Innovations In Clinical Neuroscience

JAN-FEB 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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R E V I E W 20 ICNS Innovations in Clinical Neuroscience • January–February 2018 • Volume 15 • Number 1–2 pimavanserin with strong CYP3A4 inhibitors (e.g., ketoconazole) or inducers (e.g., rifampin) warrants dose reduction or careful monitoring for efficacy, respectively. Furthermore, clinicians should exercise caution when prescribing pimavanserin concurrently with other drugs that cause prolonged QTc intervals, including class 1A antiarrhythmics (e.g., amiodarone), antipsychotics (e.g., ziprasidone), and fluoroquinolones (e.g., moxifloxacin). DISCUSSION Considerations for therapy . Given the limited number of effective, well-tolerated treatments for PDP, novel options are clearly needed. Pimavanserin represents the first FDA-approved PDP medication. 14 One clinical trial has shown pimavanserin to be efficacious, while multiple trials have demonstrated that it is well-tolerated with few side effects and no worsening of PD motor function. 22–24 Although two Phase III clinical trials failed to show improvement in the primary efficacy endpoint, the subsequent Phase III trial was successful after the investigators optimized the trial design to blunt placebo effect and implemented a primary outcome measure, the SAPS-PD, that was more sensitive to PDP improvement. 31 Furthermore, pimavanserin significantly improved sleep-wake cycle and decreased caregiver burden, suggesting enhanced quality of life (QOL) beyond attenuation of psychotic symptoms. 24 Reduced caregiver burden is particularly significant, as this could potentially delay the need for skilled nursing facility placement. Current guidelines recommend cessation or gradual withdrawal of antiparkinsonian medications, if tolerated, as the first-line therapy for PDP. 8 In many cases, this is impossible, as discontinuation worsens PD motor symptoms. For severe psychosis refractory to such medication cessation or in patients unable to tolerate cessation due to worsened motor function, certain second-generation antipsychotics are most commonly used. 10,11 Their efficacy in PDP is likely attributed to effects as 5HT 2A receptor antagonists. 16 In contrast to pimavanserin's 5HT 2A selectivity, second-generation antipsychotics also antagonize dopamine receptors and might worsen motor symptoms. Clozapine, quetiapine, and olanzapine, second generation antipsychotics studied in PDP due to their relative lack of extrapyramidal symptoms, were found to be effective, possibly effective, and not effective, respectively. Most recent guidelines endorse the use of clozapine (Level B), with a less strong recommendation for quetiapine (Level C). 10,11 Neither clozapine nor quetiapine tend to significantly worsen motor dysfunction. 32,37 However, these drugs are not without limitations. Clozapine can cause agranulocytosis, requiring frequent monitoring, and has a greater risk of other AEs, such as anticholinergic effects, hypotension, sedation, and metabolic abnormalities. The risk for agranulocytosis in particular necessitates that healthcare providers and pharmacists participate in a laborious risk evaluation and mitigation strategy (REMS) to prescribe or dispense clozapine. 10–14,38 These REMS requirements include frequent lab monitoring and documentation, which reduces clozapine's utility and results in underutilization. 39 Despite its common use due to greater tolerability relative to clozapine, clinical trial data regarding quetiapine efficacy are weak, as most studies did not display significant improvements in psychosis. 35–37 While clozapine and quetiapine display a low propensity to significantly worsen PD motor symptoms, many antipsychotics, especially first-generation antipsychotics, have higher risk of motor-related AEs that limits their usefulness in the treatment of PDP. 16 Conversely, pimavanserin appears well- tolerated, and preliminary data from ongoing extension studies show pimavanserin to be safe and effective when taken for up to eight years, with total exposure of pimavanserin in PDP exceeding 825 patient years. 25–26 These data suggest promising long-term safety with pimavanserin. Finally, the relative tolerability of pimavanserin might allow the drug to be used earlier in the disease process, whereas clozapine treatment is typically delayed, which results in initiation of medication after the point at which PDP has already caused a noteworthy decline in the patient's QOL. 40 Multiple trials have demonstrated clozapine's efficacy in PDP, and a head-to-head study showed clozapine to be more effective than quetiapine. 32–34,40,41 No head-to-head trials between pimavanserin and comparator drugs have been conducted. Comparing the pimavanserin trial data to previous clozapine trials, clozapine demonstrated a greater effect size compared to pimavanserin based on CGI-S, which was the only common efficacy outcome among key studies. 24,32 However, the clozapine trials were shorter and included fewer patients with more advanced psychosis, limiting comparisons of this data. 23,24,32,41 TABLE 2. Efficacy outcomes from ACP-103-02030 ENDPOINT PLACEBO PIMAVANSERIN 40mg TREATMENT CHANGE 95% CI (p-value) SAPS-PD -2.73 -5.79 -3.06 -4.91 to -1.20 (p=0.0014) CGI-I 3.45 2.78 -0.67 -1.06 to -0.27 (p=0.0011) CGI-S -0.44 -1.02 -0.58 -0.92 to -0.25 (p=0.007) SCOPA-night -0.49 -1.42 -0.93 -1.84 to -0.02 (p=0.446) SCOPA-day wake -0.99 -2.21 -1.22 -2.17 to -0.27 (p=0.0120) Caregiver burden 0.40 -3.94 -4.34 -7.00 to -1.67 (p=0.0016) Abbreviations—SAPS-PD: Scale for Assessment of Positive Symptoms-Parkinson's disease; CGI-I: Clinical Global Impression-Improvement; CGI-S: Clinical Global Impression-Severity; SCOPA: Scale for Outcomes of Parkinson's Disease

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