CADTH Health Technology Review

Clinical Effectiveness of Second-Generation Injectable Antipsychotic Drugs

Rapid Review

Authors: Nazia Darvesh, Danielle MacDougall, Quenby Mahood

Key Messages

• The evidence in this report is limited because statistical information was not adequately reported in included studies.

• When comparing second-generation paliperidone palmitate injections and first-generation haloperidol decanoate injections, there is little-to-no difference in treatment success or adverse events.

• When comparing second-generation risperidone injections and first-generation haloperidol decanoate and fluphenazine decanoate injections given together, there is little-to-no difference in whether patients discontinue treatment.

• Hospitalization appears higher for patients who receive haloperidol decanoate injections compared to those who receive second-generation risperidone or aripiprazole injections, but there is little-to-no difference when comparing injections of risperidone to those of haloperidol decanoate and fluphenazine decanoate given together.

• There is little-to-no difference between patients who stop treatment when comparing risperidone injections to any oral second-generation antipsychotic drugs, second-generation olanzapine injections compared to oral olanzapine, or aripiprazole injections compared to oral aripiprazole. There is little-to-no difference in adverse events between patients given aripiprazole injections compared to those given oral aripiprazole.

• Some studies showed a difference in relapse between second-generation injections compared to oral second-generation medication, while other studies showed little-to-no differences.

• Patients may experience fewer hospital days when given olanzapine injections compared to those receiving oral olanzapine.

Context and Policy Issues

The population of patients affected by psychosis is large. In 2019, 23.6 million people had schizophrenia and 39.5 million people had bipolar disorder worldwide.¹ Antipsychotic drug treatments are given to patients to manage psychosis symptoms, such as hallucinations and delusions.² These medications work to clear confusion and increase calm in people with a variety of conditions.² However, antipsychotic medications can have serious side effects such as involuntary movements, dizziness, and risk for diabetes.²

There are several antipsychotic medications on the market, and these are generally grouped into 2 categories; first-generation (FG) and second-generation (SG) antipsychotic drugs. FG drugs are older medications that block dopamine, and are referred to as typical antipsychotic drugs, whereas SG drugs block dopamine while also playing a role in controlling serotonin and are referred to as atypical antipsychotic drugs.² Although SG antipsychotic drugs were first available in Canada in the 1990s, they have been prescribed more than FG antipsychotic drugs over time because they are thought to have fewer side effects.³ Both medication types are available as oral formulations and IV or intramuscular injections, with different doses and administration frequencies.² Long-acting injectable (LAI) antipsychotic drugs are an option for patients who are unable to adhere to treatment involving frequent dosing and those who suffer from relapses.⁴ In some cases, oral administration therapies can cause immediate unwanted side effects.⁴ LAI antipsychotic drugs can therefore offer a solution to this, as they are administered every 2 or 4 weeks rather than being taken daily.⁴

Given the differences in prescription patterns, potential side effects, and treatment administration methods between antipsychotic drugs, there is a need to determine the effects of SG-LAIs when compared to other antipsychotic drugs based on generation type or route of administration. A previous CADTH report on antipsychotic medications published in 2021⁵ focused on emergency settings and another 1 published in 2019⁶ reviewed their effects in comparison to placebo. Therefore, this rapid review aims to summarize literature on the clinical safety and effectiveness of SG-LAIs compared to FG-LAIs, and SG-LAIs compared to oral SG antipsychotic drugs in non-emergency settings, in patients with schizophrenia and/or bipolar disorders.

Research Questions

1. What is the clinical effectiveness of second-generation injectable antipsychotic medications versus first-generation injectable antipsychotics?

2. What is the clinical effectiveness of second-generation injectable antipsychotic medications versus second-generation oral antipsychotics?

Methods

Literature Search Methods

A limited literature search was conducted by an information specialist on key resources including MEDLINE, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy was comprised controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were injectable second-generation antipsychotic drugs, including aripiprazole, risperidone, olanzapine, paliperidone, and ziprasidone. CADTH-developed search filters were applied to limit retrieval to health technology assessments, systematic reviews (SRs), meta-analyses (MAs), or network meta-analyses, any types of clinical trials or observational studies, or economic studies. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2017 and March 1, 2022.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1 or were duplicate publications. Studies were also excluded if the populations had dementia, the ages of patients were unclear, compared doses or frequencies of same medication, had unclear route of administration, or had no comparator group. Articles about antipsychotic use in chemotherapy, substance use, or withdrawal scenarios, and studies about rapid or short-acting antipsychotic drugs in emergency situations or combined use of antipsychotic drugs with another drug where the effect of the antipsychotic drugs could not be evaluated were also excluded. SRs in which all relevant studies were captured in other more recent or more comprehensive SRs were excluded. SRs with objectives that did not focus on SG antipsychotic drugs were also excluded. Primary studies retrieved by the search were excluded if they were captured in 1 or more included SRs.

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)⁷ for SRs and the Downs and Black checklist⁸ for randomized controlled trials (RCTs). Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 494 citations were identified in the literature search. Following screening of titles and abstracts, 444 citations were excluded and 50 potentially relevant reports from the electronic search were retrieved for full-text review. Two potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 44 publications were excluded for various reasons, and 8 publications met the inclusion criteria and were included in this report. These comprised 7 SRs and 1 RCT. Appendix 1 presents the PRISMA⁹ flow chart of the study selection.

Additional references of potential interest are provided in Appendix 6.

Summary of Study Characteristics

The scope of all 7 SRs^10-16 was broader than the topic of the current review. Some primary studies included in these SRs were out of scope with no comparator group or comparator group of no interest to the current review. Therefore, only the characteristics and results of the subset of relevant studies are described in this report.

