Oral and long‐acting antipsychotics for relapse prevention in schizophrenia‐spectrum disorders: a network meta‐analysis of 92 randomized trials including 22,645 participants

Abstract

According to current evidence and guidelines, continued antipsychotic treatment is key for preventing relapse in people with schizophrenia‐spectrum disorders, but evidence‐based recommendations for the choice of the individual antipsychotic for maintenance treatment are lacking. Although oral antipsychotics are often prescribed first line for practical reasons, long‐acting injectable antipsychotics (LAIs) are a valuable resource to tackle adherence issues since the earliest phase of disease. Medline, EMBASE, PsycINFO, CENTRAL and CINAHL databases and online registers were searched to identify randomized controlled trials comparing LAIs or oral antipsychotics head‐to‐head or against placebo, published until June 2021. Relative risks and standardized mean differences were pooled using random‐effects pairwise and network meta‐analysis. The primary outcomes were relapse and dropout due to adverse events. We used the Cochrane Risk of Bias tool to assess study quality, and the CINeMA approach to assess the confidence of pooled estimates. Of 100 eligible trials, 92 (N=22,645) provided usable data for meta‐analyses. Regarding relapse prevention, the vast majority of the 31 included treatments outperformed placebo. Compared to placebo, “high” confidence in the results was found for (in descending order of effect magnitude) amisulpride‐oral (OS), olanzapine‐OS, aripiprazole‐LAI, olanzapine‐LAI, aripiprazole‐OS, paliperidone‐OS, and ziprasidone‐OS. “Moderate” confidence in the results was found for paliperidone‐LAI 1‐monthly, iloperidone‐OS, fluphenazine‐OS, brexpiprazole‐OS, paliperidone‐LAI 1‐monthly, asenapine‐OS, haloperidol‐OS, quetiapine‐OS, cariprazine‐OS, and lurasidone‐OS. Regarding tolerability, none of the antipsychotics was significantly worse than placebo, but confidence was poor, with only aripiprazole (both LAI and OS) showing “moderate” confidence levels. Based on these findings, olanzapine, aripiprazole and paliperidone are the best choices for the maintenance treatment of schizophrenia‐spectrum disorders, considering that both LAI and oral formulations of these antipsychotics are among the best‐performing treatments and have the highest confidence of evidence for relapse prevention. This finding is of particular relevance for low‐ and middle‐income countries and constrained‐resource settings, where few medications may be selected. Results from this network meta‐analysis can inform clinical guidelines and national and international drug regulation policies.

Paliperidone palmitate vs. paliperidone extended-release for the acute treatment of adults with schizophrenia: a systematic review and pairwise and network meta-analysis

“…The assumption of transitivity was tested by extracting potential effect modifiers, such as the mean PANSS-T at baseline, sample size, and mean age, and by comparing their distribution across comparisons in the network. We determined whether the distribution differences were large enough to threaten the validity of the analysis by comparing the distribution of these possible effect modifiers across the treatments included in the network meta-analysis using the Kruskal–Wallis test and by assessing their actual impact on the treatment effect through meta-regression analyses [ 16 , 17 ]. We did not assess global statistical coherence and locally statistical coherence because due to a lack of data.…”

Practical Guidance for the Use of Long-Acting Injectable Antipsychotics in the Treatment of Schizophrenia

“…Evidence from meta-analyses of randomized controlled trials (RCTs) suggests that most LAIs are likely to be superior to placebo in preventing relapse and rehospitalisation in schizophrenia. 19 , 34 , 35 …”

“… 19 , 34 , 35 Available evidence suggests that risperidone may be equally effective in preventing relapse, but confidence seems only low-to-moderate. 19 , 34 , 35 For what regards FGA LAIs, flupentixol, fluphenazine, and zuclopenthixol seem similarly superior to placebo, with effect estimates similar to those of SGA LAIs, although confidence in relevant evidence is low-to-moderate at best. 19 , 34 , 35 In particular, findings on zuclopenthixol LAI are based on two small studies (56 total participants on zuclopenthixol LAI), thus estimates show very high uncertainty.…”

“… 19 , 34 , 35 In particular, findings on zuclopenthixol LAI are based on two small studies (56 total participants on zuclopenthixol LAI), thus estimates show very high uncertainty. 35 Interestingly, the efficacy of haloperidol decanoate for relapse prevention has been questioned by a very recent network meta-analysis, 34 while similar work had previously highlighted that it was significantly better than placebo. 34 , 35 Nonetheless, the quality of the evidence on haloperidol LAI appears inconsistent across different network meta-analyses, having been deemed by some even as very low, 19 , 34 and as moderate by others.…”

Depicting Risperidone Safety Profiles in Clinical Trials Across Different Diagnoses Using a Dopamine D2-Based Pharmacological Class Effect Query Defined by FAERS

“…Non-adherence has been identified as, by far, the biggest preventable risk factor for relapse and rehospitalization [ 3 ], and adverse events (AEs) have consistently been found to be the most common reason for discontinuing antipsychotic medication [ 4 ]. As a recent meta-analysis of 92 relapse prevention trials noted [ 5 ]: “effectiveness needs to be put into the context of tolerability, especially during long-term treatment. However, adverse effect outcomes [are] only partially and inconsistently reported, not allowing a detailed benefit-to-risk assessment.”…”