Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis

Abstract

SummaryBackgroundSchizophrenia is one of the most common, burdensome, and costly psychiatric disorders in adults worldwide. Antipsychotic drugs are its treatment of choice, but there is controversy about which agent should be used. We aimed to compare and rank antipsychotics by quantifying information from randomised controlled trials.MethodsWe did a network meta-analysis of placebo-controlled and head-to-head randomised controlled trials and compared 32 antipsychotics. We searched Embase, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov from database inception to Jan 8, 2019. Two authors independently selected studies and extracted data. We included randomised controlled trials in adults with acute symptoms of schizophrenia or related disorders. We excluded studies in patients with treatment resistance, first episode, predominant negative or depressive symptoms, concomitant medical illnesses, and relapse-prevention studies. Our primary outcome was change in overall symptoms measured with standardised rating scales. We also extracted data for eight efficacy and eight safety outcomes. Differences in the findings of the studies were explored in metaregressions and sensitivity analyses. Effect size measures were standardised mean differences, mean differences, or risk ratios with 95% credible intervals (CrIs). Confidence in the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis). The study protocol is registered with PROSPERO, number CRD42014014919.FindingsWe identified 54 417 citations and included 402 studies with data for 53 463 participants. Effect size estimates suggested all antipsychotics reduced overall symptoms more than placebo (although not statistically significant for six drugs), with standardised mean differences ranging from −0·89 (95% CrI −1·08 to −0·71) for clozapine to −0·03 (−0·59 to 0·52) for levomepromazine (40 815 participants). Standardised mean differences compared with placebo for reduction of positive symptoms (31 179 participants) varied from −0·69 (95% CrI −0·86 to −0·52) for amisulpride to −0·17 (−0·31 to −0·04) for brexpiprazole, for negative symptoms (32 015 participants) from −0·62 (−0·84 to −0·39; clozapine) to −0·10 (−0·45 to 0·25; flupentixol), for depressive symptoms (19 683 participants) from −0·90 (−1·36 to −0·44; sulpiride) to 0·04 (−0·39 to 0·47; flupentixol). Risk ratios compared with placebo for all-cause discontinuation (42 672 participants) ranged from 0·52 (0·12 to 0·95; clopenthixol) to 1·15 (0·36 to 1·47; pimozide), for sedation (30 770 participants) from 0·92 (0·17 to 2·03; pimozide) to 10·20 (4·72 to 29·41; zuclopenthixol), for use of antiparkinson medication (24 911 participants) from 0·46 (0·19 to 0·88; clozapine) to 6·14 (4·81 to 6·55; pimozide). Mean differences compared to placebo for weight gain (28 317 participants) ranged from −0·16 kg (−0·73 to 0·40; ziprasidone) to 3·21 kg (2·10 to 4·31; zotepine), for prolactin elevatio...

How and when to use clozapine

“…Similar results have been replicated by several clinical trials over the following decades (23,24), and meta-analyses of head-to-head randomized controlled trials have favored clozapine over other antipsychotics in the reduction of total symptoms(standard mean difference [SMD] = À0.39, 95% CI=À0.61 to À0.17) (25). Similarly, a recent network meta-analysis comparing multiple antipsychotics for the treatment of patients with multi-episode schizophrenia also found clozapine to have the greatest efficacy compared to 31 other antipsychotics (SMD = À0Á89,95% CI = À1Á08 to À0Á71) (18). However, another network meta-analysis of 40 randomized trials with 5172 patients comparing 12 antipsychotics for the treatment of TRS did not find superiority of clozapine compared to other antipsychotic drugs (19).…”

Polypharmacy in schizophrenia

“…Generally, antipsychotics block the listed receptors; however, a smaller group of newer antipsychotics instead exert their action via dopamine D2 partial agonism (aripiprazole, brexpiprazole and cariprazine). In general, the currently available antipsychotics are believed to show equivalence regarding antipsychotic efficacy, and treatment choice is therefore mainly based on side effect profile . The only exception is clozapine with firm evidence of superior efficacy in patients with schizophrenia not having responded to ≥2 previous antipsychotic agents (ie treatment resistance) .…”

“…In general, the currently available antipsychotics are believed to show equivalence regarding antipsychotic efficacy, and treatment choice is therefore mainly based on side effect profile . The only exception is clozapine with firm evidence of superior efficacy in patients with schizophrenia not having responded to ≥2 previous antipsychotic agents (ie treatment resistance) . Clozapine is a third‐line compound as a consequence of the risk of severe side effects, including a need to follow standardized blood monitoring due to a 0.9% risk of agranulocytosis .…”

“…Antipsychotic monotherapy is the evidence‐based and recommended treatment regimen for both acute symptom exacerbation and for maintenance treatment to prevent future symptom relapse . There is no evidence to support monotherapy with pharmaceutical compounds other than antipsychotics.…”

Comparing antipsychotics: A rose by any other name?

“…One of our lead articles this month covers a new study, published in The Lancet , that revisits the question by using an advanced statistical approach to analyze data accrued during the past decade, in addition to that from earlier studies. Huhn and colleagues 2 (including Leucht and Davis, mentioned earlier) applied network meta‐analysis to 402 studies comprising more than 53,000 patients, comparing the efficacy and tolerability of 32 oral antipsychotics in the acute treatment of schizophrenia. What they found was not surprising: Antipsychotics are more effective than placebo.…”