Study Design

The 7 SRs^10-16 were published between 2017 and 2020 and they included literature published up to 2019. Three SRs^13,14,16 MA results relevant to the current review so summary estimates were extracted for these SRs. Three SRs did not conduct MAs^10,11,15 and 1 SR¹² did not have MAs relevant to the current review; data for individual studies were extracted instead. The Saucedo Uribe et al. SR¹⁶ included 17 RCTs of which 2 were relevant to the current review. The Gentile SR¹⁰ included 51 studies of which 8 RCTs and 5 NRSs were relevant to the current review. The Keramatian et al. SR¹¹ include 35 studies of which 2 RCTs and 3 non-randomized studies (NRSs) were relevant to the current review. The Olagunju et al. SR¹³ included 26 studies of which 8 RCTs were relevant to the current review. The Peters et al. SR¹⁵ identified 31 RCTs and 5 MAs from the literature; 4 of the RCTs were relevant to this review. The Park et al. SR¹⁴ included 17 RCTs and 13 NRSs of which all but 1 NRS was relevant to the current review. The SR¹⁴ had 4 MAs that were relevant to the current report. The McDonagh et al. SR¹² from the Agency for Health care Research and Quality included 2 SRs and 29 RCTs of which 4 RCTs were relevant to the current review. These 4 RCTs were also captured in other SRs included in the current report; however, the McDonagh et al. SR¹² reported some results that were not in the other SRs. The overlap across all SRs is presented in Appendix 5.

The 1 included RCT¹⁷ was published in 2022.

Country of Origin

For SRs, 1 had a first author from Italy,¹⁰ 1 from Mexico,¹⁶ 1 from Canada,¹¹ 1 from Australia,¹³ 1 from Germany,¹⁵ 1 from South Korea,¹⁴ and 1 from the US.¹² For the included RCT,¹⁷ the first author was from China and the study was conducted across 15 centres in China.

Patient Population

Five SRs^12-16 focused on populations with schizophrenia-related conditions only, and 2 SRs^10,11 included populations with either schizophrenia- or bipolar-related disorders. Across SRs, the number of patients included in their primary studies ranged from 10 to 8,433. All SRs reported results for adult populations and for those that provided average age data, this ranged from 21.5 to 48.0 years. In the 1 included RCT,¹⁷ the population was 436 adults with schizophrenia with an average age of 34.2 years in the intervention group and 33.6 years in the comparator group.

Studies did not distinguish whether gender or sex were reported or whether nonbinary identification was recorded, so results are summarized as reported by the authors of the included studies. Based on 3 SRs,^13,15,16 males ranged from 43.1% to 86.2% across studies. One SR¹² reported on females which ranged from 22.0% to 39.2%. For the included RCT,¹⁷ both the intervention and comparator were comprised of 28.4% males and 71.6% females.

Interventions and Comparators

Five SRs^10-12,15,16 included studies that compared SG-LAIs with FG-LAIs, 6 SRs^10-15 included studies that compared SG-LAIs with oral SG antipsychotic drugs, and 1 RCT¹⁷ compared an SG-LAI plus oral placebo with oral SG antipsychotic plus placebo injection.

The SG-LAIs evaluated were aripiprazole (ARI) 50 mg to 400 mg,^10-14 olanzapine (OLA) 150 mg to 600 mg,^10,12-14 paliperidone palmitate (PP) 39 mg to 234 mg,^10-12,15,16 risperidone (RIS) 12.5 mg to 50 mg,^10-16 or ARI-LAI plus oral placebo,¹⁷ or any SG-LAI.¹⁴ Doses for any SG-LAI¹⁴ were not reported. FG-LAIs included haloperidol decanoate 25 to 200 mg,^10-12,15,16 fluphenazine decanoate 37 mg and haloperidol decanoate 114 mg together,¹⁶ zuclopenthixol decanoate,¹⁰ or any FG-LAI.¹¹ Studies did not provide the doses for zuclopenthixol decanoate LAI¹⁰ or any FG-LAI.¹¹ Oral SG antipsychotic drugs included amisulpride (AMI),¹⁴ ARI 6 mg to 30 mg,^10-14 OLA 5 mg to 20 mg,^10,12-15 quetiapine (QUE) 300 mg to 500 mg,^10,13,14 RIS 1 mg to 6 mg, ziprasidone (ZIP),¹⁴ paliperidone extended-release 6 mg to 12 mg,¹⁵ oral ARI plus placebo injection,¹⁷ or any SG antipsychotic.^10,11,13-15 The doses for AMI,¹⁴ ZIP,¹⁴ or any oral SG antipsychotic were not provided.^10,11,13-15 Specifically, 2 SRs^10,11 reporting on FG-LAI, 2 SRs^11,14 on SG-LAI, and 4 SRs^10,11,13,14 on oral SG antipsychotic did not provide the doses that were evaluated.

LAIs were provided every 2 weeks or monthly. When reported, oral SG antipsychotic drugs were given to patients daily. Five SRs^{10,11,13,14,16} did not report how often treatments were provided.

Study duration ranged from 2.5 months to 2.5 years.

Outcomes

Effectiveness

Effectiveness was measured in as efficacy failure,¹² discontinuation,^10-12,14-16 non-compliance,¹⁴ remission,^12,14 symptoms,^11,12,14-17 functioning,^11-15,17 quality of life,^11-14 stabilization,¹⁵ and satisfaction.¹⁵

Specifically, symptoms were measured as individual symptoms or by using scales such as the Positive and Negative Syndrome Scale (PANSS), the Young Mania Rating Scale (YMRS), the Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HAM-A), the Brief Psychiatric Rating Scale (BPRS), the Mongtomery-Asberg Depression Rating Scale (MADRS), and the visual analogue scale (VAS).

