 29.45
History duration ill: clozapine = 6.2 years, risperidone = 6.4 years.

Ren 2002 (Continued)
Interventions 1. Clozapine: mean dose: 350 mg/day. N = 60.

2. Risperidone: mean dose: 3.2 mg/day. N = 60.
Outcomes Mental State: PANSS positive subscore, PANSS negative subscore).

Quality of life: General quality of life inventory.
Notes
Risk of bias
Adequate sequence generation? Low risk Allocation: random, ball drawing out of a
covered box. Probably yes

for blinding

All outcomes provided.
Free of selective reporting? High risk Secondary outcomes were poorly reported.
Free of other bias? Unclear risk The allowed dose ranges were not indi-
cated.
Riedel 2005

Duration: 12 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV or ICD-10) schizophrenia, predominant negative symptoms, CGI

of 4 or more, PANSS negative subscore of 21 or more.
N = 44.

Riedel 2005 (Continued)
Sex: 27 M, 17 F.
Age: mean quetiapine = 30.6 years, mean risperidone = 39.3 years.
History: duration ill mean quetiapine = 5.4 years, mean risperidone = 2.5 years, age at
onset mean quetiapine = 25.3 years, mean risperidone = 36.9 years.
Setting: partially in- and outpatient.
Interventions 1. Quetiapine: flexible dose. Allowed dose range: 50-800 mg/day, Mean dose: 589.7 mg/
day. N = 22.
N = 22
SANS total score.
Cognitive functioning: auditory verbal memory test, Trail Making Test, Wechsler visual
memory scale.
Adverse effects: open interviews, cardiac effects (ECG), EPS (akathisia, parkinsonism,
use of antiparkinson medication, SAS), sedation, headache, nausea, insomnia, dizziness,
weight gain, laboratory (prolactin)
Unable to use:
SANS total score: no data.
Prolactin change from baseline in ng/ml: no data.
Cardiac effects: no data.
Notes
Risk of bias

for blinding

All outcomes data were analysed using both a LOCF
method and a study completer approach.
Nevertheless, it is questionable whether any
statistical method can account for such a

Riedel 2005 (Continued)
high attrition
Free of selective reporting? High risk Data on negative symptoms (SANS) and
some adverse effects were not available
Robinson 2005

Duration: 16 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) first episode schizophrenia (n = 84), schizophreniform disorder

(n = 19) or schizoaffective disorder (n = 9) (of intent-to-treat population).
N = 120.
Age: 16-40 years (mean = 23.3 years) (of intent-to-treat population).
History: duration ill mean = 2.2 years (of intent-to-treat population), age at onset mean
= 20.7 years (of intent-to-treat population).
day. N = 60.
N = 60
Outcomes Leaving the study early: inefficacy.

Global State.
Adverse effects: EPS (parkinsonism, use of antiparkinson medication, Simpson-Angus)
, weight gain
Unable to use:
Leaving the study early: incomplete data.
Weight gain: no data.
Notes
Risk of bias

Robinson 2005 (Continued)
Blinding? Unclear risk Single-blind, rater-blinded.

subjective outcomes Whether blinding was successful has not
been examined, but the compounds differ
quite substantially in side effects. This can
be a problem for blinding

Incomplete outcome data addressed? Unclear risk The overall attrition was possibly accept-
All outcomes able (28%), but data on leaving the study
early were incompletely reported. Eight pa-
tients were excluded from the analysis for
various reasons. The statistical analysis was
based on mixed model approach
Free of selective reporting? High risk Data on the general mental state (PANSS
total score) were not presented. The data
available for adverse effects were incom-
plete. Data on weight gain were missing
Free of other bias? Unclear risk Quote: .. the study was designed to de-
tect differences in our primary analysis at
alpha = 0.05 with 80% power based upon
130 subjects, the stability analysis included
only 47 subjects and therefore might lack
adequate power.
Sacchetti 2004

Blindness: single (rater-blinded).
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia, PANSS total score of 70 or more, PANSS positive
subscore of 4 or more on at least 2 items.
N = 75.
Sex: M, F: not reported.
Age: 18-65 years.
Setting: inpatient.
day. N = 25.
2. Quetiapine: flexible dose. Allowed dose range: 400-800 mg/day. Mean dose: 602.4

Sacchetti 2004 (Continued)
mg/day. N = 25.
N = 25

Mental State: PANSS total score, BPRS hostility cluster score, PANSS positive subscore,
PANSS negative subscore).
Adverse effects: EPS (BAS, SAS), weight gain.
Unable to use:
Mental State - PANSS total score, PANSS positive subscore, PANSS negative subscore:
no usable data
Notes
Risk of bias
Blinding? Unclear risk Single: rater-blind. Whether blinding was

blinding

wrong
Free of selective reporting? High risk Efficacy data (PANSS) were only presented
as percentage change without standard de-
viations, standard errors, P values or ranges.
Only interim data after recruitment of half
the patients have been presented

Sacchetti 2004 (Continued)
Sechter 2002

Duration: 26 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) chronic schizophrenia disorganised (n = 37), paranoid (n = 227)

, residual (n = 19) or undifferentiated (n = 27), PANSS between 60 and 120, recent
worsening of symptoms.
N = 310.
Sex: 170 M, 140 F.
History: duration ill mean = 11.8 years, age at onset not described
Interventions 1. Amisulpride: flexible dose. Allowed dose range: 400-1000 mg/day. Mean dose: 683
mg/day. N = 152.
day. N = 158
Global State: CGI, relapse.
negative subscore, SANS total score.
General Functioning: SOFAS total score.
Adverse effects: open interviews, death (natural causes, suicide), EPS (akathisia, hyper-
kinesia, parkinsonism, tremor, use of antiparkinson medication, AIMS, SAS), prolactin
associated side effects (amenorrhea, galactorrhea, sexual dysfunction), sedation, seizures,
weight
Notes
Risk of bias


Sechter 2002 (Continued)

Incomplete outcome data addressed? High risk The rate of participants leaving the study
All outcomes early was high (40%). The LOCF method
was used to account for people leaving the
study early. It assumes that a participant
who discontinued the study would not have
had a change of his condition if he had
remained in the study. This assumption can
obviously be wrong
Sikich 2004

Duration: 8 weeks.
Design: parallel.
Participants Diagnosis: children and adolescents with (K-SADS-P or DSM-IV) schizophrenia,

schizoaffective disorder, schizophreniform disorder, delusional disorder, major depression
with psychotic features or bipolar affective disorder with psychotic features, schizophre-
nia spectrum (n = 26), affective disorders (n = 24) subjects selected because of prominent
positive psychotic symptoms (of intent-to-treat population).
N = 51.
Sex: 30 M, 21 F.
History: duration ill not reported, age at onset mean = 12.4 years.
Interventions 1. Haloperidol: flexible dose. Allowed dose range: 1-8 mg/day. Mean dose: 5.0 mg/day.
N = 15.
2. Olanzapine: flexible dose. Allowed dose range: 2.5-20 mg/day. Mean dose: 12.3 mg/
day. N = 16.
day. N = 20

Sikich 2004 (Continued)
Global State: CGI.
Mental State: BPRS-C total score, CPRS.
Adverse effects: open interviews, cardiac effects (QTc, vital signs), EPS (akathisia, use of
antiparkinson medication, Simpson-Angus), prolactin associated side effects (amenor-
rhea, galactorrhea, gynaecomastia), sedation, gastrointestinal malfunction, weight (BMI)
, laboratory (glucose, prolactin)
Notes There is a Haloperidol Group (N = 15).
Risk of bias

tion.

for blinding

Free of selective reporting? Low risk No evidence for selective reporting.
Free of other bias? High risk Quote: ...this study has a number of lim-
itations including limited sample size, dif-
ferences in the diagnosis of participants, use
of concomitant medication, variations in
age and pupertal status

Stroup 2006
Methods Allocation: random, 2 steps of randomisation before and after availability of ziprasidone,
subjects received other medication than in previous phase 1 treatment. Re-randomised.
Duration: 26 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) chronic schizophrenia.

N = 444.
Sex: 308 M, 136 F.
Age: 18-65 years (mean olanzapine = 40.0 years, mean quetiapine = 40.1 years, mean
risperidone = 41.8 years, mean ziprasidone = 41.3 years).
Interventions 1. Olanzapine: flexible dose, allowed dose range: 7.5-30 mg/day, mean dose = 20.5 mg/
day. N = 108.
2. Quetiapine: flexible dose, allowed dose range: 200-800 mg/day, mean dose = 565.2
mg/day. N = 95.
3. Risperidone: flexible dose, allowed dose range: 1.5-6.0 mg/day, mean dose = 4.1 mg/
day. N = 104.
4. Ziprasidone: flexible dose, allowed dose range: 40-160 mg/day, mean dose = 115.9
mg/day. N = 137
Global State: CGI.
Mental State: PANSS total score.
Adverse effects: open interviews, death (suicide), EPS (akathisia), cardiac effects (ECG)
,
prolactin-associated side effects, weight gain, laboratory (prolactin, glucose, cholesterol)
Notes
Risk of bias
Adequate sequence generation? Unclear risk Random, 2 steps of randomisation before

and after availability of ziprasidone, sub-
jects received other medication than in pre-
vious phase 1 treatment. Re-randomised

for blinding

Stroup 2006 (Continued)

All outcomes main statistical analysis used a mixed ef-
fects model approach. It is unclear whether
any statistical method can account for such
high rates of leaving the study early
Free of selective reporting? High risk Use of antiparkinson medication was per-
mitted but data on this outcome have not
been presented
Free of other bias? Unclear risk Patients had a history of former intoler-
ance to atypical antipsychotic treatment
but baseline data on this was not provided
Svestka 2003

Duration: 6 weeks.
Design: parallel.
Participants Diagnosis: schizophrenia or schizoaffective disorder, first episode.

N = 42.
Sex: not reported.
Age: not reported.
Setting: inpatient.
Interventions 1. Olanzapine: fixed/flexible dose: not reported. Allowed dose range: not reported. Mean
dose: not reported. N = 21.
2. Risperidone: fixed/flexible dose: not reported. Allowed dose range: not reported. Mean
dose: not reported. N = 21
Outcomes Mental State: PANSS total score.
Notes
Risk of bias

Svestka 2003 (Continued)

for blinding

Incomplete outcome data addressed? High risk Data on subjects leaving the study early
All outcomes were not available.
Free of selective reporting? High risk Allowed study medication dose ranges were
not indicated. A publication was not avail-
able
Free of other bias? Unclear risk Insufficient information.
Tran 1997

Duration: 28 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia (n = 277), schizophreniform disorder or schizoaf-

fective disorder, BPRS score of 42 or more.
N = 339.
Sex: 220 M, 119 F.
History: duration ill not reported, age at onset mean = 23.7 years
day. N = 172.
N = 167
negative subscore, SANS total score.
Quality of life: QLS total score.
Adverse effects: open interviews, cardiac effects (ECG), death (any reason, suicide at-
tempt), EPS (akathisia, akinesia, dyskinesia, dystonia, extrapyramidal symptoms, parkin-

Tran 1997 (Continued)
sonism, tremor, use of antiparkinson medication), Prolactin associated side effects (abnor-
mal ejaculation, abnormally high prolactin value, amenorrhea, decreased libido, galac-
torrhea, gynaecomastia, impotence), sedation, backache, blurred vision, breathing dif-
ficulties, early wakening, nightmares, seizures, weight gain, laboratory (glucose, white
blood cell count)
Notes
Risk of bias

for blinding

Incomplete outcome data addressed? High risk The overall attrition was high 47.5 %. The
Free of selective reporting? High risk Adverse effects were only reported in the
case of a significant difference between
groups. Important side effects may have
been missed by this procedure

Van Nimwegen 2006

Duration: 6 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia, schizophreniform disorder or schizoaffective dis-

order, cannabis positive last month olanzapine (n = 20), risperidone (n = 23).
N = 131.
Sex: 106 M, 25 F.
Age: mean olanzapine = 24.4 years, mean risperidone = 25.1 years.
day. N = 64.
N = 67
Outcomes Quality of life: Subject well being.

Adverse effects: EPS (BAS).
Cannabis use.
Notes
Risk of bias

for blinding

All outcomes provided.
Free of selective reporting? High risk Outcome reporting was incomplete, stan-
dard deviations were not published

Van Nimwegen 2006 (Continued)
Free of other bias? Unclear risk Additional usage of cannabis.
Volavka 2002

Duration: 14 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) chronic schizophrenia (n = 135) or schizoaffective disorder (n =

22), suboptimal response to previous treatment, PANSS of 60 or more.
N = 167.
Age: 18-60 years (mean = 40.8 years) (of intent-to-treat population).
History: duration ill mean = 19.5 years (of intent-to-treat population), age at onset not
reported.
Setting: inpatient.
day (at the end of the last 6 weeks). N = 40.
2. Haloperidol: flexible dose. Allowed dose range: 10-30 mg/day. Mean dose: 25.7 mg/
day (at the end of the last 6 weeks). N = 41
Outcomes Leaving the study early. any reason, adverse events, inefficacy.
Quality of life: Quality of life scale, Nursesobservation scale for inpatient evaluation.
Cognitive Functioning: Global Neurocognitive Score.
Adverse effects: EPS (Use of antiparkinson medication, ESRS), seizures, weight gain,
laboratory (cholesterol, glucose, prolactin, white blood cell count)
Unable to use:
Quality of life scale: no data.
Notes
Risk of bias

Volavka 2002 (Continued)

for blinding

Free of selective reporting? High risk Some outcomes were reported on subgroup
from the entire sample. Quality of life data
were not presented
Free of other bias? High risk Quote: The olanzapine arm was added
in November 1997 and required a mod-
ified randomization procedure...It entails
the potential for a bias that could be man-
ifested as a cohort effect.
Wahlbeck 2000

Duration: 10 weeks.
Design: parallel.
Setting: in- and outpatient (initially inpatient).
Participants Diagnosis: (DSM-IV) schizophrenia, resistance to previous treatment. N = 20.

Age: 24-55 years (mean clozapine = 35.7 years, mean risperidone = 36.8 years) (of intent-
to-treat population).
History: duration ill mean clozapine = 12.6 years, mean risperidone = 13.1 years (of
intent-to-treat population), age at onset not reported.
Setting: in- and outpatient (initially inpatient).
day. N = 11.

Wahlbeck 2000 (Continued)
N=9
General Functioning: GAF, social functioning scale, patient global impression scale.
Satisfaction with treatment: Drug attitude inventory.
Adverse effects: death (natural causes, suicide), EPS (use of antiparkinson medication),
sedation, laboratory (white blood cell count)
Notes
Risk of bias

tion.

blinding

Incomplete outcome data addressed? High risk The overall attrition was high (35%). The
Free of selective reporting? Low risk No evidence for selective reporting.
Free of other bias? High risk The number of participants included was
rather low. Quote: ...readers have to bear
in mind, that the statistical power of this
study may hide some clinically relevant dif-
ferences in drug efficacy.

Wang 2006

Duration: 22 weeks (last 12 weeks observed).
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia (n = 24) or schizoaffective disorder (n = 12). N =

36.
Sex: 17 M, 19 F.
Age: mean = 47.0 years.
Interventions 1. Olanzapine: flexible dose. Allowed dose range: not reported. Mean dose: 13.8 mg/
day. N = 17.
2. Risperidone: flexible dose. Allowed dose range: not reported. Mean dose: 5.3 mg/day.
N = 19
Outcomes Mental State: PANSS total score, PANSS positive subscore, PANSS negative subscore.
Adverse effects: EPS (SAS), weight gain.
Unable to use:
Leaving the study early: no data.
Notes
Risk of bias

for blinding

Free of selective reporting? High risk Standard deviations for the primary out-
come were not available

Wang 2006 (Continued)
Free of other bias? High risk Dose ranges were not indicated. The study
was sponsored by the manufacturer of
risperidone
Wynn 2007
Methods Allocation: random, 33 participants were assigned to a three-arm randomisation (1:1:1,

blocks of 15) and 18 participants with a history of adverse experiences with haloperidol
were assigned to a two-arm randomisation (1:1) for risperidone and olanzapine only.
Duration: 8 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia or schizoaffective disorder. N = 51.

Sex: 43 M, 8 F.
Interventions 1. Haloperidol: fixed dose: 8 mg/day. N = 11.

2. Olanzapine: fixed dose: 15 mg/day. N = 21.
Outcomes Neurological functioning: Prepulse inhibition, EMG.
Notes
Risk of bias
Adequate sequence generation? Unclear risk Random, 33 participants were assigned to a

three-arm randomisation (1:1:1, blocks of
15) and 18 participants with a history of
adverse experiences with haloperidol were
assigned to a two-arm randomisation (1:1)
for risperidone and olanzapine only

for blinding

Wynn 2007 (Continued)

Free of selective reporting? High risk Efficay outcomes such as the general men-
tal state (PANSS total score) were not pre-
sented
Zhong 2006

Duration: 8 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia, PANSS of 60 or more, CGI-S of 4 or more. N =

673.
Sex: 510 M, 163 F.
Age: 18-65 years (mean quetiapine = 40.2 years, mean risperidone = 39.6 years).
Setting: in- and outpatient, initially inpatient.
Interventions 1. Quetiapine:flexible dose. Allowed dose range: 200-800 mg/day. Mean dose: 525 mg/
day. N = 338.
N = 335
Global State: CGI.
Adverse effects: open interviews, cardiac effects (QTc), death (natural causes, suicide),
EPS (akathisia, dystonia, parkinsonism, use of antiparkinson medication, AIMS, BAS,
SAS), sedation, prolactin associated side effects (dysmenorrhoea, galactorrhea, sexual
dysfunction) weight gain, laboratory (cholesterol, glucose, prolactin, white blood cell
count)
Notes
Risk of bias

Zhong 2006 (Continued)

for blinding

This assumption can obviously be wrong.
Data on study completers were also avail-
able. Nevertheless it is unclear whether any
statistical method can account for such a
degree of attrition
Zhou 2000

Duration: 8 weeks.
Design: parallel.
Participants Diagnosis: (CCMD-2) schizophrenia.

N = 40.
Sex: 23 M, 17 F.
Age: mean clozapine = 27.6 years, mean risperidone = 29 years.
History: duration ill mean clozapine = 2.7 years, mean risperidone = 3.2 years, age at
onset: not reported.

Zhou 2000 (Continued)
Setting: inpatient.
Interventions 1. Clozapine: fixed and flexible dose (first 2 weeks).

Allowed dose range: 25-300 mg/day (first 2 weeks), then 300 mg/day fixed. Mean dose:
not reported. N = 20.
2. Risperidone: fixed and flexible dose (first 2 weeks).
Allowed dose range: 1-6 mg/day (first 2 weeks), then 6 mg/day fixed. Mean dose: not
reported. N = 20
Outcomes Mental State: SANS.

Advers effects: EPS (akathisia, tremor, treatment emergent symptom scale), vital signs,
dry mouth hypersalivation, weight gain, sedation
Notes
Risk of bias

blinding

Incomplete outcome data addressed? Low risk No participant left the study early.
All outcomes
Free of selective reporting? Low risk No clear evidence for selective reporting.
Free of other bias? Unclear risk The description of blinding differed be-
tween the abstract (double-blind) and the
method section (single-blind)
Diagnostic tool
DSM III-R and DSM-IV - Diagnostic Statistical Manual version 3 Revised and version 4.
ICD 10 - The International Statistical Classification of Diseases and Related Health Problems.
BMI - Body Mass Index.
Rating Scales:
Global rating scales:
CGI - Clinical Global Impressions.
CGI-S - Clinical Global Impression-Severity.
CGI-I - Clinical Global Impression-Improvement.
Mental state:
BPRS - Brief Psychiatric Rating Scale.
MADRS - Montgomery-Asberg Depression Rating Scale.
MMSE - Wiing Mini Mental State Examination.
PANSS - Positive and Negative Syndrome Scale.
SANS - Scale for the Assessment of Negative Symptoms.
Side effects:
AIMS - Abnormal Involuntary Movement Scale.
BAS - Barnes Akathisia Scale.
BMI - Body mass index.
ESRS - Extrapyramidal Syndrome Rating Scale.
HAS - Hillside Akathisia Scale.
SAS - Simpson-Angus Index - for neurological side effects.
TESS - Treatment Emergent Symptom Scale.
UKU - Udvalg for kliniske ndersogelser Side Effect Rating Scale -side effect rating scale.
Quality of Life:
QoL - Quality of Life Scale.
SWN -Subjective Well-being List.
CCMD-2:
ECG:
EEG:
EPS:
GAF:
LOCF: last observation carried forward
QLS:
QTc:
SOFAS:
TESS:
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Akdede 2006 1. Allocation: randomised.

2. Participants: patients with schizophrenia.
3. Interventions: inappropriate (olanzapine and adjunctive treatment with risperidone or placebo)
Almond 1999 1. Allocation: randomised.

2. Blindness: open-label.
Alvarez 2006 1. Allocation: pooled analysis.

Alvarez-Jimenez 2006 1. Allocation: randomised.

2. Participants: drug-naive first-episode psychosis patients.
3. Interventions: risperidone versus olanzapine versus haloperidol.

(Continued)
4. Outcomes: no usable data (pooled analysis).
Antonova 2005 1. Allocation: randomised.

2. Participants: patients with chronic schizophrenia (DSM-IV).
3. Interventions: olanzapine versus risperidone versus quetiapine.
4. Outcomes: no usable data.
Apiquian 2003 1. Allocation: randomised.

Aquila 2000 1. Allocation: randomised.

Ascher-Svanum 2006 1. Allocation: not randomised, cohort study.
Bai 2003 1. Allocation: randomised.

2. Participants: DSM-IV schizophrenia patients.
3. Interventions: inappropriate (risperidone versus placebo)
Baloescu 2006 1. Allocation: not randomised, controlled trial.
Basson 2001 1. Allocation: randomised.

3. Interventions: olanzapine versus haloperidol versus risperidone.
Beasley 2001 1. Allocation: randomised.

3. Interventions: olanzapine versus clozapine versus risperidone versus haloperidol versus placebo.
Beasley 2003 1. Allocation: randomised.

Bera 2001 1. Allocation: randomised.

Beuzen 2005 1. Allocation: randomised.

Bitter 2004 1. Allocation: not randomised, cohort study.
Boylan 2004 1. Allocation: randomised.

3. Interventions: inappropriate (risperidone versus risperidone/divalproex, olanzapine versus olanzapine/
divalproex or antipsychotic monotherapy versus antipsychotic/divalproex)
Briken 2002 1. Blindness: open-label.

(Continued)
Byerly 2006 1. Allocation: randomised.

2. Blindness: double-blind.
3. Participants: patients with schizophrenia/schizoaffective disorder.
4. Interventions: quetiapine versus risperidone.
5. Outomes: no usable data.
Cai 2000 1. Blindness: open-label.
Canas 2006 1. Allocation: not randomised.
Cao 2001 1. Allocation: inadequate randomisation.

2: Blindness: not mentioned.
Cao 2003 1. Blindness: open-label.
Cao 2005 1. Blindness: open-label.
Cha 2002 1. Blindness: open-label.
Chaudhry 2006 1. Allocation: randomised.

2. Blindness: not mentioned.
Chen 1999 1. Allocation: randomised.

Chen 2002 1. Allocation: randomisation not mentioned.



Chen 2004a 1. Allocation: randomised.

Chen 2005 1. Allocation: randomisation not mentioned.

Chen 2005a 1. Allocation: randomised.

Chen 2005b 1. Allocation: randomised.

Cheng 2002 1. Allocation: randomised.


(Continued)
Chou 1999 1. Allocation: randomised.

Chowdhury 1999 1. Allocation: randomised.

2. Blindness not mentioned.
Citrome 2004 1. Allocation: randomised.

3. Interventions: inappropriate (olanzapine versus risperidone, additive divalproex)
Ciudad 2004 1. Allocation: randomized.

2. Blindness: open-label
Conley 1999 1. Allocation: randomized.

Cornblatt 2002 1. Allocation: randomized.

2. Blindness: open-label
Crespo-Facorro 2006 1. Allocation: randomized.

Cui 2002 1. Allocation: randomized.

Czekalla 2001 1. Allocation: randomized.

2. Participants: patients with schizophrenia and related psychosis (DSM-III-R and DSM-IV).
3. Interventions: olanzapine versus placebo versus haloperidol versus risperidone
David 1999 1. Allocation: randomized.

3. Interventions: olanzapine versus risperidone versus clozapine.
David 2000 1. Allocation: randomized,

2. Participants: patients with schizophrenia
3. Interventions: olanzapine versus risperidone versus haloperidol
4. Outcomes: no usable data (pooled analysis)
De Haan 2002 1. Allocation: randomized.

2. Blindness not mentioned
Ding 2004 1. Allocation: randomized.

Ding 2005 1. Allocation: randomized.


(Continued)
Dossenbach 2005 1. Allocation: randomized.

Du 2003 1. Allocation: randomized.

Du 2004 1. Allocation: randomization not mentioned.

2. Blindness not mentioned
Du 2004a 1. Allocation: randomized.

Du 2005 1. Allocation: randomized.

Earnst 1999 1. Allocation: not randomized.
Ertugrul 2006 1. Allocation: not randomized, controlled trial.
Estrella 1996 1. Allocation: randomized.

Fan 2003 1. Allocation: randomized.

Feng 2004 1. Allocation: randomized.

Gan 1999 1. Allocation: randomized.

Garca 2006 1. Allocation: randomization not mentioned.

Ge 2004 1. Allocation: randomization not mentioned.

Goldberg 2000 1. Allocation: randomization not mentioned.

4. Interventions: inappopriate (risperidone versus olanzapine versus clozapine and in crossover fashion
placebo)
Guan 2005 1. Allocation: randomized.

Guo 2001 1. Allocation: randomized.


(Continued)
Guo 2003 1. Allocation: randomized.

Hagger 1997 1. Allocation: randomized.

Han 2000 1. Allocation: randomized.

Han 2005 1. Allocation: randomized.

Harrigan 2004 1. Allocation: randomized.

He 2005 1. Allocation: randomized.

Heresco-Levy 2005 1. Allocation: randomized.

4. Interventions: inappropriate (risperidone versus olanzapine, placebo-controlled)
Hou 2001 1. Allocation: randomization not mentioned.

Hrdlicka 2001 1. Allocation: not randomized, cohort study.
Hu 2000 1. Allocation: randomized.

Hu 2005 1. Allocation: randomized.

Huang 2000 1. Allocation: randomization not mentioned.

Huang 2001 1. Allocation: randomized.

Huber 2004 1. Allocation: randomization not mentioned.

3. Participants: patients with schizophrenia, brief psychotic, schizoaffective disorder, delusional disorder
4. Interventions: inclusion into the study was independent of medication
5. Outcomes: no usable data (other aims)
Janssen-Ortho 2006 1. Allocation: randomized.


(Continued)
Jones 2006 1. Allocation: randomized.

2. Blindness: not mentioned
3. Participants: patients with schizophrenia and related disorders
4. Interventions: FGAs or SGAs other than cozapine
Karow 2002 1. Allocation: randomization not mentioned.

4. Interventions: atypical and typical neuroleptics.
Keks 2006 1. Allocation: randomization not mentioned.

Kelemen 2006 1. Allocation: randomization not mentioned.

Kim 2004 1. Allocation: not randomized, controlled trial.
Knegtering 2004 1. Allocation: randomized.

Koenigsberg 2000 1. Allocation: randomized.

3. Participants: patients with schizotypical personality disorder.
4. Interventions: inappropriate (risperidone versus placebo)
Kolff 2000 1. Allocation: randomized.

Kong 2001 1. Allocation: randomized.

Kores 2003 1. Allocation: randomization not mentioned.

2. Blindness: double-blind
4. Interventions: risperidone versus olanzapine
Lee 2005 1. Allocation: randomized.

Lee 2006 1. Allocation: randomized.

Lei 2002 1. Allocation: randomized.


(Continued)
Lewis 2004 1. Allocation: randomized.

2. Blindness: single-blind.
4. Interventions: new atypical drugs versus clozapine.
Li 2000 1. Allocation: randomized.



Li 2003a 1. Allocation: randomized.



Liang 2005 1. Allocation: randomized.

Liao 2004 1. Allocation: randomized.

Lin 2005 1. Allocation: not randomized (inadequate randomization).
Lipkovich 2005 1. Allocation: randomized.

2. Blindness: double-blind
4. Interventions: inappropriate (3 trials: olanzapine versus haloperidol, olanzapine versus risperidone, olan-
zapine versus placebo).
5. OUtcomes nousable data (pooled analysis).
Littrell 1999 1. Allocation: randomized.

Liu 1999 1. Allocation: randomized.



(Continued)

Liu 2003a 1. Allocation: randomization not mentioned.

2. Blindness. not mentioned.
Liu 2004 1. Allocation: randomization not mentioned.

Liu 2004a 1. Allocation: randomized.

Liu 2004b 1. Allocation: randomized.

Liu 2004c 1. Allocation: randomization not mentioned.

Liu 2005 1. Allocation: randomization not mentioned.

2. Blindness : not mentioned.
Liu 2005a 1. Allocation: randomized.

Liu 2005c 1. Allocation: randomized.

Loza 2005 1. Allocation: randomization not mentioned.

Lu 2002 1. Allocation: randomized.

Lu 2004 1. Allocation: randomization not mentioned.

Lu 2005 1. Allocation: randomized.

Ma 1999 1. Allocation: randomized.

Mai 2005 1. Allocation: randomized.

Malla 2004 1. Allocation: not randomized, controlled trial.
Malyarov 1999 1. Allocation: not mentioned.

(Continued)
Malykhin 2003 1. Allocation: randomization not mentioned.

Mao 2000 1. Allocation: randomization not mentioned.

Mazurek 2003 1. Allocation: randomized.

Mei 2001 1. Allocation: randomized.

Meltzer 2002 1. Allocation: randomized.

Meltzer 2004 1. Allocation: randomized.

2. Participants: Patients with schizophrenia
and schizoaffective disorder
3. Interventions: inappropriate (investigational drugs versus placebo versus haloperidol)
Mintzer 2004 1. Allocation: randomized.

Mohr 2000 1. Allocation: randomization not mentioned.

Mu 2002 1. Allocation: randomization not mentioned.

Mullen 2001 1. Allocation: randomized.

Musil 2006 1. Allocation: randomization not mentioned.

Naber 2001 1. Allocation: not randomized, pooled analysis.
Naber 2002 1. Allocation: randomization and Blindness not mentioned.

3. Interventions: atypical and typical neuroleptics
Nan 2001 1. Allocation: randomized.

Ni 2001 1. Allocation: randomized.


(Continued)
Nicholls 2003 1. Allocation: randomization not mentioned.

Opjordsmoen 2000 1. Allocation: randomization not mentioned.

Ortega-Soto 1997 1. Allocation: randomization not mentioned.

4. Interventions: olanzapine versus risperidone
5. Outcomes: no usable data.
Pan 2004 1.Allocation: not randomized (inadequate randomization).
Pan 2004a 1. Allocation: randomized.

Peng 2001 1. Allocation: randomized.

Peng 2004 1. Allocation: randomized.

Perro 1999 1. Allocation: randomized.

Peuskens 2004 1. Allocation: randomization not mentioned.

Qi 2004a 1. Allocation: randomized.

Qian 2004 1. Allocation: randomized.

Qin 2005 1. Allocation: randomized.

Rabinowitz 2005 1. Allocation: randomized.

4. Interventions: inappropriate.
Ren 2000 1. Allocation: randomized.

Ren 2004 1. Allocation: randomized.


(Continued)
Roerig 2004 1. Allocation: randomized.

3. Participants: inadequate diagnosis.
Ryu 2006 1. Allocation: randomization not mentioned.

2. Blindness. not mentioned.
Sajatovic 2002 1. Allocation: randomized.

Shao 1999 1. Allocation: randomized.

Sheng 2003 1. Allocation: randomized.

Sheng 2005 1. Allocation: randomized.

Shi 2000 1. Allocation: randomized.

Shi 2001 1. Allocation: randomized.

Shi 2004 1. Allocation: randomization not mentioned.

Simpson 2004 1. Allocation: randomization not mentioned.

4. Interventions: switch to ziprasidone from conventionals, olanzapine or risperidone.
Sowell 2002 1. Allocation: randomized.

Su 2004 1. Allocation: randomized.

Su 2005 1. Allocation: not randomized.
Sun 2000 1. Allocation: not randomized.
Sun 2001 1. Allocation: randomized.


(Continued)
Swanson 2006 1. Allocation: randomized.

Tandon 2006 1. Allocation: randomized.

Tang 2002 1. Allocation: randomization not mentioned.

Tang 2002a 1. Allocation: inadequate randomisation.
Tian 2005 1. Allocation: randomized.

Tong 2005 1. Allocation: randomized.

Tunis 2006 1. Allocation: randomized.

Van Bruggen 2003 1. Allocation: randomized.

Vaughan 2000 1. Allocation: unclear.

2. Blindness: unclear.
3. Outcomes: no usable data (other aims).
Wang 2000a 1. Allocation: randomized.

Wang 2001 1. Allocation: randomized.


Wang 2002a 1. Allocation: randomization not mentioned.





