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

Background: There is uncertainty about the efficacy and tolerability of serotonin 2A (5-HT2A) 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-HT2A 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-HT2A 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-HT2A receptor for the treatment of PDP.