Does Melatonin and Melatonin Agonists Improve the Metabolic Side Effects of Atypical Antipsychotics?: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Atypical antipsychotics (AAPs) are increasingly used for the treatment of psychotic disorders but are known to be associated with metabolic abnormalities. This study is a systematic review and meta-analysis of randomized controlled trials (RCTs) studying the effectiveness of melatonin for the amelioration of AAP-induced metabolic syndrome. The MEDLINE (accessed via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials, PsycINFO, LILACS, CINAHL, and OpenGrey databases were searched for RCTs without language restrictions. Inclusion criteria were randomized, double-blind clinical trials comparing melatonin or melatonin agonists with placebo for the amelioration of AAP-induced effects at any age with selected components of metabolic syndrome as outcome measures. Two reviewers independently selected articles and assessed quality using Cochrane risk of bias and concealment tools. Of 53 records, five RCTs were eligible for the systematic review and three for the meta-analysis. The meta-analyses showed no statistically significant difference in any anthropometric or metabolic variable considered. Analysis according to psychiatric diagnosis from one RCT showed significant decreases in diastolic blood pressure (5.5 vs. −5.7 mmHg for the placebo and melatonin groups, respectively; p=0.001), fat mass (2.7 vs. 0.2 kg, respectively; p=0.032), and triglycerides (D) (50.1 vs. −20 mg/dl, respectively; p=0.08) in the bipolar group but not the schizophrenia group. Although limited to five RCTs with small sample sizes, evidence from RCT indicates that melatonin improves AAP-induced metabolic syndrome. This beneficial effect seems more significant in patients with bipolar disorder than those with schizophrenia. Further RCTs are needed to definitively establish the potential ameliorative effect of melatonin and to justify its efficacy as an add-on therapy to curtail AAP-induced metabolic syndrome.