Secondary Logo

Journal Logo

Institutional members access full text with Ovid®

Activating and Sedating Adverse Effects of Second-Generation Antipsychotics in the Treatment of Schizophrenia and Major Depressive Disorder: Absolute Risk Increase and Number Needed to Harm

Citrome, Leslie MD, MPH

Journal of Clinical Psychopharmacology: April 2017 - Volume 37 - Issue 2 - p 138–147
doi: 10.1097/JCP.0000000000000665
Original Contributions

Purpose/Background Activating and sedating adverse effects of antipsychotics can be obstacles to their use.

Methods/Procedures This study quantified the activating and sedating properties of first-line oral second-generation antipsychotics by examining the rates of adverse reactions as reported in product labeling for the indications of schizophrenia and adjunctive treatment of major depressive disorder. Additional data sources included regulatory documents, study synopses, and published study reports. Attributable risk increase and number needed to harm (NNH) were calculated for each agent versus placebo.

Findings/Results Heterogeneity among the different antipsychotics regarding activating or sedating adverse events was observed, with some agents displaying the potential for both activating and sedating properties. For agents indicated for the treatment of schizophrenia, predominantly activating medications include lurasidone (NNH, 11 for akathisia vs 20 for somnolence) and cariprazine (NNH, 15 for akathisia vs 65 for somnolence-combined terms). Similarly activating and sedating are risperidone (NNH, 15 for akathisia vs 13 for sedation) and aripiprazole (NNH, 31 for akathisia vs 34 for somnolence). Predominantly sedating are olanzapine, quetiapine immediate and extended release, ziprasidone, asenapine, and iloperidone. Agents that are neither activating nor sedating are paliperidone and brexpiprazole. For major depressive disorder, the overall findings regarding activation and sedation appear similar to those seen with schizophrenia. Data extracted were limited to those available from registrational studies that contributed to the adverse event tables contained in the product labels. Postregistrational comparative studies may yield different outcomes.

Implications/Conclusions Differences in tolerability profiles regarding activation and sedation have implications in terms of selecting the optimal antipsychotic for a given individual.

Supplemental digital content is available in the text.

From the Department of Psychiatry & Behavioral Sciences, New York Medical College, Valhalla, NY.

Received June 6, 2016; accepted after revision December 19, 2016.

Reprints: Leslie Citrome, MD, MPH, 11 Medical Park Dr, Suite 106, Pomona, NY 10970 (e-mail:

This study was funded via a contract from Otsuka Pharmaceutical Development & Commercialization, Inc. The funder was not involved in the intellectual content of this study in terms of design, data collection, analysis, or the production of this article.

Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.