Combination Olanzapine and Samidorphan for the Management of Schizophrenia and Bipolar 1 Disorder in Adults: A Narrative Review

Abstract

Schizophrenia is a debilitating psychotic disorder characterized by positive symptoms such as delusions, hallucinations, and disorganized thoughts, and negative symptoms like lack of effect or motivation. Bipolar 1 disorder (B1D) is a psychiatric illness characterized by recurrent manic episodes in alternation with depressive episodes and interspersed periods of euthymia, ultimately resulting in psychological distress and impairment of daily functioning. Effective treatments are needed for both schizophrenia and B1D to reach the treatment goals of reducing the debilitating symptomology, improving social functioning and quality of life, and increasing the chances of recovery and more favorable long-term outcomes. To date, olanzapine is one of the most efficacious atypical antipsychotics (AAPs) for the treatment of both schizophrenia and B1D and is associated with fewer extrapyramidal effects compared to other treatments. However, compared to other AAPs, olanzapine is associated with a greater chance of metabolic syndrome, limiting its clinical use and affecting treatment compliance. Samidorphan mitigates the weight gain side effects of olanzapine by antagonizing μ-, κ-, and δ-opioid receptors. The use of combination drugs to treat psychiatric conditions is an emerging field with the goal of increasing therapeutic efficacy and decreasing undesirable side effects. Clinical trials have demonstrated combination on olanzapine and samidorphan (OLZ/SAM) treatment resulted in significantly less weight gain than olanzapine monotherapy. Clinical trial patients reported improvements in symptoms of psychosis, reduced weight gain, and overall satisfaction with their treatment. OLZ/SAM has been as shown to be a safe and effective pharmaceutical option for the clinical management of schizophrenia and B1D.

Olanzapine-Samidorphan for Schizophrenia: A Systematic Review and Meta-Analysis

“…[26][27][28]30,31 Haddad et al also had documented that OLZSAM exhibited fewer adverse effects than OLZ, and the same has been substantiated by Jawad et al, as they observed that in short-term studies, the addition of the µ-opioid receptor antagonist did not alter the safety profile of the OLZ. 15,20 Interestingly, we observed that the incidences of various adverse events were either high in the OLZ group or the OLZSAM group. In the former group, the incidence of any adverse event and any SAEs was high, though statistically insignificant, while in the latter group, the incidence of somnolence, dry mouth, headache, and drug discontinuation due to adverse events was high, and a statistically significant difference was observed for the incidence of dry mouth (p = 0.01).…”

“…This effect culminates from the antagonism of the µ-opioid receptor, inhibiting the mesolimbic reward system responsible for inducing food cravings. 15,39…”

“…This effect culminates from the antagonism of the µ-opioid receptor, inhibiting the mesolimbic reward system responsible for inducing food cravings. 15,39 As quoted, the rationale for combining samidorphan with olanzapine was to counter the weight gain induced by the latter. Our analysis substantiated the same (incidence of weight gain was higher in the OLZ group than in OLZSAM, though statistically insignificant).…”

“…[12][13][14] Attributable to SAM's mechanism (mu opioid receptor antagonism, thus inhibition of mesolimbic reward system), it was observed that the use of olanzapine-samidorphan combination (OLZSAM) in the management of schizophrenia or bipolar disorder led to reduced weight gain and decreased possibility of worsening of cardiometabolic risk factors. 10,12,15,16 The United States Food and Drug Administration (USFDA) approved the said combination in May 2021 for treating schizophrenia and bipolar disorder I in adults. 17 Of the few systematic reviews and meta-analyses, we could identify that compared OLZSAM with OLZ, all reported on the cardiometabolic profile and weight gain mitigation effects.…”