Does the Time of Drug Administration Alter the Metabolic Risk of Aripiprazole?

Abstract

Antipsychotic drugs cause metabolic abnormalities through a mechanism that involves antagonism of D2 dopamine receptors (D2R). Under healthy conditions, insulin release follows a circadian rhythm and is low at night, and in pancreatic beta-cells, D2Rs negatively regulate insulin release. Since they are sedating, many antipsychotics are dosed at night. However, the resulting reduction in overnight D2R activity may disrupt 24 h rhythms in insulin release, potentially exacerbating metabolic dysfunction. We examined retrospective clinical data from patients treated over approximately 1 year with the antipsychotic drug aripiprazole (ARPZ), a D2R partial agonist. To identify effects of timing on metabolic risk, we found cases treated with ARPZ either in the morning (n = 90) or at bedtime (n = 53), and compared hemoglobin A1c, and six secondary metabolic parameters across the two groups. After controlling for demographic and clinical factors, patients treated with ARPZ at night had a significant decrease in HDL cholesterol, while in patients who took ARPZ in the morning had no change. There was a non-significant trend toward higher serum triglycerides in the patients treated with ARPZ at night vs. morning. There were no group differences in hemoglobin A1c, BMI, total cholesterol, LDL cholesterol, or blood pressure. Patients taking APPZ at night developed a worse lipid profile, with lower HDL cholesterol and a trend toward higher triglycerides. These changes may pose additional metabolic risk factors compared to those who take ARPZ in the morning. Interventions based on drug timing may reduce some of the adverse metabolic consequences of antipsychotic drugs.

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

“…Retrospective examination of pharmacy records in SMI patients who received RIS revealed that patients taking the medication at night gained significantly more weight and had elevated HbA1c compared to patients taking RIS in the morning. Importantly, these findings extend our published work reporting similarly unfavorable lipid profiles in SMI patients taking aripiprazole at night (32). These data imply shifting the time of AP dose may be a clinical strategy to mitigate weight gain and metabolic side effects.…”

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“…One study has also found an improvement of patient’s circadian rhythm sleep disorders along with the stabilization of the patient’s bipolar disease with aripiprazole treatment [ 94 ]. In addition, this drug activates BMAL1, an important clock gene, and causes a shortening effect on the period of circadian rhythm [ 95 , 96 ]. Quetiapine is often used to treat psychosis in elderly patients with AD.…”

Fasting or the short‐term consumption of a ketogenic diet protects against antipsychotic‐induced hyperglycaemia in mice

“…While the protective effects of fasting and KDs are impressive, and similar in magnitude to those we have shown with glucose‐lowering medications such as liraglutide (Medak et al., 2020), there are limitations to the clinical translatability of our findings that should be acknowledged. First, APs cause sedation and therefore, patients typically prefer to take these medications before bed time (Chipchura et al., 2018) and usually not in the fasted state (McCreadie & Scottish Schizophrenia Lifestyle Group, 2003). Within this context, using fasting as a means to mitigate the acute hyperglycaemic effects of APs would likely be challenging.…”