Depression in Parkinson`s Disease: Investigations of Pimavanserin, a Selective 5-HT2A Receptor Antagonist/Inverse Agonist

Depression occurs in 30–50% of Parkinson’s disease (PD) patients, yet no drugs are approved specifically to treat PD patients with depressive symptoms. Few clinical studies have been conducted in these patients, and results from controlled and uncontrolled studies with drugs approved to treat Major Depressive Disorder (MDD) have shown no or limited treatment effect. There remains unmet need for effective pharmacotherapies.
A single-arm, open-label, 8-week study (NCT03482882) evaluating pimavanserin 34 mg as monotherapy or an adjunct to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) in PD patients with depressive symptoms showed a significant reduction in the 17-item Hamilton Depression Rating Scale (HAMD-17) score at week (W) 8 (least squares mean [LSM] standard error [SE] change from baseline [CFB]: −10.8 [0.63]; 95% CI: −12.0, −9.5; P < 0.0001); W8 responder rate (≥50% improvement from baseline) of 60%. Effects of adjunctive pimavanserin 34 mg were similar in Stage 1 of the placebo-controlled CLARITY study (NCT03018340; sequential parallel comparison design) in MDD patients with inadequate response to an SSRI or SSNI (W5 LSM [SE] HAMD-17 CFB: −11.5 [0.94]; 95% CI: −13.3, −9.6; responder rate: 52.9%). Overall (Stages 1&2 of the CLARITY study), pimavanserin was superior to placebo in HAMD-17 improvement (P=0.039). There was no negative impact on movement disorder assessments in each study.
Treatment effects observed in open-label studies that are consistent with those in placebo-controlled studies enhance confidence in open-label results; future controlled studies are needed to definitively demonstrate pimavanserin’s potential for improving depressive symptoms in PD patients.