Add-On Pimavanserin Promising for Resistant Major Depression

Megan Brooks

September 27, 2019

Pimavanserin (Nuplazid, Acadia Pharmaceuticals), a novel antipsychotic, when added to standard treatment with an antidepressant, showed "statistically significant and clinically relevant" improvement in symptoms for patients with resistant major depressive disorder (MDD).

"Today, the standard of care in MDD is to start patients on SSRI [selective serotonin reuptake inhibitor] or SNRI [serotonin-norepinephrine reuptake inhibitor] therapies. However, a majority of patients do not adequately respond to these initial treatments and are prescribed an adjunctive therapy to manage their symptoms," study investigator Maurizio Fava, MD, executive vice chair, Department of Psychiatry, Massachusetts General Hospital, and associate dean for clinical and translational research, Harvard Medical School, Boston, said in a news release from the drug's manufacturer, Acadia.

"Results from this study suggest pimavanserin could be an important new adjunctive treatment for MDD patients who continue to experience significant depression with their initial therapy," said Fava.

The study was published online September 24 in the Journal of Clinical Psychiatry.

As reported by Medscape Medical News, pimavanserin is already approved for the treatment of hallucinations and delusions in patients with Parkinson disease psychosis. Although most antipsychotics bind to dopamine, acetylcholine, histamine, and 5-HT2A receptors, pimavanserin targets only 5-HT2A receptors.

The study, which had a two-stage sequential parallel-comparison design, included 207 patients with MDD whose response to an SSRI or an SNRI was inadequate.

In the first stage, patients were randomly assigned in a 3:1 ratio to receive either placebo or pimavanserin in conjunction with their current SSRI or SNRI therapy for 5 weeks. After 5 weeks, patients who received placebo and who had not responded (17-item Hamilton Depression Rating Scale [HDRS-17] total score >14 and <50% reduction in score from baseline) were again randomly assigned to receive either placebo or pimavanserin (1:1 ratio) in conjunction with current therapy for another 5 weeks.

All patients who received pimavanserin in the first stage continued treatment with pimavanserin in the second stage; patients who responded to placebo in the first stage continued to receive placebo in the second stage.

Pimavanserin met the overall primary endpoint of the study through demonstration of a significant reduction in HDRS-17 total score compared to placebo (P = .039), the authors report.

Positive overall results were also observed for additional secondary study endpoints, including scores on the Clinical Global Impression Scale–Severity (P = .0084), the Clinical Global Impression Scale–Improvement (P = .0289), the Karolinska Sleepiness Scale (P = .0205), the Massachusetts General Hospital Sexual Functioning Index (P = .0003), and the Barratt Impulsiveness Scale (P = .0075), they note.

The safety and tolerability profile of pimavanserin was consistent with the existing product labeling, with no new safety findings, the authors note. The most common adverse events were dry mouth, nausea, and headache.

These phase 2 results led to the initiation earlier this year of the phase 3 study of pimavanserin as adjunctive therapy for MDD.

The study was funded by Acadia Pharmaceuticals. Several authors reported financial ties to the company. A complete list of author disclosures is available with the original article.

J Clin Psychiatry. Published online September 24, 2019. Full text

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