Is samidorphan adjunction a beacon of hope for olanzapine-induced metabolic syndrome?

Antipsychotics have been the mainstay of schizophrenia treatment. The development of second-generation antipsychotic (SGA) drugs and their promotion by the pharmaceutical industry was based on indications that these medications would have a lower risk for movement disorders and, therefore, greater tolerability than first-generation antipsychotics (1). On the other hand, the emergence of obesity and metabolic abnormalities leading to substantial increases in the risk of cardiovascular disease is a serious complication of antipsychotic use, with SGA drugs being particularly implicated (2). The mechanism by which antipsychotics induce weight gain is complicated and determined by various factors. 5-HT2C, H1, H3, and the D2 receptors are associated with antipsychotic-induced weight gain (3). Antipsychotics act as antagonists for these receptors, which may cause a significant elevation in appetite, and a reduced feeling of satiety, thereby increasing food intake (4). Olanzapine, one of the most effective and preferred SGAs in treating schizophrenia and related psychosis and mood disorders, has been reported to increase blood glucose levels robustly (5) and was strongly associated with the development of type-2 diabetes mellitus compared with other SGA drugs (6). The opioid system influences eating patterns and body weight control (7). Therefore, the combination of olanzapine with an opioid receptor antagonist, samidorphan, has been used to reduce olanzapine- related metabolic side effects. This olanzapine/ samidorphan combination (OLZ/SAM) was associated with notably less weight gain than olanzapine monotherapy. It was approved for antipsychotic- induced weight gain in schizophrenia and bipolar disorder by the U.S. Food and Drug Administration (FDA) in May 2021 (8). Samidorphan is an antagonist of μ-opioid receptors with partial agonist activity toward κ- and δ-opioid receptors. It is primarily eliminated by cytochrome P450- 3A4 (CYP3A4)-mediated hepatic metabolism and renal excretion and to a lesser extent via CYP3A5, CYP2C19, and CYP2C8 enzymes (9). The adverse effect profile of samidorphan includes somnolence and gastrointestinal side effects such as nausea and constipation. Decreased appetite, dry mouth, anxiety, headache, and orthostatic hypotension were also reported (10). In addition to a preventive role in olanzapine-induced weight gain, samidorphan was investigated in trials for several psychiatric disorders, including alcoholism (11), binge eating disorder (12), and in adjunction with antidepressants in treatment-resistant major depressive disorder (13). However, unlike OLZ/SAM for olanzapine-induced weight gain, these trials were discontinued or remained unapproved by the FDA, mostly due to insufficient evidence of effectiveness.

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