(Continued)

Wang 2005b 1. Allocation: randomized.

Weickert 2003 1. Allocation: randomized.

4. Interventions: inappropriate
Weng 1998 1. Allocation: randomization not mentioned.

Wolf 2002 1. Allocation: randomization not mentioned.

Wolf 2005 1. Allocation: randomization not mentioned.

Wu 2001 1. Allocation: randomized.




Wyszogrodzka 2006 1. Allocation: randomization not mentioned.

Xiao 2003 1. Allocation: randomized.

Xie 2005 1. Allocation: randomized.

Xin 2001 1. Allocation: randomized.

Xu 2001 1. Allocation: randomized.


(Continued)
Xu 2005 1. Allocation: randomized.

Yagdiran 2000 1. Allocation: inadequate randomization.

Yamashita 2005 1. Allocation: randomization not mentioned.

Yan 2002 1. Allocation: randomized.

Yang 1998 1. Allocation: randomized.



Yang 2004a 1. Allocation: randomized.

Ye 2005 1. Allocation: randomized.

Ye 2005a 1. Allocation: randomized.

2 Blindness: not mentioned.
Yin 2002 1. Allocation: randomization not mentioned.

Yin 2004 1. Allocation: randomized.

Yu 1999 1. Allocation: randomized.

Yu 2002 1. Allocation: randomized.

Yu 2005 1. Allocation: randomization not mentioned.

Yue 2004 1. Allocation: randomization not mentioned.


(Continued)
Zelaschi 2006 1. Allocation: not randomized, cohort study.
Zeng 2002 1. Allocation: randomization not mentioned.

Zhan 2002 1. Allocation: randomized.

Zhang 1999 1. Allocation: not randomized- inadequate randomization.
Zhang 2000 1.Allocation: inadequate randomization.
Zhang 2002 1. Allocation: randomized.

Zhang 2002a 1. Allocation: randomized.



Zhao 2004 1. Allocation: randomized.

Zhao 2005 1. Allocation: randomized.

Zheng 2001 1. Allocation: randomized.

Zheng 2003 1. Allocation: randomized.

Zhi 2005 1. Allocation: randomized.

Zhong 2003 1. Allocation: randomized.

Zhong 2006a 1. Allocation: randomized.

Zhou 2005 1. Allocation: randomized.


(Continued)
Zhu 1999 1. Allocation: randomized.



Zhu 2003a 1. Allocation: randomized.

Zoccali 2003 1. Allocation: randomization not mentioned.

3. Interventions: inappropriate (additional mirtazepine with clozapine, risperidone or olanzapine)
Characteristics of ongoing studies [ordered by study ID]
Eli Lilly 2003
Trial name or title Trial 5296

F1D-MC-S014

Blindness.: double, no further details.
Duration: 12 weeks.
Design: parallel.
Participants Diagnosis: schizophrenia or schizoaffective disorder. N=not reported.

Sex: not reported. M, not reported. F.
Age: 18-65 years.
History: duration ill not reported., age at onset not reported

Allowed dose range: not reported, Mean dose: not reported, N=not reported.
Allowed dose range: not reported. Mean dose: not reported. N=not reported
Outcomes Global state: CGI-S.

Mental State: BPRS.
Adverse effects: EPS (AIMS, BAS, SAS), Eating Behavior Assessment Scale, Insuline sensitivity index, weight,
BMI, waist circumference, visceral fat area, subcutaneous fat area, ratio of visceral fat area to subcutaneous
fat area

Eli Lilly 2003 (Continued)
Starting date October 2003
Contact information Eli Lilly and Company.
Notes
Eli Lilly 2006
Trial name or title Trial 10769

F1D-US-HGMN

Duration: 12 weeks.
Design: parallel.
Participants Diagnosis: schizophrenia or schizoaffective disorder or schizophreniform disorder. N=not reported.

Sex: not reported. M, not reported. F.
Age: 18-65 years.
History: duration ill not reported., age at onset not reported.

Allowed dose range: not reported. Mean dose: not reported. N=not reported.
Outcomes Global state: Response, remission.

Mental State: PANSS.
Service use: Psychiatric hospitalisations.
Adverse effects.
Starting date June 2006
Contact information not reported.
Notes
Gafoor 2005
Trial name or title A comparative study of quetiapine and risperidone in patients with first episode psychosis

Blindness.: rater-blinded.
Participants Diagnosis: first episode of schizophreniform psychosis (ICD-10 criteria)

Gafoor 2005 (Continued)
Interventions 1. Quetiapine
2. Risperidone.
Outcomes Global state: CGI.

Mental state: PANSS positive subscale, PANSS negative subscale, Calgary Depression Scale for Schizophrenia,
Calgary Anxiety Scale Schizophrenia.
General functioning: GAF.
Starting date Not reported.
Contact information
Notes
Lieberman 2001
Trial name or title Risperidone and clozapine in chronic schizophrenia.

Participants Severely ill treatment resistant patients.
Interventions 1. Clozapine
2. Haloperidole,
3. Risperidone 6mg, risperidone 16mg.
Outcomes Global state: CGI.

Mental state: PANSS, Overt Agression Scale.
General functioning: Social functioning and activities of daily living.
Quality of life interview.
Cognitive functioning: Cognitive test battery.
Adverse effects: EPS (ESRS).
Starting date Not reported.
Contact information
Notes
Ratna 2003
Trial name or title Improved response in Schizophrenia -IRIS.


Ratna 2003 (Continued)
Participants Diagnosis: schizophrenia.
Interventions 1. Quetiapine
2. Risperidone.
Outcomes Global state: CGI-S.

Mental state: PANSS, GAS, HAM-D.
Quality of life - SQLS and care giving inventory scores.
Adverse effects: EPS (AIMS, SAS, BAS).
Health Economics.
Starting date 1 October 2002.
Contact information Dr Lawrence Ratna

Barnet Hospital
Wellhouse Lane
Barnet
EN5 3DJ
UK
Telephone: 020 8216 4617
Fax: 020 8216 4595
Notes
Reveley 2000
Trial name or title RIS-INT-45
Methods Allocation: random, using a central randomisation procedure.

Duration: 8 weeks.
Design: parallel.
Participants Diagnosis: (DSM-IV) schizophrenia, PANSS between 60 and 120. N=not reported.
Sex: not reported.
Age: 18-65 years.
History: duration ill not reported., age at onset not reported.
Interventions 1. Olanzapine: fixed/flexible dose: not reported. Allowed dose range: not reported. Mean dose: not reported.
N=not reported.
Outcomes Efficacy.
Cognitive functioning.
Adverse effects: Sleepiness, weight gain, safety.

Reveley 2000 (Continued)
Starting date 1 April 1997
Contact information Professor Michael Reveley

Department of Psychiatry
Clinical Sciences Building
University of Leicester
Leicester Royal Infirmary
PO BOX 65
LE2 7LX
United Kingdom
Telephone: 0116 252 3242
Notes
Sireling 2003
Trial name or title Sertindole versus risperidone safety outcome study.

Blindness.: partially blinded.
Participants Diagnosis: not reported.
Interventions Sertindole versus risperidone.
Outcomes Not reported.
Starting date November 2002.
Contact information Lester.sireling@beh-mht.nhs.uk
Notes

DATA AND ANALYSES
Comparison 1. RISPERIDONE versus AMISULPRIDE
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Global state: 1a. No clinically 3 586 Risk Ratio (M-H, Random, 95% CI) 1.12 [0.83, 1.50]
significant response (as defined
2 Global state: 1b. No clinically 3 586 Risk Ratio (M-H, Random, 95% CI) 1.12 [0.82, 1.53]
important change (as defined
2.1 short term 2 276 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.50, 1.85]
2.2 medium term 1 310 Risk Ratio (M-H, Random, 95% CI) 1.27 [0.99, 1.64]
3 Global state: 1c. Relapse - 1 173 Risk Ratio (M-H, Random, 95% CI) 1.50 [0.94, 2.39]
medium term (as defined by
the original studies)
4 Leaving the study early 4 Risk Ratio (M-H, Random, 95% CI) Subtotals only
4.1 due to any reason 3 586 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.68, 1.53]
4.2 due to adverse events 4 622 Risk Ratio (M-H, Random, 95% CI) 0.93 [0.61, 1.42]
4.3 due to inefficacy 3 586 Risk Ratio (M-H, Random, 95% CI) 1.45 [0.83, 2.53]
5 Mental state: 1a. General - no 1 310 Risk Ratio (M-H, Random, 95% CI) 1.24 [1.00, 1.53]
clinically important change -
medium term (less than 50%
PANSS total reduction)
6 Mental state: 1b. General - no 1 48 Risk Ratio (M-H, Random, 95% CI) 0.69 [0.28, 1.69]
clinically important change
- short term (less than 20%
7 Mental state: 1c. General - no 1 310 Risk Ratio (M-H, Random, 95% CI) 1.29 [1.02, 1.62]
medium term (less than 50%
BPRS total reduction)
8 Mental state: 1d. General - no 1 228 Risk Ratio (M-H, Random, 95% CI) 1.29 [0.92, 1.80]
BPRS total reduction)
9 Mental state: 1e. General - 2 291 Mean Difference (IV, Random, 95% CI) -0.38 [-5.33, 4.57]
average endpoint score -
(PANSS total, high = poor)
9.1 short term 1 47 Mean Difference (IV, Random, 95% CI) -4.30 [-14.59, 5.99]
9.2 medium term 1 244 Mean Difference (IV, Random, 95% CI) 0.80 [-4.85, 6.45]
10 Mental state: 1f. General - 3 519 Mean Difference (IV, Random, 95% CI) 0.68 [-1.79, 3.14]
average endpoint score - BPRS
total score (high = poor)
10.1 short term 2 275 Mean Difference (IV, Random, 95% CI) 0.50 [-4.54, 5.53]
11 Mental state: 2a. Positive 3 519 Mean Difference (IV, Random, 95% CI) 0.03 [-1.24, 1.29]
symptoms - average endpoint
score - (PANSS positive, high =
poor)
11.2 medium term 1 244 Mean Difference (IV, Random, 95% CI) -0.30 [-2.11, 1.51]
12 Mental state: 2b. Positive 1 228 Mean Difference (IV, Random, 95% CI) 0.5 [-0.89, 1.89]
symptoms -average endpoint
score - short term (BPRS
positive, high = poor)
13 Mental state: 3a. Negative 3 519 Mean Difference (IV, Random, 95% CI) 1.00 [-0.11, 2.11]
score (PANSS negative, high =
poor)
14 Mental state: 3b. Negative 1 244 Mean Difference (IV, Random, 95% CI) 2.70 [-2.33, 7.73]
scale (SANS total, high = poor)
15 General functioning: General 1 310 Risk Ratio (M-H, Random, 95% CI) 1.11 [0.98, 1.25]
1a. No clinically important
change - medium term (less
than 50% SOFAS total score
reduction)
16 General functioning: General 2 291 Mean Difference (IV, Random, 95% CI) 2.31 [-1.28, 5.90]
1b. average endpoint score -
(SOFAS total score, high =
poor)
17 Adverse effects: 1. General - at 4 622 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.90, 1.10]
least one adverse effect
18 Adverse effects: 2. Death 1 620 Risk Ratio (M-H, Random, 95% CI) 0.42 [0.06, 2.82]
18.1 natural causes 1 310 Risk Ratio (M-H, Random, 95% CI) 0.32 [0.01, 7.81]
18.2 suicide 1 310 Risk Ratio (M-H, Random, 95% CI) 0.48 [0.04, 5.25]
19 Adverse effects: 3a. Cardiac 2 276 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
effects - QTc prolongation
20 Adverse effects: 4a. Central 1 310 Risk Ratio (M-H, Random, 95% CI) 1.44 [0.61, 3.43]
nervous system - sedation
21 Adverse effects: 4b. Central 1 310 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
nervous system - seizures
22 Adverse effects: 5a. 3 3338 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.90, 1.21]
Extrapyramidal effects
22.1 akathisia (Barnes) 3 586 Risk Ratio (M-H, Random, 95% CI) 1.25 [0.90, 1.74]
22.2 extrapyramidal 1 228 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.60, 1.30]
symptoms
22.3 hyperkinesia 2 538 Risk Ratio (M-H, Random, 95% CI) 0.75 [0.49, 1.14]
22.4 parkinsonism 2 538 Risk Ratio (M-H, Random, 95% CI) 1.13 [0.66, 1.95]
22.5 rigor 2 276 Risk Ratio (M-H, Random, 95% CI) 1.08 [0.27, 4.36]
22.6 tremor 3 586 Risk Ratio (M-H, Random, 95% CI) 1.46 [0.66, 3.21]

22.7 use of antiparkinson 3 586 Risk Ratio (M-H, Random, 95% CI) 1.07 [0.72, 1.57]
medication
23 Adverse effects: 5b 2 Mean Difference (IV, Random, 95% CI) Subtotals only
Extrapyramidal effects - scale
measured
23.1 abnormal involuntary 2 538 Mean Difference (IV, Random, 95% CI) -0.08 [-0.72, 0.55]
movement: AIMS (high =
poor)
23.2 extrapyramidal 2 538 Mean Difference (IV, Random, 95% CI) 0.03 [-0.06, 0.13]
symptoms: Simpson-Angus
Scale (high = poor)
24 Adverse effects: 6. Prolactin 2 678 Risk Ratio (M-H, Random, 95% CI) 2.34 [0.50, 10.92]
associated side effects
24.1 amenorrhea 1 140 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.06, 15.23]
24.2 galactorrhea 2 231 Risk Ratio (M-H, Random, 95% CI) 0.69 [0.16, 3.03]
24.3 sexual dysfunction (men) 2 307 Risk Ratio (M-H, Random, 95% CI) 13.17 [1.74, 99.42]
25 Adverse effects: 8a. Metabolic 2 538 Risk Ratio (M-H, Random, 95% CI) 1.75 [1.07, 2.87]
effects - weight gain
25.1 weight gain of 7 % or 1 310 Risk Ratio (M-H, Random, 95% CI) 1.71 [1.00, 2.91]
more of total body weight
25.2 as weight gain reported 1 228 Risk Ratio (M-H, Random, 95% CI) 2.04 [0.52, 7.94]
adverse event
26 Adverse effects: 8b Metabolic 3 585 Mean Difference (IV, Random, 95% CI) 0.99 [0.37, 1.61]
effects - weight gain - change
from baseline in kg
Comparison 2. RISPERIDONE versus ARIPIPRAZOLE - all data short term
No. of No. of
4 Mental state: 1a. General - 2 372 Mean Difference (IV, Random, 95% CI) -1.5 [-5.96, 2.96]
average endpoint score (PANSS
total, high = poor)
5 Mental state: 2. Positive 2 372 Mean Difference (IV, Random, 95% CI) -1.24 [-2.74, 0.26]
symptoms average endpoint
score (PANSS positive, high =
poor)
6 Mental state: 3. Negative 2 372 Mean Difference (IV, Random, 95% CI) 0.45 [-0.87, 1.78]
score - (PANSS negative, high
= poor)
9 Adverse effects: 2b. Cardiac 2 383 Mean Difference (IV, Random, 95% CI) 7.19 [2.19, 12.19]
effects - QTc abnormalities -
change from baseline in ms
10 Adverse effects: 3a. 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only
10.1 akathisia 2 384 Risk Ratio (M-H, Random, 95% CI) 1.56 [0.21, 11.45]
10.2 dystonia 1 301 Risk Ratio (M-H, Random, 95% CI) 7.14 [2.41, 21.13]
symptoms
medication
11 Adverse effects: 3b. 2 Mean Difference (IV, Random, 95% CI) Subtotals only
measured
11.1 abnormal involuntary 2 383 Mean Difference (IV, Random, 95% CI) 0.25 [-0.75, 1.24]
poor)
11.2 akathisia: Barnes 2 383 Mean Difference (IV, Random, 95% CI) 0.11 [-0.27, 0.49]
Akathisia Scale (high = poor)
Scale (high = poor)
12 Adverse effects: 4a. Prolactin 1 Risk Ratio (M-H, Random, 95% CI) Subtotals only
12.1 abnormally high 1 301 Risk Ratio (M-H, Random, 95% CI) 26.23 [12.64, 54.46]
prolactin value
12.2 dysmenorrhea 1 91 Risk Ratio (M-H, Random, 95% CI) 0.32 [0.02, 5.91]
13 Adverse effects: 4b. Prolactin - 2 383 Mean Difference (IV, Random, 95% CI) 54.71 [49.36, 60.06]
change from baseline in ng/ml
14 Adverse effects: 5a. Metabolic 1 83 Mean Difference (IV, Random, 95% CI) 22.3 [4.91, 39.69]
effects - cholesterol - change
from baseline in mg/dl
15 Adverse effects: 5b. Metabolic 1 83 Mean Difference (IV, Random, 95% CI) -6.8 [-19.70, 6.10]
effects - glucose - change from
baseline in mg/dl
16 Adverse effects: 5c. Metabolic 2 384 Risk Ratio (M-H, Random, 95% CI) 1.30 [0.55, 3.07]
effects - weight gain of 7% or
more of total body weight
17 Adverse effects: 5d. Metabolic 2 383 Mean Difference (IV, Random, 95% CI) 0.54 [-0.15, 1.24]
effects - weight gain - change
from baseline in kg

Comparison 3. RISPERIDONE versus CLOZAPINE
No. of No. of
important change - short term
(as defined by the original
studies)
4 Mental state: 1a.General - no 2 106 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.50, 1.42]
short term (less than 20 %
short term (as defined by the
original studies)
6 Mental State: 1c. General - no 1 107 Risk Ratio (M-H, Random, 95% CI) 1.05 [0.76, 1.45]
long term (less than 40% BPRS
reduction)
7 Mental State: 1d. General - no 1 29 Risk Ratio (M-H, Random, 95% CI) 1.24 [0.78, 1.98]
BPRS reduction)
8 Mental state: 1e. General - 5 468 Mean Difference (IV, Random, 95% CI) 1.49 [-3.44, 6.42]
total, high = poor)
9 Mental state: 1f. General - 4 397 Mean Difference (IV, Random, 95% CI) 3.07 [-0.01, 6.16]
average endpoint score (BPRS
total, high = poor)
9.1 short term 3 345 Mean Difference (IV, Random, 95% CI) 4.90 [2.17, 7.64]
9.2 long term 1 52 Mean Difference (IV, Random, 95% CI) -0.20 [-4.12, 3.72]
10 Mental state: 2a. Positive 6 591 Mean Difference (IV, Random, 95% CI) 1.26 [0.18, 2.35]
poor)
symptoms -average endpoint
12 Mental state: 3a. Negative 5 562 Mean Difference (IV, Random, 95% CI) -0.13 [-1.96, 1.71]
poor)
13 Mental state: 3b. Negative 2 69 Mean Difference (IV, Random, 95% CI) -0.62 [-3.74, 2.51]
score - short term (SANS total,
high = poor)
14 General functioning: 1a. 1 19 Mean Difference (IV, Random, 95% CI) 9.0 [-0.44, 18.44]
General - average endpoint
score - short term (GAF total,
high = poor)
15 General functioning: 1b. Social 1 19 Mean Difference (IV, Random, 95% CI) 47.0 [0.45, 93.55]
functioning - average endpoint
score - short term (SFS, high =
poor)
16 Cognitive functioning: 1a. 1 81 Risk Ratio (M-H, Random, 95% CI) 0.79 [0.60, 1.05]
Global - no clinically important
change in global neurocognitive
score - medium term (less than
1/2 SD)
17 Cognitive functioning: 1b. 1 50 Mean Difference (IV, Random, 95% CI) 0.33 [-0.06, 0.72]
Global - average endpoint
score - medium term - (global
neurocognitive score, high =
poor)
19 Adverse effects: 2. Death 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only
19.1 any reason 1 273 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.06, 16.18]
20 Adverse effects: 3. Cardiac 2 146 Risk Ratio (M-H, Random, 95% CI) 1.54 [0.07, 36.11]
effects
20.1 preterminal negative 1 60 Risk Ratio (M-H, Random, 95% CI) 1.54 [0.07, 36.11]
T-wave
20.2 any significant cardiac 1 86 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
effect
23.2 akinesia 1 86 Risk Ratio (M-H, Random, 95% CI) 1.0 [0.38, 2.61]
symptoms
medication
24 Adverse effects: 5b. 3 150 Mean Difference (IV, Random, 95% CI) 0.54 [-0.25, 1.34]
Extrapyramidal symptoms -
scale measured
Scale (high = poor)
24.2 extrapyramidal 1 81 Mean Difference (IV, Random, 95% CI) -0.30 [-1.91, 1.31]
symptoms: ESRS total score
(high = poor)
25 Adverse effects: 6. 5 567 Risk Ratio (M-H, Random, 95% CI) 1.69 [0.51, 5.58]
Haematological - white blood
cells - significant low white
blood cell count (as def. by the
original studies)
26 Adverse effects: 7a. Prolactin 1 86 Risk Ratio (M-H, Random, 95% CI) 2.0 [0.39, 10.35]
26.1 sexual dysfunction 1 86 Risk Ratio (M-H, Random, 95% CI) 2.0 [0.39, 10.35]
27 Adverse effects: 7b. Prolactin 2 55 Mean Difference (IV, Random, 95% CI) 28.61 [10.52, 46.69]
associated side effects - change
from baseline in ng/ml
27.1 change from baseline in 1 27 Mean Difference (IV, Random, 95% CI) 38.5 [23.30, 53.70]
ng/ml
27.2 change fom baseline in 1 28 Mean Difference (IV, Random, 95% CI) 20.0 [8.19, 31.81]
mg/ml - of men only
28 Adverse effects: 3a. Metabolic 1 31 Mean Difference (IV, Random, 95% CI) -7.10 [-34.01, 19.
- cholesterol - change from 81]
baseline in mg/dl
29 Adverse effects: 3b. Metabolic - 1 31 Mean Difference (IV, Random, 95% CI) -1.70 [-12.04, 8.64]
glucose - change from baseline
in mg/dl
30 Adverse effects: 3c. Metabolic - 2 167 Risk Ratio (M-H, Random, 95% CI) 0.61 [0.34, 1.08]
weight gain
30.1 10% of total body weight 1 81 Risk Ratio (M-H, Random, 95% CI) 0.56 [0.18, 1.76]
or more
adverse event
31 Adverse effects: 3d. Metabolic 3 373 Mean Difference (IV, Random, 95% CI) -3.30 [-5.65, -0.95]
- weight gain - change from
baseline in kg

Comparison 4. RISPERIDONE versus OLANZAPINE
No. of No. of
2.3 long term 1 266 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.71, 1.35]
3 Global state: 1c. Relapse (as 2 211 Risk Ratio (M-H, Random, 95% CI) 1.25 [0.57, 2.71]
defined by the original studies)
(less than 50% PANSS total
score reduction)
PANSS total score reduction)
7 Mental state: 1c. General - 15 2390 Mean Difference (IV, Random, 95% CI) 1.94 [0.58, 3.31]
total, high = poor)
7.3 long term 5 1431 Mean Difference (IV, Random, 95% CI) 2.59 [0.20, 4.98]
8 Mental state: 1d. General - 3 428 Mean Difference (IV, Random, 95% CI) 4.16 [0.03, 8.29]
total score, high = poor)
8.2 long term 2 393 Mean Difference (IV, Random, 95% CI) 4.28 [-1.34, 9.91]
9 Mental state: 2a. Positive 1 377 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.93, 1.04]
symptoms - no clinically
(less than 50% PANSS positive
subscore reduction)
poor)
11 Mental state: 3a. Negative 13 1702 Mean Difference (IV, Random, 95% CI) 0.44 [-0.08, 0.96]
poor)
12 Mental state: 3b. Negative 1 308 Mean Difference (IV, Random, 95% CI) 1.4 [0.37, 2.43]
score - long term (SANS total,
high = poor)
13 Quality of life: General - 2 296 Mean Difference (IV, Random, 95% CI) 5.10 [1.09, 9.10]
average endpoint score - long
term (QLS total score, high =
poor)
14 Cognitive functioning: 1 80 Risk Ratio (M-H, Random, 95% CI) 1.30 [0.88, 1.94]
1a.General - no clinically
important change - medium
term (less than SD in
Global Neurocognitive Score
improved)
15 Cognitive functioning: 1b. 1 52 Mean Difference (IV, Random, 95% CI) 0.04 [-0.31, 0.39]
General - average endpoint
score - medium term (global
neurocognitive score, high =
poor)
16 Cognitive functioning: 1 263 Mean Difference (IV, Random, 95% CI) 0.01 [-0.11, 0.13]
1c. General - average
endpoint score - long term
(neurocognitive composite
score, high = poor)
17 Service use - number of patients 3 965 Risk Ratio (M-H, Random, 95% CI) 1.34 [0.96, 1.86]
rehospitalised
19.1 any reason 1 339 Risk Ratio (M-H, Random, 95% CI) 3.09 [0.13, 75.30]
19.3 suicide attempt 5 1724 Risk Ratio (M-H, Random, 95% CI) 1.15 [0.37, 3.54]
effects

20.1 abnormal ECG 2 415 Risk Ratio (M-H, Random, 95% CI) 0.42 [0.08, 2.30]
20.2 QTc prolongation 2 853 Risk Ratio (M-H, Random, 95% CI) 2.69 [0.12, 60.00]
21 Adverse effects: 3b. Cardiac 6 1518 Mean Difference (IV, Random, 95% CI) 0.96 [-2.74, 4.67]
24.3 dyskinesia 3 580 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.36, 2.90]
symptoms
medication
measured
poor)
25.3 akathisia: ESRS subscore 1 359 Mean Difference (IV, Random, 95% CI) 0.0 [-0.27, 0.27]
for akathisia (high = poor)
25.4 dyskinesia: ESRS 3 572 Mean Difference (IV, Random, 95% CI) -0.08 [-0.76, 0.60]
subscore for dyskinesia (high =
poor)
25.5 dystonia: ESRS subscore 1 42 Mean Difference (IV, Random, 95% CI) -0.09 [-0.91, 0.73]
for dystonia (high = poor)
symptoms: ESRS total score
(high = poor)
Scale (high = poor)
25.8 parkinsonism: ESRS 3 572 Mean Difference (IV, Random, 95% CI) 0.24 [-1.09, 1.57]
subscore for parkinsonism
(high = poor)
Haematological: white blood
cells - significant low white
blood cell count (as def. by the
original studies)

27.1 abnormal ejaculation 3 531 Risk Ratio (M-H, Random, 95% CI) 4.34 [1.49, 12.69]
27.2 abnormally high 3 477 Risk Ratio (M-H, Random, 95% CI) 3.02 [0.99, 9.23]
prolactin concentration
27.4 decreased libido 3 781 Risk Ratio (M-H, Random, 95% CI) 2.48 [0.77, 8.00]
27.6 gynecomastia 5 1083 Risk Ratio (M-H, Random, 95% CI) 1.39 [0.70, 2.77]
27.7 impotence 3 531 Risk Ratio (M-H, Random, 95% CI) 2.00 [0.68, 5.89]
27.8 orgastic dysfunction 1 377 Risk Ratio (M-H, Random, 95% CI) 5.03 [0.24, 104.00]
28 Adverse effects: 7b. Prolactin - 8 Mean Difference (IV, Random, 95% CI) Subtotals only
ng/ml
ng/ml - of men only
ng/ml - of women only
- cholesterol - significant
cholesterol increase
30 Adverse effects: 8b. Metabolic 7 1391 Mean Difference (IV, Random, 95% CI) -10.36 [-14.43, -6.
- cholesterol - change from 28]
baseline in mg/dl
- glucose - abnormally high
fasting glucose value
32 Adverse effects: 8d. Metabolic - 7 1201 Mean Difference (IV, Random, 95% CI) -7.58 [-11.23, -3.93]
in mg/dl
33 Adverse effects: 8e. Metabolic - 11 2594 Risk Ratio (M-H, Random, 95% CI) 0.55 [0.43, 0.72]
weight gain
33.1 significant weight gain 8 1873 Risk Ratio (M-H, Random, 95% CI) 0.54 [0.39, 0.76]
studies)
adverse event
34 Adverse effects: 8f. Metabolic 13 2116 Mean Difference (IV, Random, 95% CI) -2.61 [-3.74, -1.48]
baseline in kg

Comparison 5. RISPERIDONE versus QUETIAPINE
No. of No. of
significant response (as def. by
the original studies)
4 Mental state: 1a General - no 2 982 Risk Ratio (M-H, Random, 95% CI) 0.90 [0.71, 1.15]
PANSS total score reduction)
clinicallly important change
BPRS total score reduction)
6 Mental state: 1c. General - 9 1953 Mean Difference (IV, Random, 95% CI) -3.09 [-5.16, -1.01]
total score, high = poor)
6.3 long term 2 743 Mean Difference (IV, Random, 95% CI) -3.11 [-5.82, -0.40]
7 Mental state: 1d. General - 1 25 Mean Difference (IV, Random, 95% CI) -1.68 [-11.69, 8.33]
average endpoint score - short
term (BPRS total score, high =
poor)
8 Mental state: 2a. Positive 1 673 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.90, 1.12]
symptoms - no clinically
(less than 40% PANSS positive
reduction)
9 Mental state: 2b. Positive 7 1264 Mean Difference (IV, Random, 95% CI) -1.82 [-2.48, -1.16]
score - (PANSS positive
subscore, high = poor)
9.1 short term 4 1037 Mean Difference (IV, Random, 95% CI) -2.10 [-3.19, -1.00]
10 Mental state: 2c. Positive 1 25 Mean Difference (IV, Random, 95% CI) -1.1 [-2.02, -0.18]
positive subscore, high = poor)
11 Mental state: 3a. Negative 1 673 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.96, 1.08]
symptoms - no clinicallly
(less than 40% PANSS negative
reduction)
12 Mental state: 3b. Negative 7 1183 Mean Difference (IV, Random, 95% CI) 0.34 [-1.26, 1.94]
score - (PANSS negative
subscore, high = poor)
13 Mental state: 3c. Negative 1 25 Mean Difference (IV, Random, 95% CI) -0.57 [-0.97, -0.17]
negative subscore, high = poor)
14 Quality of life: General - 1 22 Mean Difference (IV, Random, 95% CI) 0.5 [-12.87, 13.87]
average endpoint score - short
term (QLS total score, high =
poor)
15 Service use: Number of 2 877 Risk Ratio (M-H, Random, 95% CI) 0.75 [0.56, 1.00]
participants rehospitalised
19 Adverse effects: 3b. Cardiac 3 940 Mean Difference (IV, Random, 95% CI) -2.21 [-9.48, 5.05]
20 Adverse effects: 4. Central 8 2226 Risk Ratio (M-H, Random, 95% CI) 0.82 [0.69, 0.97]
symptoms
medication
measured

poor)
22.3 extrapyramidal 5 1077 Mean Difference (IV, Random, 95% CI) 0.59 [0.02, 1.16]
Scale (high = poor)
Haematological: Important
decline in white blood cells
24.2 dysmenorrhea 1 163 Risk Ratio (M-H, Random, 95% CI) 2.23 [0.42, 11.86]
24.4 gynecomastia 1 78 Risk Ratio (M-H, Random, 95% CI) 4.33 [1.34, 14.02]
change from baseline in mg/dl
- cholesterol - significant
cholesterol increase
27 Adverse effects: 8b. Metabolic 5 1433 Mean Difference (IV, Random, 95% CI) -8.49 [-12.23, -4.75]
- cholesterol - change from
baseline in mg/dl
- glucose - abnormally high
fasting glucose value
29 Adverse effects: 8d. Metabolic - 5 1436 Mean Difference (IV, Random, 95% CI) 0.04 [-2.83, 2.92]
in mg/dl
30 Adverse effects: 8e. Metabolic - 7 1942 Risk Ratio (M-H, Random, 95% CI) 1.03 [0.88, 1.22]
weight gain of 7% or more of
total body weight
31 Adverse effects: 8f. Metabolic 7 1446 Mean Difference (IV, Random, 95% CI) -0.71 [-2.47, 1.04]
baseline in kg
Comparison 6. RISPERIDONE versus SERTINDOLE - all data short term
No. of No. of
1 Global state - 1a. No clinically 1 187 Risk Ratio (M-H, Random, 95% CI) 1.14 [0.92, 1.40]
2 Global state - 1b. No clinically 1 187 Risk Ratio (M-H, Random, 95% CI) 1.24 [0.91, 1.68]
(less than 50% PANSS total
score reduction)
5 Mental state: 1b. General - 2 493 Mean Difference (IV, Random, 95% CI) -1.98 [-12.20, 8.24]
total, high = poor)
6 Mental state: 2. Positive 1 172 Mean Difference (IV, Random, 95% CI) 0.80 [-1.35, 2.95]
poor)
poor)
8 General functioning: General - 1 114 Mean Difference (IV, Random, 95% CI) 2.90 [-2.61, 8.41]
average endpoint score - (GAF
total, high = poor)
10 Adverse effects: 2. Death - 1 187 Risk Ratio (M-H, Random, 95% CI) 3.3 [0.14, 79.98]
suicide
12 Adverse effects: 3b. Cardiac 2 495 Mean Difference (IV, Random, 95% CI) -18.60 [-22.37, -14.
effects - QTc abnormalities - 83]
symptoms
Extrapyramidal symptom scales
poor)
15.2 akathisia: Barnes 2 500 Mean Difference (IV, Random, 95% CI) 0.22 [0.03, 0.41]

