Professional Documents
Culture Documents
Exclusion Criteria If the answer to ANY item below is met, then the patient should NOT receive a long-acting injectable
antipsychotic (LAIA).
The patient has never taken the long-acting injectable antipsychotic ordered in any formulation (e.g., oral), with the
exception of prior exposure to risperidone being an acceptable substitute for paliperidone.
The patient has a hypersensitivity to the antipsychotic ordered. Note: Consider risperidone and paliperidone cross-sensitive.
Aripiprazole only: the patient is taking a cytochrome 3A4 inducer.
Inclusion Criteria
The patient must meet ALL of the following:
Have a diagnosis of schizophrenia or schizoaffective disorder, or bipolar I disorder by DSM-IV or 5
The prescriber is a Mental Health Provider
The patient has taken and tolerated the antipsychotic ordered prior to receiving it as a LAI (see Issues for
Consideration)
OR
The patient is currently receiving the LAIA ordered
PLUS the patient meets one of the following:
The patient has relapsed or been hospitalized for the intended indication or complications of the intended
indication because of nonadherence when treated with oral antipsychotics OR
The patients care environment is such that a LAIA is a more reliable route of administration, e.g., homeless, lack
of medication supervision, or the medication cannot be stored safely
PLUS
All oral antipsychotics will be discontinued according to the schedule below
LAIA
Discontinuation of oral antipsychotics
Aripiprazole
Paliperidone
Risperidone
Haloperidol
No need for oral overlap if loading dose method is used. If no loading dose given,
supplement with oral antipsychotic for up to 3 months.
Fluphenazine
Decrease oral dose by half after first injection, then consider discontinuation after the
second injection
1
March 2015
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Monitoring
Recommended:
o Baseline and annual EKG (with all LAIAs)
o Baseline and annual metabolic parameters (i.e. weight, waist circumference, blood glucose, blood pressure,
lipids)
o Abnormal Involuntary Movement Scale (AIMS) at least annually
Issues for Consideration
Consider use of haloperidol or fluphenazine decanoate as a first-line option for consideration in the absence of
significant extrapyramidal side effects or prolactin elevation from previous trials of oral or LA formulations.
Switching from another LAIA to paliperidone LAI: Administer paliperidone LAI in place of the next scheduled injection.
Continue monthly injections of paliperidone LAI thereafter. No loading doses are required
Renewal Criteria
Documented tolerability, benefit, and improvement of adherence after at least 8 weeks of treatment.
Consider re-evaluation of appropriateness if patient adherence not improved within 1 year of therapy initiation.
Prepared: March 2015 Contact: Todd Semla, MS, Pharm.D., BCPS, VA Pharmacy Benefits Management Services
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paliperidone LAI had greater increases in BMI or weight and prolactin concentrations than either
decanoate LAIA.
5
March 2015
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Table 1: Comparison of Long-acting Injectable Antipsychotics (Frequency of LAIA administration follows package insert, unless otherwise noted)
# of
Patients
Patient
Reference
Design
Analyzed
Population
Objective(s)
Dose(s) Used
Results
PP: 453 patients, RLAI: 460
patients (analyzed)
Randomized
Change in baseline PANSS
Males: 701
score at 13 weeks: -18.6
Females: 513
points (PP) and -17.9 points
Patients with
(RLAI); Treatment difference
acute
Mean PP dose:
of change = 0.4 [CI: -1.62schizophrenia
(1) Compare
104.5mg
2.38]
efficacy
Average
13-week
Response to treatment*: 53%
outcomes of PP
duration of
Non Mean RLAI dose:
(PP) and 48.5% (RLAI);
Pandina, et al.
to RLAI
illness: 12
913
inferiority
31.7mg
Point difference of relative
1
2011
years
Double-Blind
risk = 1.2 [CI: -0.78-3.16]
Mean baseline (2) Assess
RCT
Mean
risperidone
Mean
risperidone
Mean baseline safety and
relative risk = 0.9 [CI: 0.81oral
overlap
dose:
PANSS score: tolerability
1.01
2mg
82.5 PP and
ADRs: PP=73.4% and
83.9 RLAI
RLAI=74.9%
Study Critique
Strengths:
Blinded, RCT
Multiple outcomes
studied
Large sample size
Limitations:
Mood-stabilizers and
antidepressants were
selectively limited in
the study
Short-term study
Strengths:
Average doses
Multiple outcomes
studied
Took design of Pandina
et al1 and re-studied in a
real-world setting
Large sample size
Limitations:
Open-label study
design may lead to bias
No p-values calculated
6
March 2015
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Fleischhacker,
et al. 20123
53-week
Noninferiority
Double-Blind
RCT
747
Covell, et al.