The PANSS is a 30-item scale that measures positive symptoms (excess of function), negative symptoms (loss of function), and general psychopathology.¹⁸ Each item is rated from 1 to 7; higher numbers indicate increasing psychopathology.¹⁸ It is measured using a clinical interview with the patient, and includes input from care staff or family members.¹⁸

The YMRS is an 11-item scale that measures symptoms in those with mania, during a clinical interview.^19-21 Each item has 5 severity score levels with higher scores indicating increased severity.^19-21 Four items are scored out of 8 and 7 items are scored out of 4, with the total score ranging from 0 to 60.^19-21

The HDRS can have 17, 21, or 29 items and is used by clinicians to measure depression symptoms in patients.^22,23 Each item is scored from 0 to 2 or 0 to 4 with higher numbers indicating more severity.^22,23

The HAM-A is a 14-item scale used by clinicians to measure anxiety symptoms.^24,25 Each item is given a score from 0 to 4 with higher numbers indicating more severity.^24,25

The BPRS is an 18-item scale that measures psychiatric symptoms during a clinical interview with a clinician.^26,27 Each item is rated from 0 to 7 with higher numbers indicating more severity.^26,27

The MADRS is a 10-item scale and is used by clinicians to measure depression symptoms in patients.^28,29 Each item is scored from 0 to 6 with higher numbers indicating more severity.^28,29 The total score ranges from 0 to 60.^28,29

The VAS is a continuous scale that can be used by a patient to indicate the intensity of pain across a spectrum of no pain to worst pain.³⁰

Functioning was measured using the Clinical Global Impression-Severity (CGI-S),^{11,12,14,15,17} the Clinical Global Impression-Improvement (CGI-I),^11,12,17 the Global Assessment of Function (GAF),¹³ the Scale of Functioning (SOF),¹³ the Personal and Social Performance scale (PSP),^13,17 the Social and Occupational Functioning Assessment Scale (SOFAS),¹³ the Subjective Well-Being Under Neuroleptics Scale-Short Form (SWN-S),¹⁵ and the Social Functioning Scale (SFS).¹³

The Clinical Global Impression scales measure symptoms, treatment response, and treatment efficacy.^31,32 The CGI-S and the CGI-I sections are each on 7-point scales, where higher values indicate more illness or worsening of condition, respectively.^31,32

The GAF measures social, occupational, and psychological functioning as a whole, and provides a score from 1 to 100, where higher numbers indicate more functioning in life’s activties.^33,34

The PSP is based on the SOFAS, which was part of the DSM-IV.^34-37 Both instruments assess social functioning in patients based on a 100-point scale; with higher numbers indicating higher functioning.^34-37

The SWN is a scale that patients with psychotic disorders fill out to measure illness, treatment experiences, and life satisfaction.^38,39 The long version contains 38 items, and the short version has 20 items.^38,39 Each item is given a score from 1 to 6 representing “not at all” to “very much” as a response to each statement.^38,39

The SFS is based on patient self-report and captures functioning in people with schizophrenia.^40,41 There are 76 items and most are rated on 2 to 5 point scales; with higher numbers indicating more competent behaviour.^40,41

Quality of life was measured using the Heinrichs-Carpenter QoL scale (QLS),¹³ the 12-item Short Form Health Survey (SF-12),¹³ the 36-item Short Form Health Survey (SF-36),^12,13 the Schizophrenia Quality-of-Life Scale, Revision 4 (SQLS-R4),¹³ the Wisconsin Quality-of-Life Index (W-QOLI),¹³ and the Assessment of Quality of Life (AQoL).¹³

The QLS is a 21-item scale based on a semi-structured interview used by a clinician to document the quality of life in those with schizophrenic deficit syndrome.⁴² Each item is rated on a 5- or 7-point scale with higher numbers indicating better quality of life.⁴²

The Short Form Health Surveys are self-reported by patients and measure health status in different domains including physical, mental, and emotional health.^43,44 Each item has 2 to 5 response options ranging from values representing excellent health to poor health.^43,44

The SQLS-R4 has 33 items and measures quality of life in patients with schizophrenia.^45,46 Each item is scored on a 5-point scale, and each domain is given a score from 0 to 100, representing best to worst health status, respectively.^45,46

The W-QOLI is a model that measures quality of life in 9 dimensions and can be filled out by a patient, clinician, or caregiver.^47,48 Some questions have non-hierarchical responses, while others have an order of options (e.g., satisfaction from very dissatisfied to very satisfied).^47,48

The AQoL are a group of instruments that measure different life dimensions such as independent living, mental health, and senses.^49,50 There are 4 versions that include 12, 20, 26, or 35 items; each item has 4 to 6 response options.^49,50

Satisfaction was measured using the Service Engagement Scale (SES),¹⁴ and the Treatment Satisfaction Questionnaire for Medication (TSQM).¹⁴

The SES is a 14-item questionnaire that was developed with people who had first episode psychosis, and measures engagement with community mental health services.^51,52

The TSQM is a 14-tem instrument that measures effectiveness, convenience, side effects and global satisfaction in patients.^53,54 One item uses a dichotomous response scale, while the other questions have a 7-point scale ranging from extremely satisfied to extremely dissatisfied.^53,54

Safety

Safety was measured as EPS,^11,12,14-17 hospitalizations,^11,14-16 relapse,^12,14,15 suicidal or homicidal ideation,¹² death,¹² and other adverse events (AEs).^{11,12,14,16,17} Drug-induced movements were captured by the Abnormal Involuntary Movement Scale (AIMS), the Simpson-Angus Extrapyramidal Side Effects Scale (SAS), the Extrapyramidal Symptom Rating Scale (ESRS), the Barnes Akathisia Rating Scale (BARS), and the global assessment of akathisia.

The AIMS is a 12-item scale used by clinicians to measure dyskinesias (i.e., involuntary movements) severity in patients.^31,55 Each item is scored from 0 to 4 with higher numbers indicating greater severity.^31,55

The SAS is a 10-item scale used by clinicians to measure involuntary movements in patients.^56,57 Each item is scored from 0 to 4 with higher numbers indicating more severity.^56,57

The ESRS is a scale used by clinicians to measure involuntary movements in patients.⁵⁸ It has 8 subscales with questions about movements for each that can be scored from 0 up to 6, with higher numbers indicating greater severity.⁵⁸

The BARS and the global assessment of akathisia are scales used by clinicians to measure akathisia (i.e., restlessness) in patients through observation.^59,60 For the BARS, each item is scored from 0 to 3 or 0 to 5 with higher numbers indicating more severity and for the global assessment of akathisia, the score ranges from 0 to 5 with higher numbers indicating more severe akathisia.^59,60

Additional details regarding the characteristics of included publications are provided in Appendix 2.

Summary of Critical Appraisal

Systematic Reviews

All 7 SRs^10-16 clearly stated the populations, interventions, and outcomes of interest. Six SRs^10,12-16 also clearly stated the comparators to include in the reviews upfront. Three SRs^12,14,16 established a protocol or study criteria beforehand. For 4 SRs,^10,11,13,15 it is unclear whether a protocol was written; potential bias due to protocol deviation could not be determined.