Scale (high = poor)
16 Adverse effects: 6. Prolactin 2 437 Risk Ratio (M-H, Random, 95% CI) 0.34 [0.16, 0.76]
associated side effects - sexual
dysfunction
17 Adverse effects: 7a. Metabolic 1 176 Mean Difference (IV, Random, 95% CI) 4.90 [-3.73, 13.53]
baseline in mg/dl
18 Adverse effects: 7b. Metabolic - 1 176 Mean Difference (IV, Random, 95% CI) 2.00 [-5.85, 9.85]
in mg/dl
weight gain
20 Adverse effects: 7d. Metabolic 2 328 Mean Difference (IV, Random, 95% CI) -0.99 [-1.86, -0.12]
baseline in kg
Comparison 7. RISPERIDONE versus ZIPRASIDONE
No. of No. of
studies)
5 Mental state: 1b. General - 3 1016 Mean Difference (IV, Random, 95% CI) -3.91 [-7.55, -0.27]
total, high = poor)
5.3 long term 1 516 Mean Difference (IV, Random, 95% CI) -6.01 [-10.03, -1.99]
6 Mental state: 1c. General - 1 296 Mean Difference (IV, Random, 95% CI) -0.70 [-4.33, 2.93]
avergae endpoint score - short
term (BPRS total, high = poor)
7 Mental state: 2a. Positive 1 204 Mean Difference (IV, Random, 95% CI) -2.5 [-4.62, -0.38]
score - medium term (PANSS
8 Mental State: 2b. Positive 1 296 Mean Difference (IV, Random, 95% CI) -0.5 [-1.15, 0.15]
9 Mental state: 3. Negative 2 500 Mean Difference (IV, Random, 95% CI) -0.04 [-1.20, 1.12]
poor)
10 Service use: Number of patients 2 767 Risk Ratio (M-H, Random, 95% CI) 0.87 [0.63, 1.22]
rehospitalised
12 Adverse effects: 2. Death 2 767 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.16, 4.58]
14 Adverse effects: 3b. Cardiac 3 793 Mean Difference (IV, Random, 95% CI) -2.24 [-6.39, 1.92]
symptoms
medication
Extrapyramidal symptoms -
scale measured
17.1 abnormal involuntary 1 296 Mean Difference (IV, Random, 95% CI) 0.21 [0.17, 0.25]
poor)
17.2 akathisia: Barnes 1 296 Mean Difference (IV, Random, 95% CI) 0.56 [0.51, 0.61]
17.3 extrapyramidal 1 296 Mean Difference (IV, Random, 95% CI) 0.34 [0.26, 0.42]
Scale (high = poor)

18.3 decreased libido 1 296 Risk Ratio (M-H, Random, 95% CI) 1.65 [0.70, 3.86]
18.4 erectile dysfunction 1 215 Risk Ratio (M-H, Random, 95% CI) 1.05 [0.38, 2.88]
18.6 orgastic dysfunction 2 822 Risk Ratio (M-H, Random, 95% CI) 1.44 [1.03, 2.02]
20 Adverse effects: 7a. Metabolic 2 767 Mean Difference (IV, Random, 95% CI) 8.58 [1.11, 16.04]
baseline in mg/dl
21 Adverse effects: 7b. Metabolic - 2 767 Mean Difference (IV, Random, 95% CI) 4.94 [-1.91, 11.80]
in mg/dl
weight gain of 7% or more of
total body weight
23 Adverse effects: 7d. Metabolic 1 461 Mean Difference (IV, Random, 95% CI) 1.1 [-0.15, 2.35]
baseline in kg
Comparison 8. RISPERIDONE versus CLOZAPINE - sensitivity analysis (skewed data included)
No. of No. of
1 Mental state: 1. General - 3 368 Mean Difference (IV, Random, 95% CI) 2.84 [-1.36, 7.03]
total, high = poor)
1.1 short term 2 316 Mean Difference (IV, Random, 95% CI) 5.19 [2.12, 8.26]
2 Mental state: 2. Positive 4 442 Mean Difference (IV, Random, 95% CI) 0.60 [-1.34, 2.53]
poor)
poor)

Comparison 9. RISPERIDONE versus OLANZAPINE - sensitivity analysis (skewed data excluded)
No. of No. of
1 Mental state: 1a. General - 14 2348 Mean Difference (IV, Random, 95% CI) 1.99 [0.60, 3.37]
total, high = poor)
2 Mental state: 2. General - 2 393 Mean Difference (IV, Random, 95% CI) 4.28 [-1.34, 9.91]
total, high = poor)
2.1 Long term 2 393 Mean Difference (IV, Random, 95% CI) 4.28 [-1.34, 9.91]
3 Mental state: 3. Positive 12 1663 Mean Difference (IV, Random, 95% CI) 0.62 [0.03, 1.21]
poor)
4 Adverse effects: 1. 7 Mean Difference (IV, Random, 95% CI) Subtotals only
measured
4.1 dyskinesia: ESRS subscore 2 401 Mean Difference (IV, Random, 95% CI) 0.10 [-0.42, 0.62]
for dyskinesia (high = poor)
4.2 extrapyramidal symptoms: 2 530 Mean Difference (IV, Random, 95% CI) 0.16 [-0.58, 0.90]
ESRS total score (high = poor)
Simpson-Angus Scale (high =
poor)
4.4 parkinsonism: ESRS 2 401 Mean Difference (IV, Random, 95% CI) 1.06 [-1.31, 3.42]
subscore for parkinsonism
(high = poor)
5 Adverse effects: 2. Prolactin 5 Mean Difference (IV, Random, 95% CI) Subtotals only
associated side effects - change
from baseline in ng/ml
ng/ml

Comparison 10. RISPERIDONE versus QUETIAPINE - sensitivity analysis (skewed data included)
No. of No. of
1 Mental state: 1. Positive 6 1225 Mean Difference (IV, Random, 95% CI) -1.76 [-2.48, -1.04]
poor)
1.1 short term 3 998 Mean Difference (IV, Random, 95% CI) -2.08 [-3.56, -0.60]
2 Adverse effects: 1. 4 Mean Difference (IV, Random, 95% CI) Subtotals only
measured
Simpson-Angus Scale (high =
poor)
Analysis 1.1. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 1 Global state: 1a. No
clinically significant response (as defined by the original studies).
Review: Risperidone versus other atypical antipsychotics for schizophrenia
Comparison: 1 RISPERIDONE versus AMISULPRIDE
Outcome: 1 Global state: 1a. No clinically significant response (as defined by the original studies)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Hwang 2003 10/25 14/23 18.2 % 0.66 [ 0.37, 1.18 ]
Peuskens 1999 48/113 38/115 34.3 % 1.29 [ 0.92, 1.80 ]
Sechter 2002 94/158 73/152 47.5 % 1.24 [ 1.00, 1.53 ]
Total (95% CI) 296 290 100.0 % 1.12 [ 0.83, 1.50 ]

Total events: 152 (Treatment), 125 (Control)
Heterogeneity: Tau2 = 0.04; Chi2 = 4.35, df = 2 (P = 0.11); I2 =54%
Test for overall effect: Z = 0.74 (P = 0.46)
0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Analysis 1.2. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 2 Global state: 1b. No
clinically important change (as defined by the original studies).
Outcome: 2 Global state: 1b. No clinically important change (as defined by the original studies)

M- M-
n/N n/N CI CI
1 short term
Hwang 2003 10/25 14/23 19.9 % 0.66 [ 0.37, 1.18 ]
Peuskens 1999 48/113 38/115 36.1 % 1.29 [ 0.92, 1.80 ]
Subtotal (95% CI) 138 138 56.1 % 0.96 [ 0.50, 1.85 ]

2 medium term
Sechter 2002 78/158 59/152 43.9 % 1.27 [ 0.99, 1.64 ]
Subtotal (95% CI) 158 152 43.9 % 1.27 [ 0.99, 1.64 ]

Heterogeneity: not applicable
Total (95% CI) 296 290 100.0 % 1.12 [ 0.82, 1.53 ]
0.1 0.2 0.5 1 2 5 10


Analysis 1.3. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 3 Global state: 1c. Relapse -
medium term (as defined by the original studies).
Outcome: 3 Global state: 1c. Relapse - medium term (as defined by the original studies)

M- M-
n/N n/N CI CI
Sechter 2002 29/81 22/92 100.0 % 1.50 [ 0.94, 2.39 ]
Total (95% CI) 81 92 100.0 % 1.50 [ 0.94, 2.39 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.4. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 4 Leaving the study early.
Outcome: 4 Leaving the study early
Study or subgroup Treatment Control Risk Ratio Risk Ratio

M- M-
n/N n/N CI CI
1 due to any reason
Hwang 2003 0/25 3/23 0.13 [ 0.01, 2.42 ]
Peuskens 1999 32/113 37/115 0.88 [ 0.59, 1.31 ]
Sechter 2002 69/158 54/152 1.23 [ 0.93, 1.62 ]
Subtotal (95% CI) 296 290 1.02 [ 0.68, 1.53 ]

2 due to adverse events
Hwang 2003 0/25 1/23 0.31 [ 0.01, 7.20 ]
Moller 2005 1/12 1/24 2.00 [ 0.14, 29.28 ]
Peuskens 1999 14/113 15/115 0.95 [ 0.48, 1.88 ]
Sechter 2002 20/158 21/152 0.92 [ 0.52, 1.62 ]
Subtotal (95% CI) 308 314 0.93 [ 0.61, 1.42 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.79, df = 3 (P = 0.85); I2 =0.0%
3 due to inefficacy
Hwang 2003 0/25 0/23 0.0 [ 0.0, 0.0 ]
Peuskens 1999 10/113 8/115 1.27 [ 0.52, 3.11 ]
Sechter 2002 18/158 11/152 1.57 [ 0.77, 3.22 ]
Subtotal (95% CI) 296 290 1.45 [ 0.83, 2.53 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.5. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 5 Mental state: 1a. General -
no clinically important change - medium term (less than 50% PANSS total reduction).
Outcome: 5 Mental state: 1a. General - no clinically important change - medium term (less than 50% PANSS total reduction)

M- M-
n/N n/N CI CI
Sechter 2002 94/158 73/152 100.0 % 1.24 [ 1.00, 1.53 ]
Total (95% CI) 158 152 100.0 % 1.24 [ 1.00, 1.53 ]

0.001 0.01 0.1 1 10 100 1000

Analysis 1.6. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 6 Mental state: 1b. General -
no clinically important change - short term (less than 20% PANSS total reduction).
Outcome: 6 Mental state: 1b. General - no clinically important change - short term (less than 20% PANSS total reduction)

M- M-
n/N n/N CI CI
Hwang 2003 6/25 8/23 100.0 % 0.69 [ 0.28, 1.69 ]
Total (95% CI) 25 23 100.0 % 0.69 [ 0.28, 1.69 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.7. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 7 Mental state: 1c. General -
no clinically important change - medium term (less than 50% BPRS total reduction).
Outcome: 7 Mental state: 1c. General - no clinically important change - medium term (less than 50% BPRS total reduction)

M- M-
n/N n/N CI CI
Sechter 2002 87/158 65/152 100.0 % 1.29 [ 1.02, 1.62 ]
Total (95% CI) 158 152 100.0 % 1.29 [ 1.02, 1.62 ]

0.001 0.01 0.1 1 10 100 1000

Analysis 1.8. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 8 Mental state: 1d. General -
no clinically important change - short term (less than 40% BPRS total reduction).
Outcome: 8 Mental state: 1d. General - no clinically important change - short term (less than 40% BPRS total reduction)

M- M-
n/N n/N CI CI
Peuskens 1999 48/113 38/115 100.0 % 1.29 [ 0.92, 1.80 ]
Total (95% CI) 113 115 100.0 % 1.29 [ 0.92, 1.80 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.9. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 9 Mental state: 1e. General -
average endpoint score - (PANSS total, high = poor).
Outcome: 9 Mental state: 1e. General - average endpoint score - (PANSS total, high = poor)
Mean Mean
Study or subgroup Treatment Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
1 short term
Hwang 2003 25 -28.4 (18.8) 22 -24.1 (17.2) 23.1 % -4.30 [ -14.59, 5.99 ]
Subtotal (95% CI) 25 22 23.1 % -4.30 [ -14.59, 5.99 ]

2 medium term
Sechter 2002 123 -31.4 (21) 121 -32.2 (23.9) 76.9 % 0.80 [ -4.85, 6.45 ]
Subtotal (95% CI) 123 121 76.9 % 0.80 [ -4.85, 6.45 ]

Total (95% CI) 148 143 100.0 % -0.38 [ -5.33, 4.57 ]
-10 -5 0 5 10

Analysis 1.10. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 10 Mental state: 1f. General -
average endpoint score - BPRS total score (high = poor).
Outcome: 10 Mental state: 1f. General - average endpoint score - BPRS total score (high = poor)
Mean Mean
1 short term
Hwang 2003 25 -17.7 (11.5) 22 -14.9 (10.7) 14.6 % -2.80 [ -9.15, 3.55 ]
Peuskens 1999 113 -15.2 (13.9) 115 -17.7 (14.9) 39.9 % 2.50 [ -1.24, 6.24 ]
Subtotal (95% CI) 138 137 54.5 % 0.50 [ -4.54, 5.53 ]

2 medium term
Sechter 2002 123 -19.6 (12.6) 121 -19.8 (15) 45.5 % 0.20 [ -3.28, 3.68 ]
Subtotal (95% CI) 123 121 45.5 % 0.20 [ -3.28, 3.68 ]

Total (95% CI) 261 258 100.0 % 0.68 [ -1.79, 3.14 ]
-10 -5 0 5 10

Analysis 1.11. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 11 Mental state: 2a. Positive
symptoms - average endpoint score - (PANSS positive, high = poor).
Outcome: 11 Mental state: 2a. Positive symptoms - average endpoint score - (PANSS positive, high = poor)
Mean Mean
1 short term
Hwang 2003 25 -8.3 (6.1) 22 -6.8 (6) 13.4 % -1.50 [ -4.96, 1.96 ]
Peuskens 1999 113 -8.6 (7.4) 115 -9.6 (8.5) 37.6 % 1.00 [ -1.07, 3.07 ]
Subtotal (95% CI) 138 137 50.9 % 0.15 [ -2.17, 2.47 ]

2 medium term
Sechter 2002 123 -12.1 (6.9) 121 -11.8 (7.5) 49.1 % -0.30 [ -2.11, 1.51 ]
Subtotal (95% CI) 123 121 49.1 % -0.30 [ -2.11, 1.51 ]

Total (95% CI) 261 258 100.0 % 0.03 [ -1.24, 1.29 ]
-10 -5 0 5 10

Analysis 1.12. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 12 Mental state: 2b. Positive
symptoms -average endpoint score - short term (BPRS positive, high = poor).
Outcome: 12 Mental state: 2b. Positive symptoms -average endpoint score - short term (BPRS positive, high = poor)
Mean Mean
Peuskens 1999 113 -6.7 (5.3) 115 -7.2 (5.4) 100.0 % 0.50 [ -0.89, 1.89 ]
Total (95% CI) 113 115 100.0 % 0.50 [ -0.89, 1.89 ]

-10 -5 0 5 10

Analysis 1.13. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 13 Mental state: 3a. Negative
symptoms - average endpoint score (PANSS negative, high = poor).
Outcome: 13 Mental state: 3a. Negative symptoms - average endpoint score (PANSS negative, high = poor)
Mean Mean
1 short term
Hwang 2003 25 -6.4 (4.8) 22 -5.6 (4.5) 16.5 % -0.80 [ -3.46, 1.86 ]
Peuskens 1999 113 -5.3 (6.6) 115 -6.9 (7.5) 32.6 % 1.60 [ -0.23, 3.43 ]
Subtotal (95% CI) 138 137 49.0 % 0.60 [ -1.72, 2.92 ]

2 medium term
Sechter 2002 123 -3.9 (6.1) 121 -5.1 (5.1) 51.0 % 1.20 [ -0.21, 2.61 ]
Subtotal (95% CI) 123 121 51.0 % 1.20 [ -0.21, 2.61 ]

Total (95% CI) 261 258 100.0 % 1.00 [ -0.11, 2.11 ]
-10 -5 0 5 10

Analysis 1.14. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 14 Mental state: 3b. Negative
symptoms - average endpoint scale (SANS total, high = poor).
Outcome: 14 Mental state: 3b. Negative symptoms - average endpoint scale (SANS total, high = poor)
Mean Mean
1 medium term
Sechter 2002 123 -12.1 (19.6) 121 -14.8 (20.5) 100.0 % 2.70 [ -2.33, 7.73 ]
Total (95% CI) 123 121 100.0 % 2.70 [ -2.33, 7.73 ]

-10 -5 0 5 10
Analysis 1.15. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 15 General functioning:

General 1a. No clinically important change - medium term (less than 50% SOFAS total score reduction).
Outcome: 15 General functioning: General 1a. No clinically important change - medium term (less than 50% SOFAS total score reduction)

M- M-
n/N n/N CI CI
Sechter 2002 130/158 113/152 100.0 % 1.11 [ 0.98, 1.25 ]
Total (95% CI) 158 152 100.0 % 1.11 [ 0.98, 1.25 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.16. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 16 General functioning:
General 1b. average endpoint score - (SOFAS total score, high = poor).
Outcome: 16 General functioning: General 1b. average endpoint score - (SOFAS total score, high = poor)
Mean Mean
1 short term
Hwang 2003 25 -10 (14.52) 22 -11.1 (13.9) 19.5 % 1.10 [ -7.03, 9.23 ]
Subtotal (95% CI) 25 22 19.5 % 1.10 [ -7.03, 9.23 ]

2 medium term
Sechter 2002 123 -11.9 (14.3) 121 -14.5 (17.4) 80.5 % 2.60 [ -1.40, 6.60 ]
Subtotal (95% CI) 123 121 80.5 % 2.60 [ -1.40, 6.60 ]

Total (95% CI) 148 143 100.0 % 2.31 [ -1.28, 5.90 ]
-10 -5 0 5 10

Analysis 1.17. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 17 Adverse effects: 1.
General - at least one adverse effect.
Outcome: 17 Adverse effects: 1. General - at least one adverse effect

M- M-
n/N n/N CI CI
Hwang 2003 16/25 15/23 5.4 % 0.98 [ 0.65, 1.49 ]
Moller 2005 5/12 10/24 1.4 % 1.00 [ 0.44, 2.27 ]
Peuskens 1999 76/113 87/115 34.8 % 0.89 [ 0.75, 1.05 ]
Sechter 2002 123/158 111/152 58.4 % 1.07 [ 0.94, 1.21 ]
Total (95% CI) 308 314 100.0 % 1.00 [ 0.90, 1.10 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.18. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 18 Adverse effects: 2. Death.
Outcome: 18 Adverse effects: 2. Death

M- M-
n/N n/N CI CI
1 natural causes
Sechter 2002 0/158 1/152 35.9 % 0.32 [ 0.01, 7.81 ]
Subtotal (95% CI) 158 152 35.9 % 0.32 [ 0.01, 7.81 ]

2 suicide
Sechter 2002 1/158 2/152 64.1 % 0.48 [ 0.04, 5.25 ]
Subtotal (95% CI) 158 152 64.1 % 0.48 [ 0.04, 5.25 ]

Total (95% CI) 316 304 100.0 % 0.42 [ 0.06, 2.82 ]
0.1 0.2 0.5 1 2 5 10


Analysis 1.19. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 19 Adverse effects: 3a.
Cardiac effects - QTc prolongation.
Outcome: 19 Adverse effects: 3a. Cardiac effects - QTc prolongation

M- M-
n/N n/N CI CI
Hwang 2003 0/25 0/23 0.0 [ 0.0, 0.0 ]
Peuskens 1999 0/113 0/115 0.0 [ 0.0, 0.0 ]
Total (95% CI) 138 138 0.0 [ 0.0, 0.0 ]

Heterogeneity: Tau2 = ; Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%

Test for overall effect: Z = 0.0 (P < 0.00001)
0.1 0.2 0.5 1 2 5 10

Central nervous system - sedation.
Outcome: 20 Adverse effects: 4a. Central nervous system - sedation

M- M-
n/N n/N CI CI
Sechter 2002 12/158 8/152 100.0 % 1.44 [ 0.61, 3.43 ]
Total (95% CI) 158 152 100.0 % 1.44 [ 0.61, 3.43 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.21. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 21 Adverse effects: 4b.
Central nervous system - seizures.
Outcome: 21 Adverse effects: 4b. Central nervous system - seizures

M- M-
n/N n/N CI CI
Sechter 2002 0/158 0/152 0.0 [ 0.0, 0.0 ]
Total (95% CI) 158 152 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10


Extrapyramidal effects.
Outcome: 22 Adverse effects: 5a. Extrapyramidal effects

M- M-
n/N n/N CI CI
1 akathisia (Barnes)
Hwang 2003 4/25 2/23 0.9 % 1.84 [ 0.37, 9.11 ]
Peuskens 1999 12/113 13/115 4.1 % 0.94 [ 0.45, 1.97 ]
Sechter 2002 48/158 35/152 16.2 % 1.32 [ 0.91, 1.92 ]
Subtotal (95% CI) 296 290 21.3 % 1.25 [ 0.90, 1.74 ]

2 extrapyramidal symptoms
Peuskens 1999 33/113 38/115 15.2 % 0.88 [ 0.60, 1.30 ]
Subtotal (95% CI) 113 115 15.2 % 0.88 [ 0.60, 1.30 ]

3 hyperkinesia
Peuskens 1999 11/113 14/115 4.1 % 0.80 [ 0.38, 1.69 ]
Sechter 2002 22/158 29/152 8.8 % 0.73 [ 0.44, 1.21 ]
Subtotal (95% CI) 271 267 12.9 % 0.75 [ 0.49, 1.14 ]

4 parkinsonism
Peuskens 1999 13/113 16/115 4.9 % 0.83 [ 0.42, 1.64 ]
Sechter 2002 27/158 18/152 7.4 % 1.44 [ 0.83, 2.51 ]
Subtotal (95% CI) 271 267 12.3 % 1.13 [ 0.66, 1.95 ]

5 rigor
Hwang 2003 2/25 0/23 0.3 % 4.62 [ 0.23, 91.34 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )

(. . . Continued)
M- M-
n/N n/N CI CI
Peuskens 1999 6/113 8/115 2.2 % 0.76 [ 0.27, 2.13 ]
Subtotal (95% CI) 138 138 2.4 % 1.08 [ 0.27, 4.36 ]

6 tremor
Hwang 2003 3/25 2/23 0.8 % 1.38 [ 0.25, 7.53 ]
Peuskens 1999 8/113 4/115 1.7 % 2.04 [ 0.63, 6.57 ]
Sechter 2002 4/158 4/152 1.2 % 0.96 [ 0.24, 3.78 ]
Subtotal (95% CI) 296 290 3.7 % 1.46 [ 0.66, 3.21 ]

7 use of antiparkinson medication
Hwang 2003 11/25 7/23 3.9 % 1.45 [ 0.68, 3.09 ]
Peuskens 1999 26/113 35/115 12.0 % 0.76 [ 0.49, 1.17 ]
Sechter 2002 47/158 36/152 16.4 % 1.26 [ 0.87, 1.82 ]
Subtotal (95% CI) 296 290 32.3 % 1.07 [ 0.72, 1.57 ]

Total (95% CI) 1681 1657 100.0 % 1.04 [ 0.90, 1.21 ]
0.1 0.2 0.5 1 2 5 10


Analysis 1.23. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 23 Adverse effects: 5b
Extrapyramidal effects - scale measured.
Outcome: 23 Adverse effects: 5b Extrapyramidal effects - scale measured
Mean Mean
1 abnormal involuntary movement: AIMS (high = poor)

Peuskens 1999 113 1.7 (3.88) 115 2 (3.88) 39.5 % -0.30 [ -1.31, 0.71 ]
Sechter 2002 158 -0.1 (4.1) 152 -0.16 (3.17) 60.5 % 0.06 [ -0.75, 0.87 ]
Subtotal (95% CI) 271 267 100.0 % -0.08 [ -0.72, 0.55 ]

2 extrapyramidal symptoms: Simpson-Angus Scale (high = poor)
Peuskens 1999 113 0.35 (1.7) 115 0.29 (1.7) 4.5 % 0.06 [ -0.38, 0.50 ]
Sechter 2002 158 -0.07 (0.41) 152 -0.1 (0.45) 95.5 % 0.03 [ -0.07, 0.13 ]
Subtotal (95% CI) 271 267 100.0 % 0.03 [ -0.06, 0.13 ]

-10 -5 0 5 10

Analysis 1.24. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 24 Adverse effects: 6.
Prolactin associated side effects.
Outcome: 24 Adverse effects: 6. Prolactin associated side effects

M- M-
n/N n/N CI CI
1 amenorrhea
Sechter 2002 1/71 1/69 18.7 % 0.97 [ 0.06, 15.23 ]
Subtotal (95% CI) 71 69 18.7 % 0.97 [ 0.06, 15.23 ]

2 galactorrhea
Peuskens 1999 2/47 4/44 30.2 % 0.47 [ 0.09, 2.43 ]
Sechter 2002 1/71 0/69 15.5 % 2.92 [ 0.12, 70.39 ]
Subtotal (95% CI) 118 113 45.7 % 0.69 [ 0.16, 3.03 ]

3 sexual dysfunction (men)
Peuskens 1999 6/66 0/71 17.8 % 13.97 [ 0.80, 243.24 ]
Sechter 2002 6/87 0/83 17.8 % 12.41 [ 0.71, 216.87 ]
Subtotal (95% CI) 153 154 35.6 % 13.17 [ 1.74, 99.42 ]

Total (95% CI) 342 336 100.0 % 2.34 [ 0.50, 10.92 ]
0.001 0.01 0.1 1 10 100 1000


Metabolic effects - weight gain.
Outcome: 25 Adverse effects: 8a. Metabolic effects - weight gain

M- M-
n/N n/N CI CI
1 weight gain of 7 % or more of total body weight

Sechter 2002 32/158 18/152 86.7 % 1.71 [ 1.00, 2.91 ]
Subtotal (95% CI) 158 152 86.7 % 1.71 [ 1.00, 2.91 ]

2 as weight gain reported adverse event
Peuskens 1999 6/113 3/115 13.3 % 2.04 [ 0.52, 7.94 ]
Subtotal (95% CI) 113 115 13.3 % 2.04 [ 0.52, 7.94 ]

Total (95% CI) 271 267 100.0 % 1.75 [ 1.07, 2.87 ]
0.001 0.01 0.1 1 10 100 1000


Analysis 1.26. Comparison 1 RISPERIDONE versus AMISULPRIDE, Outcome 26 Adverse effects: 8b
Metabolic effects - weight gain - change from baseline in kg.
Outcome: 26 Adverse effects: 8b Metabolic effects - weight gain - change from baseline in kg
Mean Mean
Hwang 2003 25 1.6 (2.8) 22 0.1 (3.3) 12.5 % 1.50 [ -0.26, 3.26 ]
Peuskens 1999 113 1.4 (3.37) 115 0.4 (3.37) 50.7 % 1.00 [ 0.13, 1.87 ]
Sechter 2002 158 2.1 (5) 152 1.3 (4.2) 36.8 % 0.80 [ -0.23, 1.83 ]
Total (95% CI) 296 289 100.0 % 0.99 [ 0.37, 1.61 ]

-10 -5 0 5 10
Analysis 2.1. Comparison 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term, Outcome 1 Global
state: 1a. No clinically significant response (as defined by the original studies).
Comparison: 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term

M- M-
n/N n/N CI CI
Chan 2007 11/34 24/49 26.4 % 0.66 [ 0.38, 1.16 ]
Potkin 2003 61/99 128/202 73.6 % 0.97 [ 0.81, 1.17 ]
Total (95% CI) 133 251 100.0 % 0.88 [ 0.62, 1.24 ]

0.1 0.2 0.5 1 2 5 10


Analysis 2.2. Comparison 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term, Outcome 2 Global
state: 1b. No clinically important change (as defined by the original studies).

M- M-
n/N n/N CI CI
Chan 2007 11/34 24/49 26.4 % 0.66 [ 0.38, 1.16 ]
Potkin 2003 61/99 128/202 73.6 % 0.97 [ 0.81, 1.17 ]
Total (95% CI) 133 251 100.0 % 0.88 [ 0.62, 1.24 ]

0.1 0.2 0.5 1 2 5 10


Analysis 2.3. Comparison 2 RISPERIDONE versus ARIPIPRAZOLE - all data short term, Outcome 3
Leaving the study early.

M- M-
n/N n/N CI CI
1 due to any reason
Chan 2007 10/34 11/49 15.3 % 1.31 [ 0.63, 2.74 ]
Potkin 2003 37/99 74/202 84.7 % 1.02 [ 0.75, 1.40 ]
Subtotal (95% CI) 133 251 100.0 % 1.06 [ 0.79, 1.41 ]

Chan 2007 2/34 5/49 20.0 % 0.58 [ 0.12, 2.80 ]
Potkin 2003 8/99 19/202 80.0 % 0.86 [ 0.39, 1.89 ]
Subtotal (95% CI) 133 251 100.0 % 0.79 [ 0.39, 1.61 ]

3 due to inefficacy
Chan 2007 0/34 2/49 6.7 % 0.29 [ 0.01, 5.77 ]
Potkin 2003 8/99 17/202 93.3 % 0.96 [ 0.43, 2.15 ]
Subtotal (95% CI) 133 251 100.0 % 0.89 [ 0.41, 1.93 ]

0.1 0.2 0.5 1 2 5 10


Mental state: 1a. General - average endpoint score (PANSS total, high = poor).
Outcome: 4 Mental state: 1a. General - average endpoint score (PANSS total, high = poor)
Mean Mean
Chan 2007 34 -21.1 (17.1) 49 -19.6 (18.1) 33.8 % -1.50 [ -9.16, 6.16 ]
Potkin 2003 95 -15.7 (22.31) 194 -14.2 (22.31) 66.2 % -1.50 [ -6.98, 3.98 ]
Total (95% CI) 129 243 100.0 % -1.50 [ -5.96, 2.96 ]

-10 -5 0 5 10
Mental state: 2. Positive symptoms average endpoint score (PANSS positive, high = poor).
Outcome: 5 Mental state: 2. Positive symptoms average endpoint score (PANSS positive, high = poor)
Mean Mean
Chan 2007 34 -8.1 (5.8) 49 -5.8 (6.9) 29.9 % -2.30 [ -5.04, 0.44 ]
Potkin 2003 95 -5.2 (7.3) 194 -4.41 (7.32) 70.1 % -0.79 [ -2.58, 1.00 ]
Total (95% CI) 129 243 100.0 % -1.24 [ -2.74, 0.26 ]

-10 -5 0 5 10

Mental state: 3. Negative symptoms - average endpoint score - (PANSS negative, high = poor).
Outcome: 6 Mental state: 3. Negative symptoms - average endpoint score - (PANSS negative, high = poor)
Mean Mean
Chan 2007 34 -4 (5.7) 49 -4.8 (5.1) 30.7 % 0.80 [ -1.59, 3.19 ]
Potkin 2003 95 -3.1 (6.48) 194 -3.4 (6.48) 69.3 % 0.30 [ -1.29, 1.89 ]
Total (95% CI) 129 243 100.0 % 0.45 [ -0.87, 1.78 ]

-10 -5 0 5 10
Adverse effects: 1. General - at least one adverse effect.

M- M-
n/N n/N CI CI
Chan 2007 27/34 41/49 9.9 % 0.95 [ 0.77, 1.17 ]
Potkin 2003 92/99 183/202 90.1 % 1.03 [ 0.96, 1.10 ]
Total (95% CI) 133 251 100.0 % 1.02 [ 0.95, 1.09 ]

0.1 0.2 0.5 1 2 5 10


Adverse effects: 2a. Cardiac effects - QTc prolongation.

M- M-
n/N n/N CI CI
Potkin 2003 3/99 0/202 100.0 % 14.21 [ 0.74, 272.45 ]
Total (95% CI) 99 202 100.0 % 14.21 [ 0.74, 272.45 ]

0.1 0.2 0.5 1 2 5 10

Adverse effects: 2b. Cardiac effects - QTc abnormalities - change from baseline in ms.
Outcome: 9 Adverse effects: 2b. Cardiac effects - QTc abnormalities - change from baseline in ms
Mean Mean
Chan 2007 34 8 (34) 49 -1 (39) 10.0 % 9.00 [ -6.81, 24.81 ]
Potkin 2003 99 6.31 (22.2) 201 -0.68 (21.22) 90.0 % 6.99 [ 1.72, 12.26 ]
Total (95% CI) 133 250 100.0 % 7.19 [ 2.19, 12.19 ]

-10 -5 0 5 10

Adverse effects: 3a. Extrapyramidal effects.

