Centrally-acting opioid receptor antagonists as a treatment for antipsychotic-induced weight gain: A systematic review and meta-analysis of clinical trial data.

Background: Antipsychotic-induced weight gain (AIWG) is a major concern in psychiatry, where there is a mortality gap between those with mental illness, particularly schizophrenia, and the general population. One development proposed is using centrally-acting opioid receptor antagonists (CORAs) such as naltrexone and samidorphan.

Objective: The systematic review and meta-analysis evaluated the available human clinical trial data on the effect of CORA on AIWG.

Methodology: Four online databases (MEDLINE, EMBASE, PsycINFO, and Cochrane) were searched for randomized-controlled trials (RCTs) on the topic. The primary outcome was change in bodyweight. Secondary anthropometric outcomes included percentage bodyweight change, BMI change, and absolute risk of weight gain. Meta-analysis was conducted on primary outcome.

Results: Nine RCT articles (samidorphan = 6, naltrexone = 3) and two extension studies from RCTs (both samidorphan) were identified. Meta-analysis of four RCTs (n = 1416) found olanzapine/samidorphan was associated with less weight gain than olanzapine alone (mean difference in bodyweight change: -1.18 kg; 95% CI: -1.67 to -0.68). Olanzapine/samidorphan was also superior to olanzapine for changes in BMI (-0.65 kg/m²; 95% CI: -1.1 to -0.28), waist circumference (-1.5 cm; 95% CI: -2.67 to -0.32), and risk reduction for gaining 7% body weight (-12.4%; 95% CI: -18.27 to -6.54) or 10% body weight (-10.8%; 95% CI: -16.21 to -5.45). Naltrexone did not separate from placebo for change in weight or BMI.

Conclusion: CORA, specifically samidorphan, was effective at reducing weight gain in individuals prescribed olanzapine. The small effect sizes and discrepancy between samidorphan and naltrexone suggest effects may be timing dependent, not a class effect, or dependent on the antipsychotic combination.