Six SRs^10-14,16 searched at least 2 databases and provided keywords or search strategies. For 1 SR,¹⁵ literature search was performed in 1 database, and it is unknown if it was enough to comprehensively capture relevant published literature. Five SRs^10-13,15 conducted more comprehensive literature searches involving databases and other sources such as reference lists of included studies, reference lists of other reviews, clinical trial registries, expert recommendations, and grey literature.

Four SRs^11,12,14,16 performed study selection in duplicate, 2 SRs^11,12 conducted data extraction in duplicate with independent reviewers, and 4 SRs^12-14,16 assessed the risk of bias for included studies. For SRs that did not conduct study selection or data extraction in duplicate, it is unclear if all relevant studies were included, and the completeness and accuracy of the extracted data are unknown. For the 3 SRs^10,11,15 where it is unclear if risk of bias was assessed, it may be challenging to draw conclusions since potential weakness in study conduct are unclear.

Two SRs^12,15 described study and population characteristics in sufficient detail. Five 5 SRs^{10,11,13,14,16} described some characteristics in detail, while other specifics such as treatment doses and frequencies were not provided. This limits the comparability of the studies to others, and it was difficult to determine the applicability of the findings.

Six SRs^10-12,14-16 did not report quantitative data on comparative effects between study groups for all outcomes; it was unclear to determine whether there were meaningful differences between study groups.

In the 2 SRs^13,16 that conducted relevant MAs, both combined study results appropriately and addressed heterogeneity. One SR¹³ assessed for publication bias but the other SR¹⁶ did not. Thus, in the latter,¹⁶ it is unclear whether included studies were published selectively.

For 2 SRs,^10,16 authors indicated that there were no conflicts of interest. One SR¹⁴ did not provide a conflicts of interest statement. For 2 SRs,^11,15 1 of the review authors of each study received funds from pharmaceutical companies and it is unclear how this may have affected conduct or interpretation of results. One SR¹³ indicated no conflicts of interest however the funding source of the review was unclear. In another SR,¹² conflicts were collected; however, it is unclear whether any may have been related to review and interpretation of findings.

Randomized Controlled Trial

In the 1 included RCT,¹⁷ authors clearly stated objectives and study criteria. Patients were randomized and important factors that may have influenced outcomes were balanced between study groups. The study was conducted across 15 sites in China which may increase the generalizability of the findings; however, the exclusion of those who were of childbearing age, pregnant, or breastfeeding may mean that the results could not be generalizable to these populations.

Although the trial was described as double blind, the authors stated that investigators were blind to assignment but that drug managers who administered the treatments at each site were unblinded. It is unclear if the placebos administered adequately concealed treatment since the aripiprazole and placebo injections appear different. This is a limitation since knowledge of study assignment may have introduced performance bias (e.g., patients may have been treated differently if study personnel knew what treatment they received, patients may have self-reported outcomes differently with knowledge of their assignment) or detection bias if outcome assessors were also not blinded.

Around a quarter of each study group did not complete the study because of loss to follow-up, discontinuation of treatment, consent withdrawal, adverse event (AE), clinician advice, and other reasons; the missing data were handled using the last observation carried forward method. It is unclear if reasons for dropout were related to study assignment, or if they were similar between groups. This is a limitation as results may be skewed.

Some outcome data (e.g., symptoms, functioning) were collected subjectively through questionnaires completed by patients, clinicians, or family members. This is a limitation since there may have been bias due to knowledge of study assignment, and outcomes may be unreliable.

Three review authors received funding from pharmaceutical companies. It is unclear whether and how these potential conflicts may have affected results of the review.

Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.

Summary of Findings

Appendix 4 presents the main study findings by outcome.

The summaries in this report may contain some data from the same trials as there was overlap in some of trials included within the SRs. This overlap across SRs is presented in Appendix 5. Where the same primary study results were reported in 2 or more SRs, they are presented once in this report from 1 of the included SRs.

Effectiveness of Second-Generation Versus First-Generation Injectable Antipsychotic Drugs

Effectiveness was measured as efficacy failure in 1 SR,¹² discontinuation in 2 SRs,^10,16 continuation in 1 SR,¹¹ and as symptoms using the PANSS in 1 SR.¹⁶

Efficacy Failure

Results from 1 SR¹² showed little-to-no difference in efficacy failure between PP-LAI and haloperidol decanoate LAI; these findings had low precision.

Discontinuation and Continuation

The results from 2 SRs^10,16 showed that there were no differences between RIS-LAI and haloperidol decanoate LAI and fluphenazine decanoate LAI given together, and no difference between PP-LAI and haloperidol decanoate LAI. There is uncertainty regarding these findings because data on the comparative effects and measures of variability were not reported. For results from 1 SR,¹⁰ there appeared to be higher discontinuation in the haloperidol decanoate LAI group compared to the PP-LAI group, however no statistical comparison was reported. For results from 1 SR,¹⁰ there appeared to be higher discontinuation in the zuclopenthixol decanoate LAI group compared to the RIS-LAI group. Another SR¹¹ showed what appeared to be higher treatment continuation in the RIS-LAI group compared to the FG-LAI group. However, no statistical comparison was reported in either study.

Symptoms

In 1 MA involving 2 RCTs reported in 1 SR,¹⁶ there was little-to-no difference in the PANSS score between SG-LAIs and FG-LAIs.

Safety of Second-Generation Versus First-Generation Injectable Antipsychotic Drugs

Extrapyramidal Symptoms

Two SRs^12,16 reported results for extrapyramidal symptoms (EPS). In 1 SR,¹⁶ 1 MA suggested little-to-no difference in tardive dyskinesia between SG-LAIs and FG-LAIs. In another SR,¹² there appeared to be a higher AIMS score in the haloperidol decanoate LAI group compared to the PP-LAI group, and a higher global rating of akathisia in the PP-LAI group compared to the haloperidol decanoate LAI; interpretation of the statistical information provided in the SR is unclear.