20124
12-month
Open-Label
RCT
53
Analyzed
Males: 441
Females: 306
Patients with
acute
schizophrenia
Mean PANSS
score: 81.9
(PP) and 81.2
(RLAI)
Primarily
Caucasian
Analyzed
Males: 44
Females: 9
Stable patients
with
schizophrenia
or
schizoaffective
disorder
Prescribed
fluphenazine
decanoate
(FD) or
haloperidol
decanoate
(HD), then
switched to
risperidone
LAI (RLAI)
Mean baseline
PANSS: 69.9
(HD/FD) and
(1) Compare
efficacy
outcomes of PP
to RLAI
PP Dose: initial
dose: 50mg and
39mg-156mg for
maintenance
(1) Time to
all-cause
discontinuation
comparing HD,
FD, and RLAI
after switching
patients to
RLAI from HD
and/or FD
Mean HD dose:
114.7mg
Mean FD dose:
37.5mg
to show significance
External validity with
patient race
Short-term study
Strengths:
Length of study
Efficacy and safety
outcomes
Large sample size
Limitations:
Low initial and
maintenance doses of
PP used
Strengths:
Multiple outcomes
analyzed
Length of study
Real-world
applicability of openlabel design
Limitations:
Open-label study
design may lead to bias
No report of mean
risperidone dosage
Small sample size
Did not calculate power
7
March 2015
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65.4 (RLAI)
McEvoy, et al.
20145
24-month
Double-Blind
RCT
290
Nielsen, et al.
20146
Retrospective
Cohort
4,532
Analyzed
Males: 216
Females: 74
Acute
Schizophrenia
or
schizoaffective
disorder
Baseline
PANSS score:
73 (PP) and 70
(HD)
Analyzed
Males: 2,603
Females: 1,929
Stable
schizophrenia
Average
duration of
illness: 2.5
years
Danish
patients
(1) Compare
efficacy and
safety of HD to
PP
Mean PP dose:
129-169mg
Mean HD dose:
67-83mg
(1) Compare
hospitalization
and all-cause
discontinuation
of RLAI to
first-generation
LAIs (FGALAI)
Not reported
No difference in time to
hospitalization (P=0.199)
No difference in duration of
hospitalization after failure
(P=0.744)
Strengths:
Length of study
Large sample size
Safety and efficacy
outcomes analyzed
Limitations:
Did not reach power
No evaluation of
relapse or adherence
differences
Strengths:
Large sample size
Multiple outcomes
analyzed
Limitations:
Uneven group numbers
and unmatched for
baseline characteristics
No evaluation of safety
endpoints
All medications were
given bi-weekly,
including haloperidol
decanoate
Reasons for
discontinuation were
not included
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March 2015
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9
March 2015
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Tiihonen,
et al.
20118
Weiden,
et al.
Retrospective
Study
2-year
Prospective
2,588
37
Analyzed
Males: 1605
Females: 983
Stable
schizophrenia
Finnish
patients
Analyzed
Not reported
Majority of patients
All-cause discontinuation
was less with RLAI and
HD compared to their oral
counterparts (P=0.03, HD
[HR: 0.27]; P<0.0001,
RLAI [HR: 0.75)
Study Critique
Strengths:
Length of study
Unique population
Multiple outcomes
analyzed
Real-world application
with open-label study
design
Limitations:
Open-label design may
lead to bias
Small study size
Did not calculate power
Strengths:
Large sample size
Multiple outcomes
analyzed
Unique population
Limitations:
Study design
No report of dosages to
evaluate
appropriateness
Article also looked at
depot formulations not
used in US
Strengths:
10
March 2015
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20129
Open-Label
RCT
Males: 28
Females: 9
adherence
Stable
schizophrenia,
schizophreniform, or
schizoaffective
disorder
patients (analyzed)
Length of study
Real-world application
with open-label study
design
Unique population
Limitations:
Open-label design may
lead to bias
Small study size
African
Few baseline
Americans
characteristics provided
Did not calculate power
Low doses of study
medications
*Non-adherence was defined as the number of injection visits (or outpatient visits for OAPs) that patients attended divided by the number of actual visits scheduled with an
absence of medication 1 week. Relapse was defined as an increase in positive PANSS score by >5 points.
**Non-adherence was defined as a gap in refills or injections of 14 days.
11
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Established Schizophrenia:
A number of studies have compared oral antipsychotics in regards to safety, efficacy, and
adherence in patients who have established schizophrenia. The following studies are categorized
by the LAIA used in comparison with oral antipsychotics.
Olanzapine LAI, Aripiprazole LAI, and Risperidone LAI: Efficacy
A retrospective review by Lafeuille and colleagues compared olanzapine, aripiprazole, and
risperidone LAIs to oral antipsychotics. This was a large study that included patients in the
acute-phase of schizophrenia. Patients were originally prescribed an oral antipsychotic to treat a
first-episode of schizophrenia and then included in the study if they had a relapse of symptoms.
The authors then compared patients who were stabilized and continued on oral antipsychotics to
patients who were switched to a LAI after their relapse. The authors observed all-cause
hospitalizations (including mental-health and schizophrenia-specific) and emergency room (ER)
visits to be greater in the oral antipsychotic group compared to the LAIA group. Dosages of
medications, specific oral antipsychotics compared, and PANSS data were not reported10 (Table
3)
Conclusion: Due to the retrospective design of this study, it cannot be concluded that the LAIAs
reviewed are better than oral-antipsychotics at reducing hospitalizations and ER visits.
