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Original Research Focus on Psychosis March 9, 2026

The Efficacy of Olanzapine/Samidorphan on Negative Symptoms: A Post Hoc Analysis of 56-Week Treatment in Patients With Schizophrenia

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J Clin Psychiatry 2026;87(2):25m16170

Abstract

Objective: Addressing negative symptoms of schizophrenia can be a treatment challenge. This 56-week post hoc analysis examined effects of combined olanzapine and samidorphan (OLZ/SAM) on negative symptoms.

Methods: Adults with acute schizophrenia who received 4 weeks of OLZ/SAM, olanzapine, or placebo and initiated a subsequent 52-week open-label OLZ/SAM extension study (conducted 1/2016–6/2018) were included. Data were pooled across lead-in study (conducted 12/2015– 6/2017) treatment arms. Negative symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS) Marder Negative Factor score. Changes from baseline were evaluated overall, in patients with prominent negative symptoms (defined as baseline Marder Negative Factor score ≥24), and in patients with predominant negative symptoms/low positive symptoms (baseline Marder Negative Factor score ≥24 and PANSS Mohr Positive Factor score ≤19).

Results: Patients (n=281) had mean (SD) PANSS Total and Marder Negative Factor scores of 101.7 (11.1) and 25.2 (4.6), respectively, at baseline. Least squares (LS) mean (SE) change from baseline in Marder Negative Factor score at week 56 was −8.2 (0.35). Among patients with prominent negative symptoms (baseline mean, 27.8; n=186), LS mean (SE) change in Marder Negative Factor score was −9.6 (0.44) at week 56. Similar improvement at week 56 was observed for patients with predominant negative symptoms (n=48; LS mean [SE] change, −8.9 [0.78]).

Conclusion: In this 56-week post hoc analysis of patients initially experiencing an acute exacerbation of schizophrenia, OLZ/SAM was associated with significant and durable improvement in negative symptoms of schizophrenia, overall and among both patients with prominent and predominant negative symptoms.

Trial Registration: ClinicalTrials.gov identifiers NCT02634346 (https:// clinicaltrials.gov/study/NCT02634346) and NCT02669758 (https://clinicaltrials. gov/study/NCT02669758).

J Clin Psychiatry 2026;87(2):25m16170

Author affiliations are listed at the end of this article.

Negative symptoms of schizophrenia, which affect social and emotional expression and functioning, are debilitating and difficult to treat. We investigated whether the combination medication olanzapine/samidorphan could improve negative symptoms using data from patients with schizophrenia who received up to a year or more of treatment with this medication. Patients had meaningful improvements in their negative symptoms that were large enough to likely affect their daily life. Improvements started early and were sustained over the course of treatment. Patients who had severe negative symptoms or mainly negative symptoms before treatment also had meaningful improvement.

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