Hospitalizations

Two SRs^11,16 reported results for hospitalizations. In SR,¹⁶ authors stated that the number of hospitalizations was not statistically significantly different between the RIS-LAI group and the comparator group that received haloperidol decanoate LAI and fluphenazine decanoate LAI together; however, the magnitude and precision are uncertain because data on the comparative effects and measures of variability were not reported. In another SR,¹¹ authors reported that the risk of all-cause hospitalization risk was significantly higher in the haloperidol decanoate LAI group compared to the ARI-LAI group; however, the precision is uncertain because data on the measures of variability were not reported. In this same SR,¹¹ authors stated that after adjusting for confounders, those in the FG-LAI group had a higher risk of hospitalization for any mood episode and major depressive episode compared to the RIS-LAI group; however, results are imprecise.

Suicidal or Homicidal Ideation

One SR¹² reported on suicidal or homicidal ideation, which appeared higher in the PP-LAI group compared to the haloperidol decanoate LAI group, however, there was no statistical comparison reported.

Treatment Emergent Adverse Events

Adverse events were reported in 1 SR.¹⁶ Authors stated that treatment emergent AEs were not statistically significantly different between the PP-LAI and haloperidol decanoate LAI groups, however, the magnitude and precision are uncertain because data on the comparative effects and measures of variability were not reported.

Effectiveness of Second-Generation Injectable Versus Second-Generation Oral Antipsychotic Drugs

Non-Compliance and Discontinuation

One SR¹⁴ reported non-compliance outcomes, with little-to-no difference between groups.

Four SRs^10,12,14,15 reported discontinuation outcomes. In 2 SRs^10,15 with results comparing RIS-LAI to any oral SG antipsychotic, there did not appear to be differences between groups, however, the authors did not report statistical comparisons. Based on 1 SR,¹⁰ the RIS-LAI group appeared to have a lower discontinuation rate compared to the QUE group, but a higher discontinuation rate compared to oral ARI and OLA groups. However, statistical data on comparative effects was not reported.

One SR¹⁰ showed what appeared to be a lower discontinuation rate in the PP-LAI group compared to the oral SG antipsychotic group; however, authors did not report comparative effects. One SR¹⁵ showed what appeared to be higher discontinuation rate in the PP-LAI group compared to the oral OLA group; however, data on the comparative effects was not reported.

In 1 SR¹⁵ authors stated that discontinuation rates during the treatment period was similar between PP-LAI and oral OLA groups.

Statistical analyses from 1 SR¹² suggested little-to-no difference in all-cause discontinuation and time to all-cause discontinuation between OLA-LAI and oral OLA; precision is unknown because measures of variability were not reported.

Based on SR,¹² there appeared to be more people discontinuing treatment in the oral ARI group compared to the ARI-LAI groups; statistical data on comparative effects was not reported. Other findings from this SR¹² showed little-to-no difference in time to all-cause discontinuation between ARI-LAI and oral ARI groups.

Symptoms

Four SRs^11,12,14,15 and 1 RCT¹⁷ reported on symptoms. One MA¹⁴ based on 2 RCTs showed a greater decrease in MADRS score with SG-LAI compared to the oral SG antipsychotic.

Two SRs^11,15 compared RIS-LAI to oral SG antipsychotic drugs and stated that there were no differences in symptoms between groups; however, conclusions are uncertain because data on the comparative effects and measures of variability were not reported. One SR¹¹ indicated that the RIS-LAI group had a higher number of positive clinical events and lower number of negative events; however, there were no statistical values reported.

One SR¹⁵ reported no significant differences between the PP-LAI and oral OLA groups for PANSS score; however comparative data were not reported.

One SR¹² reported little-to-no difference in baseline-to-end point least squares mean change on PANSS total score; precision is unclear because measured of variability were not reported.

One SR¹² and 1 RCT¹⁷ reported on ARI-LAI compared to oral ARI. The SR¹² showed a higher positive change in PANSS score in the oral ARI group compared to the ARI-LAI groups but data on comparative values were not reported. The SR¹² also showed little-to-no difference in non-exacerbation of psychotic symptoms; but measures of variability were not reported. The RCT¹⁷ showed little-to-no difference in PANSS outcomes between ARI-LAI and oral ARI groups.

Remission

One MA¹⁴ based on 5 RCTs showed little-to-no difference in remission between groups. Results from 1 SR¹² showed what appeared to be lower remission in the ARI-LAI group compared to the oral ARI group; however, data on comparative effects were not reported.

Stabilization

One SR¹⁵ showed little-to-no difference in time to stabilization between the RIS-LAI group compared to oral SG antipsychotic drugs group; data on measures of variability were not reported.

Functioning

Five SRs^11-15 and 1 RCT¹⁷ reported on functioning. One SR¹¹ compared RIS-LAI to oral SG antipsychotic drugs; some results suggested significant decrease in CGI-S scores in patients who switched from oral SG antipsychotic to RIS-LAI, while other results showed RIS-LAI and oral SG antipsychotic groups were similar.

One SR¹⁵ suggested negative symptoms were more favourable for a PP-LAI group compared to oral paliperidone extended-release medication but that there was little-to-no difference in functioning measured using the PSP and SWN-S scales.

Based on 1 MA¹³ that included 7 RCTs, functional outcome was better in the SG-LAI group compared to the oral SG antipsychotic group.

One RCT¹⁷ comparing ARI-LAI plus oral placebo to oral ARI plus placebo injection showed little-to-no difference in functioning scores between groups. One SR¹² did not report comparative data to form conclusions.

Quality of Life and Satisfaction

The authors of 1 SR¹⁵ stated that there were differences between patients for treatment satisfaction, convenience, and service engagement between the PP-LAI and oral paliperidone extended-release groups.

Safety of Second-Generation Injectable Versus Second-Generation Oral Antipsychotic Drugs

Extrapyramidal Symptoms

Four SRs^11,12,14,15 and 1 RCT¹⁷ reported on EPS. One NRS in 1 SR¹¹ stated that there was a decrease in EPS from baseline to 12 months in patients switched from oral SG antipsychotic drugs to RIS-LAI. Two SRs^11,15 found little-to-no difference in EPS, AIMS scores, or SAS scores; measures of variability were not reported. In 1 SR,¹¹ the RIS-LAI group appeared to have more akathisia compared to the oral SG antipsychotic group; data on comparative effects were not reported.