Olanzapine LAI: Efficacy
Detke and colleagues compared olanzapine LAI to oral olanzapine for all-cause discontinuation
in an open-label RCT with patients currently in a stable-phase of schizophrenia. There were a
total of 524 patients included and no difference was observed in all-cause discontinuation or time
to discontinuation between groups. Time to relapse was longer for patients on olanzapine LAI
and subsequent length of hospital days following the relapse was shorter for patients prescribed
olanzapine LAI. Relapse rates were also observed to be less in patients prescribed olanzapine
LAI. The authors noted no differences in adverse effects between groups.11 (Table 4)
Conclusion: This prospective trial showed positive results favoring olanzapine LAI in regards to
longer time to relapse, reduced rates of relapse, and shorter hospital stays.
12
March 2015
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Table 3: Comparison of Oral Antipsychotics to Long-acting Injectable Antipsychotics in Established Schizophrenia: Efficacy of Olanzapine LAI, Aripiprazole LAI, and
Risperidone LAI (Frequency of LAIA administration follows package insert, unless otherwise noted)
# of
Patients
Patient
Reference
Design
Analyzed
Population
Objective(s)
Dose(s) Used
Results
Study Critique
Patients: 1032 (LAIA)
Strengths:
and 2796 (oral) analyzed
Large sample size
Mean number of all-cause
Multiple outcomes
(1) Compare
re-hospitalizations: 1.25
analyzed
number of re(LAIA) and 1.61 (oral);
hospitalizations
P<0.0001
Limitations:
and ER visits
Analyzed
Mean number of mental Study design
between patients
Males: 2,132
health hospitalizations:
continued on oral
Only included one
Lafeuille, et al. Retrospective
Females: 1,696
1.24 (LAIA) and 1.59
3,828
antipsychotics
Not reported
hospital to examine ER
10
2013
Review
(oral); P<0.0001
(oral) vs. patients
visits and re Acute
Mean number of
switched to
hospitalizations
schizophrenia
schizophrenia-related
atypical long No PANSS data
hospitalizations: 1.15
acting injectable
reported
(LAIA) and 1.41 (oral);
antipsychotics
Oral antipsychotics
P=0.0005
(LAIAs)
were not reported
Mean number of all-cause
Doses were not
ER visits: 2.33 (LAIA)
reported
and 2.67 (oral); P=0.0158
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March 2015
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Table 4: Comparison of Oral Antipsychotics to Long-acting Injectable Antipsychotics in Established Schizophrenia: Efficacy of Olanzapine LAI
(Frequency of LAIA administration follows package insert, unless otherwise noted)
# of
Patients
Patient
Reference
Design
Analyzed
Population
Objective(s)
Dose(s) Used
Results
Study Critique
Patients: 264 (OLAI) and 260 (oral) Strengths:
(1) Compare time to
Analyzed
analyzed
Length of
all-cause
Males: 352
All-cause discontinuation: 53.8%
study
discontinuation
Females: 172
(OLAI) and 51.2% (oral); P=0.6
between oral
Large sample
olanzapine (oral) and
Time to discontinuation: 645 days
size
Stable
olanzapine LAI
(OLAI) and 678 days (oral);
Oral:
Multiple
2-year
schizophrenia
(OLAI)
P=0.612
13.8mg
outcomes
Detke, et al.
Prospective
524
Hospitalization days after relapse:
analyzed
11
2014
Open-Label
Mean duration
0.43 (OLAI) and 1.8 (oral); P=0.02
OLAI:
(2)
Compare
Drug dosages
RCT
of illness: 14.7
386.6mg
discontinuation rate,
Time to relapse*: 539 days (OLAI)
years
time to relapse,
and 281 days (oral); P<0.001
Limitations:
change in symptom
Relapse rate: 20.1% (OLAI) and
Open-label
Baseline
severity, and
39.6% (oral); P<0.001
study design
PANSS: 56.6
safety/tolerability
may lead to
No differences in adverse effects
between groups
bias
between groups
*Relapse was defined as hospitalization for symptoms related to schizophrenia, a 25% increase in PANSS score from baseline (if score >40) or an increase in PANSS score by 10
points (if score 40), deliberate injury to others/self-injury due to worsening psychosis, or discontinuation from the study for worsening psychosis.
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March 2015
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March 2015
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Table 5: Comparison of Oral Antipsychotics to Long-acting Injectable Antipsychotics in Established Schizophrenia: Efficacy of Aripiprazole LAI
(Frequency of LAIA administration follows package insert, unless otherwise noted)
# of
Patients
Patient
Reference
Design
Analyzed
Population
Objective(s)
Dose(s) Used
Results
Analyzed
Males: 127
(1) Total
Oral aripiprazole
Females: 54
psychiatric
for titration: 10hospitalization
30mg
Stable
rates between
6-month
schizophrenia
retrospective oral
Hospitalization rates: 14.2%
Kane, et al.
