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org
Schizophrenia treatment
The past 10 years

10
th
Annual Schizophrenia Education Day
November 10, 2012
Oliver Freudenreich, MD
Associate Professor of Psychiatry
Harvard Medical School
Medical Director, MGH Schizophrenia Program
Massachusetts General Hospital
www.mghcme.org
Disclosures
I have the following relevant financial
relationship to disclose (2011 2012):
Pfizer Research grant
Psychogenics Research grant
MGH Psychiatry Academy Honoraria
General Medical Education Honoraria
Oakstone Medical Education Honoraria
Beacon Health Strategies Consultant
Transcept Consultant
Optimal Medicine Consultant

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Learning Objectives
After participation in this educational seminar series,
participants will be able to
Outline the four stages of schizophrenia
Describe differences between first- and second-generation
antipsychotics
List clinical reasons for the use of clozapine
Erich Lindemann Mental Health Center
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Where were we in 2002?
Sports
Patriots miss 2002 post-season; QB Brady
Politics
President George W. Bush
Mitt Romney elected Governor
Culture
Best picture: Chicago
Best-selling album: The Eminem Show
Personal
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CATIE design
Funding: NIMH
Study design of this SWITCH STUDY
Double-blind, randomized, flexible-dose
Long duration: 18-month trial
Large N: almost 1500 schizophrenia patients
Representative sample
Several phases including a clozapine arm
Novel outcome: all-cause-discontinuation
CATIE=Clinical Antipsychotic Trials
of Intervention Effectiveness
Lieberman et al. NEJM 2005
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CATIE main results
Most striking
High rate of treatment
discontinuation (up to
74%)
Short median time to
discontinuation (about 6
months)
Most controversial
No effectiveness
difference between SGA
and perphenazine
Lieberman et al. NEJM 2005
CATIE=Clinical Antipsychotic Trials of Intervention
Effectiveness
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CATIE clinical summary
Main findings
Olanzapine more effective than risperidone,
quetiapine, ziprasidone and perphenazine
Perphenazine relatively well-tolerated and
effective
No cognitive benefit with 2nd generation agents
1
Disadvantage to switching
2
Substantial metabolic complications
with olanzapine

Lieberman JA and Stroup TS. Am J Psychiatry 2011;168:770.
1
Arch Gen Psychiatry 2007;64:633.
2
Am J Psychiatry 2006;163:2090.
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SGA Side effect propensity
Sedation Metabolic EPS Prolactin Other
Perphenazine
++ + ++ +
Clozapine
++++ ++++ 0 0
Olanzapine
+++ ++++ + +
Quetiapine
+++ +++ +/- 0
Risperidone
++ ++ ++ ++++
Paliperidone
++ ++ ++ ++++
Aripiprazole
+ + ++ decrease
Ziprasidone
+/- + + +/- QTc
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Antipsychotic summary
Antipsychotics are not effective for all patients and
rarely effective for all symptom domains
SGAs are not a homogeneous class
1

Clozapine remains the gold standard for refractory
psychosis
2
Also FDA approved for suicidality in schizophrenia
Might have survival benefit
The distinction between FGA and SGA should be
abandoned. (But: no better nomenclature)
1
Leucht at al. Lancet 2009;373:31.
2
Hill and Freudenreich. Clin Schizophr Rel Psychoses (in press).
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EARLY INTERVENTION
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Early course schizophrenia
Prodromal Period Post-Psychotic Period
Initiation of Antipsychotic
Psychosis
Positive Sx
Negative Sx
Depression
Based on Hfner, ABC Schizophreniestudie
5 years 1-2 years*
*DUP
Psychosis
Threshold
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Prodromal schizophrenia
Pre-psychotic phase
1
Premorbid phase = CLINICALLY SILENT
Prodromal period
Change in thinking and feeling
Unspecific anxiety, depression; attenuated psychotic symptoms (late)
Social withdrawal
Impaired function
Problem
Prodrome can only be diagnosed in retrospect
Transition risk for ARMS not 100%
2
18% after 6 months
22% after 1 year
29% after 2 years
36% after 3 years
1
Klosterkoetter et al. Dtsch Arztebl Int 2008;105:532.
2
Fusar-Poli P. Arch Gen Psychiatry 2012;69:220.
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SOHO Remission
60.3
45.4
57
28.1
0 10 20 30 40 50 60 70
Symptoms
Function
Subjective Well-
being
Combined
remission
Percent
Lambert et al., Acta 2008
N=392 never-treated patients
SOHO = Schizophrenia Outpatient Health Outcomes
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Clinical staging
STAGE DEFINITION
0 Increased risk, no symptoms
1a Mild/unspecific symptoms
1b Moderate but subthreshold symptoms
2 First episode of illness
3a Incomplete remission
3b Recurrence
3c Multiple relapses
4 Unremitting illness
McGorry 2006, McGorry 2009
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DSM-V Attenuated Psychosis Syndrome
(Draft Criteria for section III)
A. Characteristic symptoms
Attenuated positive symptoms with insight
B. Frequency/currency
Once per week in past month
C. Progression
D. Distress/disability/treatment seeking
E. Symptoms not better explained by
Depression, mania, substance use, ADD,
F. Never had frank psychosis
www.dsm5.org
Carpenter WT and van Os J. Am J Psychiatry 2011;168:460.
Fleischhacker WW and DeLisi L. Curr Opin Psychiatry 2012;25:327.
DSM-IV
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Prevention
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Indicated prevention trial
Amminger GP et al. Arch Gen Psychiatry 2010;67:146.
5%
28%
-3 FA
Placebo
12 weeks