In 1 SR¹⁵ with results comparing PP-LAI to oral paliperidone extended-release medication, results were unclear.

In 1 SR,¹² there appeared to be fewer EPS in the ORA-LAI group compared to the oral OLA group; data on comparative effects were not reported.

One SR¹² comparing ARI-LAI to oral ARI did not report comparative data on EPS to form conclusions.

One RCT¹⁷ comparing ARI-LAI plus oral placebo to oral ARI plus placebo injection stated no difference between groups in EPS scales; however, no comparative effects were reported.

Relapse

One SR¹⁵ suggested little-to-no difference in relapse between RIS-LAI and oral SG antipsychotic groups.

In 1 MA¹⁴ based on 2 RCTs, the RIS-LAI group had a longer time to relapse compared to the oral ARI group.

In 1 SR¹² comparing ARI-LAI with oral ARI, there was little-to-no difference in the estimated relapse rate. In the same SR,¹² there appeared to be little-to-no difference in the ORA-LAI group compared to oral OLA in the rate of relapse and a difference between groups on time to relapse with data on comparative effects not reported; relapse findings are unclear since the results from these 2 outcomes are different.

Hospitalization

In 1 SR¹⁵ there appeared to be higher hospitalization in the RIS-LAI compared to the oral SG antipsychotic group; however data on comparative effects were not reported.

In 1 MA¹⁴ based on 2 RCTs, the OLA-LAI group had a shorter number of hospital days compared to the oral OLA group.

Other AEs

In 1 SR,¹¹ some results showed little-to-no difference in AEs between RIS-LAI and oral SG antipsychotic group while other results showed a higher percentage of patients in the RIS-LAI group with somnolence, headache, tremors, and skin rash compared to oral SG antipsychotic group but data on these comparative effects were not reported.

One SR¹⁵ comparing PP-LAI to oral paliperidone extended-release medication, results were unclear.

In 1 SR,¹² there appeared to be higher AEs and higher discontinuation due to AEs in the ORA-LAI group compared to the oral OLA group, and fewer overall AEs and fewer withdrawal due to AEs in the ARI-LAI group compared to the oral ARI group. Data on comparative effects were not reported for these findings.

One RCT¹⁷ comparing ARI-LAI plus oral placebo to oral ARI plus placebo injection stated little-to-no difference between groups in treatment emergent AEs and injection site reactions.

Suicidality and Death

In 1 RCT reported in 1 SR,¹² there appeared to be little-to-no difference in suicidality in the ARI-LAI group compared to the oral ARI group; data on comparative effects were not reported.

In 1 RCT reported in 1 SR,¹² there appeared to be more deaths in the oral ORA group compared to the OLA-LIS group; data on comparative effects were not reported.

Limitations

Limitations of the body of evidence were few results on SG-LAIs compared to FG-LAIs in recently published literature, a lack of statistical findings to form conclusions, unclear comparability across studies due to using different outcome measures to determine safety and effectiveness, unclear generalizability to the Canadian population, and unclear quality of the evidence. Five SRs^10-12,15,16 published between 2017 and 2019 had data comparing SG-LAIs and FG-LAIs; however, there were few datum for each outcome, since for this comparison, efficacy failure, continuation, symptoms, suicidal or homicidal ideation and AEs were only reported in 1 primary study from these SRs.

The summaries from included SRs did not report quantitative findings sufficiently. In most cases, authors of SRs did not provide data on comparative effects or measures of variability between groups, and instead reported primary study-level frequency or percentage values for each study groups. In some cases, these data were supplemented with a narrative statement on statistical significance without providing statistical data. It is therefore challenging to derive conclusions from this evidence.

Another limitation was the variety of ways that effectiveness or safety were measured in included studies. The evidence included 7 scales to measure symptoms, 9 instruments to measure functioning, 8 scales to measure quality of life, 2 questionnaires to measure satisfaction, and 4 scales to measure EPS. Given the variability in measurement tools and their results, it is unclear how outcomes can be compared across studies.

Given that most of the evidence base was from SRs which included primary studies from different countries, it is unclear how generalizable the results are to the Canadian population.

In 3 of the 7 included SRs, it was unclear whether risk of bias assessment was conducted, which is another limitation since there is missing information about the quality and strength of the evidence.

Conclusions and Implications for Decision- or Policy-Making

A rapid review was conducted to determine the clinical effectiveness of SG-LAI compared to FG-LAI or oral SG antipsychotic drugs for patients with schizophrenia or bipolar disorders. Seven SRs^10-16 and 1 RCT¹⁷ were found, which were published between 2017 and 2019. These studies reported effects on discontinuation, continuation, symptoms, remission, stabilization, functioning, quality of life, satisfaction, and AEs such as EPS, relapse, hospitalization, suicide or suicidal ideation, or death. Five SRs^10-12,15,16 reported outcomes comparing SG-LAI to FG-LAI, and 6 SRs^10-15 and 1 RCT¹⁷ reported outcomes comparing SG-LAI to oral SG antipsychotic drugs.

For the comparison of SG-LAI to FG-LAI, 2 SRs^12,16 indicated little-to-no difference in efficacy failure between PP-LAI and haloperidol decanoate LAI groups, and little-to-no change in symptom severity between SG-LAI and FG-LAI groups. Three SRs^11,12,16 showed little-to-no difference in tardive dyskinesia between SG-LAI and FG-LAI, EPS between PP-LAI and haloperidol decanoate LAI, treatment emergent AEs between PP-LAI and haloperidol decanoate LAI, or in hospitalizations between RIS-LAI and haloperidol decanoate LAI and fluphenazine decanoate LAI given together. However, a higher risk of hospitalization was reported in patients given FG-LAI compared to RIS-LAI, and between those given haloperidol decanoate LAI compared to those given ARI-LAI, although the precision of these latter findings is uncertain because data on the measures of variability were not reported.