Open-Label
Aripiprazole
181
antipsychotic
(ALAI) and 41.5% (OAP);
12
2013
Mirror-Image
400mg once(OAP) use vs.
P<0.0001
Mean
duration
Trial
monthly (7.2%
of illness: 15.7 prospective
of patients used
aripiprazole LAI
years
300mg once(ALAI) use at 6
monthly)
months
Baseline
PANSS: 76.7
Analyzed
Standard-dose LAI: 265
Males: 406
patients, oral: 266 patients,
Females: 256
low-dose LAI: 131 patients
analyzed
Stable
Relapse rates at week 26*:
Oral: 10-30mg
schizophrenia
7.12% (standard-dose LAI),
(1) Evaluate
7.76% (oral), and 21.8%
relapse rates of
(low-dose LAI); standard Standard-dose
Primarily
38-week
aripiprazole LAI
dose LAI was non-inferior to
aripiprazole:
Caucasian and
(standard-dose
NonFleischhacker,
oral (P=0.7871) and superior
400mg/month
African
662
LAI) 400mg
Inferiority
et al. 201413
(P=0.0006) to low-dose LAI
American
Double-Blind
compared to oral
Similar outcomes found at 38
Low-dose
onceRCT
and aripiprazole
weeks: standard-dose LAI
monthly
Baseline
LAI 50mg (lowvs. oral (P=0.992) and
aripiprazole:
PANSS: 58
dose LAI)
standard dose LAI vs. low50mg
(standard-dose
dose LAI (P<0.0001)
LAI), 56.6
(oral
Decreases observed in
aripiprazole
PANSS: standard-dose LAI
[oral]), and
vs. oral; -2.24 points
56.1 (low-dose
(P<0.05) and standard-dose
Study Critique
Strengths:
Sample size
Duration of study
Real-world
applicability with
open-label study
design
Limitations:
Open-label study
design
Historical control
Strengths:
Large sample size
Duration of study
Double-blind
RCT
Multiple
outcomes
analyzed
Limitations:
Did not reach
power in lowdose LAI arm
16
March 2015
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LAI)
17
March 2015
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18
March 2015
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Table 6: Comparison of Oral Antipsychotics to Long-acting Injectable Antipsychotics in Established Schizophrenia: Efficacy and Adherence of First-Generation LAIs
(Frequency of LAIA administration follows package insert, unless otherwise noted)
# of
Patients
Reference
Design
Analyzed Patient Population
Objective(s)
Dose(s) Used
Results
Study Critique
Randomized
Oral: 15 patients, HD: 7
Males: 20
Strengths:
patients (analyzed)
Females: 5
Length of study
No difference in patients
Real-world application
remaining exacerbation Schizophrenia
of open-label design
free; P=0.77
or
Multiple outcomes
schizoaffective (1) Compare
Total change in baseline
analyzed
48-week
long-term
disorder;
PANSS scores at 48-weeks:
Oral: 493mg
Glick, et
Prospective
efficacy and
Unknown if
-2.0 (oral) and 0.6 (HD); No Limitations:
22
al. 200514
Open-Label
tolerability of
stable or
p-value reported
Small sample size
HD: 170mg
RCT
quetiapine (oral)
unstable
Change in baseline PANSS
No power calculation
and HD
Negative scores at 48
No baseline PANSS
Mean duration
weeks: -3.2 (oral) and -0.5
score reported
of illness: 15
(HD); P<0.05
Olfson, et
al. 200715
Retrospective
Review
Zhu, et al.
200816
1-year
Prospective
Observational
2,695
299
Analyzed
Males: 1,578
Females: 1,117
Stable
schizophrenia,
schizophreniform, or
schizoaffective
disorder
Stable
schizophrenia
or
schizoaffective
Strengths:
Large sample size
(1) Assess
adherence of
antipsychotic
treatment of
patients on FD,
HD, and RLAI
(1) Comparison
of time to
medication
discontinuation
Not provided
Fluphenazine
decanoate: 25mg
Fluphenazine
Limitations:
No power evaluation
Study design
Uneven group sizes
Used refills to identify
adherence
No doses reported
Adherence differences
not clinically significant
Strengths:
Large sample size
Prospective design
19
March 2015
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Trial
disorder
oral: 12mg
Haloperidol oral:
10.7mg
Haloperidol
decanoate:
100mg
Limitations:
Medication fills were
analyzed electronically
Uneven group sizes
20
March 2015
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21
March 2015
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Table 7: Comparison of Oral Antipsychotics to Long-acting Injectable Antipsychotics in Established Schizophrenia: Adherence of Risperidone LAI
(Frequency of LAIA administration follows package insert, unless otherwise noted)
# of
Patients
Patient
Reference
Design
Analyzed
Population
Objective(s)
Dose(s) Used
Results
Study Critique
RLAI: 280 patients, OAPs:
11,541 (analyzed)
Strengths:
Patients were more likely
Large sample size
initiated on RLAI if they
Multiple outcomes
were >65 years old, had a
analyzed
history of alcohol abuse,
Analyzed
Veteran population
had an inpatient psychiatric
Males: 11,040
hospitalization in <12
Females: 781
Limitations:
(1) Identify if
months, or had >12
RLAI versus
Study design
outpatient visits (P<0.05)
OAPs improves
Stable
Uneven group sizes
Mohamed, et Retrospective
Patients were less likely to
11,821
adherence;
schizophrenia
Not reported
17
al. 2009
Review
discontinue oral risperidone, No report of doses
measured by
or
Used medical record for
olanzapine, clozapine, or
schizoaffective time to treatment
evaluation of drug
quetiapine vs. RLAI within
discontinuation
disorder
discontinuation, as
2 years (P<0.01)
identified by first and
No difference was observed
Veterans
last days of prescription
in discontinuation of
coverage, not taking into
ziprasidone vs. RLAI
account the length of
(P=0.55)
effectiveness due to
Patients were more likely to
differences in half-lives
discontinue aripiprazole vs.
