There is an increased risk for somatic serious adverse events (SAEs) with antipsychotic drug therapy compared with placebo, according to a study published in The Lancet Psychiatry.

In this systematic review and meta-analysis, researchers included double-blind, single-blind, and open-label randomized controlled trials (RCTs) comparing second-generation antipsychotic drugs with placebo across any indications. Studies were pulled from a literature search using MEDLINE, EMBASE, Cochrane CENTRAL, BIOSIS, PsycINFO, PubMed, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform from inception.

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Researchers expanded their search to include first-generation antipsychotics that were used as additional active comparators to second-generation antipsychotics in placebo-controlled trials. The last search was done on January 27, 2017. The primary outcome was the number of patients with at least 1 somatic SAE per study group. Data were analyzed using the common-effect Mantel-Haenszel meta-analysis model with odds ratios (ORs).

The main dataset included 314 trials (N=67,642) with details on individual SAEs. Most of the patients’ illnesses were in the diagnostic categories of schizophrenia (42%), bipolar disorder (30%), major depressive disorder (11%), and dementia (6%). Somatic SAEs were reported for a minimum of 698 (1.63%) to a maximum of 862 (2.02%) of the patients randomly assigned to antipsychotics (n=42,600) and for 343 (1.37%) to 419 (1.67%) of patients randomly assigned to placebo (n=25,042).

Psychiatric SAEs were reported in 1038 (2.43%) to 1161 (2.72%) of patients randomly assigned to antipsychotics (n=42,606) and 846 (3.39%) to 921 (3.69%) of patients randomly assigned to placebo (n=24,992). These results indicate an increased risk for somatic and psychiatric SAEs for patients exposed to antipsychotic drugs.

Limitations of this study included the inability to obtain details about specific SAEs for 54 studies, lack of information about SAEs in 229 studies, and only having protocols in 72 studies. Researchers cannot exclude the possibility that information on somatic SAEs was intentionally suppressed or left unpublished because of unfavorable safety data. Some SAEs might not have been assessed or reported. Funding by pharmaceutical companies could have theoretically promoted tendencies to under-report SAEs. Nonadherence to study medication might have diluted the differential effect. Within individual studies, the patients most vulnerable with SAEs were often excluded from RCTs. The available RCTs were predominantly short-term.

The study researchers indicated that the risk for somatic SAEs with antipsychotics “is not negligible and there are possible under-estimations, but it might be acceptable in physically fit adults in disorders for which the individual antipsychotics are officially licensed (in particular schizophrenia), because substantial benefit from reduction of symptoms can be expected, and because there is statistical uncertainty as to whether the risk is increased. Individual patients sharing risk factors with the older population (eg, somatic comorbidities, polypharmacy, higher age), and possibly children and adolescents, can be more vulnerable.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Schneider-Thomas J, Efthimiou O, Huhn M, et al. Second-generation antipsychotic drugs and short-term somatic serious adverse events: a systematic review and meta-analysis [published online July 15, 2019]. Lancet Psychiatry. doi: 10.1016/S2215-0366(19)30223-8