Adverse effects of antipsychotic drugs on metabolism depend on drug dosing and feeding times

Antipsychotic drugs (AP) are highly efficacious treatments for psychiatric disorders but are associated with significant metabolic side effects. The circadian clock maintains metabolic homeostasis by sustaining daily rhythms in feeding, fasting and hormone regulation but how circadian rhythms interact with AP and its associated metabolic side effects is not well known. In these studies, we investigated the impact of time of AP dosing on the development of metabolic side effects. In mice, AP dosing at the start of the light cycle (AM) resulted in significant increase in food intake, weight gain compared with equivalent dose before the onset of darkness (PM). Time of AP dosing also impacted circadian gene expression, metabolic hormones and inflammatory pathways and their diurnal expression patterns. To examine the possibility of time-dependent AP effects in humans, we conducted a retrospective examination of weight and metabolic outcomes in patients who received risperidone (RIS) for the treatment of serious mental illness. Using pharmacy records to estimate the time of RIS dosing, we observed a significant association between time of dosing and severity of RIS-induced metabolic side effects. Eating within a restricted time window (Time restricted feeding/eating, TRF/TRE) has been shown in both mouse and human studies to be an effective therapeutic intervention against obesity and metabolic disease. We demonstrate, for the first time, that TRF is an effective intervention to reduce AP-induced metabolic side effects in mice. These studies identify highly effective and translatable interventions to mitigate AP-induced metabolic side effects.