Effects of antipsychotics on circadian rhythms in humans: a systematic review and meta-analysis

Antipsychotics are widely used to treat psychiatric illness and insomnia. However, the etiology of insomnia is multifactorial, including disrupted circadian rhythms. Several studies show that antipsychotics might modulate even healthy circadian rhythms. The purpose of this systematic review is to integrate current knowledge about the effects of antipsychotics on the circadian rhythms in humans, and to conduct a meta- analysis with the available data. Nine electronic databases were searched. We followed the PRISMA guidelines and included randomized controlled trials (RCTs), non-RCTs, case-control studies, case series, and case reports. Of 7,217 articles, 70 were included. The available data was mainly from healthy individuals, or patients having schizophrenia, but the findings showed a transdiagnostic impact on circadian parameters. This was consistently seen as decreased amplitude of cortisol, melatonin, and body temperature. Particularly, a meta-analysis of 16 RCTs measuring cortisol rhythm showed that antipsychotics, especially atypical antipsychotics, decreased the cortisol area under the curve and morning cortisol level, compared to placebo. The data with melatonin or actigraphy was limited. Overall, this evidence about the circadian effect of antipsychotics showed a need for longitudinal, real-time monitoring of specific circadian markers to differentiate a change in amplitude from a shift in phasing, and for knowledge about optimal timing of administration of antipsychotics, according to individual baseline circadian parameters. Standardizing selection criteria and outcome methods could facilitate good quality intervention studies and evidence-based treatment guidelines. This is relevant considering the accumulating evidence of the high prevalence and unfavorable impact of disrupted circadian rhythms in psychiatric disorders.