Investigators deem phase 2 study using pimavanserin to treat major depressive disorder a success.
Investigators are on the verge of adding another adjunctive therapy to treat major depressive disorder (MDD).
In the phase 2 CLARITY study, led by Maurizio Fava, MD, Massachusetts General Hospital, investigators examined the efficacy and safety of pimavanserin, a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist already approved for treating Parkinson disease, as an adjunctive therapy for patients with MDD.
The investigators conducted a multicenter, randomized, double-blind, placebo-controlled study involving patients with MDD with an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).
The team used a 2-stage sequential parallel-comparison design, where patients were initially randomized in a 3:1 ratio with a placebo or pimavanserin added to ongoing SSRI or SNRI therapy. After 5 weeks, the placebo nonresponders were randomized to either a placebo or pimavanserin for an additional 5 weeks.
The primary objective was to evaluate efficacy, with secondary objectives to evaluate safety and tolerability, effects on disability, clinician’s global assessment, patient-reported quality of life, perception of treatment, sleepiness, sexual functioning, impulsivity, and irritability.
The investigators found that the drug significantly reduced the 17-item Hamilton Depression Rating Scale (HDRS-17) total score compared to placebo (P =.039).
Pimavanserin also showed positive overall results observed for additional secondary study endpoints with nominal p-values including: Clinical Global Impression-Severity (P =.0084), Clinical Global Impression-Improvement (P =.0289), Karolinska Sleepiness Scale (P =.0205), Massachusetts General Hospital Sexual Functioning Index (P =.0003), and Barratt Impulsiveness Scale (P =.0075).
There was an 8-21-day screening period in the study, followed by a 10-week double-blind treatment period, and a 30-day safety follow-up period.
Clinical visits occurred weekly throughout the 10-week study.
“For the combined Stages 1 and 2, LS mean difference in the severe subgroup was −3.6 (1.4) for the HDRS-17 (P = .011) and −1.14 (.47) for the SDS (Sheehan Disability Scale) (P = .014),” the authors wrote. “At week 5 in Stage 1, LS mean difference in the severe subgroup was −7.0 (2.1) for the HDRS-17 (P = .0014; effect size: 0.933) and −2.0 (0.68) for the SDS (P = .0054; effect size: 0.815).”
There were no significant differences were observed for HDRS-17 or SDS during Stage 2.
There were significant differences in the prespecified subgroup analyses by background antidepressant from placebo (P <.05) observed both for patients receiving an SSRI and for patients receiving SNRI as a background therapy from weeks 2-5 in stage 1.
Some of the common adverse events included dry mouth, nausea, and headaches. There was also a pair of serious adverse events that occurred in bladder stones and prostate cancer in the placebo group and an incidence of acute myocardial infarction in the pimavanserin group.
Treatment-related events occurred in 27.1% of the placebo group and 48.1% of pimavanserin group during stage 1 and 3.4% of the placebo group and 13.8% of the pimavanserin group during stage 2.
Pimavanserin demonstrated a receptor-binding profile, similar to other drugs with antidepressant activity.
“Pimavanserin demonstrated robust efficacy in patients with MDD and an inadequate response to an SSRI or SNRI,” the authors wrote. “Tolerability was consistent with previous experience.”
MDD currently impacts 300 million people globally, causing substantial morbidity and mortality.
While drug therapy is proven effective, less than 33% of patients achieve remission. There are only a few atypical antipsychotics approved by the US Food and Drug Administration (FDA) for use in adjunctive treatment of patients with an inadequate response to antidepressants.
Currently available atypical antipsychotics may reduce symptoms, but their use is often limited by associated weight gain, metabolic effects, and extrapyramidal effects.
The study, “A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Adjunctive Pimavanserin in Patients With Major Depressive Disorder and an Inadequate Response to Therapy (CLARITY),” was published online in The Journal of Clinical Psychiatry.