M- M-
n/N n/N CI CI
1 akathisia
Chan 2007 4/34 1/49 37.4 % 5.76 [ 0.67, 49.35 ]
Potkin 2003 14/99 40/202 62.6 % 0.71 [ 0.41, 1.25 ]
Subtotal (95% CI) 133 251 100.0 % 1.56 [ 0.21, 11.45 ]

2 dystonia
Potkin 2003 14/99 4/202 100.0 % 7.14 [ 2.41, 21.13 ]
Subtotal (95% CI) 99 202 100.0 % 7.14 [ 2.41, 21.13 ]

Chan 2007 8/34 6/49 25.3 % 1.92 [ 0.73, 5.04 ]
Potkin 2003 31/99 63/202 74.7 % 1.00 [ 0.70, 1.43 ]
Subtotal (95% CI) 133 251 100.0 % 1.18 [ 0.68, 2.06 ]

4 parkinsonism
Potkin 2003 0/99 7/202 100.0 % 0.14 [ 0.01, 2.35 ]
Subtotal (95% CI) 99 202 100.0 % 0.14 [ 0.01, 2.35 ]

5 tremor
Potkin 2003 2/99 19/202 100.0 % 0.21 [ 0.05, 0.90 ]
Subtotal (95% CI) 99 202 100.0 % 0.21 [ 0.05, 0.90 ]

0.001 0.01 0.1 1 10 100 1000

(Continued . . . )

(. . . Continued)
M- M-
n/N n/N CI CI
Chan 2007 14/34 12/49 100.0 % 1.68 [ 0.89, 3.17 ]
Subtotal (95% CI) 34 49 100.0 % 1.68 [ 0.89, 3.17 ]

0.001 0.01 0.1 1 10 100 1000

Adverse effects: 3b. Extrapyramidal effects - scale measured.
Outcome: 11 Adverse effects: 3b. Extrapyramidal effects - scale measured
Mean Mean

Chan 2007 34 0.4 (1.7) 49 -0.4 (2.5) 45.8 % 0.80 [ -0.10, 1.70 ]
Potkin 2003 99 -0.6 (2.87) 201 -0.38 (2.87) 54.2 % -0.22 [ -0.91, 0.47 ]
Subtotal (95% CI) 133 250 100.0 % 0.25 [ -0.75, 1.24 ]

2 akathisia: Barnes Akathisia Scale (high = poor)
Chan 2007 34 0.5 (1.4) 49 0.1 (1) 31.0 % 0.40 [ -0.15, 0.95 ]
Potkin 2003 99 0.14 (0.86) 201 0.16 (0.86) 69.0 % -0.02 [ -0.23, 0.19 ]
Subtotal (95% CI) 133 250 100.0 % 0.11 [ -0.27, 0.49 ]
-10 -5 0 5 10
(Continued . . . )

(. . . Continued)
Mean Mean
Chan 2007 34 1.3 (2.4) 49 -0.2 (2.3) 48.2 % 1.50 [ 0.47, 2.53 ]
Potkin 2003 99 -0.18 (3.58) 201 -0.13 (3.58) 51.8 % -0.05 [ -0.91, 0.81 ]
Subtotal (95% CI) 133 250 100.0 % 0.70 [ -0.82, 2.22 ]

-10 -5 0 5 10
Adverse effects: 4a. Prolactin associated side effects.
Outcome: 12 Adverse effects: 4a. Prolactin associated side effects

M- M-
n/N n/N CI CI
1 abnormally high prolactin value

Potkin 2003 90/99 7/202 100.0 % 26.23 [ 12.64, 54.46 ]
Subtotal (95% CI) 99 202 100.0 % 26.23 [ 12.64, 54.46 ]

2 dysmenorrhea
Potkin 2003 0/28 3/63 100.0 % 0.32 [ 0.02, 5.91 ]
Subtotal (95% CI) 28 63 100.0 % 0.32 [ 0.02, 5.91 ]

0.001 0.01 0.1 1 10 100 1000


Adverse effects: 4b. Prolactin - change from baseline in ng/ml.
Outcome: 13 Adverse effects: 4b. Prolactin - change from baseline in ng/ml
Mean Mean
Chan 2007 34 55.4 (42.3) 49 -9 (96.4) 3.1 % 64.40 [ 33.89, 94.91 ]
Potkin 2003 99 47.9 (24.4) 201 -6.5 (18.31) 96.9 % 54.40 [ 48.97, 59.83 ]
Total (95% CI) 133 250 100.0 % 54.71 [ 49.36, 60.06 ]

-10 -5 0 5 10

Adverse effects: 5a. Metabolic effects - cholesterol - change from baseline in mg/dl.
Outcome: 14 Adverse effects: 5a. Metabolic effects - cholesterol - change from baseline in mg/dl
Mean Mean
Chan 2007 34 19.2 (27.9) 49 -3.1 (52.3) 100.0 % 22.30 [ 4.91, 39.69 ]
Total (95% CI) 34 49 100.0 % 22.30 [ 4.91, 39.69 ]

-10 -5 0 5 10
Adverse effects: 5b. Metabolic effects - glucose - change from baseline in mg/dl.
Outcome: 15 Adverse effects: 5b. Metabolic effects - glucose - change from baseline in mg/dl
Mean Mean
Chan 2007 34 -2.7 (27.6) 49 4.1 (32) 100.0 % -6.80 [ -19.70, 6.10 ]
Total (95% CI) 34 49 100.0 % -6.80 [ -19.70, 6.10 ]

-10 -5 0 5 10

Adverse effects: 5c. Metabolic effects - weight gain of 7% or more of total body weight.
Outcome: 16 Adverse effects: 5c. Metabolic effects - weight gain of 7% or more of total body weight

M- M-
n/N n/N CI CI
Chan 2007 4/34 2/49 23.2 % 2.88 [ 0.56, 14.86 ]
Potkin 2003 11/99 22/202 76.8 % 1.02 [ 0.52, 2.02 ]
Total (95% CI) 133 251 100.0 % 1.30 [ 0.55, 3.07 ]

0.1 0.2 0.5 1 2 5 10

Adverse effects: 5d. Metabolic effects - weight gain - change from baseline in kg.
Outcome: 17 Adverse effects: 5d. Metabolic effects - weight gain - change from baseline in kg
Mean Mean
Chan 2007 34 1.5 (2.5) 49 0.9 (2.2) 44.4 % 0.60 [ -0.44, 1.64 ]
Potkin 2003 99 1.5 (3.9) 201 1 (3.81) 55.6 % 0.50 [ -0.43, 1.43 ]
Total (95% CI) 133 250 100.0 % 0.54 [ -0.15, 1.24 ]

-10 -5 0 5 10

Analysis 3.1. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 1 Global state: 1a. No clinically
significant response (as defined by the original studies).
Comparison: 3 RISPERIDONE versus CLOZAPINE

M- M-
n/N n/N CI CI
Azorin 2001 121/135 116/138 85.0 % 1.07 [ 0.97, 1.17 ]
Bondolfi 1998 14/43 15/43 2.1 % 0.93 [ 0.52, 1.69 ]
Breier 1999 12/15 9/14 3.4 % 1.24 [ 0.78, 1.98 ]
Heinrich 1994 20/40 8/20 1.9 % 1.25 [ 0.67, 2.32 ]
McGurk 2005 32/54 30/53 7.0 % 1.05 [ 0.76, 1.45 ]
Wahlbeck 2000 3/9 6/11 0.6 % 0.61 [ 0.21, 1.78 ]
Total (95% CI) 296 279 100.0 % 1.07 [ 0.98, 1.16 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.2. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 2 Global state: 1b. No clinically
important change - short term (as defined by the original studies).
Outcome: 2 Global state: 1b. No clinically important change - short term (as defined by the original studies)

M- M-
n/N n/N CI CI
Azorin 2001 79/135 77/138 90.1 % 1.05 [ 0.85, 1.29 ]
Heinrich 1994 20/40 8/20 9.9 % 1.25 [ 0.67, 2.32 ]
Total (95% CI) 175 158 100.0 % 1.07 [ 0.88, 1.30 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.3. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 3 Leaving the study early.

M- M-
n/N n/N CI CI
1 due to any reason
Atmaca 2003 1/14 1/14 1.00 [ 0.07, 14.45 ]
Azorin 2001 34/135 38/138 0.91 [ 0.61, 1.36 ]
Bondolfi 1998 9/43 9/43 1.00 [ 0.44, 2.27 ]
Daniel 1996 3/10 0/10 7.00 [ 0.41, 120.16 ]
Heinrich 1994 23/40 6/20 1.92 [ 0.93, 3.94 ]
McGurk 2005 31/54 25/53 1.22 [ 0.84, 1.75 ]
Volavka 2002 19/41 18/40 1.03 [ 0.64, 1.66 ]
Wahlbeck 2000 1/9 6/11 0.20 [ 0.03, 1.40 ]
Subtotal (95% CI) 346 329 1.10 [ 0.86, 1.41 ]

Azorin 2001 12/135 16/138 0.77 [ 0.38, 1.56 ]
Bondolfi 1998 1/43 1/43 1.00 [ 0.06, 15.48 ]
Daniel 1996 2/10 0/10 5.00 [ 0.27, 92.62 ]
Heinrich 1994 3/40 4/20 0.38 [ 0.09, 1.52 ]
McGurk 2005 1/54 7/53 0.14 [ 0.02, 1.10 ]
Volavka 2002 2/41 8/40 0.24 [ 0.06, 1.08 ]
Wahlbeck 2000 1/9 2/11 0.61 [ 0.07, 5.70 ]
Subtotal (95% CI) 332 315 0.55 [ 0.31, 0.98 ]

3 due to inefficacy
Azorin 2001 9/135 1/138 9.20 [ 1.18, 71.63 ]
Bondolfi 1998 4/43 2/43 2.00 [ 0.39, 10.35 ]
0.001 0.01 0.1 1 10 100 1000

(Continued . . . )

(. . . Continued)
M- M-
n/N n/N CI CI
Daniel 1996 0/10 0/10 0.0 [ 0.0, 0.0 ]
Heinrich 1994 10/40 1/20 5.00 [ 0.69, 36.37 ]
McGurk 2005 21/54 8/53 2.58 [ 1.25, 5.30 ]
Volavka 2002 2/41 2/40 0.98 [ 0.14, 6.59 ]
Wahlbeck 2000 0/9 1/11 0.40 [ 0.02, 8.78 ]
Subtotal (95% CI) 332 315 2.51 [ 1.43, 4.40 ]

0.001 0.01 0.1 1 10 100 1000

Analysis 3.4. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 4 Mental state: 1a.General - no
clinically important change - short term (less than 20 % PANSS total reduction).
Outcome: 4 Mental state: 1a.General - no clinically important change - short term (less than 20 % PANSS total reduction)

M- M-
n/N n/N CI CI
Bondolfi 1998 14/43 15/43 76.5 % 0.93 [ 0.52, 1.69 ]
Wahlbeck 2000 3/9 6/11 23.5 % 0.61 [ 0.21, 1.78 ]
Total (95% CI) 52 54 100.0 % 0.84 [ 0.50, 1.42 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.5. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 5 Mental state: 1b. General - no
clinically important change - short term (as defined by the original studies).
Outcome: 5 Mental state: 1b. General - no clinically important change - short term (as defined by the original studies)

M- M-
n/N n/N CI CI
Azorin 2001 79/135 77/138 100.0 % 1.05 [ 0.85, 1.29 ]
Total (95% CI) 135 138 100.0 % 1.05 [ 0.85, 1.29 ]

0.1 0.2 0.5 1 2 5 10

Analysis 3.6. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 6 Mental State: 1c. General - no
clinically important change - long term (less than 40% BPRS reduction).
Outcome: 6 Mental State: 1c. General - no clinically important change - long term (less than 40% BPRS reduction)

M- M-
n/N n/N CI CI
McGurk 2005 32/54 30/53 100.0 % 1.05 [ 0.76, 1.45 ]
Total (95% CI) 54 53 100.0 % 1.05 [ 0.76, 1.45 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.7. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 7 Mental State: 1d. General - no
clinically important change - short term (less than 20% BPRS reduction).
Outcome: 7 Mental State: 1d. General - no clinically important change - short term (less than 20% BPRS reduction)

M- M-
n/N n/N CI CI
Breier 1999 12/15 9/14 100.0 % 1.24 [ 0.78, 1.98 ]
Total (95% CI) 15 14 100.0 % 1.24 [ 0.78, 1.98 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.8. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 8 Mental state: 1e. General -
average endpoint score (PANSS total, high = poor).
Outcome: 8 Mental state: 1e. General - average endpoint score (PANSS total, high = poor)
Mean Mean
1 short term
Atmaca 2003 13 78.26 (4.62) 13 77.06 (5.28) 33.8 % 1.20 [ -2.61, 5.01 ]
Azorin 2001 130 -29.9 (23.9) 126 -37.5 (22.5) 27.1 % 7.60 [ 1.92, 13.28 ]
Bondolfi 1998 43 -27.4 (23.6) 43 -23.2 (21.5) 16.4 % -4.20 [ -13.74, 5.34 ]
Wahlbeck 2000 9 63 (17) 10 76 (22) 6.6 % -13.00 [ -30.59, 4.59 ]
Subtotal (95% CI) 195 192 84.0 % 0.75 [ -5.35, 6.85 ]

2 medium term
Volavka 2002 41 -3.1 (22.31) 40 -6.7 (22.31) 16.0 % 3.60 [ -6.12, 13.32 ]
Subtotal (95% CI) 41 40 16.0 % 3.60 [ -6.12, 13.32 ]

Total (95% CI) 236 232 100.0 % 1.49 [ -3.44, 6.42 ]
-10 -5 0 5 10

Analysis 3.9. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 9 Mental state: 1f. General -
average endpoint score (BPRS total, high = poor).
Outcome: 9 Mental state: 1f. General - average endpoint score (BPRS total, high = poor)
Mean Mean
1 short term
Azorin 2001 130 -17.7 (13.6) 126 -23.2 (13.2) 38.3 % 5.50 [ 2.22, 8.78 ]
Breier 1999 15 35.8 (9.89) 14 32 (6.37) 18.9 % 3.80 [ -2.22, 9.82 ]
Heinrich 1994 40 -13.9 (16.6) 20 -16.9 (16.1) 10.5 % 3.00 [ -5.73, 11.73 ]
Subtotal (95% CI) 185 160 67.7 % 4.90 [ 2.17, 7.64 ]

2 long term
McGurk 2005 22 31.3 (6.5) 30 31.5 (7.9) 32.3 % -0.20 [ -4.12, 3.72 ]
Subtotal (95% CI) 22 30 32.3 % -0.20 [ -4.12, 3.72 ]

Total (95% CI) 207 190 100.0 % 3.07 [ -0.01, 6.16 ]
-10 -5 0 5 10

Analysis 3.10. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 10 Mental state: 2a. Positive
symptoms - average endpoint score (PANSS positive, high = poor).
Outcome: 10 Mental state: 2a. Positive symptoms - average endpoint score (PANSS positive, high = poor)
Mean Mean
1 short term
Azorin 2001 130 -8.3 (7.4) 126 -10.4 (6.6) 40.1 % 2.10 [ 0.38, 3.82 ]
Bondolfi 1998 43 -8.3 (10.7) 43 -6.7 (7.1) 8.0 % -1.60 [ -5.44, 2.24 ]
Breier 1999 15 9.53 (4.73) 14 7.43 (2.21) 16.7 % 2.10 [ -0.56, 4.76 ]
Ren 2002 60 20.8 (7.9) 60 19.7 (5.4) 20.1 % 1.10 [ -1.32, 3.52 ]
Wahlbeck 2000 9 15 (7) 10 17 (6) 3.4 % -2.00 [ -7.89, 3.89 ]
Subtotal (95% CI) 257 253 88.3 % 1.28 [ -0.01, 2.57 ]

2 medium term
Volavka 2002 41 -1.9 (7.3) 40 -2.3 (7.3) 11.7 % 0.40 [ -2.78, 3.58 ]
Subtotal (95% CI) 41 40 11.7 % 0.40 [ -2.78, 3.58 ]

Total (95% CI) 298 293 100.0 % 1.26 [ 0.18, 2.35 ]
-10 -5 0 5 10

Analysis 3.11. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 11 Mental state: 2b. Positive
symptoms -average endpoint score - short term (BPRS positive, high = poor).
Outcome: 11 Mental state: 2b. Positive symptoms -average endpoint score - short term (BPRS positive, high = poor)
Mean Mean
Breier 1999 15 9.53 (4.73) 14 7.43 (2.21) 100.0 % 2.10 [ -0.56, 4.76 ]
Total (95% CI) 15 14 100.0 % 2.10 [ -0.56, 4.76 ]

-10 -5 0 5 10

Analysis 3.12. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 12 Mental state: 3a. Negative
Mean Mean
1 short term
Azorin 2001 130 -7.1 (7.2) 126 -8.8 (6.8) 26.2 % 1.70 [ -0.02, 3.42 ]
Bondolfi 1998 43 -6 (6.5) 43 -6.1 (6.1) 19.8 % 0.10 [ -2.56, 2.76 ]
Ren 2002 60 18.6 (7.2) 60 19.9 (7.1) 20.5 % -1.30 [ -3.86, 1.26 ]
Wahlbeck 2000 9 17 (4) 10 21 (4) 14.7 % -4.00 [ -7.60, -0.40 ]
Subtotal (95% CI) 242 239 81.2 % -0.55 [ -2.80, 1.71 ]

2 medium term
Volavka 2002 41 -0.2 (6.48) 40 -1.6 (6.48) 18.8 % 1.40 [ -1.42, 4.22 ]
Subtotal (95% CI) 41 40 18.8 % 1.40 [ -1.42, 4.22 ]

Total (95% CI) 283 279 100.0 % -0.13 [ -1.96, 1.71 ]
-10 -5 0 5 10

Analysis 3.13. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 13 Mental state: 3b. Negative
symptoms - average endpoint score - short term (SANS total, high = poor).
Outcome: 13 Mental state: 3b. Negative symptoms - average endpoint score - short term (SANS total, high = poor)
Mean Mean
Breier 1999 15 47.6 (9.42) 14 48.93 (8.43) 23.1 % -1.33 [ -7.83, 5.17 ]
Zhou 2000 20 34.5 (5.7) 20 34.9 (5.8) 76.9 % -0.40 [ -3.96, 3.16 ]
Total (95% CI) 35 34 100.0 % -0.62 [ -3.74, 2.51 ]

-10 -5 0 5 10
Analysis 3.14. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 14 General functioning: 1a.
General - average endpoint score - short term (GAF total, high = poor).
Outcome: 14 General functioning: 1a. General - average endpoint score - short term (GAF total, high = poor)
Mean Mean
Wahlbeck 2000 9 44 (10) 10 35 (11) 100.0 % 9.00 [ -0.44, 18.44 ]
Total (95% CI) 9 10 100.0 % 9.00 [ -0.44, 18.44 ]

-10 -5 0 5 10

Analysis 3.15. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 15 General functioning: 1b.
Social functioning - average endpoint score - short term (SFS, high = poor).
Outcome: 15 General functioning: 1b. Social functioning - average endpoint score - short term (SFS, high = poor)
Mean Mean
Wahlbeck 2000 9 734 (54) 10 687 (49) 100.0 % 47.00 [ 0.45, 93.55 ]
Total (95% CI) 9 10 100.0 % 47.00 [ 0.45, 93.55 ]

-10 -5 0 5 10
Analysis 3.16. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 16 Cognitive functioning: 1a.
Global - no clinically important change in global neurocognitive score - medium term (less than 1/2 SD).
Outcome: 16 Cognitive functioning: 1a. Global - no clinically important change in global neurocognitive score - medium term (less than 1/2 SD)

M- M-
n/N n/N CI CI
Volavka 2002 26/41 32/40 100.0 % 0.79 [ 0.60, 1.05 ]
Total (95% CI) 41 40 100.0 % 0.79 [ 0.60, 1.05 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.17. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 17 Cognitive functioning: 1b.
Global - average endpoint score - medium term - (global neurocognitive score, high = poor).
Outcome: 17 Cognitive functioning: 1b. Global - average endpoint score - medium term - (global neurocognitive score, high = poor)
Mean Mean
Volavka 2002 26 0.29 (0.68) 24 -0.04 (0.72) 100.0 % 0.33 [ -0.06, 0.72 ]
Total (95% CI) 26 24 100.0 % 0.33 [ -0.06, 0.72 ]

-10 -5 0 5 10
Analysis 3.18. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 18 Adverse effects: 1. General -
at least one adverse effect.

M- M-
n/N n/N CI CI
Azorin 2001 111/135 107/138 57.4 % 1.06 [ 0.94, 1.19 ]
Heinrich 1994 19/40 15/20 42.6 % 0.63 [ 0.42, 0.96 ]
Total (95% CI) 175 158 100.0 % 0.85 [ 0.51, 1.42 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.19. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 19 Adverse effects: 2. Death.

M- M-
n/N n/N CI CI
1 any reason
Azorin 2001 1/135 1/138 1.02 [ 0.06, 16.18 ]
Subtotal (95% CI) 135 138 1.02 [ 0.06, 16.18 ]

2 natural causes
Wahlbeck 2000 0/9 0/11 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 9 11 0.0 [ 0.0, 0.0 ]

3 suicide
Wahlbeck 2000 0/9 0/11 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 9 11 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.20. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 20 Adverse effects: 3. Cardiac
effects.
Outcome: 20 Adverse effects: 3. Cardiac effects

M- M-
n/N n/N CI CI
1 preterminal negative T-wave

Heinrich 1994 1/40 0/20 1.54 [ 0.07, 36.11 ]
Subtotal (95% CI) 40 20 1.54 [ 0.07, 36.11 ]

2 any significant cardiac effect
Bondolfi 1998 0/43 0/43 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 43 43 0.0 [ 0.0, 0.0 ]

Total (95% CI) 83 63 1.54 [ 0.07, 36.11 ]
0.1 0.2 0.5 1 2 5 10


Analysis 3.21. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 21 Adverse effects: 4a. Central
nervous system - sedation.

M- M-
n/N n/N CI CI
Azorin 2001 19/135 33/138 43.1 % 0.59 [ 0.35, 0.98 ]
Bondolfi 1998 13/43 20/43 36.6 % 0.65 [ 0.37, 1.13 ]
Heinrich 1994 5/40 3/20 6.4 % 0.83 [ 0.22, 3.14 ]
Wahlbeck 2000 0/9 1/11 1.2 % 0.40 [ 0.02, 8.78 ]
Zhou 2000 4/20 12/20 12.6 % 0.33 [ 0.13, 0.86 ]
Total (95% CI) 247 232 100.0 % 0.58 [ 0.41, 0.81 ]

0.001 0.01 0.1 1 10 100 1000


Analysis 3.22. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 22 Adverse effects: 4b. Central
nervous system - seizures.

M- M-
n/N n/N CI CI
Azorin 2001 3/135 12/138 84.4 % 0.26 [ 0.07, 0.89 ]
Volavka 2002 0/41 4/40 15.6 % 0.11 [ 0.01, 1.95 ]
Total (95% CI) 176 178 100.0 % 0.22 [ 0.07, 0.70 ]

0.001 0.01 0.1 1 10 100 1000


Analysis 3.23. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 23 Adverse effects: 5a.

M- M-
n/N n/N CI CI
1 akathisia
Zhou 2000 0/20 4/20 100.0 % 0.11 [ 0.01, 1.94 ]
Subtotal (95% CI) 20 20 100.0 % 0.11 [ 0.01, 1.94 ]

2 akinesia
Bondolfi 1998 7/43 7/43 100.0 % 1.00 [ 0.38, 2.61 ]
Subtotal (95% CI) 43 43 100.0 % 1.00 [ 0.38, 2.61 ]

3 dystonia
Bondolfi 1998 2/43 1/43 100.0 % 2.00 [ 0.19, 21.24 ]
Subtotal (95% CI) 43 43 100.0 % 2.00 [ 0.19, 21.24 ]

Azorin 2001 38/135 18/138 54.1 % 2.16 [ 1.30, 3.59 ]
Heinrich 1994 10/40 7/20 45.9 % 0.71 [ 0.32, 1.59 ]
Subtotal (95% CI) 175 158 100.0 % 1.30 [ 0.44, 3.85 ]

5 parkinsonism
Bondolfi 1998 17/43 27/43 100.0 % 0.63 [ 0.41, 0.97 ]
Subtotal (95% CI) 43 43 100.0 % 0.63 [ 0.41, 0.97 ]

6 tremor
0.001 0.01 0.1 1 10 100 1000

(Continued . . . )

(. . .Continued)
M- M-
n/N n/N CI CI
Zhou 2000 4/20 8/20 100.0 % 0.50 [ 0.18, 1.40 ]
Subtotal (95% CI) 20 20 100.0 % 0.50 [ 0.18, 1.40 ]

Atmaca 2003 3/14 0/14 3.7 % 7.00 [ 0.39, 124.14 ]
Bondolfi 1998 3/43 3/43 13.0 % 1.00 [ 0.21, 4.68 ]
Breier 1999 10/15 2/14 17.4 % 4.67 [ 1.23, 17.68 ]
Heinrich 1994 2/40 0/20 3.5 % 2.56 [ 0.13, 50.95 ]
Volavka 2002 13/41 5/40 35.4 % 2.54 [ 1.00, 6.46 ]
Wahlbeck 2000 6/9 3/11 27.0 % 2.44 [ 0.84, 7.13 ]
Subtotal (95% CI) 162 142 100.0 % 2.57 [ 1.47, 4.48 ]

0.001 0.01 0.1 1 10 100 1000


Analysis 3.24. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 24 Adverse effects: 5b.
Extrapyramidal symptoms - scale measured.
Outcome: 24 Adverse effects: 5b. Extrapyramidal symptoms - scale measured
Mean Mean

Breier 1999 15 12.33 (1.63) 14 11.36 (1.08) 63.0 % 0.97 [ -0.03, 1.97 ]
Heinrich 1994 20 0.15 (3.58) 20 0.1 (3.58) 12.8 % 0.05 [ -2.17, 2.27 ]
Subtotal (95% CI) 35 34 75.8 % 0.81 [ -0.10, 1.73 ]

2 extrapyramidal symptoms: ESRS total score (high = poor)
Volavka 2002 41 4.8 (3.6) 40 5.1 (3.8) 24.2 % -0.30 [ -1.91, 1.31 ]
Subtotal (95% CI) 41 40 24.2 % -0.30 [ -1.91, 1.31 ]

Total (95% CI) 76 74 100.0 % 0.54 [ -0.25, 1.34 ]
-10 -5 0 5 10

Analysis 3.25. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 25 Adverse effects: 6.
Haematological - white blood cells - significant low white blood cell count (as def. by the original studies).
Outcome: 25 Adverse effects: 6. Haematological - white blood cells - significant low white blood cell count (as def. by the original studies)

M- M-
n/N n/N CI CI
Azorin 2001 5/135 1/138 5.11 [ 0.61, 43.18 ]
Bondolfi 1998 1/43 0/43 3.00 [ 0.13, 71.65 ]
McGurk 2005 0/54 0/53 0.0 [ 0.0, 0.0 ]
Volavka 2002 2/41 2/40 0.98 [ 0.14, 6.59 ]
Wahlbeck 2000 0/9 1/11 0.40 [ 0.02, 8.78 ]
Total (95% CI) 282 285 1.69 [ 0.51, 5.58 ]

0.1 0.2 0.5 1 2 5 10



M- M-
n/N n/N CI CI
1 sexual dysfunction
Bondolfi 1998 4/43 2/43 100.0 % 2.00 [ 0.39, 10.35 ]
Total (95% CI) 43 43 100.0 % 2.00 [ 0.39, 10.35 ]

0.1 0.2 0.5 1 2 5 10


Prolactin associated side effects - change from baseline in ng/ml.
Outcome: 27 Adverse effects: 7b. Prolactin associated side effects - change from baseline in ng/ml
Mean Mean
1 change from baseline in ng/ml

Breier 1999 14 50.7 (27.9) 13 12.2 (7.7) 46.5 % 38.50 [ 23.30, 53.70 ]
Subtotal (95% CI) 14 13 46.5 % 38.50 [ 23.30, 53.70 ]

2 change fom baseline in mg/ml - of men only
Volavka 2002 16 32 (12.2) 12 12 (18) 53.5 % 20.00 [ 8.19, 31.81 ]
Subtotal (95% CI) 16 12 53.5 % 20.00 [ 8.19, 31.81 ]

Total (95% CI) 30 25 100.0 % 28.61 [ 10.52, 46.69 ]
-10 -5 0 5 10

Metabolic - cholesterol - change from baseline in mg/dl.
Outcome: 28 Adverse effects: 3a. Metabolic - cholesterol - change from baseline in mg/dl
Mean Mean
Volavka 2002 14 9.2 (36.7) 17 16.3 (39.6) 100.0 % -7.10 [ -34.01, 19.81 ]
Total (95% CI) 14 17 100.0 % -7.10 [ -34.01, 19.81 ]

-10 -5 0 5 10
Metabolic - glucose - change from baseline in mg/dl.
Outcome: 29 Adverse effects: 3b. Metabolic - glucose - change from baseline in mg/dl
Mean Mean
Volavka 2002 14 2.7 (12.2) 17 4.4 (17.1) 100.0 % -1.70 [ -12.04, 8.64 ]
Total (95% CI) 14 17 100.0 % -1.70 [ -12.04, 8.64 ]

-10 -5 0 5 10

Analysis 3.30. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 30 Adverse effects: 3c.
Metabolic - weight gain.
Outcome: 30 Adverse effects: 3c. Metabolic - weight gain

M- M-
n/N n/N CI CI
1 10% of total body weight or more

Volavka 2002 4/41 7/40 25.2 % 0.56 [ 0.18, 1.76 ]
Subtotal (95% CI) 41 40 25.2 % 0.56 [ 0.18, 1.76 ]

Bondolfi 1998 10/43 16/43 74.8 % 0.63 [ 0.32, 1.22 ]
Subtotal (95% CI) 43 43 74.8 % 0.63 [ 0.32, 1.22 ]

Total (95% CI) 84 83 100.0 % 0.61 [ 0.34, 1.08 ]
0.1 0.2 0.5 1 2 5 10


Analysis 3.31. Comparison 3 RISPERIDONE versus CLOZAPINE, Outcome 31 Adverse effects: 3d.
Metabolic - weight gain - change from baseline in kg.
Outcome: 31 Adverse effects: 3d. Metabolic - weight gain - change from baseline in kg
Mean Mean
Atmaca 2003 13 0.54 (0.72) 13 6.52 (3.41) 31.7 % -5.98 [ -7.87, -4.09 ]
Azorin 2001 134 0.2 (5.43) 136 2.4 (5.43) 35.6 % -2.20 [ -3.50, -0.90 ]
Volavka 2002 39 2.3 (2.8) 38 4.2 (4.7) 32.8 % -1.90 [ -3.63, -0.17 ]
Total (95% CI) 186 187 100.0 % -3.30 [ -5.65, -0.95 ]

-10 -5 0 5 10

Analysis 4.1. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 1 Global state: 1a. No
Comparison: 4 RISPERIDONE versus OLANZAPINE

M- M-
n/N n/N CI CI
Conley 2001 109/188 108/189 15.2 % 1.01 [ 0.85, 1.21 ]
Gureje 2003 28/30 29/32 21.2 % 1.03 [ 0.89, 1.19 ]
Jeste 2003 39/87 38/89 4.1 % 1.05 [ 0.75, 1.47 ]
McEvoy 2007 47/133 48/133 4.4 % 0.98 [ 0.71, 1.35 ]
Robinson 2005 30/60 36/60 4.3 % 0.83 [ 0.60, 1.16 ]
Sikich 2004 6/20 2/16 0.2 % 2.40 [ 0.56, 10.32 ]
Tran 1997 147/167 136/172 50.6 % 1.11 [ 1.01, 1.22 ]
Total (95% CI) 685 691 100.0 % 1.06 [ 0.99, 1.13 ]

0.1 0.2 0.5 1 2 5 10


Analysis 4.2. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 2 Global state: 1b. No
clinically important change (as defined by the original studies).

M- M-
n/N n/N CI CI
1 short term
Conley 2001 117/188 124/189 50.7 % 0.95 [ 0.81, 1.10 ]
Jeste 2003 60/87 57/89 26.5 % 1.08 [ 0.87, 1.33 ]
Sikich 2004 6/20 2/16 0.5 % 2.40 [ 0.56, 10.32 ]
Subtotal (95% CI) 295 294 77.8 % 1.00 [ 0.87, 1.16 ]

2 medium term
Robinson 2005 30/60 36/60 11.0 % 0.83 [ 0.60, 1.16 ]
Subtotal (95% CI) 60 60 11.0 % 0.83 [ 0.60, 1.16 ]

3 long term
McEvoy 2007 47/133 48/133 11.2 % 0.98 [ 0.71, 1.35 ]
Subtotal (95% CI) 133 133 11.2 % 0.98 [ 0.71, 1.35 ]

Total (95% CI) 488 487 100.0 % 0.98 [ 0.88, 1.09 ]
0.1 0.2 0.5 1 2 5 10


Analysis 4.3. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 3 Global state: 1c. Relapse (as
defined by the original studies).
Outcome: 3 Global state: 1c. Relapse (as defined by the original studies)

M- M-
n/N n/N CI CI
1 short term
Dollfus 2005 5/40 6/36 38.1 % 0.75 [ 0.25, 2.25 ]
Subtotal (95% CI) 40 36 38.1 % 0.75 [ 0.25, 2.25 ]

2 long term
Keefe 2006 17/75 8/60 61.9 % 1.70 [ 0.79, 3.67 ]
Subtotal (95% CI) 75 60 61.9 % 1.70 [ 0.79, 3.67 ]

Total (95% CI) 115 96 100.0 % 1.25 [ 0.57, 2.71 ]
0.1 0.2 0.5 1 2 5 10


Analysis 4.4. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 4 Leaving the study early.