700 mg EPA
480 mg DHA
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Duration of Untreated Psychosis (DUP)
Prolonged DUP
1,2
Poorer response
Worse outcome
.
DUP can be reduced
3
Clinical advantage at
baseline, 2-year
3
and 5-
year f/u
4
Sustained information
campaign is key
5
Focus on outliers
6
Social toxicity
Stigmatization
Loss of job
Interrupted schooling
Loss of friendships
Loss of family support
Criminal record
Accidental death
Accidental homicide
Shame and demoralization
1
Perkins et al. 2005,
2
Marshall et al. 2005
3
Melle et al. 2004, 2008;
4
Larsen et al. 2011
5
Joa et al. 2008
6
Lloyd-Evans et al., Br J Psychiatry 2011;198:256.
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Early use of clozapine
75.4
16.7
75
0
10
20
30
40
50
60
70
80
1st 2nd 3rd
Response in %
Agid O et al. J Clin Psychiatry 2011;72:1439.
1
st
and 2
nd
antipsychotic:
Risperidone
Olanzapine

3
rd
antipsychotic:
Clozapine
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Lifestyle intervention and metformin for
antipsychotic-induced weight gain
N = 128
Wu RR, et al. JAMA 2008;299:185-193.
12-week placebo-controlled trial, metformin 750 mg/day
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MGH resident call room
wwwc.mentalfloss.com/.../07/the-end-is-near.jpg
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New Antipsychotics 2002-2012
2002 Aripiprazole (ABILIFY); Nov 15
2003 Risperidone LAI (RISPERDAL CONSTA); Oct 29
2004
2005
2006 Paliperidone (INVEGA); Dec 19
2007
2008
2009 Iloperidone (FANAPT); May 6
Paliperidone LAI (INVEGA SUSTENNA); Jul 31
Asenapine (SAPHRIS); Aug 13
Olanzapine LAI (ZYPREXA RELPREVV); Dec 11
2010 Lurasidone (LATUDA); Oct 28
2011
2012
LAI = Long-acting injectable
Paliperidone = 9-hydroxy-risperidone
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Seige cycle
The first reports sounded in every respect
extremely favorable; but before long it
became clear that [these drugs] did not satisfy
the traditional conditions of cito, tuto et
jucunde [quickly, safely, and pleasantly]at
least, that even in small doses they caused all
kinds of unpleasant or detrimental side
effects. Finally most of them found a small,
limited, special territory within which the
conscientious physician uses them.
Max Seige, 1912
Snelders S et al. Bull Hist Med 2006;80:95.
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Sequential antipsychotic trials
Select
Lowest-risk choice
Patient factors
Early ancillary treatments
Behavioral prevention
1,2
Adjunctive metformin
2,3
Monitor
Clinical response
Follow guidelines (e.g., ADA,
Mt. Sinai, MGH)
4
Adjust
Switch antipsychotics
Add behavioral treatment
5
Treat medical morbidities
However beautiful the
strategy, you should
occasionally look at the
results.

-Sir Winston Churchill
1
Wu et al., JAMA 2008,
2
Wu et al., Am J Psych 2008,
3
Wang M et al. Schizophr Res 2012 (in press)
4
ADA 2004, Marder et al., Am J Psych 2004, Goff et al, J Clin Psych 2005;
5
Dixon et al., Schiz Bull 2010
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Phase-specific treatment
GOALS KEY DECISIONS
Prodrome Delay psychosis
Prevent schizophrenia?
Treat with antipsychotic?
Acute
Psychosis
Keep DUP short
Achieve initial response
and early positive
symptoms remission
Which antipsychotic?
Problems: early non-response
(positive Sx)
Engagement
Post-psychotic
Phase
Achieve sustained
remission
Recovery and QOL
Prevent medical morbidity
Treat for how long?
Problems: early relapse and
residual Sx (adherence); risk-
benefit
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Did we make progress?
No new breakthrough
medications
No cure
Incremental progress
Medications are only tools
New is not better
Clozapine is unique
Real choice
New (re-discovered)
prevention paradigm
Early intervention
Illness staging
Clarification of goals
Remission and recovery
Mens sana in corpore sano
Insel TR. Nature 2010;468:187.
A decade of refinement,
Not revolution.
Pincus HA and Naber D. Curr Opin Psychiatry 2012;25:513.
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John Umstead Hospital, Butner, NC, ca. 1995
Those were the days...
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MCQ FGA vs. SGA
In general, all second-generation antipsychotics
are:

A. Causing similar weight gain.
B. Essentially interchangeable.
C. Less likely to cause tardive dyskinesia
compared to haloperidol.
D. More effective than first-generation
antipsychotics.
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MCQ Clozapine
Clozapine is a good antipsychotic for patients
with schizophrenia who are:

A. Against regular blood work.
B. Experiencing suicidal ideation.
C. In their first episode of psychosis.
D. Obese.