RLAI (P=0.0001)
Analyzed
Males: 1,030
Strengths:
Females: 592
OAP: 277 patients, RLAI:
Large sample size
1345 patients (analyzed)
(1) Compare
Stable
Prospective design
2-year
long-term
RLAI: 42.9mg
schizophrenia
Length of study
Olivares, et
Prospective
treatment
or
OAPs most commonly used:
1622
18
al. 2009
Observational
schizoaffective outcomes of
risperidone and olanzapine
OAP doses not
Limitations:
Trial
OAPs to RLAI at
disorder
specified
Doses of oral
24 months
Duration of
Adherence*: 81.8% (RLAI)
antipsychotics not
illness: 12.6
and 63.4% (OAP); P<0.001
provided
years (RLAI)
and 10.9 years
22
March 2015
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(oral)
Rosenheck,
et al. 201119
Open-Label
RCT (VA
Cooperative
Study)
369
Acute
schizophrenia
or
schizoaffective
disorder
Veterans
(1) Assess
hospitalization
rates within two
years comparing
OAPs to RLAI
in unstable
patients
(2) Assess
differences in
adherence
between groups
RLAI: 25mg
(17%), 37.5mg
(31%), and
50mg (50%)
Leatherman,
et al. 201420
Post-Hoc
Analysis
369
Acute
schizophrenia
or
schizoaffective
disorder
Veterans
(1) Identify if
clinical
subgroups in the
Rosenheck9 trial
observed a
benefit in RLAI
vs. OAPs
RLAI: 25mg
(17%), 37.5mg
(31%), and
50mg (50%)
Strengths:
Large sample size
Veteran population
Real-world applicability
with open-label study
design
Limitations:
Did not reach power
Open-label study design
may lead to bias
Strengths:
Large sample size
Veteran population
Limitations:
Study design
Did not reach power
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Bitter and colleagues conducted a comparative prospective study between risperidone LAI and
oral antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone)
to determine a difference in all-cause medication discontinuation, as well as time to all-cause
discontinuation. Patients included were in the stable-phase of schizophrenia. All-cause
medication discontinuation was observed to be less in the risperidone LAI group compared to all
oral antipsychotics studied. Risperidone LAI also had significantly longer to all-cause
discontinuation compared to oral antipsychotics. Of note, doses were not reported for external
validity evaluations.27 Lastly, a 30-month prospective study by Buckley and colleagues
compared oral antipsychotics (olanzapine, aripiprazole, ziprasidone, paliperidone, quetiapine,
and iloperidone) to risperidone LAI. Patients included were reported to be stable and have a
diagnosis of schizophrenia or schizoaffective disorder. The authors did not observe a significant
difference in time to relapse or time to hospitalization between risperidone LAI and oral
antipsychotics. Anorexia was reported to be more common in patients in the risperidone LAI
group. Of note, a power calculation was not provided.28 (Table 8)
Conclusion: Trials evaluating differences in safety and efficacy between risperidone LAI and
oral antipsychotics in patients with stable-phase schizophrenia have conflicting results. Some
studies showed decreases in PANSS scores from baseline in the risperidone LAI group compared
to oral antipsychotics, while others did not find the same difference. Similar conflicts were
observed in adverse effect differences, as well as improvement in relapse and remission rates.
Conversely, the one study that looked at acute-phase schizophrenia observed a decrease in
PANSS scores from baseline in the risperidone LAI group compared to oral olanzapine, as well
as greater weight gain in the olanzapine group and more EPSE in the risperidone LAI group.
More studies need to be conducted to confirm these findings.