M- M-
n/N n/N CI CI
1 due to any reason
Atmaca 2003 1/14 1/14 0.1 % 1.00 [ 0.07, 14.45 ]
Conley 2001 53/188 43/189 3.4 % 1.24 [ 0.87, 1.75 ]
Dollfus 2005 10/40 9/36 0.7 % 1.00 [ 0.46, 2.18 ]
Gureje 2003 21/33 15/32 2.0 % 1.36 [ 0.87, 2.13 ]
Jeste 2003 24/87 18/89 1.4 % 1.36 [ 0.80, 2.33 ]
Keefe 2006 104/158 95/159 14.3 % 1.10 [ 0.93, 1.31 ]
Lieberman 2005 253/341 216/336 40.3 % 1.15 [ 1.04, 1.28 ]
McEvoy 2006 12/16 12/19 2.1 % 1.19 [ 0.76, 1.85 ]
McEvoy 2007 95/133 91/133 16.6 % 1.04 [ 0.89, 1.22 ]
Purdon 2000 14/21 9/21 1.2 % 1.56 [ 0.87, 2.78 ]
Sacchetti 2004 5/25 5/25 0.3 % 1.00 [ 0.33, 3.03 ]
Sikich 2004 10/20 2/16 0.2 % 4.00 [ 1.02, 15.72 ]
Stroup 2006 45/70 46/68 7.2 % 0.95 [ 0.75, 1.21 ]
Tran 1997 88/167 73/172 8.1 % 1.24 [ 0.99, 1.56 ]
Volavka 2002 19/41 13/39 1.4 % 1.39 [ 0.80, 2.42 ]
Wang 2006 8/19 5/17 0.5 % 1.43 [ 0.58, 3.54 ]
Subtotal (95% CI) 1373 1365 100.0 % 1.14 [ 1.07, 1.21 ]

Conley 2001 22/188 17/189 13.9 % 1.30 [ 0.71, 2.37 ]
Dollfus 2005 3/40 4/36 4.0 % 0.68 [ 0.16, 2.81 ]
Jeste 2003 5/87 5/89 5.3 % 1.02 [ 0.31, 3.41 ]
Keefe 2006 24/158 15/159 13.7 % 1.61 [ 0.88, 2.95 ]
Lieberman 2005 34/341 62/336 20.0 % 0.54 [ 0.37, 0.80 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )

(. . . Continued)
M- M-
n/N n/N CI CI
McEvoy 2006 0/16 1/19 0.9 % 0.39 [ 0.02, 9.01 ]
McEvoy 2007 13/133 14/133 11.3 % 0.93 [ 0.45, 1.90 ]
Purdon 2000 3/21 2/21 3.0 % 1.50 [ 0.28, 8.08 ]
Sikich 2004 4/20 0/16 1.1 % 7.29 [ 0.42, 126.07 ]
Stroup 2006 7/70 13/68 8.9 % 0.52 [ 0.22, 1.23 ]
Tran 1997 17/167 17/172 13.0 % 1.03 [ 0.54, 1.95 ]
Volavka 2002 2/41 1/39 1.6 % 1.90 [ 0.18, 20.15 ]
Wang 2006 4/19 2/17 3.4 % 1.79 [ 0.37, 8.57 ]
Subtotal (95% CI) 1301 1294 100.0 % 0.96 [ 0.71, 1.30 ]

3 due to inefficacy
Conley 2001 2/188 5/189 1.9 % 0.40 [ 0.08, 2.05 ]
Dollfus 2005 3/40 2/36 1.7 % 1.35 [ 0.24, 7.63 ]
Gureje 2003 11/33 6/32 6.1 % 1.78 [ 0.75, 4.23 ]
Jeste 2003 3/87 1/89 1.0 % 3.07 [ 0.33, 28.94 ]
Keefe 2006 18/158 20/159 11.7 % 0.91 [ 0.50, 1.65 ]
Lieberman 2005 91/341 48/336 29.0 % 1.87 [ 1.36, 2.56 ]
McEvoy 2006 6/16 6/19 5.6 % 1.19 [ 0.48, 2.97 ]
McEvoy 2007 12/133 15/133 8.6 % 0.80 [ 0.39, 1.64 ]
Purdon 2000 4/21 1/21 1.1 % 4.00 [ 0.49, 32.87 ]
Robinson 2005 3/60 4/60 2.3 % 0.75 [ 0.18, 3.21 ]
Sikich 2004 4/20 2/16 2.0 % 1.60 [ 0.33, 7.65 ]
Stroup 2006 18/70 15/68 11.7 % 1.17 [ 0.64, 2.12 ]
Tran 1997 28/167 24/172 15.5 % 1.20 [ 0.73, 1.98 ]
Volavka 2002 2/41 4/39 1.8 % 0.48 [ 0.09, 2.45 ]
Subtotal (95% CI) 1375 1369 100.0 % 1.28 [ 1.02, 1.60 ]

0.1 0.2 0.5 1 2 5 10


Analysis 4.5. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 5 Mental state: 1a. General -
no clinically important change (less than 50% PANSS total score reduction).
Outcome: 5 Mental state: 1a. General - no clinically important change (less than 50% PANSS total score reduction)

M- M-
n/N n/N CI CI
1 short term
Dollfus 2005 1/38 2/33 0.1 % 0.43 [ 0.04, 4.57 ]
Subtotal (95% CI) 38 33 0.1 % 0.43 [ 0.04, 4.57 ]

2 long term
Gureje 2003 28/30 29/32 29.5 % 1.03 [ 0.89, 1.19 ]
Tran 1997 147/167 136/172 70.4 % 1.11 [ 1.01, 1.22 ]
Subtotal (95% CI) 197 204 99.9 % 1.09 [ 1.00, 1.18 ]

Total (95% CI) 235 237 100.0 % 1.09 [ 1.00, 1.18 ]
0.001 0.01 0.1 1 10 100 1000


Analysis 4.6. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 6 Mental state: 1b. General -
no clinically important change - short term (less than 20% PANSS total score reduction).
Outcome: 6 Mental state: 1b. General - no clinically important change - short term (less than 20% PANSS total score reduction)

M- M-
n/N n/N CI CI
Conley 2001 109/188 108/189 78.9 % 1.01 [ 0.85, 1.21 ]
Jeste 2003 39/87 38/89 21.1 % 1.05 [ 0.75, 1.47 ]
Total (95% CI) 275 278 100.0 % 1.02 [ 0.88, 1.19 ]

0.1 0.2 0.5 1 2 5 10


Analysis 4.7. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 7 Mental state: 1c. General -
Outcome: 7 Mental state: 1c. General - average endpoint score (PANSS total, high = poor)
Mean Mean
1 short term
Atmaca 2003 13 78.26 (4.62) 13 74.86 (6.41) 10.1 % 3.40 [ -0.90, 7.70 ]
Conley 2001 175 -12.8 (15.9) 181 -12.9 (16.1) 16.9 % 0.10 [ -3.22, 3.42 ]
Dollfus 2005 38 -16.9 (18.8) 33 -17.5 (17.7) 2.6 % 0.60 [ -7.90, 9.10 ]
Jeste 2003 83 -12.3 (18.04) 88 -12.3 (15.67) 7.2 % 0.0 [ -5.08, 5.08 ]
Mori 2004 19 71.5 (12) 20 69.4 (10.8) 3.6 % 2.10 [ -5.08, 9.28 ]
Svestka 2003 21 49.48 (17.7) 21 49.29 (10.17) 2.4 % 0.19 [ -8.54, 8.92 ]
Wang 2006 11 -15 (22.31) 12 -9 (22.31) 0.6 % -6.00 [ -24.25, 12.25 ]
Subtotal (95% CI) 360 368 43.5 % 0.97 [ -1.10, 3.05 ]

2 medium term
McEvoy 2006 6 -0.3 (6.86) 10 -7.7 (9.8) 2.8 % 7.40 [ -0.79, 15.59 ]
Stroup 2006 69 -8 (22.31) 66 -8.2 (22.31) 3.3 % 0.20 [ -7.33, 7.73 ]
Volavka 2002 41 -3.1 (22.31) 39 -9.1 (22.31) 2.0 % 6.00 [ -3.78, 15.78 ]
Subtotal (95% CI) 116 115 8.0 % 4.11 [ -0.71, 8.93 ]

3 long term
Gureje 2003 30 -16.3 (16.3) 32 -28.2 (20.8) 2.2 % 11.90 [ 2.63, 21.17 ]
Keefe 2006 148 -9.5 (15.5) 153 -12.4 (16) 14.7 % 2.90 [ -0.66, 6.46 ]
Lieberman 2005 333 -9.31 (22.31) 330 -11.27 (22.31) 16.2 % 1.96 [ -1.44, 5.36 ]
McEvoy 2007 37 -18.5 (9.91) 37 -18.4 (9.73) 9.3 % -0.10 [ -4.57, 4.37 ]
Tran 1997 165 -24.9 (23.2) 166 -28.1 (28) 6.1 % 3.20 [ -2.34, 8.74 ]
Subtotal (95% CI) 713 718 48.5 % 2.59 [ 0.20, 4.98 ]

Total (95% CI) 1189 1201 100.0 % 1.94 [ 0.58, 3.31 ]
-10 -5 0 5 10

Analysis 4.8. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 8 Mental state: 1d. General -
average endpoint score (BPRS total score, high = poor).
Outcome: 8 Mental state: 1d. General - average endpoint score (BPRS total score, high = poor)
Mean Mean
1 short term
Sikich 2004 19 27 (20) 16 22 (12) 12.5 % 5.00 [ -5.74, 15.74 ]
Subtotal (95% CI) 19 16 12.5 % 5.00 [ -5.74, 15.74 ]

2 long term
Gureje 2003 30 -8.8 (9.2) 32 -16.4 (12.3) 33.9 % 7.60 [ 2.21, 12.99 ]
Tran 1997 165 -15.2 (13.3) 166 -17 (16.5) 53.7 % 1.80 [ -1.43, 5.03 ]
Subtotal (95% CI) 195 198 87.5 % 4.28 [ -1.34, 9.91 ]

Total (95% CI) 214 214 100.0 % 4.16 [ 0.03, 8.29 ]
-10 -5 0 5 10

Analysis 4.9. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 9 Mental state: 2a. Positive
symptoms - no clinically important change - short term (less than 50% PANSS positive subscore reduction).
Outcome: 9 Mental state: 2a. Positive symptoms - no clinically important change - short term (less than 50% PANSS positive subscore reduction)

M- M-
n/N n/N CI CI
Conley 2001 174/188 178/189 100.0 % 0.98 [ 0.93, 1.04 ]
Total (95% CI) 188 189 100.0 % 0.98 [ 0.93, 1.04 ]

0.1 0.2 0.5 1 2 5 10


Analysis 4.10. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 10 Mental state: 2b. Positive
symptoms - average endpoint score (PANSS positive, high = poor).
Outcome: 10 Mental state: 2b. Positive symptoms - average endpoint score (PANSS positive, high = poor)
Mean Mean
1 short term
Conley 2001 175 -4.6 (5.3) 181 -4.1 (65.4) 0.3 % -0.50 [ -10.06, 9.06 ]
Dollfus 2005 39 -1.9 (3.91) 33 -1.1 (4.7) 7.6 % -0.80 [ -2.82, 1.22 ]
Jeste 2003 83 -3.6 (7.02) 88 -4 (5.72) 8.4 % 0.40 [ -1.53, 2.33 ]
Mori 2004 19 10.8 (2.2) 20 11.6 (3.1) 11.0 % -0.80 [ -2.48, 0.88 ]
Wang 2006 11 -4.5 (7.3) 12 -2.36 (7.3) 0.9 % -2.14 [ -8.11, 3.83 ]
Subtotal (95% CI) 327 334 28.1 % -0.48 [ -1.53, 0.57 ]

2 medium term
McEvoy 2006 6 -0.5 (1.71) 10 -2.9 (4.11) 3.7 % 2.40 [ -0.49, 5.29 ]
Stroup 2006 69 -2.3 (7.3) 66 -3.4 (7.3) 5.1 % 1.10 [ -1.36, 3.56 ]
Volavka 2002 41 -1.9 (7.3) 39 -3.3 (7.3) 3.0 % 1.40 [ -1.80, 4.60 ]
Subtotal (95% CI) 116 115 11.8 % 1.58 [ -0.03, 3.20 ]

3 long term
Gureje 2003 30 -4.1 (5.4) 32 -6.2 (5.8) 4.0 % 2.10 [ -0.69, 4.89 ]
Keefe 2006 148 -3.6 (5.5) 153 -4.3 (4.9) 22.3 % 0.70 [ -0.48, 1.88 ]
McEvoy 2007 37 -6.6 (3.16) 37 -7.1 (3.1) 15.2 % 0.50 [ -0.93, 1.93 ]
Purdon 2000 21 -1.19 (3.14) 21 -2.14 (4.33) 5.9 % 0.95 [ -1.34, 3.24 ]
Tran 1997 165 -6.9 (6.4) 166 -7.2 (8.1) 12.5 % 0.30 [ -1.27, 1.87 ]
Subtotal (95% CI) 401 409 60.0 % 0.68 [ -0.04, 1.40 ]

Total (95% CI) 844 858 100.0 % 0.46 [ -0.09, 1.02 ]
-10 -5 0 5 10

Analysis 4.11. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 11 Mental state: 3a. Negative
Mean Mean
1 short term
Conley 2001 175 -2.8 (5.3) 181 -2.6 (5.4) 22.0 % -0.20 [ -1.31, 0.91 ]
Dollfus 2005 39 -4.9 (5.5) 33 -5.2 (5.9) 3.9 % 0.30 [ -2.35, 2.95 ]
Jeste 2003 83 -4.3 (6.38) 88 -3.8 (6.1) 7.7 % -0.50 [ -2.37, 1.37 ]
Mori 2004 19 25.6 (4.8) 20 22.8 (3.3) 4.0 % 2.80 [ 0.20, 5.40 ]
Wang 2006 11 -4.17 (6.48) 12 -3.48 (6.48) 1.0 % -0.69 [ -5.99, 4.61 ]
Subtotal (95% CI) 327 334 38.6 % 0.19 [ -0.85, 1.22 ]

2 medium term
McEvoy 2006 6 0 (4.16) 10 -0.7 (2.21) 2.1 % 0.70 [ -2.90, 4.30 ]
Stroup 2006 69 -1.5 (6.48) 66 -0.4 (6.48) 5.7 % -1.10 [ -3.29, 1.09 ]
Volavka 2002 41 -0.2 (6.48) 39 -1.6 (6.48) 3.4 % 1.40 [ -1.44, 4.24 ]
Subtotal (95% CI) 116 115 11.1 % 0.00 [ -1.58, 1.59 ]

3 long term
Gureje 2003 30 -4.1 (5.3) 32 -6.3 (6.6) 3.1 % 2.20 [ -0.77, 5.17 ]
Keefe 2006 148 -1.6 (4.9) 153 -2.5 (5.3) 20.5 % 0.90 [ -0.25, 2.05 ]
McEvoy 2007 37 -3.6 (3.16) 37 -3.5 (3.1) 13.4 % -0.10 [ -1.53, 1.33 ]
Purdon 2000 21 -0.67 (5.99) 21 -2.76 (5.81) 2.1 % 2.09 [ -1.48, 5.66 ]
Tran 1997 165 -6.2 (6.6) 166 -7.3 (7.8) 11.2 % 1.10 [ -0.46, 2.66 ]
Subtotal (95% CI) 401 409 50.2 % 0.81 [ 0.07, 1.54 ]

Total (95% CI) 844 858 100.0 % 0.44 [ -0.08, 0.96 ]
-10 -5 0 5 10

Analysis 4.12. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 12 Mental state: 3b. Negative
symptoms - average endpoint score - long term (SANS total, high = poor).
Outcome: 12 Mental state: 3b. Negative symptoms - average endpoint score - long term (SANS total, high = poor)
Mean Mean
Tran 1997 151 -2.9 (3.8) 157 -4.3 (5.3) 100.0 % 1.40 [ 0.37, 2.43 ]
Total (95% CI) 151 157 100.0 % 1.40 [ 0.37, 2.43 ]

-10 -5 0 5 10
Analysis 4.13. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 13 Quality of life: General -
average endpoint score - long term (QLS total score, high = poor).
Outcome: 13 Quality of life: General - average endpoint score - long term (QLS total score, high = poor)
Mean Mean
Gureje 2003 26 -4.9 (19.2) 30 -11.9 (13.4) 20.7 % 7.00 [ -1.80, 15.80 ]
Tran 1997 122 -8.8 (16.9) 118 -13.4 (18.6) 79.3 % 4.60 [ 0.10, 9.10 ]
Total (95% CI) 148 148 100.0 % 5.10 [ 1.09, 9.10 ]

-10 -5 0 5 10

Analysis 4.14. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 14 Cognitive functioning:
1a.General - no clinically important change - medium term (less than SD in Global Neurocognitive Score
improved).
Outcome: 14 Cognitive functioning: 1a.General - no clinically important change - medium term (less than SD in Global Neurocognitive Score improved)

M- M-
n/N n/N CI CI
Volavka 2002 26/41 19/39 100.0 % 1.30 [ 0.88, 1.94 ]
Total (95% CI) 41 39 100.0 % 1.30 [ 0.88, 1.94 ]

0.1 0.2 0.5 1 2 5 10

Analysis 4.15. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 15 Cognitive functioning: 1b.
General - average endpoint score - medium term (global neurocognitive score, high = poor).
Outcome: 15 Cognitive functioning: 1b. General - average endpoint score - medium term (global neurocognitive score, high = poor)
Mean Mean
Volavka 2002 26 0.29 (0.68) 26 0.25 (0.59) 100.0 % 0.04 [ -0.31, 0.39 ]
Total (95% CI) 26 26 100.0 % 0.04 [ -0.31, 0.39 ]

-10 -5 0 5 10

Analysis 4.16. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 16 Cognitive functioning: 1c.
General - average endpoint score - long term (neurocognitive composite score, high = poor).
Outcome: 16 Cognitive functioning: 1c. General - average endpoint score - long term (neurocognitive composite score, high = poor)
Mean Mean
Keefe 2006 131 0.18 (0.46) 132 0.17 (0.51) 100.0 % 0.01 [ -0.11, 0.13 ]
Total (95% CI) 131 132 100.0 % 0.01 [ -0.11, 0.13 ]

-10 -5 0 5 10

Analysis 4.17. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 17 Service use - number of
patients rehospitalised.
Outcome: 17 Service use - number of patients rehospitalised

M- M-
n/N n/N CI CI
1 short term
Dollfus 2005 6/40 4/36 7.7 % 1.35 [ 0.41, 4.40 ]
Subtotal (95% CI) 40 36 7.7 % 1.35 [ 0.41, 4.40 ]

2 medium term
Stroup 2006 16/104 12/108 22.1 % 1.38 [ 0.69, 2.78 ]
Subtotal (95% CI) 104 108 22.1 % 1.38 [ 0.69, 2.78 ]

3 long term
Lieberman 2005 51/341 38/336 70.2 % 1.32 [ 0.89, 1.96 ]
Subtotal (95% CI) 341 336 70.2 % 1.32 [ 0.89, 1.96 ]

Total (95% CI) 485 480 100.0 % 1.34 [ 0.96, 1.86 ]
0.1 0.2 0.5 1 2 5 10


Analysis 4.18. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 18 Adverse effects: 1.

M- M-
n/N n/N CI CI
Conley 2001 69/188 73/189 8.3 % 0.95 [ 0.73, 1.23 ]
Dollfus 2005 23/40 28/36 5.7 % 0.74 [ 0.54, 1.02 ]
Gureje 2003 20/33 9/32 1.6 % 2.15 [ 1.16, 4.00 ]
Jeste 2003 62/87 61/89 13.9 % 1.04 [ 0.86, 1.26 ]
Keefe 2006 40/158 41/159 4.2 % 0.98 [ 0.67, 1.43 ]
Lieberman 2005 232/341 235/336 35.9 % 0.97 [ 0.88, 1.08 ]
McEvoy 2006 9/16 14/19 2.3 % 0.76 [ 0.46, 1.27 ]
McEvoy 2007 66/133 71/133 10.0 % 0.93 [ 0.74, 1.17 ]
Sikich 2004 17/20 15/16 10.9 % 0.91 [ 0.73, 1.13 ]
Stroup 2006 26/104 29/108 2.9 % 0.93 [ 0.59, 1.47 ]
Tran 1997 40/167 45/172 4.3 % 0.92 [ 0.63, 1.32 ]
Total (95% CI) 1287 1289 100.0 % 0.96 [ 0.88, 1.03 ]

0.1 0.2 0.5 1 2 5 10


Analysis 4.19. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 19 Adverse effects: 2. Death.

M- M-
n/N n/N CI CI
1 any reason
Tran 1997 1/167 0/172 3.09 [ 0.13, 75.30 ]
Subtotal (95% CI) 167 172 3.09 [ 0.13, 75.30 ]

2 natural causes
Dollfus 2005 0/40 0/36 0.0 [ 0.0, 0.0 ]
Jeste 2003 0/87 1/89 0.34 [ 0.01, 8.26 ]
Subtotal (95% CI) 127 125 0.34 [ 0.01, 8.26 ]

3 suicide attempt
Conley 2001 2/188 5/189 0.40 [ 0.08, 2.05 ]
Gureje 2003 1/33 0/32 2.91 [ 0.12, 68.95 ]
Lieberman 2005 2/341 2/336 0.99 [ 0.14, 6.95 ]
McEvoy 2007 1/133 2/133 0.50 [ 0.05, 5.45 ]
Tran 1997 7/167 1/172 7.21 [ 0.90, 57.97 ]
Subtotal (95% CI) 862 862 1.15 [ 0.37, 3.54 ]

4 suicide
Dollfus 2005 0/40 0/36 0.0 [ 0.0, 0.0 ]
Jeste 2003 0/87 0/89 0.0 [ 0.0, 0.0 ]
McEvoy 2007 0/133 0/133 0.0 [ 0.0, 0.0 ]
Stroup 2006 1/104 0/108 3.11 [ 0.13, 75.59 ]
Subtotal (95% CI) 364 366 3.11 [ 0.13, 75.59 ]

0.1 0.2 0.5 1 2 5 10


Analysis 4.20. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 20 Adverse effects: 3a.
Cardiac effects.
Outcome: 20 Adverse effects: 3a. Cardiac effects

M- M-
n/N n/N CI CI
1 abnormal ECG
Dollfus 2005 1/40 1/36 19.6 % 0.90 [ 0.06, 13.87 ]
Tran 1997 1/167 4/172 25.6 % 0.26 [ 0.03, 2.28 ]
Subtotal (95% CI) 207 208 45.2 % 0.42 [ 0.08, 2.30 ]

2 QTc prolongation
Jeste 2003 3/87 4/89 36.4 % 0.77 [ 0.18, 3.33 ]
Lieberman 2005 7/341 0/336 18.5 % 14.78 [ 0.85, 257.77 ]
Subtotal (95% CI) 428 425 54.8 % 2.69 [ 0.12, 60.00 ]

Total (95% CI) 635 633 100.0 % 1.03 [ 0.23, 4.64 ]
0.1 0.2 0.5 1 2 5 10


Analysis 4.21. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 21 Adverse effects: 3b.
Cardiac effects - QTc abnormalities - change from baseline in ms.
Mean Mean
Conley 2001 188 -1.3 (25.7) 189 1.2 (20.2) 30.6 % -2.50 [ -7.17, 2.17 ]
Jeste 2003 73 4.1 (36.57) 78 -2.5 (32.15) 9.5 % 6.60 [ -4.41, 17.61 ]
Lieberman 2005 218 0.2 (26.6) 231 1.2 (27.4) 28.6 % -1.00 [ -6.00, 4.00 ]
Sikich 2004 19 402 (25) 16 402 (23) 5.0 % 0.0 [ -15.92, 15.92 ]
Stroup 2006 85 -4.4 (30.4) 89 -5.1 (33) 12.3 % 0.70 [ -8.72, 10.12 ]
Tran 1997 165 4.4 (35.1) 167 -4.9 (44.9) 14.0 % 9.30 [ 0.64, 17.96 ]
Total (95% CI) 748 770 100.0 % 0.96 [ -2.74, 4.67 ]

-10 -5 0 5 10


M- M-
n/N n/N CI CI
Conley 2001 69/188 73/189 15.5 % 0.95 [ 0.73, 1.23 ]
Dollfus 2005 10/40 5/36 1.2 % 1.80 [ 0.68, 4.77 ]
Gureje 2003 20/33 9/32 2.9 % 2.15 [ 1.16, 4.00 ]
Jeste 2003 12/87 12/89 2.0 % 1.02 [ 0.49, 2.15 ]
Keefe 2006 31/158 41/159 6.5 % 0.76 [ 0.50, 1.15 ]
Lieberman 2005 96/341 104/336 18.9 % 0.91 [ 0.72, 1.15 ]
McEvoy 2006 4/16 6/19 1.0 % 0.79 [ 0.27, 2.32 ]
McEvoy 2007 66/133 71/133 18.8 % 0.93 [ 0.74, 1.17 ]
Sikich 2004 17/20 15/16 20.4 % 0.91 [ 0.73, 1.13 ]
Stroup 2006 23/104 30/108 5.0 % 0.80 [ 0.50, 1.28 ]
Tran 1997 40/167 45/172 8.0 % 0.92 [ 0.63, 1.32 ]
Total (95% CI) 1287 1289 100.0 % 0.93 [ 0.84, 1.04 ]

0.1 0.2 0.5 1 2 5 10


Central nervous system - seizures.

M- M-
n/N n/N CI CI
Dollfus 2005 0/40 0/36 0.0 [ 0.0, 0.0 ]
Jeste 2003 0/87 1/89 0.34 [ 0.01, 8.26 ]
Tran 1997 0/167 2/172 0.21 [ 0.01, 4.26 ]
Volavka 2002 0/41 0/39 0.0 [ 0.0, 0.0 ]
Total (95% CI) 335 336 0.26 [ 0.03, 2.35 ]

0.1 0.2 0.5 1 2 5 10



M- M-
n/N n/N CI CI
1 akathisia
Dollfus 2005 2/40 1/36 1.1 % 1.80 [ 0.17, 19.02 ]
Gureje 2003 5/33 6/32 5.1 % 0.81 [ 0.27, 2.39 ]
Keefe 2006 20/158 14/159 14.4 % 1.44 [ 0.75, 2.74 ]
Lieberman 2005 20/341 15/336 14.1 % 1.31 [ 0.68, 2.52 ]
McEvoy 2007 30/133 27/133 28.3 % 1.11 [ 0.70, 1.76 ]
Sikich 2004 0/20 2/16 0.7 % 0.16 [ 0.01, 3.15 ]
Stroup 2006 3/104 6/108 3.3 % 0.52 [ 0.13, 2.02 ]
Tran 1997 45/167 27/172 33.0 % 1.72 [ 1.12, 2.63 ]
Subtotal (95% CI) 996 992 100.0 % 1.30 [ 1.02, 1.66 ]

2 akinesia
Dollfus 2005 6/40 2/36 6.6 % 2.70 [ 0.58, 12.54 ]
McEvoy 2007 36/133 32/133 91.9 % 1.13 [ 0.75, 1.70 ]
Tran 1997 1/167 0/172 1.5 % 3.09 [ 0.13, 75.30 ]
Subtotal (95% CI) 340 341 100.0 % 1.21 [ 0.82, 1.79 ]

3 dyskinesia
Gureje 2003 1/33 1/32 14.7 % 0.97 [ 0.06, 14.85 ]
Jeste 2003 3/87 2/89 35.3 % 1.53 [ 0.26, 8.96 ]
Tran 1997 3/167 4/172 50.0 % 0.77 [ 0.18, 3.40 ]
Subtotal (95% CI) 287 293 100.0 % 1.02 [ 0.36, 2.90 ]

0.001 0.01 0.1 1 10 100 1000

(Continued . . . )

(. . .Continued)
M- M-
n/N n/N CI CI
4 dystonia
Dollfus 2005 1/40 0/36 19.8 % 2.71 [ 0.11, 64.43 ]
Jeste 2003 0/87 2/89 21.4 % 0.20 [ 0.01, 4.20 ]
Tran 1997 10/167 3/172 58.8 % 3.43 [ 0.96, 12.26 ]
Subtotal (95% CI) 294 297 100.0 % 1.79 [ 0.37, 8.77 ]

Conley 2001 45/188 38/189 34.2 % 1.19 [ 0.81, 1.74 ]
Jeste 2003 8/87 14/89 19.0 % 0.58 [ 0.26, 1.32 ]
Stroup 2006 12/104 4/108 13.0 % 3.12 [ 1.04, 9.35 ]
Tran 1997 51/167 31/172 33.8 % 1.69 [ 1.14, 2.51 ]
Subtotal (95% CI) 546 558 100.0 % 1.33 [ 0.83, 2.13 ]

6 parkinsonism
Dollfus 2005 1/40 0/36 1.8 % 2.71 [ 0.11, 64.43 ]
Gureje 2003 1/33 0/32 1.8 % 2.91 [ 0.12, 68.95 ]
Jeste 2003 1/87 4/89 3.8 % 0.26 [ 0.03, 2.24 ]
Robinson 2005 9/60 5/60 16.6 % 1.80 [ 0.64, 5.06 ]
Tran 1997 37/167 22/172 76.1 % 1.73 [ 1.07, 2.81 ]
Subtotal (95% CI) 387 389 100.0 % 1.65 [ 1.08, 2.51 ]

7 rigor
Dollfus 2005 0/40 1/36 35.5 % 0.30 [ 0.01, 7.16 ]
Gureje 2003 1/33 2/32 64.5 % 0.48 [ 0.05, 5.09 ]
Subtotal (95% CI) 73 68 100.0 % 0.41 [ 0.06, 2.70 ]

8 tremor
Dollfus 2005 1/40 2/36 6.0 % 0.45 [ 0.04, 4.76 ]
Gureje 2003 2/33 3/32 10.9 % 0.65 [ 0.12, 3.62 ]
0.001 0.01 0.1 1 10 100 1000

(Continued . . . )

(. . .Continued)
M- M-
n/N n/N CI CI
Jeste 2003 1/87 6/89 7.6 % 0.17 [ 0.02, 1.39 ]
Keefe 2006 11/158 13/159 42.9 % 0.85 [ 0.39, 1.84 ]
Tran 1997 11/167 7/172 32.6 % 1.62 [ 0.64, 4.08 ]
Subtotal (95% CI) 485 488 100.0 % 0.87 [ 0.48, 1.57 ]

Atmaca 2003 3/14 0/14 0.4 % 7.00 [ 0.39, 124.14 ]
Conley 2001 61/188 53/189 17.7 % 1.16 [ 0.85, 1.57 ]
Dollfus 2005 3/40 5/36 1.9 % 0.54 [ 0.14, 2.10 ]
Gureje 2003 9/33 4/32 2.9 % 2.18 [ 0.75, 6.38 ]
Jeste 2003 11/87 13/89 5.5 % 0.87 [ 0.41, 1.83 ]
Keefe 2006 76/158 65/159 21.1 % 1.18 [ 0.92, 1.51 ]
Lieberman 2005 32/341 25/336 10.1 % 1.26 [ 0.76, 2.08 ]
McEvoy 2007 11/133 15/133 5.6 % 0.73 [ 0.35, 1.54 ]
Purdon 2000 9/21 3/21 2.5 % 3.00 [ 0.94, 9.55 ]
Robinson 2005 19/60 10/60 6.4 % 1.90 [ 0.97, 3.74 ]
Sikich 2004 10/20 9/16 7.5 % 0.89 [ 0.48, 1.64 ]
Tran 1997 55/167 34/172 14.7 % 1.67 [ 1.15, 2.41 ]
Volavka 2002 13/41 5/39 3.7 % 2.47 [ 0.97, 6.29 ]
Subtotal (95% CI) 1303 1296 100.0 % 1.28 [ 1.06, 1.55 ]

0.001 0.01 0.1 1 10 100 1000


Mean Mean

Keefe 2006 150 0.12 (3.67) 152 0.09 (2.91) 100.0 % 0.03 [ -0.72, 0.78 ]
Subtotal (95% CI) 150 152 100.0 % 0.03 [ -0.72, 0.78 ]

Keefe 2006 150 0.01 (1.13) 153 -0.18 (0.92) 51.8 % 0.19 [ -0.04, 0.42 ]
Sacchetti 2004 25 1.1 (0.86) 25 -0.2 (0.86) 48.2 % 1.30 [ 0.82, 1.78 ]
Subtotal (95% CI) 175 178 100.0 % 0.72 [ -0.36, 1.81 ]

