Comparing Pros, Cons of Antipsychotics for Multi-Episode Schizophrenia

Investigators compared the efficacy and tolerability of 32 oral antipsychotic agents for the acute treatment of multi-episode schizophrenia in adults.

For adults with acute symptoms of schizophrenia, newer and older antipsychotics that are available in Europe or the United States reduced overall symptoms and resulted in lower all-cause discontinuation rates compared with placebo; however, there were large differences in adverse events between treatments, according to study results published in Lancet.

Investigators conducted a network meta-analysis of placebo-controlled and head-to-head randomized controlled trials in adults with acute symptoms of schizophrenia or related disorders. In addition, they compared and ranked 32 antipsychotic agents. The primary outcome was change in overall schizophrenia symptoms. Secondary outcomes included discontinuation (either all-cause or due to inefficacy); changes in positive, negative, and depressive symptoms; quality of life; and social functioning.

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Data from 53,463 individuals (mean age, 37.4 years; 56.02% men; illness duration, 11.9 years) from 54,417 citations and 402 studies were included in the study. Of the 32 antipsychotic agents assessed, 26 were linked to significant symptom improvement compared with placebo.  

Compared with placebo, standardized mean differences varied from -0.69 for amisulpride to -0.17 for brexpiprazole for reduction of positive symptoms, from -0.62 for clozapine to -0.10 for flupentixol for negative symptoms, and from -0.90 for sulpiride to 0.04 for flupentixol for depressive symptoms. 

Risk ratios varied from 0.52 (clopenthixol) to 1.15 (pimozide) for all-cause discontinuation, from 0.92 (pimozide) to 10.20 (zuclopenthixol) for sedation, and from 0.46 (clozapine) to 6.14 (pimozide) for use of antiparkinson medication compared with placebo. In addition, mean differences ranged from -0.16 kg (ziprasidone) to 3.21 kg (zotepine) for weight gain, from -77.05 ng/mL (clozapine) to 48.51 ng/mL (paliperidone) for prolactin elevation, and -from 2.21 ms to 23.90 ms for QTc prolongation.

The investigators noted several limitations to the meta-analysis such as variations in study characteristics that changed over the 60-year duration, small sample sizes in older studies, and the exclusion of suicidal patients or patients with severe illness. The population of mainland China was excluded because of perceived low quality of the data, according to the investigators’ findings. Consequently, the study findings lack generalization due to too many exclusions.

“Because so many antipsychotic options are available, our results should help health-care providers find the most suitable drug for the individual patient, balancing side-effect profiles and the efficacy of different drugs,” the investigators noted. In addition, “Clinicians must remember that reported results are averages and that response and side-effects might vary considerably in individual patients,” concluded the investigators.

Disclosures: See original article for full disclosure information.


Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy of tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis (published online September 12, 2019). Lancet. doi:10.1016/S0140-6736(19)31135-3