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

Article type: Research Article

Authors: Yasue, Ichiro^{a; b} | Matsunaga, Shinji^{a; *} | Kishi, Taro^{a; *} | Fujita, Kiyoshi^{b; c} | Iwata, Nakao^a

Affiliations: [a] Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan | [b] Department of Psychiatry, Okehazama Hospital, Toyoake, Aichi, Japan | [c] The Neuroscience Research Center, Toyoake, Aichi, Japan

Correspondence: [*] Correspondence to: Shinji Matsunaga, MD, PhD, Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan. Tel.: +81 562 93 9250; Fax: +81 562 93 1831; E-mail: [email protected].

Correspondence: [*] Correspondence to: Taro Kishi, MD, PhD, Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan. Tel.: +81 562 93 9250; Fax: +81 562 93 1831; E-mail: [email protected].

Abstract: 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.

Keywords: 5-HT_2A, meta-analysis, Parkinson’s disease, pimavanserin, psychosis

DOI: 10.3233/JAD-150818

Journal: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 733-740, 2016