REVIEW OF: Bugarski-Kirola D et al, Lancet Psychiatry 2022;9(1):46–58

STUDY TYPE: Randomized placebo-controlled trial

Negative symptoms of schizophrenia—including apathy, asociality, and blunted affect—predict disease burden and are difficult to treat. We lack FDA-approved therapies, and we don’t know whether antipsychotics with novel mechanisms of action have efficacy for negative symptoms. Pimavanserin (Nuplazid) is a novel antipsychotic approved for psychotic symptoms in Parkinson’s disease. Rather than antagonizing the dopamine D2 receptor, pimavanserin appears to work by blocking the 5-HT2A receptor, where it is both an antagonist and an inverse agonist (as an antagonist, it blocks the receptor; as an inverse agonist, it binds to the receptor and induces the opposite effects as an agonist). An earlier trial found benefits for pimavanserin augmentation in major depression (Fava M et al, J Clin Psychiatry 2019;80(6):19m12928), and the current study is the first to test pimavanserin augmentation for negative symptoms of schizophrenia.

This was a randomized, double-blind, placebo-controlled trial of pimavanserin as an adjunct to ongoing antipsychotic medication, in 403 stable adult outpatients ages 18–55 (mean 38) with schizophrenia and predominant negative symptoms in North America and Europe (specifically, patients scored at least 20 on the negative symptom domain of the Positive and Negative Syndrome Scale [PANSS]). Patients were treated with either pimavanserin (starting dose 20 mg daily, dose range 10–34 mg daily) or placebo, in addition to their current antipsychotic, for 26 weeks. The primary outcome was change in the Negative Symptom Assessment (NSA-16) from baseline to week 26. The secondary endpoint was change in the Personal and Social Performance (PSP) scale, which assesses functioning in four areas: socially useful activities; personal and social relationships; self-care; and disturbing and aggressive behaviors. A total of 86% of subjects completed the trial.

After 26 weeks, the pimavanserin group showed a significantly greater reduction in negative symptoms versus placebo (-10.4 vs -8.5 points on the NSA-16), corresponding to a small effect size (0.21), but no change in PSP score (difference 0.0). In post-hoc analyses, the effect size for the NSA-16 was greater in patients who received the 34 mg dose of pimavanserin (0.34), as well as in men, patients from Europe, and patients with chronic negative symptoms (lasting longer than five years). Adverse effects were similar between study groups (35%–40%), most commonly headache and somnolence, and were typically mild. Pimavanserin was associated with a modest but statistically significant increase in the QT interval as compared to placebo (4.5 vs 0.0 ms). There were no clinically relevant effects of pimavanserin on vital signs, weight, glucose, or lipids in this six-month study.

Potential limitations included the flexible dosing schedule, as only 54% of patients were increased to a 34 mg pimavanserin dose. The study participants were stable outpatients with chronic schizophrenia who primarily suffered from negative symptoms, which may limit the generalizability of the study findings. We also don’t know whether response to pimavanserin will vary depending on the antipsychotic it is combined with.

CARLAT TAKE

Adjunctive pimavanserin may improve negative symptoms in patients with stable, chronic schizophrenia. However, the overall effect is small, and the price of the medication is high ($4,000 monthly).