25
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Table 8: Comparison of Oral Antipsychotics to Long-acting Injectable Antipsychotics in Established Schizophrenia: Efficacy of Risperidone LAI
(Frequency of LAIA administration follows package insert, unless otherwise noted)
# of
Patients
Reference
Design
Analyzed Patient Population
Objective(s)
Dose(s) Used
Results
Olanzapine: 207 patients,
RLAI: 155 patients
Randomized
(analyzed)
Males: 312
Females: 235
RLAI: 40.7mg
Improvement from
(1) Assess
baseline in PANSS total
Acute
53-week
efficacy of oral
scores at 12 months was
schizophrenia
Risperidone oral
Keks, et al.
Prospective
362
olanzapine (oral)
greater in RLAI group
or
overlap: 2.2mg
21
2007
Open-Label
(-25.8) vs. oral group
schizoaffective to RLAI
RCT
(2) Assess safety Olanzapine:
(-23.7); P<0.0001
disorder
EPS: 25% (RLAI) and
Mean duration
14.6mg
15% (oral); P<0.05
of illness: 9
years
Weight: +1.7kg (RLAI)
and +4kg (oral); P<0.05
Oral: 275 patients, RLAI:
266 patients (analyzed)
Improvement in PANSS
Analyzed
Oral: 2mg (86
for oral and RLAI was
Males: 414
patients), 4mg
greater than baseline
Females: 226
(126 patients),
(P<0.001); no between(1) Evaluate
Stable
6mg (109
group difference was
12-week
safety and
schizophrenia
patients)
observed
Chue, et al.
Prospective
efficacy of oral
541
Primarily
A significant decrease in
22
2005
Doublerisperidone (oral)
Caucasian
RLAI: 25mg (88
prolactin was noted for
Blind RCT
compared to
patients), 50mg
each group; RLAI:
+Mean
RLAI
(126 patients),
P<0.001 (-4.8) and Oral:
duration of
75mg (105
P=0.012 (-0.9); greater
illness: ~11
patients)
decrease in the RLAI
years
group (P=0.025)
No other differences in
adverse effects were noted
48-week
(1) Evaluation of
Oral: 25 patients, RLAI:
Randomized
Bai, et al.
Prospective
differences in
20 patients (analyzed)
Males: 25
45
Not reported
200723
Single-Blind
safety and
Females: 25
No significant difference
RCT
efficacy between
in PANSS total scores
Study Critique
Strengths:
Large sample size
Length of study
Multiple outcomes
analyzed
Real-world applicability
with open-label study
design
Limitations:
Open-label study design
may lead to bias
Strengths:
Large sample size
Double-blind RCT
Multiple outcomes
analyzed
Limitations:
Short study duration
Patients were not
randomized for dose
Strengths:
Length of study
RCT design
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Olivares, et
al. 200918
2-year
Prospective
Observation
al
Trial
1622
Macfadden,
et al. 201024
2-year
Prospective
Open-Label
RCT
349
Stable
schizophrenia
Baseline
PANSS: 65.2
(RLAI) and
70.2 (oral
risperidone)
Analyzed
Males: 1,030
Females: 592
Stable
schizophrenia
or
schizoaffective
disorder
Duration of
illness: 12.6
years (RLAI)
and 10.9 years
(oral)
Analyzed
Males: 210
Females: 139
Stable
schizophrenia
Primarily
Asian patients
Mean PANSS
score: 68.6
(RLAI) and
69.1 (oral
aripiprazole
[oral])
Mean duration
of illness: 9.9
years
A significant difference in
prolactin levels was
observed: 8.8 points (oral)
and -17.3 points (RLAI)
(1) Compare
long-term
treatment
outcomes of
OAPs to RLAI at
24 months
RLAI: 42.9mg
(1) Time to
relapse
comparing oral
vs. RLAI
(2) Time to
remission
comparing the
two therapies
RLAI: 41.8mg
Oral: 19.9mg
Limitations:
No power calculation
No report of mean
dosages
Single-blind
Small sample size
Strengths:
Large sample size
Prospective design
Length of study
Limitations:
Doses of oral
antipsychotics not
provided
Strengths:
Large sample size
Real-world applicability
of open-label design
Length of study
Multiple outcomes
analyzed
Limitations:
Open-label study design
may lead to bias
27
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Gaebel, et
al. 201025
2-year
Prospective
Open-Label
RCT
666
Cordon, et
al. 201226
2-year
Prospective
Open-Label
RCT
370
Analyzed
Males: 386
Females: 280
Stable
schizophrenia
or
schizoaffective
disorder
Mean duration
of illness: ~10
years
Mean baseline
PANSS scores:
72.7 (RLAI)
and 73.2 (oral
quetiapine
[oral])
Randomized
Males: 220
Females: 154
Stable
schizophrenia
or
schizoaffective
disorder
Mean duration
of illness: 9.9
years (RLAI)
and 8.1 years
(oral)
Mean PANSS
score: 72.7
(RLAI) and
76.1 (oral
aripiprazole
[oral])
(1) Time to
relapse
comparing oral
vs. RLAI
RLAI: 33.6mg
Oral: 413.4mg
(1) Time to
relapse
comparing oral
vs. RLAI
RLAI: 35.6mg
Oral: 15.1mg
Strengths:
Large sample size
Length of study
Real-world applicability
of open-label design
Multiple outcomes
analyzed
Limitations:
Open-label study design
may lead to bias
Strengths:
Large sample size
Length of study
Real-world applicability
of open-label design
Multiple outcomes
analyzed
Limitations:
Study did not reach
power
Uneven group sizes
Open-label study design
may lead to bias
28
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Bitter, et al.
