Pimavanserin for the treatment of psychosis in Alzheimer’s disease: A literature review

Table 1 Jadad questionnaire

Jadad score calculation
Item	Score (Yes = 1)
Was the study described as randomized	0/1
Was the method used to generate sequence of randomization described and appropriate?	0/1
Was the study described as double-blind?	0/1
Was the method of blinding described and appropriate?	0/1
Was there a description of withdrawals and dropouts?	0/1

Table 2 Summary of publications

Ref.	Year	Number of participants	Age (yr)	Setting	Comparators	Duration
Ballard et al[44]	2018	181 (pimavanserin n = 90; placebo n = 91)	≥ 50	Nursing homes	17 mg × 2 tablets pimavanserin vs placebo (2 tablets)	12 wk
Ballard et al[45]	2019	181 (pimavanserin n = 90; placebo n = 91)	≥ 50	Nursing homes	34 mg pimavanserin vs placebo	12 wk

Table 3 Summary Ballard et al[44], 2018

Ref.	Outcomes	Tolerability	Limitations
Ballard et al[44], 2018	Primary outcome: At week 6: (1) Significant improvement in NPI-NH psychosis score (mean change was -3.76 points (SE 0.65) for pimavanserin group and -1.93 points (0.63) for placebo (mean difference -1.84 [95%CI: -3.64, -0.04]; P = 0.045) without negative effects on cognition or motor function; (2) Response (≥ 30% improvement) in 55% (pimavanserin) vs 37% (placebo); and (3) In NPI-NH < 12 subgroup: Mean change of the score from baseline to week 6 was -0.58 (95%CI: -2.10, 0.95) for pimavanserin vs -0.16 (-1.60 to 1.28) for placebo [mean difference -0.42 (95%CI: -2.52, 1.68)], Cohen’s d = –0.77; P = 0.694. At week 12: No significant advantage for pimavanserin vs placebo was observed for the overall study population [treatment difference -0.51 (95%CI: -2.23, 1.21); P = 0.561]. Secondary outcome: At weeks 6 and 12: No significant differences between placebo and pimavanserin for ADCS–CGIC, NPI–NH agitation/aggression, NPI–NH sleep and nighttime behavior disorders, and CMAI–SF	Adverse events (pimavanserin vs placebo). Most common: (1) Agitation (21% vs 14%); (2) Aggression (10% vs 4%); (3) Falls (21% vs 21%); (4) Urinary tract infection (20% vs 25%); and (5) Peripheral edema (8% vs 2%). Less common: (1) Weight loss (-0.7 kg vs -0.1 kg); (2) QTc prolongation (9.4 ms vs -0.2 ms); and (3) Death (4 vs 4)	Limitations: (1) Study was not sufficiently powered to control for secondary outcomes; (2) Limited number of participants in severe psychosis subcategory or prior history of antipsychotic use; (3) Biomarker confirmation for patients diagnosed with Alzheimer’s was not possible in the nursing home patients; (4) Possibility of trial participants inclusion of non-Alzheimer’s type and mixed dementia; (5) High attrition rate: 26% (pimavanserin) and 20% (placebo); and (6) Absence of active comparator to assess efficacy/tolerability between pimavanserin and other antipsychotics. Strengths: (1) Rigorous diagnosis of psychosis – high completion rate at week 12; (2) Participants assessed in the community care homes providing access to the elderly population to be included in the clinical study; and (3) Researchers were able to study frail, elderly participants in their “natural” environment

CI: Confidence interval; NPI–NH: Neuropsychiatric Inventory-Nursing Home version; CMAI–SF: Cohen-Mansfield Agitation Inventory- Short Form; ADCS–CGIC: Alzheimer’s disease Cooperative Study- Clinical Global Impression of Change.

Table 4 Summary Ballard et al[45], 2019

Ref.	Outcomes	Tolerability	Limitations
Ballard et al[45], 2019	For overall population: Adjusted mean change from baseline at week 6 (adjusted mean, MMRM analysis) for the NPI-NH psychosis score was -3.76 (0.65) for pimavanserin vs -1.93 (0.63) for placebo (delta = -1.84, 95% confidence interval (CI) [-3.64, -0.04], Cohen’s d = -0.32, P = 0.045); For patients with NPI-NH scores > 12: The mean change at week 6 was -10.15 (95%CI: -12.50, -7.80) for pimavanserin vs -5.72 (95%CI: -8.14, -3.30) for placebo (delta = -4.43 (95%CI: -7.81, -1.04), Cohen’s d effect size of -0.73, P = 0.011); In the more severe subgroup, pimavanserin was superior to placebo at week 6 in treating both hallucinations (P = 0.046) and delusions (P = 0.034); At week 6, 66.7% of those in the pimavanserin group improved to an NPI-NH psychosis score < 6 vs 32.0% of those in the placebo group (difference = 34.7%); At week 12, 45.5% of both pimavanserin and placebo-treated patients had an NPI-NH psychosis score < 6; The proportion with a baseline NPI-NH psychosis score ≥ 12 achieving a response was significantly (P < 0.05) greater with pimavanserin vs placebo	Incidence of aggression was 14.3% in the severe psychosis subgroup vs 10.0% in overall population; Incidence of agitation was 17.9% in severe subgroup and 21.1% in general population; Other side effects included falls, UTI, contusion, respiratory tract infections, anemia, edema, cellulitis, anxiety, increase in urea or potassium	Small sample size in subgroup; Subgroup analysis was secondary
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CI: Confidence interval; NPI–NH: Neuropsychiatric Inventory-Nursing Home version; UTI: Urinary tract infections.