This document discusses long-acting injectable antipsychotics (LAIs) available in Canada. It describes first generation LAIs such as fluphenazine decanoate and second generation LAIs including paliperidone palmitate and risperidone microspheres. Recent meta-analyses and clinical trials have found that LAIs are more effective than oral antipsychotics at preventing relapse, though results are mixed depending on the specific LAI. LAIs have also been shown to reduce rates of rehospitalization compared to oral medications due to improved treatment adherence outside of clinical trial settings.

2. LAIs Available in Canada
First generation
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Second generation
• Paliperidone palmitate
• Risperidone microspheres
Fluphenazine decanoate
Flupenthixol decanoate
Haloperidol decanoate
Pipotiazine palmitate
Zuclopenthixol decanoate

3. Second Generation LAIs Available in Canada
LAI
Indication
Properties
Mechanism
Paliperidone
palmitate
Schizophrenia
Prolonged-release
injectable suspension for
intramuscular
administration
Due to its extremely low water
solubility, paliperidone
palmitate slowly dissolves at the
injection site and is enzymatically
hydrolyzed to paliperidone, which is
taken up in the systemic circulation
Risperidone
microspheres
Schizophrenia and
related disorders
Powder for injectable
prolonged-release
suspension for
intramuscular
administration
Combination of the release profile
and dosing regimens (IM injections
every 2 weeks) results in sustained
therapeutic concentrations
Bipolar disorder

4. LAI Evidence
 Davis et al (1994)
• Meta-analysis suggested significant superiority for LAIs
compared to orals
 Cochrane Reviews (1999 - 2007)
• Earlier reviews showed no convincing difference
 Leucht et al (2011)
• Recent review showed significant advantages for LAIs
Manchanda R, Chue P, Malla A, et al. Long-acting injectable antipsychotics: evidence of effectiveness and use. Can J Psychiatry.
2013;58(5 Suppl 1):5S–13S.

5. Cochrane Review of LAIs
Critiques/criticisms of the Evidence
 Use of inpatient samples
 Short-term trials (few weeks)
 Inappropriate randomization
Abhijnhan A, Adams CE, David A, Ozbilen M. Depot fluspirilene for schizophrenia. Cochrane Database Syst Rev. 2007;1:CD001718.
Da Silva Freire Coutinho E, Fenton M, Quraishi SN. Zuclopenthixol decanoate for schizophrenia and other serious mental illnesses.
Cochrane Database Syst Rev. 1999;3:CD001164.

6. Recent Meta-Analysis
Leucht et al. (2011)
Kishimoto et al. (2012)
10 RCTs; n = 1700
21 RCTs; n = 5176
> 1 yr; outpatient only
> 6 months; inpatient & outpatient
Inclusion Criteria (narrower)
Inclusion Criteria (broader)
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Schizophrenia or related disorders
Any diagnostic system, any age, and gender
Only long-term studies defined as 1 year or longer
Outpatient studies
Studies with less than 25% inpatients or with an initial
inpatient phase were eligible
Excluded trials with inappropriate randomisation processes
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≥17 years old
Diagnosis of schizophrenia or schizoaffective disorder
Included studies having other diagnoses, such as
schizophreniform disorder
Studies with a duration of at least 24 weeks that provided
information about relapse-related information, such as
study-defined relapse or rehospitalization
Excluded penfluridol, a once-weekly oral antipsychotic,
considering it neither a LAI or oral antipsychotic
Leucht C, Heres S, Kane JM, et al. Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review
and meta-analysis of randomised long-term trials. Schizophr Res. 2011;127(1-3):83–92.
Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in
schizophrenia: A meta-analysis of randomized trials. Schizophr Bull. 2013 Jan 2. Epub ahead of print. P 1-22.

7. Relapse (Primary Outcome)
 Leucht et al (2011)
• 21.6% LAIs vs 33.3% oral AP (P = 0.0009) - Highly significant
 Kishimoto et al (2013)
• 25.8% LAIs vs 31.4% oral AP (P = 0.41) – Not significant
• Results similar when narrower criteria used
• Fluphenazine LAI 30.6% vs 41.9% oral AP (P = 0.02)
• Not significant for other LAIs (haloperidol, olanzapine,
risperidone, zuclopenthixol) compared to oral APs
Leucht C, Heres S, Kane JM, et al. Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review and meta-analysis of
randomised long-term trials. Schizophr Res. 2011;127(1-3):83–92.
Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: A metaanalysis of randomized trials. Schizophr Bull. 2013 Jan 2. Epub ahead of print. P 1-22.

8. Secondary Outcomes
 Rehospitalization rates
 Drop out/discontinuation rates
• From all cause
• Adverse events
 Non-adherence
All of the above findings not significant
Leucht C, Heres S, Kane JM, et al. Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review and meta-analysis of
randomised long-term trials. Schizophr Res. 2011;127(1-3):83–92.
Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: A metaanalysis of randomized trials. Schizophr Bull. 2013 Jan 2. Epub ahead of print. P 1-22.

9. Adherence, Rehospitalization and LAIs
Register based case linked study in Finland
• 2588 patients with schizophrenia discharged after first
hospitalization 2000-2007
• 1406 (54.3%) either did not collect an AP prescription or
used their medication for less than 30 days
• Risk of rehospitalization for patients on LAIs was about onethird of those on oral antipsychotics
.
Tiihonen J. et al. A Nationwide Cohort Study of Oral and Depot Antipsychotics After First Hospitalization for Schizophrenia. American
Journal of Psychiatry. 2011;168(6):603

10. Poor Adherence is Not Reflected in
Clinical Trials
 Patients are:
• Highly selected,
• Motivated, and
• Closely monitored
 Patients participating in RCTs are more likely to be
willing to take treatment and to be cooperative, thereby
obscuring any observable differences

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Module 2