3 akathisia: ESRS subscore for akathisia (high = poor)
Conley 2001 179 -0.1 (1.3) 180 -0.1 (1.3) 100.0 % 0.0 [ -0.27, 0.27 ]
Subtotal (95% CI) 179 180 100.0 % 0.0 [ -0.27, 0.27 ]

4 dyskinesia: ESRS subscore for dyskinesia (high = poor)
Conley 2001 179 -0.4 (2.7) 180 -0.4 (2.7) 55.3 % 0.0 [ -0.56, 0.56 ]
Jeste 2003 83 2.3 (3.6) 88 3.1 (3.7) 26.8 % -0.80 [ -1.89, 0.29 ]
Purdon 2000 21 0.19 (1.72) 21 -0.57 (2.87) 17.9 % 0.76 [ -0.67, 2.19 ]
Subtotal (95% CI) 283 289 100.0 % -0.08 [ -0.76, 0.60 ]

5 dystonia: ESRS subscore for dystonia (high = poor)
Purdon 2000 21 -0.14 (1.65) 21 -0.05 (0.97) 100.0 % -0.09 [ -0.91, 0.73 ]
Subtotal (95% CI) 21 21 100.0 % -0.09 [ -0.91, 0.73 ]

Conley 2001 179 -0.9 (4) 180 -1.2 (4) 60.4 % 0.30 [ -0.53, 1.13 ]
-10 -5 0 5 10
(Continued . . . )

(. . . Continued)
Mean Mean
Dollfus 2005 39 1 (5.9) 33 1.3 (6.1) 5.3 % -0.30 [ -3.09, 2.49 ]
Jeste 2003 83 -2.1 (5.38) 88 -1.7 (5.63) 15.2 % -0.40 [ -2.05, 1.25 ]
Volavka 2002 41 4.8 (3.6) 39 3.8 (3.1) 19.1 % 1.00 [ -0.47, 2.47 ]
Subtotal (95% CI) 342 340 100.0 % 0.30 [ -0.35, 0.94 ]

Keefe 2006 149 -0.06 (3.16) 153 -0.73 (2.92) 30.3 % 0.67 [ -0.02, 1.36 ]
Robinson 2005 56 1.4 (0.58) 56 1.2 (0.58) 41.0 % 0.20 [ -0.01, 0.41 ]
Sacchetti 2004 25 2.2 (3.58) 25 -1 (3.58) 9.7 % 3.20 [ 1.22, 5.18 ]
Sikich 2004 19 2.1 (2.2) 16 1.9 (2.4) 14.0 % 0.20 [ -1.34, 1.74 ]
Wang 2006 11 -0.17 (3.58) 12 -0.2 (3.58) 5.1 % 0.03 [ -2.90, 2.96 ]
Subtotal (95% CI) 260 262 100.0 % 0.62 [ -0.08, 1.33 ]

8 parkinsonism: ESRS subscore for parkinsonism (high = poor)
Conley 2001 179 -0.5 (2.7) 180 -0.7 (2.7) 53.2 % 0.20 [ -0.36, 0.76 ]
Jeste 2003 83 5.5 (4.6) 88 6.4 (6) 31.7 % -0.90 [ -2.50, 0.70 ]
Purdon 2000 21 1.33 (5.36) 21 -1.43 (4.32) 15.1 % 2.76 [ -0.18, 5.70 ]
Subtotal (95% CI) 283 289 100.0 % 0.24 [ -1.09, 1.57 ]

-10 -5 0 5 10

Analysis 4.26. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 26 Adverse effects: 6.
Haematological: white blood cells - significant low white blood cell count (as def. by the original studies).
Outcome: 26 Adverse effects: 6. Haematological: white blood cells - significant low white blood cell count (as def. by the original studies)

M- M-
n/N n/N CI CI
Gureje 2003 1/33 0/32 28.8 % 2.91 [ 0.12, 68.95 ]
Tran 1997 1/167 7/172 40.8 % 0.15 [ 0.02, 1.18 ]
Volavka 2002 2/41 0/39 30.4 % 4.76 [ 0.24, 96.16 ]
Total (95% CI) 241 243 100.0 % 1.00 [ 0.09, 10.59 ]

0.1 0.2 0.5 1 2 5 10



M- M-
n/N n/N CI CI
1 abnormal ejaculation
Conley 2001 3/135 0/138 7.15 [ 0.37, 137.20 ]
Gureje 2003 1/18 0/20 3.32 [ 0.14, 76.60 ]
Tran 1997 12/108 3/112 4.15 [ 1.20, 14.29 ]
Subtotal (95% CI) 261 270 4.34 [ 1.49, 12.69 ]

2 abnormally high prolactin concentration
Dollfus 2005 4/40 1/36 3.60 [ 0.42, 30.74 ]
Jeste 2003 13/34 1/28 10.71 [ 1.49, 76.88 ]
Tran 1997 157/167 88/172 1.84 [ 1.58, 2.14 ]
Subtotal (95% CI) 241 236 3.02 [ 0.99, 9.23 ]

3 amenorrhea
Conley 2001 11/53 9/51 1.18 [ 0.53, 2.60 ]
Dollfus 2005 1/40 0/36 2.71 [ 0.11, 64.43 ]
Lieberman 2005 16/88 11/92 1.52 [ 0.75, 3.09 ]
McEvoy 2006 0/6 0/1 0.0 [ 0.0, 0.0 ]
McEvoy 2007 16/34 10/32 1.51 [ 0.81, 2.81 ]
Sikich 2004 1/6 0/7 3.43 [ 0.16, 71.36 ]
Tran 1997 4/59 1/60 4.07 [ 0.47, 35.33 ]
Subtotal (95% CI) 286 279 1.50 [ 1.02, 2.22 ]

4 decreased libido
0.1 0.2 0.5 1 2 5 10

(Continued . . . )

(. . .Continued)
M- M-
n/N n/N CI CI
Conley 2001 3/188 1/189 3.02 [ 0.32, 28.73 ]
Gureje 2003 1/33 1/32 0.97 [ 0.06, 14.85 ]
Tran 1997 6/167 2/172 3.09 [ 0.63, 15.09 ]
Subtotal (95% CI) 388 393 2.48 [ 0.77, 8.00 ]

5 galactorrhea
Conley 2001 3/53 1/51 2.89 [ 0.31, 26.85 ]
Lieberman 2005 14/341 7/336 1.97 [ 0.81, 4.82 ]
McEvoy 2006 0/6 1/1 0.10 [ 0.01, 1.55 ]
McEvoy 2007 3/34 3/32 0.94 [ 0.20, 4.33 ]
Sikich 2004 1/6 1/7 1.17 [ 0.09, 14.92 ]
Stroup 2006 2/23 0/35 7.50 [ 0.38, 149.46 ]
Tran 1997 2/59 0/60 5.08 [ 0.25, 103.68 ]
Subtotal (95% CI) 522 522 1.59 [ 0.77, 3.28 ]

6 gynecomastia
Conley 2001 1/188 1/189 1.01 [ 0.06, 15.95 ]
Gureje 2003 1/33 0/32 2.91 [ 0.12, 68.95 ]
McEvoy 2007 13/133 9/133 1.44 [ 0.64, 3.26 ]
Sikich 2004 2/20 2/16 0.80 [ 0.13, 5.07 ]
Tran 1997 1/167 0/172 3.09 [ 0.13, 75.30 ]
Subtotal (95% CI) 541 542 1.39 [ 0.70, 2.77 ]

7 impotence
Conley 2001 4/135 1/138 4.09 [ 0.46, 36.11 ]
Gureje 2003 2/18 1/20 2.22 [ 0.22, 22.49 ]
Tran 1997 4/108 3/112 1.38 [ 0.32, 6.03 ]
Subtotal (95% CI) 261 270 2.00 [ 0.68, 5.89 ]

0.1 0.2 0.5 1 2 5 10

(Continued . . . )

(. . .Continued)
M- M-
n/N n/N CI CI
8 orgastic dysfunction
Conley 2001 2/188 0/189 5.03 [ 0.24, 104.00 ]
Subtotal (95% CI) 188 189 5.03 [ 0.24, 104.00 ]

Conley 2001 36/135 34/138 1.08 [ 0.72, 1.62 ]
Dollfus 2005 3/40 4/36 0.68 [ 0.16, 2.81 ]
Jeste 2003 1/87 0/89 3.07 [ 0.13, 74.30 ]
Lieberman 2005 91/341 91/336 0.99 [ 0.77, 1.26 ]
McEvoy 2006 4/16 2/19 2.38 [ 0.50, 11.32 ]
McEvoy 2007 36/133 37/133 0.97 [ 0.66, 1.44 ]
Stroup 2006 30/104 18/108 1.73 [ 1.03, 2.91 ]
Subtotal (95% CI) 856 859 1.07 [ 0.90, 1.28 ]

0.1 0.2 0.5 1 2 5 10


Prolactin - change from baseline in ng/ml.
Mean Mean

Lieberman 2005 341 15.4 (27.7) 336 -6.1 (22) 24.1 % 21.50 [ 17.73, 25.27 ]
Keefe 2006 130 18.75 (31.23) 136 -9.73 (23.15) 19.0 % 28.48 [ 21.85, 35.11 ]
McEvoy 2006 11 15.4 (17.91) 16 -4.1 (9.2) 11.6 % 19.50 [ 8.00, 31.00 ]
McEvoy 2007 37 12.1 (15.88) 37 -15.9 (15.57) 18.0 % 28.00 [ 20.83, 35.17 ]
Sikich 2004 19 37.2 (19.8) 16 30 (12.9) 12.3 % 7.20 [ -3.72, 18.12 ]
Stroup 2006 104 22 (29.6) 108 -5.1 (37.4) 14.9 % 27.10 [ 18.04, 36.16 ]
Subtotal (95% CI) 642 649 100.0 % 22.84 [ 17.69, 27.98 ]

2 change from baseline in ng/ml - of men only
Jeste 2003 22 32.9 (24.11) 18 9.7 (5.01) 36.8 % 23.20 [ 12.86, 33.54 ]
Volavka 2002 16 32 (12.2) 14 14 (9.8) 63.2 % 18.00 [ 10.12, 25.88 ]
Subtotal (95% CI) 38 32 100.0 % 19.91 [ 13.64, 26.18 ]

3 change from baseline in ng/ml - of women only
Jeste 2003 32 60.3 (32.13) 39 18.9 (12.05) 100.0 % 41.40 [ 29.64, 53.16 ]
Subtotal (95% CI) 32 39 100.0 % 41.40 [ 29.64, 53.16 ]

-10 -5 0 5 10

Metabolic - cholesterol - significant cholesterol increase.
Outcome: 29 Adverse effects: 8a. Metabolic - cholesterol - significant cholesterol increase

M- M-
n/N n/N CI CI
McEvoy 2007 18/133 23/133 100.0 % 0.78 [ 0.44, 1.38 ]
Total (95% CI) 133 133 100.0 % 0.78 [ 0.44, 1.38 ]

0.1 0.2 0.5 1 2 5 10


Outcome: 30 Adverse effects: 8b. Metabolic - cholesterol - change from baseline in mg/dl
Mean Mean
Jeste 2003 68 95.5 (20.78) 73 100.36 (21.53) 22.1 % -4.86 [ -11.84, 2.12 ]
Keefe 2006 113 -2.38 (25.38) 111 8.97 (31.41) 20.2 % -11.35 [ -18.84, -3.86 ]
Lieberman 2005 341 -2.1 (35.1) 336 9.7 (38.5) 29.0 % -11.80 [ -17.35, -6.25 ]
McEvoy 2006 11 -4 (27.2) 16 0.2 (31.6) 3.2 % -4.20 [ -26.52, 18.12 ]
McEvoy 2007 37 11.4 (28.28) 37 15.7 (26.16) 9.2 % -4.30 [ -16.71, 8.11 ]
Stroup 2006 104 -2.6 (39.8) 108 17.9 (34.3) 13.1 % -20.50 [ -30.52, -10.48 ]
Volavka 2002 14 9.2 (36.7) 22 20.1 (26.8) 3.2 % -10.90 [ -33.15, 11.35 ]
Total (95% CI) 688 703 100.0 % -10.36 [ -14.43, -6.28 ]

-10 -5 0 5 10

Analysis 4.31. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 31 Adverse effects: 8c.
Metabolic - glucose - abnormally high fasting glucose value.
Outcome: 31 Adverse effects: 8c. Metabolic - glucose - abnormally high fasting glucose value

M- M-
n/N n/N CI CI
Gureje 2003 1/33 1/32 9.4 % 0.97 [ 0.06, 14.85 ]
McEvoy 2007 6/133 14/133 81.5 % 0.43 [ 0.17, 1.08 ]
Tran 1997 1/167 1/172 9.1 % 1.03 [ 0.06, 16.33 ]
Total (95% CI) 333 337 100.0 % 0.50 [ 0.22, 1.16 ]

0.1 0.2 0.5 1 2 5 10


Analysis 4.32. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 32 Adverse effects: 8d.
Outcome: 32 Adverse effects: 8d. Metabolic - glucose - change from baseline in mg/dl
Mean Mean
Jeste 2003 67 114.78 (30.94) 73 120.9 (46.22) 7.5 % -6.12 [ -19.05, 6.81 ]
Lieberman 2005 341 6.7 (36.9) 336 15 (51.3) 23.6 % -8.30 [ -15.04, -1.56 ]
McEvoy 2006 11 32.2 (111.1) 16 23.6 (60.8) 0.3 % 8.60 [ -63.50, 80.70 ]
McEvoy 2007 37 4.8 (10.34) 37 8.6 (9.67) 41.8 % -3.80 [ -8.36, 0.76 ]
Sikich 2004 19 79 (19.8) 16 97.2 (14.4) 9.5 % -18.20 [ -29.56, -6.84 ]
Stroup 2006 104 4.8 (43.9) 108 14.8 (41.6) 9.3 % -10.00 [ -21.52, 1.52 ]
Volavka 2002 14 2.7 (12.2) 22 14.3 (25.5) 8.1 % -11.60 [ -24.03, 0.83 ]
Total (95% CI) 593 608 100.0 % -7.58 [ -11.23, -3.93 ]

-10 -5 0 5 10

Analysis 4.33. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 33 Adverse effects: 8e.
Metabolic - weight gain.
Outcome: 33 Adverse effects: 8e. Metabolic - weight gain

M- M-
n/N n/N CI CI
1 significant weight gain (as defined by the original studies)
Conley 2001 18/188 44/189 12.3 % 0.41 [ 0.25, 0.68 ]
Jeste 2003 4/87 12/89 4.6 % 0.34 [ 0.11, 1.02 ]
Lieberman 2005 42/341 92/336 16.8 % 0.45 [ 0.32, 0.63 ]
McEvoy 2006 2/16 2/19 1.8 % 1.19 [ 0.19, 7.50 ]
McEvoy 2007 77/133 106/133 21.1 % 0.73 [ 0.61, 0.86 ]
Sacchetti 2004 7/25 4/25 4.6 % 1.75 [ 0.58, 5.24 ]
Stroup 2006 14/104 29/108 10.8 % 0.50 [ 0.28, 0.89 ]
Volavka 2002 4/41 13/39 5.0 % 0.29 [ 0.10, 0.82 ]
Subtotal (95% CI) 935 938 77.0 % 0.54 [ 0.39, 0.76 ]

Gureje 2003 2/33 5/32 2.5 % 0.39 [ 0.08, 1.86 ]
Keefe 2006 17/158 22/159 10.5 % 0.78 [ 0.43, 1.41 ]
Tran 1997 13/167 28/172 10.0 % 0.48 [ 0.26, 0.89 ]
Subtotal (95% CI) 358 363 23.0 % 0.60 [ 0.39, 0.90 ]

Total (95% CI) 1293 1301 100.0 % 0.55 [ 0.43, 0.72 ]
0.001 0.01 0.1 1 10 100 1000


Analysis 4.34. Comparison 4 RISPERIDONE versus OLANZAPINE, Outcome 34 Adverse effects: 8f.
Outcome: 34 Adverse effects: 8f. Metabolic - weight gain - change from baseline in kg
Mean Mean
Atmaca 2003 13 0.54 (0.72) 13 8.92 (3.13) 8.6 % -8.38 [ -10.13, -6.63 ]
Conley 2001 155 1.5 (3.5) 161 3.3 (5.1) 10.1 % -1.80 [ -2.76, -0.84 ]
Dollfus 2005 35 0.7 (2.5) 32 2.1 (3.2) 9.3 % -1.40 [ -2.78, -0.02 ]
Gureje 2003 32 4.47 (4.54) 32 4.88 (7.4) 6.1 % -0.41 [ -3.42, 2.60 ]
Jeste 2003 78 0.6 (2.2) 81 1.4 (4.1) 10.0 % -0.80 [ -1.82, 0.22 ]
Keefe 2006 150 0.81 (6.26) 152 3 (7.87) 8.9 % -2.19 [ -3.79, -0.59 ]
Lieberman 2005 300 0.4 (6.9) 307 4.3 (7) 9.8 % -3.90 [ -5.01, -2.79 ]
McEvoy 2006 16 1.8 (5.2) 19 2.8 (14.38) 2.1 % -1.00 [ -7.95, 5.95 ]
McEvoy 2007 37 6.48 (10.58) 37 10.87 (10.64) 3.6 % -4.39 [ -9.22, 0.44 ]
Sikich 2004 19 4.9 (3.6) 16 7.1 (4.1) 6.9 % -2.20 [ -4.78, 0.38 ]
Tran 1997 165 2.32 (4.83) 166 4.13 (5.88) 9.7 % -1.81 [ -2.97, -0.65 ]
Volavka 2002 39 2.3 (2.8) 38 5.4 (4.6) 8.7 % -3.10 [ -4.81, -1.39 ]
Wang 2006 11 1.5 (2.8) 12 3.4 (4.4) 6.2 % -1.90 [ -4.89, 1.09 ]
Total (95% CI) 1050 1066 100.0 % -2.61 [ -3.74, -1.48 ]

Heterogeneity: Tau2 = 3.04; Chi2 = 69.46, df = 12 (P<0.00001); I2 =83%
-10 -5 0 5 10

Analysis 5.1. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 1 Global state: 1a. No clinically
significant response (as def. by the original studies).
Comparison: 5 RISPERIDONE versus QUETIAPINE
Outcome: 1 Global state: 1a. No clinically significant response (as def. by the original studies)

M- M-
n/N n/N CI CI
Conley 2005 13/13 12/12 28.3 % 1.00 [ 0.86, 1.16 ]
McEvoy 2007 47/133 56/134 12.4 % 0.85 [ 0.62, 1.15 ]
Potkin 2006 77/153 100/156 21.7 % 0.79 [ 0.65, 0.96 ]
Zhong 2006 247/335 248/338 37.6 % 1.00 [ 0.92, 1.10 ]
Total (95% CI) 634 640 100.0 % 0.93 [ 0.82, 1.05 ]

0.1 0.2 0.5 1 2 5 10


Analysis 5.2. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 2 Global state: 1b. No clinically
important change (as defined by the original studies).

M- M-
n/N n/N CI CI
1 short term
Conley 2005 13/13 12/12 28.9 % 1.00 [ 0.86, 1.16 ]
Potkin 2006 85/153 113/156 25.6 % 0.77 [ 0.65, 0.91 ]
Zhong 2006 195/335 206/338 32.6 % 0.96 [ 0.84, 1.08 ]
Subtotal (95% CI) 501 506 87.1 % 0.91 [ 0.78, 1.06 ]

2 long term
McEvoy 2007 47/133 56/134 12.9 % 0.85 [ 0.62, 1.15 ]
Subtotal (95% CI) 133 134 12.9 % 0.85 [ 0.62, 1.15 ]

Total (95% CI) 634 640 100.0 % 0.90 [ 0.79, 1.02 ]
0.1 0.2 0.5 1 2 5 10


Analysis 5.3. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 3 Leaving the study early.

M- M-
n/N n/N CI CI
1 due to any reason
Atmaca 2003 1/14 0/14 0.1 % 3.00 [ 0.13, 67.91 ]
Conley 2005 4/13 5/12 0.6 % 0.74 [ 0.26, 2.12 ]
Lieberman 2005 253/341 277/377 37.4 % 1.01 [ 0.93, 1.10 ]
McEvoy 2006 12/16 13/15 5.0 % 0.87 [ 0.61, 1.22 ]
McEvoy 2007 95/133 95/134 19.7 % 1.01 [ 0.86, 1.17 ]
Potkin 2006 14/153 24/156 1.7 % 0.59 [ 0.32, 1.11 ]
Riedel 2005 10/22 9/22 1.4 % 1.11 [ 0.56, 2.19 ]
Sacchetti 2004 5/25 4/25 0.5 % 1.25 [ 0.38, 4.12 ]
Stroup 2006 45/70 53/63 12.6 % 0.76 [ 0.62, 0.94 ]
Zhong 2006 167/335 184/338 21.1 % 0.92 [ 0.79, 1.06 ]
Subtotal (95% CI) 1122 1156 100.0 % 0.94 [ 0.87, 1.02 ]

Conley 2005 0/13 2/12 1.9 % 0.19 [ 0.01, 3.52 ]
Lieberman 2005 34/341 49/337 33.6 % 0.69 [ 0.45, 1.03 ]
McEvoy 2006 0/16 3/15 2.0 % 0.13 [ 0.01, 2.40 ]
McEvoy 2007 13/133 13/134 19.7 % 1.01 [ 0.49, 2.09 ]
Riedel 2005 3/22 0/22 2.0 % 7.00 [ 0.38, 128.02 ]
Stroup 2006 7/70 11/63 15.3 % 0.57 [ 0.24, 1.39 ]
Zhong 2006 25/335 19/338 25.5 % 1.33 [ 0.75, 2.36 ]
Subtotal (95% CI) 930 921 100.0 % 0.84 [ 0.56, 1.27 ]

3 due to inefficacy
0.1 0.2 0.5 1 2 5 10

(Continued . . . )

(. . . Continued)
M- M-
n/N n/N CI CI
Conley 2005 3/13 3/12 2.8 % 0.92 [ 0.23, 3.72 ]
Lieberman 2005 91/341 92/337 34.8 % 0.98 [ 0.76, 1.25 ]
McEvoy 2006 6/16 6/15 6.6 % 0.94 [ 0.39, 2.27 ]
McEvoy 2007 12/133 17/134 9.8 % 0.71 [ 0.35, 1.43 ]
Riedel 2005 5/22 3/22 3.2 % 1.67 [ 0.45, 6.14 ]
Stroup 2006 18/70 22/63 15.4 % 0.74 [ 0.44, 1.24 ]
Zhong 2006 46/335 82/338 27.3 % 0.57 [ 0.41, 0.79 ]
Subtotal (95% CI) 930 921 100.0 % 0.79 [ 0.62, 1.01 ]

0.1 0.2 0.5 1 2 5 10

Analysis 5.4. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 4 Mental state: 1a General - no
clinically important change - short term (less than 30% PANSS total score reduction).
Outcome: 4 Mental state: 1a General - no clinically important change - short term (less than 30% PANSS total score reduction)

M- M-
n/N n/N CI CI
Potkin 2006 77/153 100/156 43.8 % 0.79 [ 0.65, 0.96 ]
Zhong 2006 247/335 248/338 56.2 % 1.00 [ 0.92, 1.10 ]
Total (95% CI) 488 494 100.0 % 0.90 [ 0.71, 1.15 ]

0.1 0.2 0.5 1 2 5 10


Analysis 5.5. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 5 Mental state: 1b. General - no
clinicallly important change - short term (less than 20% BPRS total score reduction).
Outcome: 5 Mental state: 1b. General - no clinicallly important change - short term (less than 20% BPRS total score reduction)

M- M-
n/N n/N CI CI
Conley 2005 10/13 9/12 100.0 % 1.03 [ 0.66, 1.60 ]
Total (95% CI) 13 12 100.0 % 1.03 [ 0.66, 1.60 ]

0.1 0.2 0.5 1 2 5 10


Analysis 5.6. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 6 Mental state: 1c. General -
average endpoint score (PANSS total score, high = poor).
Outcome: 6 Mental state: 1c. General - average endpoint score (PANSS total score, high = poor)
Mean Mean
1 short term
Atmaca 2003 13 78.26 (4.62) 14 77.24 (6.08) 17.1 % 1.02 [ -3.04, 5.08 ]
Mori 2004 19 71.5 (12) 20 72.9 (15.1) 5.3 % -1.40 [ -9.94, 7.14 ]
Potkin 2006 152 -27.7 (22.31) 156 -20.5 (22.31) 12.8 % -7.20 [ -12.18, -2.22 ]
Riedel 2005 22 -29.7 (22.31) 22 -30.4 (22.31) 2.4 % 0.70 [ -12.48, 13.88 ]
Zhong 2006 318 -18.1 (25) 328 -15.1 (25.36) 18.0 % -3.00 [ -6.88, 0.88 ]
Subtotal (95% CI) 524 540 55.5 % -2.44 [ -5.69, 0.81 ]

2 medium term
McEvoy 2006 6 -0.3 (6.86) 8 -1.3 (19.23) 2.0 % 1.00 [ -13.41, 15.41 ]
Stroup 2006 69 -8 (22.31) 63 2 (22.31) 6.4 % -10.00 [ -17.62, -2.38 ]
Subtotal (95% CI) 75 71 8.4 % -6.27 [ -16.48, 3.94 ]

3 long term
Lieberman 2005 333 -9.31 (22.31) 329 -6.08 (22.31) 21.2 % -3.23 [ -6.63, 0.17 ]
McEvoy 2007 37 -18.5 (9.91) 44 -15.6 (10.68) 14.9 % -2.90 [ -7.39, 1.59 ]
Subtotal (95% CI) 370 373 36.1 % -3.11 [ -5.82, -0.40 ]

Total (95% CI) 969 984 100.0 % -3.09 [ -5.16, -1.01 ]
-10 -5 0 5 10

Analysis 5.7. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 7 Mental state: 1d. General -
average endpoint score - short term (BPRS total score, high = poor).
Outcome: 7 Mental state: 1d. General - average endpoint score - short term (BPRS total score, high = poor)
Mean Mean
Conley 2005 13 52.15 (12.34) 12 53.83 (13.14) 100.0 % -1.68 [ -11.69, 8.33 ]
Total (95% CI) 13 12 100.0 % -1.68 [ -11.69, 8.33 ]

-10 -5 0 5 10
Analysis 5.8. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 8 Mental state: 2a. Positive
symptoms - no clinically important change - short term (less than 40% PANSS positive reduction).
Outcome: 8 Mental state: 2a. Positive symptoms - no clinically important change - short term (less than 40% PANSS positive reduction)

M- M-
n/N n/N CI CI
Zhong 2006 220/335 222/338 100.0 % 1.00 [ 0.90, 1.12 ]
Total (95% CI) 335 338 100.0 % 1.00 [ 0.90, 1.12 ]

0.1 0.2 0.5 1 2 5 10


Analysis 5.9. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 9 Mental state: 2b. Positive
symptoms - average endpoint score - (PANSS positive subscore, high = poor).
Outcome: 9 Mental state: 2b. Positive symptoms - average endpoint score - (PANSS positive subscore, high = poor)
Mean Mean
1 short term
Mori 2004 19 10.8 (2.2) 20 13.3 (4.3) 9.5 % -2.50 [ -4.63, -0.37 ]
Potkin 2006 152 -8.7 (6.16) 156 -5.9 (6.24) 22.5 % -2.80 [ -4.18, -1.42 ]
Riedel 2005 22 -7.6 (7.3) 22 -3.8 (7.3) 2.3 % -3.80 [ -8.11, 0.51 ]
Zhong 2006 318 -5.6 (7.13) 328 -4.5 (7.24) 35.2 % -1.10 [ -2.21, 0.01 ]
Subtotal (95% CI) 511 526 69.5 % -2.10 [ -3.19, -1.00 ]

2 medium term
McEvoy 2006 6 -0.5 (1.71) 8 0.6 (5.94) 2.3 % -1.10 [ -5.44, 3.24 ]
Stroup 2006 69 -2.3 (7.3) 63 0.2 (7.3) 6.9 % -2.50 [ -4.99, -0.01 ]
Subtotal (95% CI) 75 71 9.2 % -2.15 [ -4.31, 0.01 ]

3 long term
McEvoy 2007 37 -6.6 (3.16) 44 -5.3 (3.38) 21.2 % -1.30 [ -2.73, 0.13 ]
Subtotal (95% CI) 37 44 21.2 % -1.30 [ -2.73, 0.13 ]

Total (95% CI) 623 641 100.0 % -1.82 [ -2.48, -1.16 ]
-10 -5 0 5 10

Analysis 5.10. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 10 Mental state: 2c. Positive
symptoms - average endpoint score - short term (BPRS positive subscore, high = poor).
Outcome: 10 Mental state: 2c. Positive symptoms - average endpoint score - short term (BPRS positive subscore, high = poor)
Mean Mean
Conley 2005 13 -1.77 (1.31) 12 -0.67 (1.02) 100.0 % -1.10 [ -2.02, -0.18 ]
Total (95% CI) 13 12 100.0 % -1.10 [ -2.02, -0.18 ]

-10 -5 0 5 10
Analysis 5.11. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 11 Mental state: 3a. Negative
symptoms - no clinicallly important change - short term (less than 40% PANSS negative reduction).
Outcome: 11 Mental state: 3a. Negative symptoms - no clinicallly important change - short term (less than 40% PANSS negative reduction)

M- M-
n/N n/N CI CI
Zhong 2006 295/335 293/338 100.0 % 1.02 [ 0.96, 1.08 ]
Total (95% CI) 335 338 100.0 % 1.02 [ 0.96, 1.08 ]

0.1 0.2 0.5 1 2 5 10


Analysis 5.12. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 12 Mental state: 3b. Negative
symptoms - average endpoint score - (PANSS negative subscore, high = poor).
Outcome: 12 Mental state: 3b. Negative symptoms - average endpoint score - (PANSS negative subscore, high = poor)
Mean Mean
1 short term
Mori 2004 19 25.6 (4.8) 20 23.8 (4.6) 12.3 % 1.80 [ -1.15, 4.75 ]
Potkin 2006 152 -4 (4.93) 156 -2.5 (5) 19.3 % -1.50 [ -2.61, -0.39 ]
Riedel 2005 22 -4.2 (6.48) 22 -12.8 (6.48) 9.6 % 8.60 [ 4.77, 12.43 ]
Zhong 2006 284 -4.1 (6.74) 281 -3.7 (6.71) 19.3 % -0.40 [ -1.51, 0.71 ]
Subtotal (95% CI) 477 479 60.6 % 1.46 [ -1.19, 4.11 ]

2 medium term
McEvoy 2006 6 0 (4.16) 8 -1.1 (6.22) 6.1 % 1.10 [ -4.35, 6.55 ]
Stroup 2006 69 -1.5 (6.48) 63 0.2 (6.48) 15.1 % -1.70 [ -3.91, 0.51 ]
Subtotal (95% CI) 75 71 21.3 % -1.30 [ -3.35, 0.75 ]

3 long term
McEvoy 2007 37 -3.63 (3.16) 44 -2.8 (3.45) 18.2 % -0.83 [ -2.27, 0.61 ]
Subtotal (95% CI) 37 44 18.2 % -0.83 [ -2.27, 0.61 ]

Total (95% CI) 589 594 100.0 % 0.34 [ -1.26, 1.94 ]
-10 -5 0 5 10

Analysis 5.13. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 13 Mental state: 3c. Negative
symptoms - average endpoint score - short term (BPRS negative subscore, high = poor).
Outcome: 13 Mental state: 3c. Negative symptoms - average endpoint score - short term (BPRS negative subscore, high = poor)
Mean Mean
Conley 2005 13 -0.15 (0.51) 12 0.42 (0.51) 100.0 % -0.57 [ -0.97, -0.17 ]
Total (95% CI) 13 12 100.0 % -0.57 [ -0.97, -0.17 ]

-10 -5 0 5 10
Analysis 5.14. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 14 Quality of life: General -
average endpoint score - short term (QLS total score, high = poor).
Outcome: 14 Quality of life: General - average endpoint score - short term (QLS total score, high = poor)
Mean Mean
Conley 2005 12 28.4 (15.93) 10 27.9 (15.93) 100.0 % 0.50 [ -12.87, 13.87 ]
Total (95% CI) 12 10 100.0 % 0.50 [ -12.87, 13.87 ]

-10 -5 0 5 10

Analysis 5.15. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 15 Service use: Number of
participants rehospitalised.
Outcome: 15 Service use: Number of participants rehospitalised

M- M-
n/N n/N CI CI
1 medium term
Stroup 2006 16/104 19/95 23.0 % 0.77 [ 0.42, 1.41 ]
Subtotal (95% CI) 104 95 23.0 % 0.77 [ 0.42, 1.41 ]

2 long term
Lieberman 2005 51/341 68/337 77.0 % 0.74 [ 0.53, 1.03 ]
Subtotal (95% CI) 341 337 77.0 % 0.74 [ 0.53, 1.03 ]

Total (95% CI) 445 432 100.0 % 0.75 [ 0.56, 1.00 ]
0.1 0.2 0.5 1 2 5 10


Analysis 5.16. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 16 Adverse effects: 1. General
- at least one adverse effect.