For the comparison of SG-LAI to oral SG antipsychotic drugs, 2 SRs^12,14 suggested little-to-no difference in non-compliance between RIS-LAI and oral SG antipsychotic, OLA-LAI and oral OLA, and ARI-LAI and oral ARI groups. Two other SRs^11,15 showed little-to-no difference in symptom severity scores, depression, and mania between RIS-LAI and oral SG antipsychotic drugs; however, these SRs did not assess risk of bias or report quantitative data. Results from 2 SRs^12,15 and 1 RCT¹⁷ suggested little-to-no difference in symptom severity between PP-LAI and oral OLA, between OLA-LIS and oral OLA, and between ARI-LAI and oral ARI. One MA¹⁴ based on 2 studies suggested a greater decrease in depression in patients given RIS-compared to patients given oral ARI or QUE.

One MA¹⁴ based on 5 studies suggested little-to-no difference in remission between SG-LAI and oral SG antipsychotic groups and another MA¹³ based on 7 RCTs suggested that patients given SG-LAI had more favourable psychosocial function compared to those given oral SG antipsychotic.

When comparing RIS-LAI to oral SG antipsychotic drugs, 1 SR¹⁵ suggested little-to-no difference in time to stabilization or relapse between patients who received RIS-LAI and those who received oral SG antipsychotic. Another SR¹¹ found that illness severity decreased in patients who switched from oral SG antipsychotic to RIS-LAI. Both SRs^11,15 also showed little-to-no difference in EPS between these groups.

One RCT¹⁷ reported little-to-no difference in illness severity, improvements from treatment, or social performance between ARI-LAI and oral ARI, and data from 2 SRs^11,12 showed little-to-no difference in quality of life between ARI-LAI and oral ARI groups. One RCT¹⁷ showed little-to-no difference between ARI-LAI compared to oral ARI for AEs and injection site reactions.

Based on 1 SR,¹⁵ PP-LAI was more favourable than oral paliperidone extended-release for negative symptoms measured on some functioning scales, but there was no difference between groups on other functioning scales; PP-LAI was more favourable than oral paliperidone extended-release tablets for treatment satisfaction, convenience, and service engagement.

One SR¹² showed that time to relapse differed between patients receiving OLA-LAI and those receiving oral OLA, however there was little-to-no difference in the rate of relapse. One MA¹⁴ suggested that mean hospital days were lower for the OLA-LAI group compared to the oral OLA group. Based on an SR¹² that reported on ARI-LAI compared to oral ARI, findings suggested little-to-no difference in relapse rate between groups, but that the OLA-LAI group had a longer time to relapse compared to the oral OLA group. Based on MA data,¹⁴ patients given RIS-LAI showed longer time to relapse compared to those given oral ARI.

Based on the poor reporting of quantitative information and unclear quality of studies, the evidence in this report is insufficient to answer the research questions definitively. Future studies of strong methodological quality using standardized outcome measures and applying appropriate quantitative analyses are needed to determine conclusively the clinical effectiveness of SG injectable versus FG injectable antipsychotic drugs and versus SG oral antipsychotic medications.

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Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 2: Characteristics of Included Publications

Note that this appendix was not copy-edited.

Table 2: Characteristics of Included Systematic Reviews

AE = adverse event; AMI = amisulpride; ARI = aripiprazole; FG = first-generation; LAI = long-acting injectable; MA = meta-analysis; NR = not reported; NRS = non-randomized study; OLA = olanzapine; PP = paliperidone palmitate; QUE = quetiapine; RCT = randomized controlled trial; RIS = risperidone; SG = second-generation; SR = systematic review; ZIP = ziprasidone.

^aThe publication indicates the authors received no funding for the article, the acknowledgement section mentions the research was support by an Australian Government Research Training Programme Scholarship.

^bOne included primary study enrolled patients aged 15 years and older; it is included since the mean age of the population is an adult age.

Table 3: Characteristics of Included Randomized Controlled Trial

AE = adverse event; AP = antipsychotic; ARI = aripiprazole; LAI = long-acting injectable; mg = milligrams; PANSS = Positive and Negative Syndrome Scale; RCT = randomized controlled trial; SD = standard deviation.

Appendix 3: Critical Appraisal of Included Publications

Note that this appendix was not copy-edited.

Table 4: Strengths and Limitations of Systematic Reviews and Meta-Analyses Using AMSTAR 2⁷

AMSTAR 2 = A MeaSurement Tool to Assess systematic Reviews 2; LAI = long-acting injectable; PROSPERO = The International Prospective Register of Systematic Reviews.

Table 5: Strengths and Limitations of an RCT Using the Downs and Black Checklist⁸

AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; CGI-S = Clinical Global Impression-Severity; PANSS = Positive and Negative Syndrome Scale; PSP = Personal and Social Performance scale; SAS = Simpson-Angus Extrapyramidal Side Effects Scale.

Appendix 4: Main Study Findings and Authors’ Conclusions

Note that this appendix was not copy-edited.

Table 6: Second-Generation Injectable Antipsychotic Drugs Versus First-Generation Injectable Antipsychotic Drugs — Effectiveness

CI = confidence interval; FG = first-generation; HR = hazard ratio; LAI = long-acting injectable; MA = meta-analysis; MD = mean difference; mg = milligrams; PANSS = Positive and Negative Syndrome Scale; PP = paliperidone palmitate; RIS = risperidone; SG-LAI = second-generation long-acting injectable; SR = systematic review.

^aIt is unclear why the dose values for the McEvoy et al. (2014) study, which were reported in the McDonagh et al. (2017) and Gentile (2019) SRs, is different; the original McEvoy et al. (2014) was not consulted for this report.

Table 7: Second-Generation Injectable Versus First-Generation Injectable Antipsychotic Drugs — Safety

AE = adverse event; AIMS = Abnormal Involuntary Movement Scale; ARI = aripiprazole; EPS = extrapyramidal symptoms; FG = first-generation; LAI = long-acting injectable; mg = milligrams; OR = odds ratio; PP = paliperidone palmitate; RIS = risperidone; SAS = Simpson-Angus Extrapyramidal Side Effects Scale; SR = systematic review.

