Olanzapine/Samidorphan in Young Adults With Schizophrenia, Schizophreniform Disorder, or Bipolar I Disorder Who Are Early in Their Illness

Abstract

Objective: Patients with early-phase schizophrenia or bipolar I disorder (BD-I) are at greater risk for antipsychotic-associated weight gain. This 12-week, randomized, double-blind study conducted between June 2017 and December 2021 evaluated weight effects of combination olanzapine and samidorphan (OLZ/SAM) versus olanzapine in early-phase illness. Methods: Young adults (16-39 years) with DSM-5 schizophrenia, schizophreniform disorder, or BD-I, < 4 years since symptom onset, body mass index < 30 kg/m 2 , and < 24 weeks' cumulative antipsychotic exposure were randomized to OLZ/SAM (5-20/10 mg/d) or olanzapine (5-20 mg/d). Primary endpoint was percent change from baseline body weight at week 12. Secondary endpoints, tested hierarchically, were proportions of patients with ≥ 10% or ≥ 7% weight gain, waist circumference change, and Clinical Global Impressions-Severity (CGI-S) change. Results: Of 428 patients (OLZ/SAM, n = 213; olanzapine, n = 215), 408 had ≥ 1 postbaseline weight assessment and were analyzed. Percent weight change was significantly lower with OLZ/SAM versus olanzapine (4.91% vs 6.77%; leastsquares mean [LSM] [SE] difference, −1.87% [0.75]; P = .012). Although fewer patients treated with OLZ/SAM had ≥ 10% weight gain, the difference was not statistically significant versus olanzapine (21.9% vs 30.4%, respectively; OR = 0.64; 95% CI = 0.39 to 1.05); hierarchical testing precluded further statistical evaluation of secondary endpoints. Proportions of patients with ≥ 7% weight gain (33.1% vs 44.8%; OR = 0.61, 95% CI = 0.39 to 0.94) and waist circumference change (2.99 vs 3.90 cm; LSM [SE] difference, −0.92 cm [0.58]; 95% CI = −2.06 to 0.22) favored OLZ/SAM. LSM (SE) CGI-S change with OLZ/SAM was −0.82 (0.06). OLZ/SAM and olanzapine had similar safety profiles, including small, similar metabolic parameter changes. Conclusions: In patients with early-phase schizophrenia, schizophreniform disorder, or BD-I, OLZ/SAM treatment resulted in less weight gain versus olanzapine. Trial Registration: ClinicalTrials.gov identifier: NCT03187769

Effects of Combined Therapy of Olanzapine and Samidorphan on Safety and Metabolic Parameters in Schizophrenia Patients: A Meta-Analysis

“…During the preliminary assessment of the title and abstract, 163 duplicate and 55 irrelevant studies were removed. Furthermore, after excluding 14 studies by further reading their full texts, only five studies 14 , 15 , 18 , 24 , 25 were included in this meta-analysis, all from the English literature.…”

“…Another systematic review on the application of SAM in conjunction with OLZ for the treatment of SCZ and bipolar I disorder found 17 that the combination therapy tended to reduce weight gain in adult patients with SCZ compared to OLZ monotherapy, however, there was no significant difference in metabolic effects. Subsequently, two studies 18 , 19 on the treatment of SCZ with the OLZ/SAM were reported, and one randomized controlled trial (RCT) confirmed that 18 OLZ/SAM treatment decreased the risk of weight gain. Briefly, higher-quality evidence regarding the specific reduction of weight gain and metabolic disturbances induced by OLZ during treatment of SCZ with OLZ/SAM is still lacking.…”

Shared and unique characteristics of metabolic syndrome in psychotic disorders: a review

“…As a second-line intervention, pharmacological treatment of metabolic alterations and weight loss treatment in PSD patients may be considered and is discussed in detail elsewhere ( 96 , 105 – 108 ) and in Section 4.4. Concerning non-pharmacological and mixed interventions for metabolic dysregulation in PSD, a systematic review of 23 randomized controlled trials suggested that cognitive/behavioral interventions and pharmacological adjuncts both showed modest but significant effects in preventing weight gain.…”

“…If the patient has not successfully reached their targets after 3 months, pharmacological interventions such as anti-hypertensive, lipid-lowering, and diabetes therapy should be considered, according to current recommendations ( 96 , 105 – 108 ). For instance, potential approaches may include metformin, topiramate, aripiprazole augmentation for clozapine patients, or liraglutide, if necessary ( 96 , 105 – 108 ). Metformin is often preferred for its tolerability and effectiveness ( 105 ).…”

“…For instance, potential approaches may include metformin, topiramate, aripiprazole augmentation for clozapine patients, or liraglutide, if necessary ( 96 , 105 – 108 ). Metformin is often preferred for its tolerability and effectiveness ( 105 ). Indeed, a systematic review of 17 randomized controlled trials involving 1,388 participants, various medications, including metformin, H2 antagonists, and monoamine modulators, showed potential for preventing weight gain and BMI increase in people with limited certainty of evidence, while topiramate did not appear effective; however, further research is needed to confirm these findings ( 89 ).…”