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

Background: Schizophrenia 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.

Methods: We 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.

Findings: We 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 elevation (21 569 participants) from -77·05 ng/mL (-120·23 to -33·54; clozapine) to 48·51 ng/mL (43·52 to 53·51; paliperidone) and for QTc prolongation (15 467 participants) from -2·21 ms (-4·54 to 0·15; lurasidone) to 23·90 ms (20·56 to 27·33; sertindole). Conclusions for the primary outcome did not substantially change after adjusting for possible effect moderators or in sensitivity analyses (eg, when excluding placebo-controlled studies). The confidence in evidence was often low or very low.

Interpretation: There are some efficacy differences between antipsychotics, but most of them are gradual rather than discrete. Differences in side-effects are more marked. These findings will aid clinicians in balancing risks versus benefits of those drugs available in their countries. They should consider the importance of each outcome, the patients' medical problems, and preferences.

Funding: German Ministry of Education and Research and National Institute for Health Research.

Figure 1

Network plot of overall efficacy The size of the nodes corresponds to the number of participants assigned to each treatment. Treatments with direct comparisons are linked with a line; its thickness corresponds to the number of trials evaluating the comparison.

Figure 2

Change in efficacy outcomes (A) Overall change in symptoms. (B) Positive symptoms. (C) Negative symptoms. (D) Depressive symptoms. (E) Social functioning. (F) All-cause discontinuation. Treatments are ranked according to their surface under the curve cumulative ranking and compared with placebo. Effect sizes are presented as standardised mean difference or risk ratio with 95% CrIs. The evidence is graded using the CINeMA system (Confidence in Network Meta-Analysis), an adaption of the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach for network meta-analysis. Colours indicate the confidence in the evidence: green=high, blue=moderate, grey=low, red=very low. N_T=total number of trials reporting the outcome (percentage of sample). n_T=total number of participants available for the respective outcome (percentage of sample). SMD=standardised mean difference. CrI=credible interval. RR=risk ratio. AMI=amisulpride. ARI=aripiprazole. ASE=asenapine. BRE=brexpiprazole. CAR=cariprazine. CLO=clozapine. CPX=clopenthixol. CPZ=chlorpromazine. FLU=fluphenazine. FPX=flupentixol. HAL=haloperidol. ILO=iloperidone. LEV=levomepromazine. LOX=loxapine. LUR=lurasidone. MOL=molindone. OLA=olanzapine. PAL=paliperidone. PBO=placebo. PEN=penfluridol. PERA=perazine. PERPH=perphenazine. PIM=pimozide. QUE=quetiapine. RIS=risperidone. SER=sertindole. SUL=sulpiride. THIOR=thioridazine. THIOT=thiotixene. TRIFLU=trifluoperazine. ZIP=ziprasidone. ZOT=zotepine. ZUC=zuclopenthixol.

Figure 2

Change in efficacy outcomes (A) Overall change in symptoms. (B) Positive symptoms. (C) Negative symptoms. (D) Depressive symptoms. (E) Social functioning. (F) All-cause discontinuation. Treatments are ranked according to their surface under the curve cumulative ranking and compared with placebo. Effect sizes are presented as standardised mean difference or risk ratio with 95% CrIs. The evidence is graded using the CINeMA system (Confidence in Network Meta-Analysis), an adaption of the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach for network meta-analysis. Colours indicate the confidence in the evidence: green=high, blue=moderate, grey=low, red=very low. N_T=total number of trials reporting the outcome (percentage of sample). n_T=total number of participants available for the respective outcome (percentage of sample). SMD=standardised mean difference. CrI=credible interval. RR=risk ratio. AMI=amisulpride. ARI=aripiprazole. ASE=asenapine. BRE=brexpiprazole. CAR=cariprazine. CLO=clozapine. CPX=clopenthixol. CPZ=chlorpromazine. FLU=fluphenazine. FPX=flupentixol. HAL=haloperidol. ILO=iloperidone. LEV=levomepromazine. LOX=loxapine. LUR=lurasidone. MOL=molindone. OLA=olanzapine. PAL=paliperidone. PBO=placebo. PEN=penfluridol. PERA=perazine. PERPH=perphenazine. PIM=pimozide. QUE=quetiapine. RIS=risperidone. SER=sertindole. SUL=sulpiride. THIOR=thioridazine. THIOT=thiotixene. TRIFLU=trifluoperazine. ZIP=ziprasidone. ZOT=zotepine. ZUC=zuclopenthixol.