201327
1-year
Prospective
Observation
al Trial
9,567
Buckley, et
al. 201428
30-month
Prospective
Open-Label
RCT
305
Analyzed
Males: 3,805
Females: 5,762
Stable
schizophrenia
Analyzed
Males: 218
Females: 87
Stable
schizophrenia
or
schizoaffective
disorder
Duration of
illness: ~16
years
(1) Comparison
of relapse
between patients
prescribed OAPs
vs. RLAI
Not reported
RLAI: 50mg
(38%), 37.5mg
(22%), 25mg
(22%), 12.5mg
(6%), 62.5mg
(5%), 75mg (5%)
Oral: olanzapine
23mg,
aripiprazole
23.4mg,
ziprasidone
142.8mg,
paliperidone
8.3mg, quetiapine
525mg, and
iloperidone 12mg
(RLAI);P<0.0001 and
-7.66 points (oral);
P=0.0873
Adverse events were
similar between groups
RLAI: 1095 patients, Oral:
8472 patients (analyzed)
All-cause medication
discontinuation was less in
the RLAI group vs. all oral
antipsychotics (P<0.01)
Time to all-cause
discontinuation was
significantly longer in the
RLAI group (215 days) vs.
olanzapine (136 days),
aripiprazole (102 days),
ziprasidone (93 days),
quetiapine (89 days),
clozapine (76 days),
amisulpride (73 days), and
risperidone (55 days)
No difference in time to
relapse P=0.13
No difference in time to
hospitalization (P=0.305)
Strengths:
Large sample size
Limitations:
Uneven group sizes
Doses not reported
Study design
Oral medications
grouped together
Strengths:
Large sample size
Length of study
Real-world applicability
with open-label design
Limitations:
Open-label study design
may lead to bias
No power calculation
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*Relapse was defined as the time from the day the subject took the first dose of medication to day of relapse. Time in remission was defined as the simultaneous attainment of a
score of 3 on PANSS items: delusions, concept disorganization, hallucinatory behavior, unusual thought content, mannerisms and posturing, blunted affect, passive/apathetic
social withdrawal, and/or lack of spontaneity and flow of conversation.
** Relapse was defined as psychiatric hospitalization, increase in PANSS of 25% or increase of 10 points if baseline PANSS was 40, deliberate self-injury, emergence of
suicidal/homicidal ideations, violent behavior resulting in injury to another person or property, CGI-Change score of 6, or exceeding dose of 50mg/2 weeks of risperidone LAI or
750mg of quetiapine.
Relapse was defined as psychiatric hospitalization, increase in PANSS of 25% or increase of 10 points if baseline PANSS was 40, CGI-Change score of 6, deliberate selfinjury, suicidal/homicidal ideations, violent behavior resulting in injury to another person or property, or exceeding dose of 50mg/2 weeks of risperidone LAI or 30mg of
aripiprazole. Remission was defined as a score of 3 on PANSS items (blunted affect, passive/apathetic social withdrawal, lack of spontaneity and flow of conversation,
disorganization, and psychoticism) maintained for 6 months.
Relapse was defined as psychiatric hospitalization for worsening symptoms, increase in psychiatric care, CGI-I score of 6 or 7, deliberate self-injury, suicidal/homicidal
ideation, violent behavior resulting in injury to another person or property damage.
30
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symptoms and combination with oral agents may target more symptoms on top of the positive
symptoms. No specific safety and tolerability endpoints were studied.41 (Table 9)
Conclusion: Although the current literature suggests polypharmacy may have an advantage over
monotherapy when using first-generation depot antipsychotics in efficacy outcomes, neither
study looked specifically at adverse effects or safety outcomes. Currently, there is not enough
evidence to say conclusively that the proposed benefits outweigh the risks.
32
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Table 9: Use of Concurrent Oral Antipsychotics with Long-acting Injectable Antipsychotics (Frequency of LAIA administration follows package insert, unless otherwise noted)
# of
Patients
Patient
Reference
Design
Analyzed
Population
Objective(s)
Dose(s) Used
Results
Study Critique
Analyzed
46% of patients
Males: 67
received
Females: 57
concomitant oral
Majority of
APs
patients had
Concomitant use
stable
Low dose LAI:
was more common
schizophrenia
Haloperidol <75mg
with high dose
Strengths:
or
Fluphenazine <40mg
LAIAs (P=0.006)
Multiple doses for
schizoaffective
Risperidone <50mg
60 patients were on
comparison
disorder
(1) Frequency
low-dose LAIAs, 46
(81.5%)
of occurrence of Medium dose LAI:
patients on medium- Limitations:
Aggarwal,
Bipolar
concomitant use Haloperidol 75-200mg
Retrospective
dose LAIAs, and 18
Study design
et al.