M- M-
n/N n/N CI CI
Conley 2005 7/13 5/12 1.8 % 1.29 [ 0.56, 2.99 ]
Lieberman 2005 232/341 220/337 30.4 % 1.04 [ 0.94, 1.16 ]
McEvoy 2006 9/16 10/15 3.9 % 0.84 [ 0.48, 1.48 ]
McEvoy 2007 66/133 77/134 16.1 % 0.86 [ 0.69, 1.08 ]
Potkin 2006 29/153 22/156 4.6 % 1.34 [ 0.81, 2.23 ]
Riedel 2005 8/22 17/22 3.4 % 0.47 [ 0.26, 0.86 ]
Stroup 2006 26/104 32/95 6.0 % 0.74 [ 0.48, 1.15 ]
Zhong 2006 256/335 258/338 33.7 % 1.00 [ 0.92, 1.09 ]
Total (95% CI) 1117 1109 100.0 % 0.96 [ 0.85, 1.08 ]

0.1 0.2 0.5 1 2 5 10


Analysis 5.17. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 17 Adverse effects: 2. Death.

M- M-
n/N n/N CI CI
1 natural causes
Potkin 2006 0/153 0/156 0.0 [ 0.0, 0.0 ]
Zhong 2006 0/335 0/338 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 488 494 0.0 [ 0.0, 0.0 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%
2 suicide attempt
Lieberman 2005 2/341 1/337 1.98 [ 0.18, 21.69 ]
McEvoy 2007 1/133 0/134 3.02 [ 0.12, 73.53 ]
Subtotal (95% CI) 474 471 2.30 [ 0.34, 15.65 ]

3 suicide
McEvoy 2007 0/133 2/134 0.20 [ 0.01, 4.16 ]
Stroup 2006 1/104 0/95 2.74 [ 0.11, 66.53 ]
Zhong 2006 0/335 0/338 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 572 567 0.71 [ 0.05, 9.16 ]

0.1 0.2 0.5 1 2 5 10


Analysis 5.18. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 18 Adverse effects: 3a.

M- M-
n/N n/N CI CI
Lieberman 2005 7/341 6/337 1.15 [ 0.39, 3.40 ]
Zhong 2006 0/335 0/338 0.0 [ 0.0, 0.0 ]
Total (95% CI) 676 675 1.15 [ 0.39, 3.40 ]

0.1 0.2 0.5 1 2 5 10

Analysis 5.19. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 19 Adverse effects: 3b.
Mean Mean
Lieberman 2005 218 0.2 (26.6) 214 5.9 (27.8) 36.2 % -5.70 [ -10.83, -0.57 ]
Stroup 2006 85 -4.4 (30.4) 81 1.9 (33.3) 24.7 % -6.30 [ -16.01, 3.41 ]
Zhong 2006 168 1.3 (18.3) 174 -2.3 (19) 39.1 % 3.60 [ -0.35, 7.55 ]
Total (95% CI) 471 469 100.0 % -2.21 [ -9.48, 5.05 ]

-10 -5 0 5 10

Analysis 5.20. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 20 Adverse effects: 4. Central
nervous system - sedation.
Outcome: 20 Adverse effects: 4. Central nervous system - sedation

M- M-
n/N n/N CI CI
Conley 2005 5/13 3/12 2.0 % 1.54 [ 0.46, 5.09 ]
Lieberman 2005 96/341 103/337 27.1 % 0.92 [ 0.73, 1.16 ]
McEvoy 2006 4/16 5/15 2.3 % 0.75 [ 0.25, 2.28 ]
McEvoy 2007 66/133 77/134 28.1 % 0.86 [ 0.69, 1.08 ]
Potkin 2006 10/153 15/156 4.6 % 0.68 [ 0.32, 1.47 ]
Riedel 2005 5/22 17/22 4.3 % 0.29 [ 0.13, 0.66 ]
Stroup 2006 23/104 22/95 9.3 % 0.95 [ 0.57, 1.60 ]
Zhong 2006 66/335 89/338 22.3 % 0.75 [ 0.57, 0.99 ]
Total (95% CI) 1117 1109 100.0 % 0.82 [ 0.69, 0.97 ]

0.1 0.2 0.5 1 2 5 10



M- M-
n/N n/N CI CI
1 akathisia
Lieberman 2005 20/341 16/337 1.24 [ 0.65, 2.34 ]
McEvoy 2007 30/133 25/134 1.21 [ 0.75, 1.94 ]
Potkin 2006 11/153 1/156 11.22 [ 1.47, 85.82 ]
Riedel 2005 8/22 0/22 17.00 [ 1.04, 277.61 ]
Stroup 2006 3/104 6/95 0.46 [ 0.12, 1.78 ]
Zhong 2006 28/335 13/338 2.17 [ 1.15, 4.12 ]
Subtotal (95% CI) 1088 1082 1.61 [ 0.89, 2.94 ]

2 akinesia
McEvoy 2007 36/133 33/134 1.10 [ 0.73, 1.65 ]
Subtotal (95% CI) 133 134 1.10 [ 0.73, 1.65 ]

3 dystonia
Zhong 2006 18/335 1/338 18.16 [ 2.44, 135.27 ]
Subtotal (95% CI) 335 338 18.16 [ 2.44, 135.27 ]

Stroup 2006 12/104 7/95 1.57 [ 0.64, 3.81 ]
Zhong 2006 73/335 43/338 1.71 [ 1.21, 2.42 ]
Subtotal (95% CI) 439 433 1.69 [ 1.23, 2.34 ]

0.001 0.01 0.1 1 10 100 1000

(Continued . . . )

(. . .Continued)
M- M-
n/N n/N CI CI
5 parkinsonism
Riedel 2005 8/22 0/22 17.00 [ 1.04, 277.61 ]
Zhong 2006 0/335 0/338 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 357 360 17.00 [ 1.04, 277.61 ]

6 rigor
Potkin 2006 11/153 5/156 2.24 [ 0.80, 6.30 ]
Subtotal (95% CI) 153 156 2.24 [ 0.80, 6.30 ]

Atmaca 2003 3/14 0/14 7.00 [ 0.39, 124.14 ]
Conley 2005 2/13 3/12 0.62 [ 0.12, 3.07 ]
Lieberman 2005 32/341 11/337 2.87 [ 1.47, 5.61 ]
McEvoy 2007 11/133 5/134 2.22 [ 0.79, 6.21 ]
Riedel 2005 9/22 2/22 4.50 [ 1.09, 18.50 ]
Zhong 2006 23/335 19/338 1.22 [ 0.68, 2.20 ]
Subtotal (95% CI) 858 857 1.98 [ 1.16, 3.39 ]

0.001 0.01 0.1 1 10 100 1000


Mean Mean

Potkin 2006 153 0.3 (2.47) 156 -0.1 (2.5) 56.9 % 0.40 [ -0.15, 0.95 ]
Zhong 2006 320 -0.25 (4.11) 329 -0.5 (4.17) 43.1 % 0.25 [ -0.39, 0.89 ]
Subtotal (95% CI) 473 485 100.0 % 0.34 [ -0.08, 0.75 ]

Sacchetti 2004 25 1.1 (0.86) 25 -0.3 (0.86) 48.3 % 1.40 [ 0.92, 1.88 ]
Zhong 2006 321 0.01 (0.72) 329 -0.09 (0.73) 51.7 % 0.10 [ -0.01, 0.21 ]
Subtotal (95% CI) 346 354 100.0 % 0.73 [ -0.54, 2.00 ]

Conley 2005 13 -1.3 (3.15) 12 -1.64 (3.15) 5.0 % 0.34 [ -2.13, 2.81 ]
Potkin 2006 153 0.8 (15.65) 156 -0.1 (2.5) 4.9 % 0.90 [ -1.61, 3.41 ]
Riedel 2005 22 0.8 (1.04) 22 0.17 (1.04) 39.5 % 0.63 [ 0.02, 1.24 ]
Sacchetti 2004 25 2.2 (3.58) 25 -0.4 (3.58) 7.5 % 2.60 [ 0.62, 4.58 ]
Zhong 2006 321 -0.21 (3.58) 328 -0.41 (3.62) 43.1 % 0.20 [ -0.35, 0.75 ]
Subtotal (95% CI) 534 543 100.0 % 0.59 [ 0.02, 1.16 ]

-10 -5 0 5 10

Analysis 5.23. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 23 Adverse effects: 6.
Haematological: Important decline in white blood cells.
Outcome: 23 Adverse effects: 6. Haematological: Important decline in white blood cells

M- M-
n/N n/N CI CI
Zhong 2006 0/335 1/338 100.0 % 0.34 [ 0.01, 8.23 ]
Total (95% CI) 335 338 100.0 % 0.34 [ 0.01, 8.23 ]

0.1 0.2 0.5 1 2 5 10



M- M-
n/N n/N CI CI
1 amenorrhea
Lieberman 2005 16/88 5/82 2.98 [ 1.14, 7.77 ]
McEvoy 2006 0/6 0/3 0.0 [ 0.0, 0.0 ]
McEvoy 2007 16/34 10/42 1.98 [ 1.03, 3.78 ]
Potkin 2006 0/48 1/56 0.39 [ 0.02, 9.30 ]
Subtotal (95% CI) 176 183 2.14 [ 1.26, 3.64 ]

2 dysmenorrhea
Zhong 2006 4/77 2/86 2.23 [ 0.42, 11.86 ]
Subtotal (95% CI) 77 86 2.23 [ 0.42, 11.86 ]

3 galactorrhea
Lieberman 2005 14/88 6/82 2.17 [ 0.88, 5.39 ]
McEvoy 2006 0/6 0/3 0.0 [ 0.0, 0.0 ]
McEvoy 2007 3/34 0/42 8.60 [ 0.46, 160.96 ]
Stroup 2006 2/37 0/23 3.16 [ 0.16, 62.99 ]
Zhong 2006 2/77 0/86 5.58 [ 0.27, 114.39 ]
Subtotal (95% CI) 242 236 2.65 [ 1.19, 5.91 ]

4 gynecomastia
McEvoy 2007 13/39 3/39 4.33 [ 1.34, 14.02 ]
Subtotal (95% CI) 39 39 4.33 [ 1.34, 14.02 ]

0.001 0.01 0.1 1 10 100 1000

(Continued . . . )

(. . .Continued)
M- M-
n/N n/N CI CI
Lieberman 2005 91/341 69/337 1.30 [ 0.99, 1.71 ]
McEvoy 2006 4/16 2/15 1.88 [ 0.40, 8.78 ]
McEvoy 2007 36/133 35/134 1.04 [ 0.70, 1.54 ]
Potkin 2006 0/153 1/156 0.34 [ 0.01, 8.28 ]
Stroup 2006 2/104 0/95 4.57 [ 0.22, 94.02 ]
Zhong 2006 3/335 0/338 7.06 [ 0.37, 136.20 ]
Subtotal (95% CI) 1082 1075 1.24 [ 0.99, 1.54 ]

0.001 0.01 0.1 1 10 100 1000


Prolactin - change from baseline in mg/dl.
Outcome: 25 Adverse effects: 7b. Prolactin - change from baseline in mg/dl
Mean Mean
Lieberman 2005 341 15.4 (27.7) 337 -9.3 (25.7) 18.7 % 24.70 [ 20.68, 28.72 ]
McEvoy 2006 11 15.4 (17.91) 13 -13.2 (18.02) 13.0 % 28.60 [ 14.18, 43.02 ]
McEvoy 2007 37 12.1 (15.88) 44 -18.7 (17.64) 17.2 % 30.80 [ 23.50, 38.10 ]
Potkin 2006 153 40.3 (43.29) 156 -10.1 (44.96) 15.8 % 50.40 [ 40.56, 60.24 ]
Stroup 2006 104 22 (29.6) 95 -8.3 (18.5) 17.5 % 30.30 [ 23.50, 37.10 ]
Zhong 2006 231 35.5 (30.4) 209 -11.5 (33.25) 17.9 % 47.00 [ 41.03, 52.97 ]
Total (95% CI) 877 854 100.0 % 35.28 [ 26.19, 44.36 ]

-10 -5 0 5 10

Metabolic - cholesterol - significant cholesterol increase.
Outcome: 26 Adverse effects: 8a. Metabolic - cholesterol - significant cholesterol increase

M- M-
n/N n/N CI CI
McEvoy 2007 18/133 23/134 0.79 [ 0.45, 1.39 ]
Zhong 2006 0/335 0/338 0.0 [ 0.0, 0.0 ]
Total (95% CI) 468 472 0.79 [ 0.45, 1.39 ]

0.1 0.2 0.5 1 2 5 10


Outcome: 27 Adverse effects: 8b. Metabolic - cholesterol - change from baseline in mg/dl
Mean Mean
Lieberman 2005 341 -2.1 (35.1) 337 5.3 (38.6) 39.4 % -7.40 [ -12.96, -1.84 ]
McEvoy 2006 11 -4 (27.2) 13 -13 (24.5) 3.2 % 9.00 [ -11.87, 29.87 ]
McEvoy 2007 37 11.4 (28.28) 44 25.2 (29.58) 8.5 % -13.80 [ -26.43, -1.17 ]
Stroup 2006 104 -2.63 (9.8) 95 4.8 (37) 22.0 % -7.43 [ -15.10, 0.24 ]
Zhong 2006 233 -6.45 (36.2) 218 4.9 (38.3) 26.9 % -11.35 [ -18.24, -4.46 ]
Total (95% CI) 726 707 100.0 % -8.49 [ -12.23, -4.75 ]

-10 -5 0 5 10

Analysis 5.28. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 28 Adverse effects: 8c.
Metabolic - glucose - abnormally high fasting glucose value.
Outcome: 28 Adverse effects: 8c. Metabolic - glucose - abnormally high fasting glucose value

M- M-
n/N n/N CI CI
McEvoy 2007 6/133 10/134 85.6 % 0.60 [ 0.23, 1.62 ]
Zhong 2006 2/335 1/338 14.4 % 2.02 [ 0.18, 22.15 ]
Total (95% CI) 468 472 100.0 % 0.72 [ 0.29, 1.79 ]

0.1 0.2 0.5 1 2 5 10


Analysis 5.29. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 29 Adverse effects: 8d.
Outcome: 29 Adverse effects: 8d. Metabolic - glucose - change from baseline in mg/dl
Mean Mean
Lieberman 2005 341 6.7 (36.9) 337 6.8 (45.9) 21.0 % -0.10 [ -6.37, 6.17 ]
McEvoy 2006 11 32.2 (111.1) 13 -23.3 (44) 0.2 % 55.50 [ -14.38, 125.38 ]
McEvoy 2007 37 4.8 (10.34) 44 6.2 (11.08) 37.9 % -1.40 [ -6.07, 3.27 ]
Stroup 2006 104 4.8 (43.9) 95 -0.2 (41.9) 5.8 % 5.00 [ -6.92, 16.92 ]
Zhong 2006 234 4.5 (26) 220 3.9 (26.7) 35.1 % 0.60 [ -4.25, 5.45 ]
Total (95% CI) 727 709 100.0 % 0.04 [ -2.83, 2.92 ]

-10 -5 0 5 10

Analysis 5.30. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 30 Adverse effects: 8e.
Metabolic - weight gain of 7% or more of total body weight.
Outcome: 30 Adverse effects: 8e. Metabolic - weight gain of 7% or more of total body weight

M- M-
n/N n/N CI CI
Lieberman 2005 42/341 49/337 19.0 % 0.85 [ 0.58, 1.24 ]
McEvoy 2006 2/16 2/15 0.8 % 0.94 [ 0.15, 5.84 ]
McEvoy 2007 77/133 67/134 56.4 % 1.16 [ 0.93, 1.45 ]
Riedel 2005 1/22 3/22 0.6 % 0.33 [ 0.04, 2.96 ]
Sacchetti 2004 7/25 9/25 4.2 % 0.78 [ 0.34, 1.76 ]
Stroup 2006 14/104 12/95 5.4 % 1.07 [ 0.52, 2.19 ]
Zhong 2006 33/335 34/338 13.6 % 0.98 [ 0.62, 1.54 ]
Total (95% CI) 976 966 100.0 % 1.03 [ 0.88, 1.22 ]

0.1 0.2 0.5 1 2 5 10


Analysis 5.31. Comparison 5 RISPERIDONE versus QUETIAPINE, Outcome 31 Adverse effects: 8f.
Outcome: 31 Adverse effects: 8f. Metabolic - weight gain - change from baseline in kg
Mean Mean
Atmaca 2003 13 0.54 (0.72) 14 4.41 (2.21) 20.4 % -3.87 [ -5.09, -2.65 ]
Conley 2005 13 -0.65 (2.43) 12 -1.2 (11.22) 5.5 % 0.55 [ -5.93, 7.03 ]
Lieberman 2005 300 0.4 (6.9) 305 0.5 (7) 20.7 % -0.10 [ -1.21, 1.01 ]
McEvoy 2006 16 1.8 (5.2) 15 0.5 (8.91) 7.6 % 1.30 [ -3.88, 6.48 ]
McEvoy 2007 37 6.48 (10.58) 44 5.69 (11.47) 8.4 % 0.79 [ -4.02, 5.60 ]
Riedel 2005 22 1.72 (3.57) 22 2.93 (4.02) 16.5 % -1.21 [ -3.46, 1.04 ]
Zhong 2006 309 2.12 (6.68) 324 1.64 (6.66) 20.9 % 0.48 [ -0.56, 1.52 ]
Total (95% CI) 710 736 100.0 % -0.71 [ -2.47, 1.04 ]

-10 -5 0 5 10

Analysis 6.1. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 1 Global
state - 1a. No clinically significant response (as defined by the original studies).
Comparison: 6 RISPERIDONE versus SERTINDOLE - all data short term
Outcome: 1 Global state - 1a. No clinically significant response (as defined by the original studies)

M- M-
n/N n/N CI CI
Azorin 2006 62/89 60/98 100.0 % 1.14 [ 0.92, 1.40 ]
Total (95% CI) 89 98 100.0 % 1.14 [ 0.92, 1.40 ]

0.1 0.2 0.5 1 2 5 10

Analysis 6.2. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 2 Global
state - 1b. No clinically important change (as defined by the original studies).
Outcome: 2 Global state - 1b. No clinically important change (as defined by the original studies)

M- M-
n/N n/N CI CI
Azorin 2006 46/89 41/98 100.0 % 1.24 [ 0.91, 1.68 ]
Total (95% CI) 89 98 100.0 % 1.24 [ 0.91, 1.68 ]

0.1 0.2 0.5 1 2 5 10


Analysis 6.3. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 3 Leaving
the study early.

M- M-
n/N n/N CI CI
1 due to any reason

Azorin 2006 28/89 39/98 45.0 % 0.79 [ 0.53, 1.17 ]
Kane 2005 30/105 74/216 55.0 % 0.83 [ 0.59, 1.19 ]
Subtotal (95% CI) 194 314 100.0 % 0.81 [ 0.63, 1.06 ]

Azorin 2006 9/89 12/98 58.6 % 0.83 [ 0.37, 1.87 ]
Kane 2005 5/105 17/216 41.4 % 0.61 [ 0.23, 1.60 ]
Subtotal (95% CI) 194 314 100.0 % 0.73 [ 0.39, 1.35 ]

3 due to inefficacy
Azorin 2006 5/89 8/98 21.7 % 0.69 [ 0.23, 2.03 ]
Kane 2005 14/105 37/216 78.3 % 0.78 [ 0.44, 1.38 ]
Subtotal (95% CI) 194 314 100.0 % 0.76 [ 0.46, 1.25 ]

0.1 0.2 0.5 1 2 5 10


Analysis 6.4. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 4 Mental
state: 1a. General - no clinically important change (less than 50% PANSS total score reduction).
Outcome: 4 Mental state: 1a. General - no clinically important change (less than 50% PANSS total score reduction)

M- M-
n/N n/N CI CI
Azorin 2006 62/89 60/98 100.0 % 1.14 [ 0.92, 1.40 ]
Total (95% CI) 89 98 100.0 % 1.14 [ 0.92, 1.40 ]

0.1 0.2 0.5 1 2 5 10

state: 1b. General - average endpoint score (PANSS total, high = poor).
Outcome: 5 Mental state: 1b. General - average endpoint score (PANSS total, high = poor)
Mean Mean
Azorin 2006 82 -25.8 (22.4) 90 -29.3 (23.9) 47.5 % 3.50 [ -3.42, 10.42 ]
Kane 2005 105 -19.01 (22.31) 216 -12.07 (22.31) 52.5 % -6.94 [ -12.14, -1.74 ]
Total (95% CI) 187 306 100.0 % -1.98 [ -12.20, 8.24 ]

-10 -5 0 5 10

state: 2. Positive symptoms - average endpoint score (PANSS positive, high = poor).
Outcome: 6 Mental state: 2. Positive symptoms - average endpoint score (PANSS positive, high = poor)
Mean Mean
Azorin 2006 82 -7.2 (6.5) 90 -8 (7.9) 100.0 % 0.80 [ -1.35, 2.95 ]
Total (95% CI) 82 90 100.0 % 0.80 [ -1.35, 2.95 ]

-10 -5 0 5 10
state: 3. Negative symptoms - average endpoint score (PANSS negative, high = poor).
Outcome: 7 Mental state: 3. Negative symptoms - average endpoint score (PANSS negative, high = poor)
Mean Mean
Azorin 2006 82 -6.4 (6.4) 90 -7.7 (5.8) 100.0 % 1.30 [ -0.53, 3.13 ]
Total (95% CI) 82 90 100.0 % 1.30 [ -0.53, 3.13 ]

-10 -5 0 5 10

Analysis 6.8. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 8 General
functioning: General - average endpoint score - (GAF total, high = poor).
Outcome: 8 General functioning: General - average endpoint score - (GAF total, high = poor)
Mean Mean
Azorin 2006 55 -18.2 (14.3) 59 -21.1 (15.7) 100.0 % 2.90 [ -2.61, 8.41 ]
Total (95% CI) 55 59 100.0 % 2.90 [ -2.61, 8.41 ]

-10 -5 0 5 10
Analysis 6.9. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 9 Adverse
effects: 1. General - at least one adverse effect.

M- M-
n/N n/N CI CI
Azorin 2006 72/89 84/98 36.4 % 0.94 [ 0.83, 1.07 ]
Kane 2005 89/105 185/216 63.6 % 0.99 [ 0.90, 1.09 ]
Total (95% CI) 194 314 100.0 % 0.97 [ 0.90, 1.05 ]

0.1 0.2 0.5 1 2 5 10


Analysis 6.10. Comparison 6 RISPERIDONE versus SERTINDOLE - all data short term, Outcome 10
Adverse effects: 2. Death - suicide.
Outcome: 10 Adverse effects: 2. Death - suicide

M- M-
n/N n/N CI CI
Azorin 2006 1/89 0/98 100.0 % 3.30 [ 0.14, 79.98 ]
Total (95% CI) 89 98 100.0 % 3.30 [ 0.14, 79.98 ]

0.1 0.2 0.5 1 2 5 10

Adverse effects: 3a. Cardiac effects - QTc prolongation.

M- M-
n/N n/N CI CI
Azorin 2006 4/89 22/98 80.0 % 0.20 [ 0.07, 0.56 ]
Kane 2005 1/105 9/216 20.0 % 0.23 [ 0.03, 1.78 ]
Total (95% CI) 194 314 100.0 % 0.21 [ 0.08, 0.51 ]

0.001 0.01 0.1 1 10 100 1000


Adverse effects: 3b. Cardiac effects - QTc abnormalities - change from baseline in ms.
Mean Mean
Azorin 2006 83 411 (27) 91 429.6 (29.1) 20.4 % -18.60 [ -26.94, -10.26 ]
Kane 2005 105 4.1 (15.6) 216 22.7 (22.4) 79.6 % -18.60 [ -22.82, -14.38 ]
Total (95% CI) 188 307 100.0 % -18.60 [ -22.37, -14.83 ]

-10 -5 0 5 10
Adverse effects: 4. Central nervous system - sedation.

M- M-
n/N n/N CI CI
Azorin 2006 7/89 8/98 27.3 % 0.96 [ 0.36, 2.55 ]
Kane 2005 15/105 25/216 72.7 % 1.23 [ 0.68, 2.24 ]
Total (95% CI) 194 314 100.0 % 1.15 [ 0.69, 1.92 ]

0.1 0.2 0.5 1 2 5 10


Adverse effects: 5a. Extrapyramidal effects.

M- M-
n/N n/N CI CI
1 akathisia
Kane 2005 12/105 11/216 100.0 % 2.24 [ 1.02, 4.92 ]
Subtotal (95% CI) 105 216 100.0 % 2.24 [ 1.02, 4.92 ]

Azorin 2006 25/89 18/98 100.0 % 1.53 [ 0.90, 2.61 ]
Subtotal (95% CI) 89 98 100.0 % 1.53 [ 0.90, 2.61 ]

3 parkinsonism
Kane 2005 10/105 5/216 100.0 % 4.11 [ 1.44, 11.73 ]
Subtotal (95% CI) 105 216 100.0 % 4.11 [ 1.44, 11.73 ]

4 tremor
Azorin 2006 3/89 5/98 100.0 % 0.66 [ 0.16, 2.69 ]
Subtotal (95% CI) 89 98 100.0 % 0.66 [ 0.16, 2.69 ]

0.001 0.01 0.1 1 10 100 1000


Adverse effects: 5b. Extrapyramidal symptom scales.
Outcome: 15 Adverse effects: 5b. Extrapyramidal symptom scales
Mean Mean

Azorin 2006 74 -0.7 (3.3) 82 -0.8 (3) 31.2 % 0.10 [ -0.89, 1.09 ]
Kane 2005 105 -0.8 (2.87) 216 -1.2 (2.87) 68.8 % 0.40 [ -0.27, 1.07 ]
Subtotal (95% CI) 179 298 100.0 % 0.31 [ -0.25, 0.86 ]

Azorin 2006 86 -0.1 (2.2) 93 -0.5 (1.8) 10.3 % 0.40 [ -0.19, 0.99 ]
Kane 2005 105 -0.9 (0.86) 216 -1.1 (0.86) 89.7 % 0.20 [ 0.00, 0.40 ]
Subtotal (95% CI) 191 309 100.0 % 0.22 [ 0.03, 0.41 ]

Azorin 2006 86 -0.2 (3.5) 93 -1.1 (3) 47.1 % 0.90 [ -0.06, 1.86 ]
Kane 2005 105 -1.4 (3.58) 216 -1.3 (3.58) 52.9 % -0.10 [ -0.93, 0.73 ]
Subtotal (95% CI) 191 309 100.0 % 0.37 [ -0.61, 1.35 ]

-10 -5 0 5 10

Adverse effects: 6. Prolactin associated side effects - sexual dysfunction.
Outcome: 16 Adverse effects: 6. Prolactin associated side effects - sexual dysfunction

M- M-
n/N n/N CI CI
Kane 2005 5/82 25/168 72.3 % 0.41 [ 0.16, 1.03 ]
Subtotal (95% CI) 82 168 72.3 % 0.41 [ 0.16, 1.03 ]

Azorin 2006 2/89 10/98 27.7 % 0.22 [ 0.05, 0.98 ]
Subtotal (95% CI) 89 98 27.7 % 0.22 [ 0.05, 0.98 ]

Total (95% CI) 171 266 100.0 % 0.34 [ 0.16, 0.76 ]
0.001 0.01 0.1 1 10 100 1000


Adverse effects: 7a. Metabolic - cholesterol - change from baseline in mg/dl.
Mean Mean
Kane 2005 60 8.1 (27.3) 116 3.2 (28.4) 100.0 % 4.90 [ -3.73, 13.53 ]
Total (95% CI) 60 116 100.0 % 4.90 [ -3.73, 13.53 ]

-10 -5 0 5 10
Adverse effects: 7b. Metabolic - glucose - change from baseline in mg/dl.
Mean Mean
Kane 2005 60 3.8 (20.8) 116 1.8 (32) 100.0 % 2.00 [ -5.85, 9.85 ]
Total (95% CI) 60 116 100.0 % 2.00 [ -5.85, 9.85 ]

-10 -5 0 5 10

Adverse effects: 7c. Metabolic - weight gain.
Outcome: 19 Adverse effects: 7c. Metabolic - weight gain

M- M-
n/N n/N CI CI
Azorin 2006 14/89 20/98 100.0 % 0.77 [ 0.41, 1.43 ]
Total (95% CI) 89 98 100.0 % 0.77 [ 0.41, 1.43 ]

0.1 0.2 0.5 1 2 5 10

Adverse effects: 7d. Metabolic - weight gain - change from baseline in kg.
Mean Mean
Azorin 2006 89 1.5 (3.7) 97 2.1 (3.9) 56.7 % -0.60 [ -1.69, 0.49 ]
Kane 2005 53 2.4 (3.1) 89 3.9 (4.6) 43.3 % -1.50 [ -2.77, -0.23 ]
Total (95% CI) 142 186 100.0 % -0.99 [ -1.86, -0.12 ]

-10 -5 0 5 10

Analysis 7.1. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 1 Global state: 1a. No
Comparison: 7 RISPERIDONE versus ZIPRASIDONE

M- M-
n/N n/N CI CI
Addington 2004 128/147 127/149 100.0 % 1.02 [ 0.93, 1.12 ]
Total (95% CI) 147 149 100.0 % 1.02 [ 0.93, 1.12 ]

0.1 0.2 0.5 1 2 5 10

Analysis 7.2. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 2 Global state: 1b. No
clinically important change - short term (as defined by the original studies).
Outcome: 2 Global state: 1b. No clinically important change - short term (as defined by the original studies)

M- M-
n/N n/N CI CI
Addington 2004 59/147 74/149 100.0 % 0.81 [ 0.63, 1.04 ]
Total (95% CI) 147 149 100.0 % 0.81 [ 0.63, 1.04 ]

0.1 0.2 0.5 1 2 5 10


Analysis 7.3. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 3 Leaving the study early.

M- M-
n/N n/N CI CI
1 due to any reason

Addington 2004 43/147 55/149 6.5 % 0.79 [ 0.57, 1.10 ]
Lieberman 2005 253/341 147/185 75.4 % 0.93 [ 0.85, 1.03 ]
Stroup 2006 45/70 106/137 18.1 % 0.83 [ 0.68, 1.01 ]
Subtotal (95% CI) 558 471 100.0 % 0.90 [ 0.83, 0.98 ]

Addington 2004 11/147 7/149 21.6 % 1.59 [ 0.63, 4.00 ]
Lieberman 2005 34/341 28/185 52.4 % 0.66 [ 0.41, 1.05 ]
Stroup 2006 7/70 19/137 25.9 % 0.72 [ 0.32, 1.63 ]
Subtotal (95% CI) 558 471 100.0 % 0.82 [ 0.50, 1.32 ]

3 due to inefficacy
Addington 2004 12/147 22/149 21.5 % 0.55 [ 0.28, 1.08 ]
Lieberman 2005 91/341 44/185 46.0 % 1.12 [ 0.82, 1.53 ]
Stroup 2006 18/70 42/137 32.6 % 0.84 [ 0.52, 1.34 ]
Subtotal (95% CI) 558 471 100.0 % 0.88 [ 0.60, 1.27 ]

0.1 0.2 0.5 1 2 5 10


Analysis 7.4. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 4 Mental state: 1a. General -
no clinically important change - short term (less than 50% PANSS total reduction).
Outcome: 4 Mental state: 1a. General - no clinically important change - short term (less than 50% PANSS total reduction)

M- M-
n/N n/N CI CI
Addington 2004 128/147 127/149 100.0 % 1.02 [ 0.93, 1.12 ]
Total (95% CI) 147 149 100.0 % 1.02 [ 0.93, 1.12 ]

0.1 0.2 0.5 1 2 5 10


Analysis 7.5. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 5 Mental state: 1b. General -
Outcome: 5 Mental state: 1b. General - average endpoint score (PANSS total, high = poor)
Mean Mean
1 short term
Addington 2004 147 -27.3 (7.3) 149 -25.8 (7.3) 47.9 % -1.50 [ -3.16, 0.16 ]
Subtotal (95% CI) 147 149 47.9 % -1.50 [ -3.16, 0.16 ]

2 medium term
Stroup 2006 69 -8 (22.31) 135 -1.7 (22.31) 19.8 % -6.30 [ -12.77, 0.17 ]
Subtotal (95% CI) 69 135 19.8 % -6.30 [ -12.77, 0.17 ]

3 long term
Lieberman 2005 333 -9.31 (22.31) 183 -3.3 (22.31) 32.3 % -6.01 [ -10.03, -1.99 ]
Subtotal (95% CI) 333 183 32.3 % -6.01 [ -10.03, -1.99 ]

Total (95% CI) 549 467 100.0 % -3.91 [ -7.55, -0.27 ]
-10 -5 0 5 10

Analysis 7.6. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 6 Mental state: 1c. General -
avergae endpoint score - short term (BPRS total, high = poor).
Outcome: 6 Mental state: 1c. General - avergae endpoint score - short term (BPRS total, high = poor)
Mean Mean
Addington 2004 147 -15.9 (15.91) 149 -15.2 (15.91) 100.0 % -0.70 [ -4.33, 2.93 ]
Total (95% CI) 147 149 100.0 % -0.70 [ -4.33, 2.93 ]

-10 -5 0 5 10
Analysis 7.7. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 7 Mental state: 2a. Positive
symptoms - average endpoint score - medium term (PANSS positive, high = poor).
Outcome: 7 Mental state: 2a. Positive symptoms - average endpoint score - medium term (PANSS positive, high = poor)
Mean Mean
Stroup 2006 69 -2.3 (7.3) 135 0.2 (7.3) 100.0 % -2.50 [ -4.62, -0.38 ]
Total (95% CI) 69 135 100.0 % -2.50 [ -4.62, -0.38 ]

-10 -5 0 5 10

Analysis 7.8. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 8 Mental State: 2b. Positive
symptoms - average endpoint score - short term (BPRS positive, high = poor).
Outcome: 8 Mental State: 2b. Positive symptoms - average endpoint score - short term (BPRS positive, high = poor)
Mean Mean
Addington 2004 147 -6 (2.87) 149 -5.5 (2.87) 100.0 % -0.50 [ -1.15, 0.15 ]
Total (95% CI) 147 149 100.0 % -0.50 [ -1.15, 0.15 ]

-10 -5 0 5 10

Analysis 7.9. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 9 Mental state: 3. Negative
Mean Mean
1 short term
Addington 2004 147 -6.4 (6.48) 149 -6.4 (6.48) 61.8 % 0.0 [ -1.48, 1.48 ]
Subtotal (95% CI) 147 149 61.8 % 0.0 [ -1.48, 1.48 ]

2 medium term
Stroup 2006 69 -1.5 (6.48) 135 -1.4 (6.48) 38.2 % -0.10 [ -1.98, 1.78 ]
Subtotal (95% CI) 69 135 38.2 % -0.10 [ -1.98, 1.78 ]

Total (95% CI) 216 284 100.0 % -0.04 [ -1.20, 1.12 ]
-10 -5 0 5 10

Analysis 7.10. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 10 Service use: Number of
patients rehospitalised.
Outcome: 10 Service use: Number of patients rehospitalised

M- M-
n/N n/N CI CI
1 medium term
Stroup 2006 16/104 22/137 31.3 % 0.96 [ 0.53, 1.73 ]
Subtotal (95% CI) 104 137 31.3 % 0.96 [ 0.53, 1.73 ]

2 long term
Lieberman 2005 51/341 33/185 68.7 % 0.84 [ 0.56, 1.25 ]
Subtotal (95% CI) 341 185 68.7 % 0.84 [ 0.56, 1.25 ]

Total (95% CI) 445 322 100.0 % 0.87 [ 0.63, 1.22 ]
0.1 0.2 0.5 1 2 5 10


Analysis 7.11. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 11 Adverse effects: 1.

