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SAN FRANCISCO -- When added to standard treatment for patients with major depressive disorder (MDD), the atypical antipsychotic pimavanserin (Nuplazid) significantly improved symptoms of depression, according to the phase II CLARITY trial.

At the end of the 10-week study, adjunctive pimavanserin met the primary endpoint of significantly reducing depression symptoms compared with placebo, as measured by the 17-item Hamilton Depression Rating Scale (HAMD-17) total score (mean difference -1.7, P=0.039), reported Bryan Dirks, MD, executive director of clinical research at Acadia Pharmaceuticals in San Diego.

During stage 1 of the study (weeks 1-5), patients on selective serotonin or norepinephrine reuptake inhibitors (SSRIs or SNRIs) saw a significant improvement with the addition of 34 mg pimavanserin daily (n=52) compared with placebo (n=155) on their HAMD-17 total scores (difference -4.0, P=0.003).

Improvements with pimavanserin -- an FDA approved drug for hallucinations and delusions associated with Parkinson's disease psychosis -- were seen as early as week 1 (difference -1.7, P=0.04), Dirks said during a poster presentation at the annual meeting of the American Psychiatric Association here.

Stage 2 was less successful (weeks 6-10). This part of the trial randomized 58 non-responders from the stage 1 placebo group to either pimavanserin or more placebo, but found no significant between-group difference in HAMD-17 score after 5 weeks.

The multicenter study included adults with MDD with a major depressive episode defined by the DSM-5 criteria and SCID-5-CT, who were unresponsive or failed multiple classes of antidepressant drugs, including citalopram (Celexa), desvenlafaxine (Khedezla, Pristiq), duloxetine (Cymbalta, Irenka), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), paroxetine (Pexeva, Paxil, Brisdelle), sertraline (Zoloft), and venlafaxine or venlafaxine XR (Effexor, Effexor XR). All patients had MDD for at least a year prior to the trial, with a Montgomery-Asberg Depression Rating Scale score over 20 and a minimum Clinical Global Impressions (CGI)-severity score of 4.

CLARITY met a key secondary endpoint, with a significant reduction in the pooled stage 1 and 2 Sheehan Disability Scale score -- which measures functional impairment on daily life -- in favor of the adjunctive pimavanserin arm (difference -8.4, P=0.004). Additionally, seven of 11 other secondary endpoints were also met, including reductions in:

• CGI-severity score (-0.4, P=0.008)
• Karolinska sleepiness scale (-0.6, P=0.02)
• Massachusetts General Hospital-Sexual Functioning Index (-0.47, P=0.0003)

Overall, these findings are particularly promising for the millions of patients with MDD who don't adequately respond to standard antidepressant treatment with an SSRI or SNRI, Dirks told 番茄社区app.

Building upon these positive findings, Dirks noted that Acadia is continuing to study pimavanserin in phase III trials.

"Last month, we initiated the phase III CLARITY program. Based on the feedback we received from the FDA, if we're successful in the phase III program, we plan to use the phase II CLARITY study and positive study results from at least one of the two phase III studies to support a supplemental NDA submission for pimavanserin for the adjunctive treatment of MDD for patients with an inadequate response to an SSRI or SNRI therapy," he said.

Pimavanserin works as a potent 5-hydroxytryptamine2A (5-HT_2A) receptor antagonist/inverse agonist, which additionally has activity as a 5-HT_2C antagonist/inverse agonist. But the agent does not have activity at adrenergic, dopaminergic, histaminergic, or muscarinic receptors.

The treatment was generally well tolerated -- 73% of pimavanserin-treated patients experienced at least one treatment-emergent adverse event (AE) compared with 55% of placebo patients during stage 1. Some of the most commonly reported AEs reported with pimavanserin included headache, dizziness, nausea, upper respiratory infection, urinary tract infection, sinusitis, and increased appetite.

Acadia is also currently investigating pimavanserin for dementia-related psychosis, schizophrenia adjunctive therapy, and negative symptoms of schizophrenia adjunctive therapy.

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