124
disorder
Review
Fluphenazine 40-75mg
patients were on
40
2012
No evaluation of
(2.4%)
high-dose LAIAs
(2) Reasons for
Risperidone 50mg
adherence
combination
Hispanic patients
No safety or
Primarily
(P=0.01) and
High dose LAI:
efficacy endpoints
African
patients with a
Haloperidol >200mg
American
Small sample size
history of substance
Fluphenazine >75mg
(47%) and
abuse (P=0.04) were
Risperidone >50mg
Caucasian
more likely to be on
(21%) males;
concomitant OAPs
17% were
LAIAs were most
Hispanic, and
often combined with
14.5% were
the oral counterpart
termed other
Monotherapy: 5,480 Strengths:
Monotherapy/Polypharmacy Dose
Large sample size
Analyzed
patients,
Males: 5,620
(1) Compare
Polypharmacy:
Amisulpride: 341mg/416mg
NonLimitations:
Females: 7761 effectiveness of Aripiprazole: 20mg/23mg
7,901 patients
Katona L, Interventional
antipsychotic
Study design
Stable
Time
to
all-cause
Clozapine: 96mg/125mg
et al.
Retrospective13,381
monotherapy
schizophrenia
discontinuation:
Low clozapine,
41
2014
Prospective
Haloperidol: 4.2mg/4.4mg
vs.
or
Flupentixol
LAI:
quetiapine
Trial
Olanzapine: 10mg/11mg
schizoaffective polypharmacy
polypharmacy >
(monotherapy),
Quetiapine: 214mg/356mg
disorder
monotherapy (all
and haloperidol
Risperidone: 3.2mg/3.9mg
P<0.01) when paired
doses used
33
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Ziprasidone: 100mg/112mg
Zuclopenthixol: 32mg/38mg
Flupentixol LAI*: 2.6mg/2.7mg
Fluphenazine LAI*: 2.2mg/1.8mg
Haloperidol LAI*: 4.1mg/4.0mg
Risperidone LAI*: 2.5mg/2.7mg
Zuclopenthixol LAI*: 10mg/11mg
with clozapine,
haloperidol,
olanzapine,
quetiapine, and
zuclopenthixol;
Fluphenazine
decanoate:
monotherapy >
polypharmacy
(P=0.000) when
paired with
ziprasidone, and
polypharmacy >
monotherapy (all
P<0.01) when paired
with quetiapine and
risperidone;
Haloperidol
decanoate:
polypharmacy >
monotherapy
(P=0.0011) when
paired with
risperidone;
Risperidone LAI:
monotherapy >
polypharmacy (all
P<0.01) when
compared to all oral
antipsychotics;
Zuclopenthixol
LAI: polypharmacy
> monotherapy (all
P<0.01) when paired
with clozapine,
haloperidol,
risperidone, and
zuclopenthixol
Combinations of
3+ medications
were not included
No safety
endpoints
evaluated
34
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Summary:
1. Is there evidence to choose one long-acting injectable antipsychotic (LAIA) over the
others? Are they all the same in regards efficacy/safety?
a. Evidence does not support the use of any specific long-acting injectable
antipsychotics over another.
2. Is the place in therapy of LAIAs only for patients who are non-adherent? What is the
evidence in regards to adherence?
a. Due to the conflicting evidence and lack of reproducible studies with positive
results, it cannot be concluded that safety, efficacy, and adherence are
significantly better in patients prescribed LAIA; however, other factors for
consideration may include: patient preference, decreased pill burden, patient
environment, mental capacity, substance use disorder, etc. Systematic reviews by
Zhornitsky and colleagues, Haddad and colleagues, Kane and colleagues, and
Kirson and colleagues also concluded that results are inconclusive to say that
LAIAs improve adherence, as well other endpoints in regards to relapse rates,
time to discontinuation, and hospitalizations compared to oral antipsychotics.42-45
Similarly, a commentary paper by Stroup also concluded that adherence
outcomes are variable across studies and it is unclear if adherence is enhanced.46
3. What is the evidence for/against combining oral antipsychotics and LAIAs?
a. Evidence does not support or refute the combination of oral antipsychotics with
LAIAs due to the absence of controlled and naturalistic studies evaluating the
question. One would expect adherence to decrease with polypharmacy and
adverse events would increase. Risk versus benefit still needs to be evaluated.
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46. Stroup TS. What is the role of long-acting injectable antipsychotics in the treatment of
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Document Completed By: Chelsea Carr, Pharm.D., Eric Johnson, Pharm.D., Colleen Hall,
Pharm.D., BCPP, and Matthew Fuller, Pharm.D., BCPP, BCPS, FASHP
Contact: Todd Semla, MS, Pharm.D., BCPS, FCCP, AGSF
39
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