Effect of Miricorilant, a Selective Glucocorticoid Receptor Modulator, on Olanzapine-Associated Weight Gain in Healthy Subjects: A Proof-of-Concept Study

• Published in: Journal of clinical psychopharmacology Vol. 41; no. 6; p. 632
• Main Authors: Hunt, Hazel J, Donaldson, Kirsteen, Strem, Mark, Tudor, Iulia Cristina, Sweet-Smith, Suzanne, Sidhu, Sharan
• Format: Journal Article
• Language: English
• Published: United States 01.11.2021
• Subjects: Adult; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - adverse effects; Antipsychotic Agents - pharmacology; Double-Blind Method; Drug Therapy, Combination; Female; Healthy Volunteers; Humans; Male; Middle Aged; Olanzapine - administration & dosage; Olanzapine - adverse effects; Olanzapine - pharmacology; Proof of Concept Study; Receptors, Glucocorticoid - drug effects; Thymine - administration & dosage; Thymine - adverse effects; Thymine - analogs & derivatives; Thymine - pharmacology; Weight Gain - drug effects; Young Adult
• ISSN: 1533-712X
• DOI: 10.1097/JCP.0000000000001470

Antipsychotic medications, including olanzapine, are associated with substantial weight gain and metabolic disturbances. We sought to determine whether coadministration of miricorilant, a selective glucocorticoid receptor modulator, with olanzapine can ameliorate these effects. Sixty-six healthy men were enrolled in a 2-week, randomized, double-blind, placebo-controlled trial. The primary objective was to evaluate changes in body weight after 14 days coadministration of olanzapine (10 mg) + miricorilant (600 mg) compared with olanzapine (10 mg) + placebo. Secondary objectives included evaluating (a) the safety and tolerability of the combination; (b) the effects of the combination on glucose, insulin, insulin resistance, and triglycerides; and (c) the impact of the combination on hepatic enzymes. Subjects administered olanzapine + miricorilant gained less weight than subjects administered olanzapine + placebo (mean weight gain on day 15, 3.91 kg vs 4.98 kg; difference between groups, -1.07 kg; 95% confidence interval, -1.94 to -0.19; P = 0.017]). Compared with the placebo group, coadministration of miricorilant with olanzapine was associated with smaller increases in insulin (difference, -3.74 mIU/L; P = 0.007), homeostatic model assessment of insulin resistance (difference, -0.47; P = 0.007), triglycerides (difference, -0.29 mmol/L; P = 0.057), aspartate aminotransferase (difference, -32.24 IU/L; P = 0.009), and alanine aminotransferase (difference, -49.99 IU/L; P = 0.030). Miricorilant may provide a promising option for ameliorating the detrimental effects of olanzapine, and investigation of this medication in patients affected by antipsychotic-induced weight gain is warranted. Two phase 2 studies of miricorilant in patients with recent and long-standing antipsychotic-induced weight gain are currently in progress.