^aAIMS Global Severity Score (incidence of AIMS > 2).

^bSAS Mean Score (Incidence of SAS ≥ 1).

^dIt is unclear why the dose values for the McEvoy et al. (2014) study, which were reported in the McDonagh et al. (2017) and Saucedo Uribe et al. (2020) SRs, is different; the original McEvoy et al. (2014) was not consulted for this report.

Table 8: Second-Generation Injectable Versus Second-Generation Oral Antipsychotic Drugs — Effectiveness

ARI = aripiprazole; BPRS = Barnes Akathisia Rating Scale; CGI-I = Clinical Global Impression-Improvement; CGI-S = Clinical Global Impression-Severity; CI = confidence interval; HAM-A = Hamilton Anxiety Rating Scale; HDRS = Hamilton Depression Rating Scale; HR = hazard ratio; LAI = long-acting injectable; MA = meta-analysis; MADRS = Mongtomery-Asberg Depression Rating Scale; mg = milligrams; NA = not applicable; NR = not reported; OLA = olanzapine; PANSS = Positive and Negative Syndrome Scale; PP = paliperidone palmitate; PP1M = paliperidone palmitate one monthly; PSP = Personal and Social Performance scale; QUE = quetiapine; RCT = randomized controlled trial; RIS = risperidone; RR = relative risk; SE = standard error; SMD = standardized mean difference; SG = second-generation; SR = systematic review; TSQM = Treatment Satisfaction Questionnaire for Medication; VAS = visual analogue scale; YMRS = Young Mania Rating Scale.

Appendix 6: References of Potential Interest

Previous CADTH Reports

Brankston G, Picheca L. Antipsychotic drugs or benzodiazepines for rapid tranquilization in mental health facilities or emergency department settings. C J Health Technol. 2021;1(8).

Narain T, Ford C. Atypical injectable antipsychotics for schizophrenia or bipolar disorder: a review of clinical effectiveness and cost-effectiveness (CADTH Rapid response reports). Ottawa (ON): CADTH; 2019.

Results Already in an Included Systematic Review

Pacchiarotti I, Tiihonen J, Kotzalidis GD, et al. Long-acting injectable antipsychotics (LAIs) for maintenance treatment of bipolar and schizoaffective disorders: a systematic review. Eur Neuropsychopharmacol. 2019;29(4):457-470. PubMed

Rapinesi C, Kotzalidis GD, Mazzarini L, et al. Long-Acting Injectable (LAI) aripiprazole formulations in the treatment of schizophrenia and bipolar disorder: a systematic review. Clin Drug Investig. 2019;39(8):713-735. PubMed

Alphs L, Bossie C, Mao L, Lee E, Starr HL. Treatment effect with paliperidone palmitate compared with oral antipsychotics in patients with recent-onset versus more chronic schizophrenia and a history of criminal justice system involvement. Early Interv Psychiatry. 2018;12(1):55-65. PubMed

Butler M, Urosevic S, Desai P, et al. Treatment for Bipolar Disorder in Adults: A Systematic Review (AHRQ Comparative Effectiveness Reviews). Rockville (MD): Agency for Healthcare Research and Quality (US); 2018.

Huang M, Yu L, Pan F, et al. A randomized, 13-week study assessing the efficacy and metabolic effects of paliperidone palmitate injection and olanzapine in first-episode schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry. 2018;81:122-130. PubMed

Prajapati AR, Wilson J, Song F, Maidment I. Second-generation antipsychotic long-acting injections in bipolar disorder: systematic review and meta-analysis. Bipolar Disord. 2018;20(8):687-696. PubMed

Stroup TS, Bareis NA, Rosenheck RA, Swartz MS, McEvoy JP. Heterogeneity of treatment effects of long-acting injectable antipsychotic medications. J Clin Psychiatry. 2018;80(1):27. PubMed

Gentile S. Safety concerns associated with second-generation antipsychotic long-acting injection treatment. a systematic update. Horm Mol Biol Clin Investig. 2017;36(2):23. PubMed

Reviews Not Focused on Second-Generation Antipsychotic Drugs

Ostuzzi G, Bertolini F, Del Giovane C, et al. Maintenance treatment with long-acting injectable antipsychotics for people With nonaffective psychoses: a network meta-analysis. Am J Psychiatry. 2021;178(5):424-436. PubMed

Ostuzzi G, Bighelli I, So R, Furukawa TA, Barbui C. Does formulation matter? A systematic review and meta-analysis of oral versus long-acting antipsychotic studies. Schizophr Res. 2017;183:10-21. PubMed

Unclear Population Age and Drug Administration Routes

Sabe M, Zhao N, Crippa A, Kaiser S. Antipsychotics for negative and positive symptoms of schizophrenia: dose-response meta-analysis of randomized controlled acute phase trials. NPJ Schizophr. 2021;7(1):43. PubMed

Guinart D, Misawa F, Rubio JM, et al. Outcomes of neuroleptic malignant syndrome with depot versus oral antipsychotics: a systematic review and pooled, patient-level analysis of 662 case reports. J Clin Psychiatry. 2020;82(1):24. PubMed

Azorin JM, Simon N. Dopamine receptor partial agonists for the treatment of bipolar disorder. Drugs. 2019;79(15):1657-1677. PubMed

Salgueiro M, Segarra R. Long-acting injectable second-generation antipsychotics in first-episode psychosis: a narrative review. Int Clin Psychopharmacol. 2019;34(2):51-56. PubMed

Ineligible Due to Combination Treatments

Kishi T, Ikuta T, Matsuda Y, et al. Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta-analysis of randomized controlled trials. Mol Psychiatry. 2021;26(8):4146-4157. PubMed

Nuechterlein KH, Ventura J, Subotnik KL, et al. A randomized controlled trial of cognitive remediation and long-acting injectable risperidone after a first episode of schizophrenia: improving cognition and work/school functioning. Psychol Med. 2020:1-10. PubMed

Foster A, Buckley P, Lauriello J, Looney S, Schooler N. Combination antipsychotic therapies: an analysis from a longitudinal pragmatic trial. J Clin Psychopharmacol. 2017;37(5):595-599. PubMed