Serotonin 2A Receptor Inverse Agonist as a Treatment for Parkinson’s Disease Psychosis: A Systematic Review and Meta-analysis of Serotonin 2A Receptor Negative Modulators

Abstract

Background:

There is uncertainty about the efficacy and tolerability of serotonin 2A (5-HT_2A) receptor negative modulators for Parkinson’s disease psychosis (PDP).

Objective:

This is the first meta-analysis of randomized placebo-controlled trials (RCTs) testing negative modulators of the 5-HT_2A receptor as a treatment for PDP.

Methods:

The primary outcome was the Scale for Assessment of Positive Symptoms (SAPS)-hallucinations (H) and -delusions (D) scores (SAPS-H+D). Other outcome measures were SAPS-H, SAPS-D, the Unified Parkinson’s Disease Rating Scale Part II and III (UPDRS-II+III), discontinuation rates, and individual adverse events.

Results:

Four RCTs were identified that met inclusion criteria, all assessing the 5-HT_2A inverse agonist pimavanserin (including 417 drug-treated and 263 placebo-treated PDP patients). Pimavanserin significantly decreased SAPS-H+D scores compared to placebo [weighted mean differences (WMD) = –2.26, 95% confidence interval (95% CI) = –3.86 to –0.67, p = 0.005, I² = 30% , N = 4 studies, n = 502 patients]. Moreover, pimavanserin was superior to placebo for reducing SAPS-H (WMD = –2.15, 95% CI = –3.45 to –0.86, p = 0.001, I² = 0% , N = 2, n = 237) and SAPS-D scores (WMD = –1.32, 95% CI = –2.32 to –0.32, p = 0.010, I² = 0% , N = 2, n = 237). Pimavanserin was associated with less orthostatic hypotension than placebo (risk ratio = 0.33, 95% CI = 0.15–0.75, p = 0.008, I² = 0% , number needed to harm = 17, p = 0.01, N = 3, n = 476). There were no significant differences in rates of all-cause discontinuation, adverse events, and death, UPDRS-II+III scores, and incidences of individual adverse events (other than orthostatic hypotension) between pimavanserin and placebo groups.

Conclusions:

Pooled RCT results suggest that pimavanserin is beneficial for the treatment of PDP and is well tolerated. We did not identify other negative modulators of the 5-HT_2A receptor for the treatment of PDP.