Clinical Summary: The Efficacy of Olanzapine/Samidorphan on Negative Symptoms: A Post Hoc Analysis of 56-Week Treatment in Patients With Schizophrenia
Negative symptoms remain one of the hardest-to-treat drivers of poor functioning in schizophrenia, and gains in motivation, interest, and expressive functioning often lag behind improvement in acute psychosis. This analysis asks a practical question for long-term treatment: whether improvement in negative symptoms with olanzapine/samidorphan persists and deepens over 56 weeks, including in patients with prominent or predominantly negative symptoms at baseline.
Key Findings
- In the overall analysis, LS mean (SE) changes from baseline at week 56 were −7.6 (0.35) on the PANSS Negative Subscale and −8.2 (0.35) on the Marder Negative Factor, compared with −4.1 (0.24) and −4.5 (0.24) at week 4.
- Among patients with prominent negative symptoms at baseline (n = 186), LS mean (SE) changes at week 56 were −8.7 (0.44) on the PANSS Negative Subscale and −9.6 (0.44) on the Marder Negative Factor; corresponding week 4 changes were −4.6 (0.31) and −5.0 (0.32).
- Among patients with predominant negative symptoms at baseline (n = 48), LS mean (SE) change in Marder Negative Factor score was −4.7 (0.58) at week 4 and −8.9 (0.78) at week 56.
- The cohort started with substantial symptom burden, with mean (SD) baseline PANSS Total score of 101.7 (11.1) and mean (SD) baseline Marder Negative Factor score of 25.2 (4.6).
- Week 56 improvements exceeded anchor-based minimal improvement thresholds cited in the discussion: −3.8 and −5.0 for the Marder Negative Factor and −5.0 for the PANSS Negative Symptoms Subscale.
Negative symptoms improved early and continued to improve through 56 weeks with olanzapine/samidorphan, including in patients with prominent or predominantly negative symptoms at baseline. For patients in whom negative symptoms are a major treatment target, this supports considering OLZ/SAM as a long-term option when olanzapine-class efficacy is desired.
Practice Implications
- Track negative symptoms longitudinally rather than judging response only during the acute phase, because LS mean changes improved from −4.1 to −7.6 on the PANSS Negative Subscale and from −4.5 to −8.2 on the Marder Negative Factor between weeks 4 and 56.
- Pay particular attention to patients with high baseline negative symptom burden, since the prominent negative symptoms subgroup (n = 186) showed larger absolute week 56 improvements of −8.7 on the PANSS Negative Subscale and −9.6 on the Marder Negative Factor.
- Do not assume negative symptom improvement is only a byproduct of reduced positive symptoms; patients with predominant negative symptoms at baseline (n = 48) still showed a week 56 Marder Negative Factor change of −8.9 (0.78).
- Interpret the long-term signal cautiously in shared decision-making because the 52-week extension had no placebo or active control group, and the OLZ/SAM, placebo, and olanzapine groups in ENLIGHTEN-1 (weeks 1–4) were combined for this analysis.
