Pimavanserin Also Effective as Adjunct Treatment for Major Depressive Disorder

Approved for treatment of psychosis in Parkinson’s disease (PD) and with positive clinical trial results for treatment of psychosis in other forms of dementia, pimavanserin (Nuplazid; Acadia, Pharmaceuticals, San Diego, CA) may also be effective as adjunctive treatment for major depressive disorder (MDD). 

After 5 weeks of adjunctive treatment with pimavanserin vs placebo, participants had a mean decrease of 4.0 ⁺/- 1.09, (P = .0003) points on the Hamilton Depression Rating Scale-17 (HDRS-17) and −1.2 ⁺/- 0.40 (P = .0036) on the Sheehan Disability Scale (SDS). 

At 5 weeks, those who were treated with but had not responded to placebo were rerandomized to receive pimavanserin or placebo. Pooled sequential parallel analyses of showed the least squares (LS) mean difference was −1.7 ⁺/- 0.85 (P = .039) on the HDRS-17 and −0.8 ⁺/- 0.29 (P = .004) on the SDS.

Early and sustained separation of pimavanserin from placebo (P < .05) occurred at 1 week. The most common adverse events with pimavanserin were dry mouth, nausea, and headache.

“Today, the standard of care in MDD is to start (therapy with an) SSRI or SNRI therapies. However, a majority do not adequately respond to these initial treatments and are prescribed an adjunctive therapy to manage their symptoms,” said Maurizio Fava, MD, executive vice chair, department of psychiatry, Massachusetts General Hospital, and associate dean for clinical and translational research, Harvard Medical School. “Results from this study suggest pimavanserin could be an important new adjunctive treatment for (people with) MDD who continue to experience significant depression with their initial therapy.”

Pimavanserin is a selective serotonin inverse agonist and antagonist that preferentially targets 5-HT2A receptors. In vitro, pimavanserin demonstrated no appreciable binding affinity for dopamine (including D2), histamine, muscarinic, or adrenergic receptors. 

These data are from the phase 2 CLARITY study (NCT03018340) published in the Journal of Clinical Psychiatry. Participants were adults with confirmed inadequate response to selective serotonin reuptake inhibitors (SSRI) or serotonin norepinephrine reuptake inhibitors (SNRI) for MDD. After randomizations, participants took pimavanserin or placebo in addition to the SNRI or SSRI they were already taking.