M- M-
n/N n/N CI CI
Addington 2004 122/147 113/149 53.2 % 1.09 [ 0.97, 1.23 ]
Lieberman 2005 232/341 119/185 42.9 % 1.06 [ 0.93, 1.20 ]
Stroup 2006 26/104 38/137 3.9 % 0.90 [ 0.59, 1.38 ]
Total (95% CI) 592 471 100.0 % 1.07 [ 0.98, 1.17 ]

0.1 0.2 0.5 1 2 5 10


Analysis 7.12. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 12 Adverse effects: 2. Death.

M- M-
n/N n/N CI CI
1 suicide attempt
Lieberman 2005 2/341 1/185 49.9 % 1.09 [ 0.10, 11.89 ]
Subtotal (95% CI) 341 185 49.9 % 1.09 [ 0.10, 11.89 ]

2 suicide
Stroup 2006 1/104 2/137 50.1 % 0.66 [ 0.06, 7.17 ]
Subtotal (95% CI) 104 137 50.1 % 0.66 [ 0.06, 7.17 ]

Total (95% CI) 445 322 100.0 % 0.84 [ 0.16, 4.58 ]
0.1 0.2 0.5 1 2 5 10


Analysis 7.13. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 13 Adverse effects: 3a.

M- M-
n/N n/N CI CI
Addington 2004 0/147 0/149 0.0 [ 0.0, 0.0 ]
Lieberman 2005 7/341 2/185 1.90 [ 0.40, 9.05 ]
Total (95% CI) 488 334 1.90 [ 0.40, 9.05 ]

0.1 0.2 0.5 1 2 5 10

Analysis 7.14. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 14 Adverse effects: 3b.
Mean Mean
Addington 2004 123 408.9 (28.5) 113 409.6 (45.3) 18.2 % -0.70 [ -10.45, 9.05 ]
Lieberman 2005 218 0.2 (26.6) 148 1.3 (26.8) 55.5 % -1.10 [ -6.68, 4.48 ]
Stroup 2006 85 -4.4 (30.4) 106 1.3 (25.7) 26.3 % -5.70 [ -13.81, 2.41 ]
Total (95% CI) 426 367 100.0 % -2.24 [ -6.39, 1.92 ]

-10 -5 0 5 10

Analysis 7.15. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 15 Adverse effects: 4.

M- M-
n/N n/N CI CI
Addington 2004 26/147 31/149 29.8 % 0.85 [ 0.53, 1.36 ]
Lieberman 2005 96/341 45/185 46.8 % 1.16 [ 0.85, 1.57 ]
Stroup 2006 23/104 18/137 23.4 % 1.68 [ 0.96, 2.95 ]
Total (95% CI) 592 471 100.0 % 1.15 [ 0.83, 1.59 ]

0.1 0.2 0.5 1 2 5 10



M- M-
n/N n/N CI CI
1 akathisia
Addington 2004 30/147 19/149 45.4 % 1.60 [ 0.94, 2.71 ]
Lieberman 2005 20/341 14/185 38.3 % 0.78 [ 0.40, 1.50 ]
Stroup 2006 3/104 7/137 16.3 % 0.56 [ 0.15, 2.13 ]
Subtotal (95% CI) 592 471 100.0 % 1.02 [ 0.55, 1.89 ]

Stroup 2006 12/104 5/137 100.0 % 3.16 [ 1.15, 8.69 ]
Subtotal (95% CI) 104 137 100.0 % 3.16 [ 1.15, 8.69 ]

3 tremor
Addington 2004 14/147 15/149 100.0 % 0.95 [ 0.47, 1.89 ]
Subtotal (95% CI) 147 149 100.0 % 0.95 [ 0.47, 1.89 ]

Addington 2004 49/147 33/149 71.7 % 1.51 [ 1.03, 2.20 ]
Lieberman 2005 32/341 14/185 28.3 % 1.24 [ 0.68, 2.26 ]
Subtotal (95% CI) 488 334 100.0 % 1.42 [ 1.03, 1.96 ]

0.001 0.01 0.1 1 10 100 1000


Extrapyramidal symptoms - scale measured.
Outcome: 17 Adverse effects: 5b. Extrapyramidal symptoms - scale measured
Mean Mean

Addington 2004 147 -0.04 (0.17) 149 -0.25 (0.17) 100.0 % 0.21 [ 0.17, 0.25 ]
Subtotal (95% CI) 147 149 100.0 % 0.21 [ 0.17, 0.25 ]

Addington 2004 147 0.28 (0.21) 149 -0.28 (0.22) 100.0 % 0.56 [ 0.51, 0.61 ]
Subtotal (95% CI) 147 149 100.0 % 0.56 [ 0.51, 0.61 ]

Addington 2004 147 -0.23 (0.33) 149 -0.57 (0.33) 100.0 % 0.34 [ 0.26, 0.42 ]
Subtotal (95% CI) 147 149 100.0 % 0.34 [ 0.26, 0.42 ]

-10 -5 0 5 10


M- M-
n/N n/N CI CI
Addington 2004 8/105 4/110 100.0 % 2.10 [ 0.65, 6.75 ]
Subtotal (95% CI) 105 110 100.0 % 2.10 [ 0.65, 6.75 ]

2 amenorrhea
Addington 2004 3/42 3/39 20.4 % 0.93 [ 0.20, 4.33 ]
Lieberman 2005 16/88 8/56 79.6 % 1.27 [ 0.58, 2.78 ]
Subtotal (95% CI) 130 95 100.0 % 1.19 [ 0.60, 2.39 ]

3 decreased libido
Addington 2004 13/147 8/149 100.0 % 1.65 [ 0.70, 3.86 ]
Subtotal (95% CI) 147 149 100.0 % 1.65 [ 0.70, 3.86 ]

4 erectile dysfunction
Addington 2004 7/105 7/110 100.0 % 1.05 [ 0.38, 2.88 ]
Subtotal (95% CI) 105 110 100.0 % 1.05 [ 0.38, 2.88 ]

5 galactorrhea
Addington 2004 2/42 0/39 50.0 % 4.65 [ 0.23, 93.95 ]
Stroup 2006 2/37 0/41 50.0 % 5.53 [ 0.27, 111.50 ]
Subtotal (95% CI) 79 80 100.0 % 5.07 [ 0.61, 42.45 ]

0.1 0.2 0.5 1 2 5 10

(Continued . . . )

(. . .Continued)
M- M-
n/N n/N CI CI
6 orgastic dysfunction
Addington 2004 6/147 3/149 6.0 % 2.03 [ 0.52, 7.95 ]
Lieberman 2005 91/341 35/185 94.0 % 1.41 [ 1.00, 1.99 ]
Subtotal (95% CI) 488 334 100.0 % 1.44 [ 1.03, 2.02 ]

0.1 0.2 0.5 1 2 5 10

Prolactin - change from baseline in ng/ml.
Mean Mean
Lieberman 2005 341 15.4 (27.7) 185 -4.5 (21.8) 63.7 % 19.90 [ 15.60, 24.20 ]
Stroup 2006 104 22 (29.6) 137 -3.6 (26.9) 36.3 % 25.60 [ 18.34, 32.86 ]
Total (95% CI) 445 322 100.0 % 21.97 [ 16.60, 27.34 ]

-10 -5 0 5 10

Mean Mean
Lieberman 2005 341 -2.1 (35.1) 185 -9.2 (70.7) 47.3 % 7.10 [ -3.75, 17.95 ]
Stroup 2006 104 -2.6 (39.8) 137 -12.5 (41) 52.7 % 9.90 [ -0.38, 20.18 ]
Total (95% CI) 445 322 100.0 % 8.58 [ 1.11, 16.04 ]

-10 -5 0 5 10
Mean Mean
Lieberman 2005 341 6.7 (36.9) 185 2.3 (53) 63.7 % 4.40 [ -4.18, 12.98 ]
Stroup 2006 104 4.8 (43.9) 137 -1.1 (45.6) 36.3 % 5.90 [ -5.48, 17.28 ]
Total (95% CI) 445 322 100.0 % 4.94 [ -1.91, 11.80 ]

-10 -5 0 5 10

Analysis 7.22. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 22 Adverse effects: 7c.
Metabolic - weight gain of 7% or more of total body weight.
Outcome: 22 Adverse effects: 7c. Metabolic - weight gain of 7% or more of total body weight

M- M-
n/N n/N CI CI
Addington 2004 20/147 10/149 31.8 % 2.03 [ 0.98, 4.18 ]
Lieberman 2005 42/341 12/185 44.0 % 1.90 [ 1.03, 3.52 ]
Stroup 2006 14/104 8/137 24.2 % 2.31 [ 1.00, 5.29 ]
Total (95% CI) 592 471 100.0 % 2.03 [ 1.35, 3.06 ]

0.001 0.01 0.1 1 10 100 1000

Analysis 7.23. Comparison 7 RISPERIDONE versus ZIPRASIDONE, Outcome 23 Adverse effects: 7d.
Mean Mean
Lieberman 2005 300 0.4 (6.9) 161 -0.7 (6.3) 100.0 % 1.10 [ -0.15, 2.35 ]
Total (95% CI) 300 161 100.0 % 1.10 [ -0.15, 2.35 ]

-10 -5 0 5 10

Analysis 8.1. Comparison 8 RISPERIDONE versus CLOZAPINE - sensitivity analysis (skewed data
included), Outcome 1 Mental state: 1. General - average endpoint score (BPRS total, high = poor).
Comparison: 8 RISPERIDONE versus CLOZAPINE - sensitivity analysis (skewed data included)
Outcome: 1 Mental state: 1. General - average endpoint score (BPRS total, high = poor)
Mean Mean
1 short term
Azorin 2001 130 -17.7 (13.6) 126 -23.2 (13.2) 43.9 % 5.50 [ 2.22, 8.78 ]
Heinrich 1994 40 -13.9 (16.6) 20 -16.9 (16.1) 16.7 % 3.00 [ -5.73, 11.73 ]
Subtotal (95% CI) 170 146 60.6 % 5.19 [ 2.12, 8.26 ]

2 long term
McGurk 2005 22 31.3 (6.5) 30 31.5 (7.9) 39.4 % -0.20 [ -4.12, 3.72 ]
Subtotal (95% CI) 22 30 39.4 % -0.20 [ -4.12, 3.72 ]

Total (95% CI) 192 176 100.0 % 2.84 [ -1.36, 7.03 ]
-10 -5 0 5 10

Analysis 8.2. Comparison 8 RISPERIDONE versus CLOZAPINE - sensitivity analysis (skewed data included),
Outcome 2 Mental state: 2. Positive symptoms - average endpoint score (PANSS positive, high = poor).
Mean Mean
1 short term
Azorin 2001 130 -8.3 (7.4) 126 -10.4 (6.6) 47.0 % 2.10 [ 0.38, 3.82 ]
Bondolfi 1998 43 -8.3 (10.7) 43 -6.7 (7.1) 18.9 % -1.60 [ -5.44, 2.24 ]
Wahlbeck 2000 9 15 (7) 10 17 (6) 9.4 % -2.00 [ -7.89, 3.89 ]
Subtotal (95% CI) 182 179 75.3 % 0.24 [ -2.72, 3.19 ]

2 medium term
Volavka 2002 41 -1.9 (7.3) 40 -2.3 (7.3) 24.7 % 0.40 [ -2.78, 3.58 ]
Subtotal (95% CI) 41 40 24.7 % 0.40 [ -2.78, 3.58 ]

Total (95% CI) 223 219 100.0 % 0.60 [ -1.34, 2.53 ]
-10 -5 0 5 10

Analysis 8.3. Comparison 8 RISPERIDONE versus CLOZAPINE - sensitivity analysis (skewed data included),
Outcome 3 Mental state: 3. Negative symptoms - average endpoint score (PANSS negative, high = poor).
Mean Mean
1 short term
Azorin 2001 130 -7.1 (7.2) 126 -8.8 (6.8) 32.1 % 1.70 [ -0.02, 3.42 ]
Bondolfi 1998 43 -6 (6.5) 43 -6.1 (6.1) 25.0 % 0.10 [ -2.56, 2.76 ]
Wahlbeck 2000 9 17 (4) 10 21 (4) 19.0 % -4.00 [ -7.60, -0.40 ]
Subtotal (95% CI) 182 179 76.1 % -0.39 [ -3.37, 2.59 ]

2 medium term
Volavka 2002 41 -0.2 (6.48) 40 -1.6 (6.48) 23.9 % 1.40 [ -1.42, 4.22 ]
Subtotal (95% CI) 41 40 23.9 % 1.40 [ -1.42, 4.22 ]

Total (95% CI) 223 219 100.0 % 0.14 [ -2.02, 2.31 ]
-10 -5 0 5 10

Analysis 9.1. Comparison 9 RISPERIDONE versus OLANZAPINE - sensitivity analysis (skewed data
excluded), Outcome 1 Mental state: 1a. General - average endpoint score (PANSS total, high = poor).
Comparison: 9 RISPERIDONE versus OLANZAPINE - sensitivity analysis (skewed data excluded)
Outcome: 1 Mental state: 1a. General - average endpoint score (PANSS total, high = poor)
Mean Mean
1 short term
Atmaca 2003 13 78.26 (4.62) 13 74.86 (6.41) 10.4 % 3.40 [ -0.90, 7.70 ]
Conley 2001 175 -12.8 (15.9) 181 -12.9 (16.1) 17.3 % 0.10 [ -3.22, 3.42 ]
Dollfus 2005 38 -16.9 (18.8) 33 -17.5 (17.7) 2.7 % 0.60 [ -7.90, 9.10 ]
Jeste 2003 83 -12.3 (18.04) 88 -12.3 (15.67) 7.4 % 0.0 [ -5.08, 5.08 ]
Mori 2004 19 71.5 (12) 20 69.4 (10.8) 3.7 % 2.10 [ -5.08, 9.28 ]
Wang 2006 11 -15 (22.31) 12 -9 (22.31) 0.6 % -6.00 [ -24.25, 12.25 ]
Subtotal (95% CI) 339 347 42.0 % 1.02 [ -1.11, 3.15 ]

2 medium term
McEvoy 2006 6 -0.3 (6.86) 10 -7.7 (9.8) 2.9 % 7.40 [ -0.79, 15.59 ]
Stroup 2006 69 -8 (22.31) 66 -8.2 (22.31) 3.4 % 0.20 [ -7.33, 7.73 ]
Volavka 2002 41 -3.1 (22.31) 39 -9.1 (22.31) 2.0 % 6.00 [ -3.78, 15.78 ]
Subtotal (95% CI) 116 115 8.2 % 4.11 [ -0.71, 8.93 ]

3 long term
Gureje 2003 30 -16.3 (16.3) 32 -28.2 (20.8) 2.2 % 11.90 [ 2.63, 21.17 ]
Keefe 2006 148 -9.5 (15.5) 153 -12.4 (16) 15.1 % 2.90 [ -0.66, 6.46 ]
Lieberman 2005 333 -9.31 (22.31) 330 -11.27 (22.31) 16.6 % 1.96 [ -1.44, 5.36 ]
McEvoy 2007 37 -18.5 (9.91) 37 -18.4 (9.73) 9.6 % -0.10 [ -4.57, 4.37 ]
Tran 1997 165 -24.9 (23.2) 166 -28.1 (28) 6.2 % 3.20 [ -2.34, 8.74 ]
Subtotal (95% CI) 713 718 49.7 % 2.59 [ 0.20, 4.98 ]

Total (95% CI) 1168 1180 100.0 % 1.99 [ 0.60, 3.37 ]
-10 -5 0 5 10

excluded), Outcome 2 Mental state: 2. General - average endpoint score (BPRS total, high = poor).
Outcome: 2 Mental state: 2. General - average endpoint score (BPRS total, high = poor)
Mean Mean
1 Long term
Gureje 2003 30 -8.8 (9.2) 32 -16.4 (12.3) 42.8 % 7.60 [ 2.21, 12.99 ]
Tran 1997 165 -15.2 (13.3) 166 -17 (16.5) 57.2 % 1.80 [ -1.43, 5.03 ]
Total (95% CI) 195 198 100.0 % 4.28 [ -1.34, 9.91 ]

-10 -5 0 5 10

excluded), Outcome 3 Mental state: 3. Positive symptoms - average endpoint score (PANSS positive, high =
poor).
Mean Mean
1 short term
Conley 2001 175 -4.6 (5.3) 181 -4.1 (65.4) 0.4 % -0.50 [ -10.06, 9.06 ]
Dollfus 2005 39 -1.9 (3.91) 33 -1.1 (4.7) 8.5 % -0.80 [ -2.82, 1.22 ]
Jeste 2003 83 -3.6 (7.02) 88 -4 (5.72) 9.4 % 0.40 [ -1.53, 2.33 ]
Wang 2006 11 -4.5 (7.3) 12 -2.36 (7.3) 1.0 % -2.14 [ -8.11, 3.83 ]
Subtotal (95% CI) 308 314 19.3 % -0.28 [ -1.62, 1.07 ]

2 medium term
McEvoy 2006 6 -0.5 (1.71) 10 -2.9 (4.11) 4.2 % 2.40 [ -0.49, 5.29 ]
Stroup 2006 69 -2.3 (7.3) 66 -3.4 (7.3) 5.7 % 1.10 [ -1.36, 3.56 ]
Volavka 2002 41 -1.9 (7.3) 39 -3.3 (7.3) 3.4 % 1.40 [ -1.80, 4.60 ]
Subtotal (95% CI) 116 115 13.3 % 1.58 [ -0.03, 3.20 ]

3 long term
Gureje 2003 30 -4.1 (5.4) 32 -6.2 (5.8) 4.5 % 2.10 [ -0.69, 4.89 ]
Keefe 2006 148 -3.6 (5.5) 153 -4.3 (4.9) 25.1 % 0.70 [ -0.48, 1.88 ]
McEvoy 2007 37 -6.6 (3.16) 37 -7.1 (3.1) 17.1 % 0.50 [ -0.93, 1.93 ]
Purdon 2000 21 -1.19 (3.14) 21 -2.14 (4.33) 6.7 % 0.95 [ -1.34, 3.24 ]
Tran 1997 165 -6.9 (6.4) 166 -7.2 (8.1) 14.1 % 0.30 [ -1.27, 1.87 ]
Subtotal (95% CI) 401 409 67.4 % 0.68 [ -0.04, 1.40 ]

Total (95% CI) 825 838 100.0 % 0.62 [ 0.03, 1.21 ]
-10 -5 0 5 10

excluded), Outcome 4 Adverse effects: 1. Extrapyramidal effects - scale measured.
Outcome: 4 Adverse effects: 1. Extrapyramidal effects - scale measured
Mean Mean
1 dyskinesia: ESRS subscore for dyskinesia (high = poor)

Conley 2001 179 -0.4 (2.7) 180 -0.4 (2.7) 86.8 % 0.0 [ -0.56, 0.56 ]
Purdon 2000 21 0.19 (1.72) 21 -0.57 (2.87) 13.2 % 0.76 [ -0.67, 2.19 ]
Subtotal (95% CI) 200 201 100.0 % 0.10 [ -0.42, 0.62 ]

Conley 2001 179 -0.9 (4) 180 -1.2 (4) 79.9 % 0.30 [ -0.53, 1.13 ]
Jeste 2003 83 -2.1 (5.38) 88 -1.7 (5.63) 20.1 % -0.40 [ -2.05, 1.25 ]
Subtotal (95% CI) 262 268 100.0 % 0.16 [ -0.58, 0.90 ]

Keefe 2006 149 -0.06 (3.16) 153 -0.73 (2.92) 35.3 % 0.67 [ -0.02, 1.36 ]
Robinson 2005 56 1.4 (0.58) 56 1.2 (0.58) 44.6 % 0.20 [ -0.01, 0.41 ]
Sacchetti 2004 25 2.2 (3.58) 25 -1 (3.58) 13.1 % 3.20 [ 1.22, 5.18 ]
Wang 2006 11 -0.17 (3.58) 12 -0.2 (3.58) 7.1 % 0.03 [ -2.90, 2.96 ]
Subtotal (95% CI) 241 246 100.0 % 0.75 [ -0.10, 1.59 ]

4 parkinsonism: ESRS subscore for parkinsonism (high = poor)
Conley 2001 179 -0.5 (2.7) 180 -0.7 (2.7) 66.6 % 0.20 [ -0.36, 0.76 ]
Purdon 2000 21 1.33 (5.36) 21 -1.43 (4.32) 33.4 % 2.76 [ -0.18, 5.70 ]
Subtotal (95% CI) 200 201 100.0 % 1.06 [ -1.31, 3.42 ]

-10 -5 0 5 10

excluded), Outcome 5 Adverse effects: 2. Prolactin associated side effects - change from baseline in ng/ml.
Outcome: 5 Adverse effects: 2. Prolactin associated side effects - change from baseline in ng/ml
Mean Mean

Lieberman 2005 341 15.4 (27.7) 336 -6.1 (22) 39.1 % 21.50 [ 17.73, 25.27 ]
Keefe 2006 130 18.75 (31.23) 136 -9.73 (23.15) 20.7 % 28.48 [ 21.85, 35.11 ]
McEvoy 2006 11 15.4 (17.91) 16 -4.1 (9.2) 8.7 % 19.50 [ 8.00, 31.00 ]
McEvoy 2007 37 12.1 (15.88) 37 -15.9 (15.57) 18.6 % 28.00 [ 20.83, 35.17 ]
Stroup 2006 104 22 (29.6) 108 -5.1 (37.4) 12.9 % 27.10 [ 18.04, 36.16 ]
Subtotal (95% CI) 623 633 100.0 % 24.70 [ 21.08, 28.33 ]

-10 -5 0 5 10

Analysis 10.1. Comparison 10 RISPERIDONE versus QUETIAPINE - sensitivity analysis (skewed data
included), Outcome 1 Mental state: 1. Positive symptoms - average endpoint score (PANSS positive, high =
poor).
Comparison: 10 RISPERIDONE versus QUETIAPINE - sensitivity analysis (skewed data included)
Mean Mean
1 short term
Potkin 2006 152 -8.7 (6.16) 156 -5.9 (6.24) 25.0 % -2.80 [ -4.18, -1.42 ]
Riedel 2005 22 -7.6 (7.3) 22 -3.8 (7.3) 2.7 % -3.80 [ -8.11, 0.51 ]
Zhong 2006 318 -5.6 (7.13) 328 -4.5 (7.24) 37.7 % -1.10 [ -2.21, 0.01 ]
Subtotal (95% CI) 492 506 65.5 % -2.08 [ -3.56, -0.60 ]

2 medium term
McEvoy 2006 6 -0.5 (1.71) 8 0.6 (5.94) 2.7 % -1.10 [ -5.44, 3.24 ]
Stroup 2006 69 -2.3 (7.3) 63 0.2 (7.3) 8.1 % -2.50 [ -4.99, -0.01 ]
Subtotal (95% CI) 75 71 10.8 % -2.15 [ -4.31, 0.01 ]

3 long term
McEvoy 2007 37 -6.6 (3.16) 44 -5.3 (3.38) 23.7 % -1.30 [ -2.73, 0.13 ]
Subtotal (95% CI) 37 44 23.7 % -1.30 [ -2.73, 0.13 ]

Total (95% CI) 604 621 100.0 % -1.76 [ -2.48, -1.04 ]
-10 -5 0 5 10

Analysis 10.2. Comparison 10 RISPERIDONE versus QUETIAPINE - sensitivity analysis (skewed data
included), Outcome 2 Adverse effects: 1. Extrapyramidal effects - scale measured.
Comparison: 10 RISPERIDONE versus QUETIAPINE - sensitivity analysis (skewed data included)
Outcome: 2 Adverse effects: 1. Extrapyramidal effects - scale measured
Mean Mean

Conley 2005 13 -1.3 (3.15) 12 -1.64 (3.15) 15.3 % 0.34 [ -2.13, 2.81 ]
Potkin 2006 153 0.8 (15.65) 156 -0.1 (2.5) 14.9 % 0.90 [ -1.61, 3.41 ]
Sacchetti 2004 25 2.2 (3.58) 25 -0.4 (3.58) 20.6 % 2.60 [ 0.62, 4.58 ]
Zhong 2006 321 -0.21 (3.58) 328 -0.41 (3.62) 49.3 % 0.20 [ -0.35, 0.75 ]
Subtotal (95% CI) 512 521 100.0 % 0.82 [ -0.31, 1.95 ]

-10 -5 0 5 10
ADDITIONAL TABLES
Table 1. Suggested design of future study
Methods Allocation: randomised - clearly described generation of sequence and concealment of allocation.
Blindness.: double - described and tested.
Duration: 6 months minimum.
Participants Diagnosis: schizophrenia (operational criteria).

N=2700.*
Age: any.
Sex: both.
History: any.
Interventions 1. Risperidone: dose ~ 4-8 mg/day. N=300.

2. Amisulpride: dose ~ 400-800 mg/day. N=300.
3. Aripiprazole: dose ~ 10-30 mg/day. N=300.
4. Clozapine: dose ~ 300-800 mg/day. N=300.
5. Olanzapine: dose ~ 10-20 mg/day. N=300.
6. Quetiapine: dose ~300-800 mg/day. N=300.
7. Sertindole: dose ~ 12-24 mg/day. N=300.
8. Ziprasidone: dose ~ 120-160 mg/day. N=300.

Table 1. Suggested design of future study (Continued)
9. Zotepine: dose ~ 100-300 mg/day. N=300.
Outcomes Leaving study early (any reason, adverse events, inefficacy).

Service outcomes: hospitalised, time in hospital, attending out patient clinics.
Global impression: CGI**, relapse.
Mental state: PANSS.
Adverse events: UKU.
Employment, family satisfaction, patient satisfaction.
* power calculation suggested 300/group would allow good chance of showing a 10% difference between groups for primary outcome.
** Primary outcome
WHATS NEW
Last assessed as up-to-date: 21 May 2008.
Date Event Description
12 December 2012 Amended Contact details updated.
CONTRIBUTIONS OF AUTHORS
Katja Komossa: protocol development, searching, study selection, data extraction, report writing.
Christine Rummel: protocol development, searching, study selection, data extraction.
Stefan Leucht: protocol development, searching, study selection, data extraction, report writing.
Werner Kissling: protocol development.
Heike Hunger: helped with data extraction and writing.
Franziska Schmid: helped with data extraction and writing.
Sandra Schwarz: helped with data extraction and writing.

DECLARATIONS OF INTEREST
Katja Komossa: none known.
Stefan Leucht: has received speaker/consultancy/advisory board honoraria from SanofiAventis, BMS, EliLilly, Essex Pharma, Glaxo-
SmithKline, Janssen/Johnson and Johnson, Lundbeck and Pfizer including the fees and travel expenses for attending these functions;
and he has received funding for research projects from EliLilly and SanofiAventis.
Christine Rummel received lecture honoraria and travel grants to attend scientific meetings from AstraZeneca, Janssen-Cilag, Eli Lilly
and Pfizer.
Werner Kissling: received speaker or consultancy honoraria from SanofiAventis, BMS, Lilly, Janssen, Lundbeck, Bayer and Pfizer.
Heike Hunger: none known.
Franziska Schmid: none known.
Sandra Schwarz: none known.
SOURCES OF SUPPORT
Internal sources
Psychiatrische Klinik , Klinikum rechts der Isar, TU Mnchen, Friestaat Bayern, Germany.
External sources
Bundesministerium fr Bildung und Forschung, Nr FKZ: 01 KG 0606, GZ:GF-GFKG01100506, Germany.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

The review was slightly adapted to new functions available in Review Manager 5, namely the risk of bias table.
INDEX TERMS
Medical Subject Headings (MeSH)

Antipsychotic Agents [adverse effects; therapeutic use]; Benzodiazepines [therapeutic use]; Clozapine [therapeutic use]; Dibenzoth-
iazepines [therapeutic use]; Imidazoles [therapeutic use]; Indoles [therapeutic use]; Piperazines [therapeutic use]; Quinolones [thera-
peutic use]; Randomized Controlled Trials as Topic; Risperidone [adverse effects; therapeutic use]; Schizophrenia [ drug therapy];
Sulpiride [analogs & derivatives; therapeutic use]; Thiazoles [therapeutic use]
MeSH check words

Humans


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Risperidone versus other atypical antipsychotics for

Komossa K, Rummel-Kluge C, Schwarz S, Schmid F, Hunger H, Kissling W, Leucht S

Risperidone versus other atypical antipsychotics for schizophrenia (Review)

Risperidone versus other atypical antipsychotics for schizophrenia (Review) iii

Risperidone versus other atypical antipsychotics for schizophrenia (Review) v

Risperidone versus other atypical antipsychotics for schizophrenia (Review) vi

Risperidone versus other atypical antipsychotics for schizophrenia (Review) vii

Risperidone versus other atypical antipsychotics for schizophrenia (Review) viii

Risperidone versus other atypical antipsychotics for

Editorial group: Cochrane Schizophrenia Group.

PLAIN LANGUAGE SUMMARY

Description of the condition

Types of outcome measures

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 4

1. Data extraction Measures of treatment effect

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 5

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 6

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 7

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 8

5.2 Comparators 6.4 Service use

6.5.1 Global state scales

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 9

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 10

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 11

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 12

Other potential sources of bias

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 14

1.3.10 Negative symptoms - average score at endpoint -

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 15

1.5.9 Metabolic - weight gain

1.5.10 Metabolic - weight gain - mean change from baseline

1.6 Publication bias

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 16

2.4.10 Metabolic - weight gain of 7% or more of total body

2.6 Sensitivity analysis

3.1 Global state

3.1.2 Global state - no clinically important change - short

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 17

3.3.3 General - no clinically important change - long term -

3.3.4 General - no clinically important change - short term -

There was no significant difference (1 RCT, n = 107, RR 1.05 CI

There was no significant difference, in the short term (4 RCTs, n

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 18

3.6.2 Death 3.6.9 Prolactin associated side effects

3.6.10 Prolactin - change from baseline in ng/ml

3.6.11 Metabolic - cholesterol - change from baseline in

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 19

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 20

4.7.3 Cardiac effects

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 21

4.7.9 Haematological - white blood cells - number of

4.7.10 Prolactin associated side effects

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 22

5.3.1 General - no clinically important change - short term -

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 23

5.3.5 Positive symptoms - short term - less than 40% PANSS

5.6.5 Central nervous system - sedation

5.3.10 Negative symptoms - average endpoint score - short

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 24

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 25

6.4.4 Cardiac effects - mean change of QTc interval from

6.4.5 Central nervous system - sedation

Risperidone versus other atypical antipsychotics for schizophrenia (Review) 26