Figure 3

Change in overall symptoms league table Antipsychotics are reported in order of surface under the curve cumulative ranking. Results of the network meta-analysis are presented in the left lower half and results from pairwise meta-analysis in the upper right half, if available. Comparisons between treatments should be read from left to right and the estimate is in the cell in common between the column-defining treatment and the row-defining treatment. In the left lower half, standard mean differences lower than 0 favour the column-defining treatment and in the upper right half, those lower than 0 favour the row-defining treatment. Cells in bold print indicate significant results. NA=not available. AMI=amisulpride. ARI=aripiprazole. ASE=asenapine. BRE=brexpiprazole. CAR=cariprazine. CLO=clozapine. CPX=clopenthixol. CPZ=chlorpromazine. FLU=fluphenazine. FPX=flupentixol. HAL=haloperidol. ILO=iloperidone. LEV=levomepromazine. LOX=loxapine. LUR=lurasidone. MOL=molindone. OLA=olanzapine. PAL=paliperidone. PBO=placebo. PEN=penfluridol. PERA=perazine. PERPH=perphenazine. PIM=pimozide. QUE=quetiapine. RIS=risperidone. SER=sertindole. SUL=sulpiride. THIOR=thioridazine. THIOT=thiotixene. TRIFLU=trifluoperazine. ZIP=ziprasidone. ZOT=zotepine. ZUC=zuclopenthixol.

Figure 4

Change in side-effect outcomes (A) Weight gain in kg. (B) Use of antiparkinson medication. (C) Akathisia. (D) Prolactin elevation in ng/mL. (E) QTc prolongation in ms. (F) Sedation. (G) At least one anticholinergic side-effect. Treatments are ranked according to their surface under the curve cumulative ranking and compared with placebo. Effect sizes are presented as mean difference or risk ratio with 95% CrIs. The evidence is graded using CINeMA system (Confidence in Network Meta-Analysis), an adaption of the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach for network meta-analysis. Colours indicate the confidence in the evidence: green=high, blue=moderate, grey=low, red=very low. N_T=total number of trials reporting the outcome (percentage of sample). n_T=total number of participants available for the respective outcome (percentage of sample). MD=Mean difference. CrI=credible interval. RR=risk ratio. AMI=amisulpride. ARI=aripiprazole. ASE=asenapine. BRE=brexpiprazole. CAR=cariprazine. CLO=clozapine. CPX=clopenthixol. CPZ=chlorpromazine. FLU=fluphenazine. FPX=flupentixol. HAL=haloperidol. ILO=iloperidone. LEV=levomepromazine. LOX=loxapine. LUR=lurasidone. MOL=molindone. OLA=olanzapine. PAL=paliperidone. PBO=placebo. PEN=penfluridol. PERA=perazine. PERPH=perphenazine. PIM=pimozide. QUE=quetiapine. RIS=risperidone. SER=sertindole. SUL=sulpiride. THIOR=thioridazine. THIOT=thiotixene. TRIFLU=trifluoperazine. ZIP=ziprasidone. ZOT=zotepine. ZUC=zuclopenthixol. *Results for clozapine and zotepine might be statistical artifacts caused by two small outlier studies.

Figure 4

Change in side-effect outcomes (A) Weight gain in kg. (B) Use of antiparkinson medication. (C) Akathisia. (D) Prolactin elevation in ng/mL. (E) QTc prolongation in ms. (F) Sedation. (G) At least one anticholinergic side-effect. Treatments are ranked according to their surface under the curve cumulative ranking and compared with placebo. Effect sizes are presented as mean difference or risk ratio with 95% CrIs. The evidence is graded using CINeMA system (Confidence in Network Meta-Analysis), an adaption of the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach for network meta-analysis. Colours indicate the confidence in the evidence: green=high, blue=moderate, grey=low, red=very low. N_T=total number of trials reporting the outcome (percentage of sample). n_T=total number of participants available for the respective outcome (percentage of sample). MD=Mean difference. CrI=credible interval. RR=risk ratio. AMI=amisulpride. ARI=aripiprazole. ASE=asenapine. BRE=brexpiprazole. CAR=cariprazine. CLO=clozapine. CPX=clopenthixol. CPZ=chlorpromazine. FLU=fluphenazine. FPX=flupentixol. HAL=haloperidol. ILO=iloperidone. LEV=levomepromazine. LOX=loxapine. LUR=lurasidone. MOL=molindone. OLA=olanzapine. PAL=paliperidone. PBO=placebo. PEN=penfluridol. PERA=perazine. PERPH=perphenazine. PIM=pimozide. QUE=quetiapine. RIS=risperidone. SER=sertindole. SUL=sulpiride. THIOR=thioridazine. THIOT=thiotixene. TRIFLU=trifluoperazine. ZIP=ziprasidone. ZOT=zotepine. ZUC=zuclopenthixol. *Results for clozapine and zotepine might be statistical artifacts caused by two small outlier studies.