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Purpose of Review: Parkinson disease dementia (PDD) is a multisystem disorder involving motor and nonmotor symptoms. Therapeutic options for management of cognitive and neuropsychiatric symptoms are relatively limited when compared to motor symptoms and have been an active area of study. We present the reader with a critical appraisal of evidence for approved and recently investigated therapies in the management of PDD, particularly highlighting recent findings in the management of cognitive impairment and psychotic symptoms. Recent Findings.: Several disappointing trials for treatment of cognitive impairment in PDD leave rivastigmine as the only on-label treatment option; evidence supporting possible benefit of other therapies is reviewed. Several clinical trials are currently ongoing and studying novel treatment options for cognitive impairment in PDD. Pimavanserin has demonstrated efficacy for management of Parkinson disease psychosis. In a randomized clinical trial, integrated outpatient palliative care, in addition to standard care, improved multiple aspects of care in this patient population compared to standard care alone. Summary: Rivastigmine, in particular transdermal administration due to greater tolerability, has the best evidence for treatment of cognitive impairment in PDD. Evidence for other acetylcholinesterase inhibitors and memantine is mostly supportive but less conclusive. Research is ongoing to overcome this unmet need for treatment options for cognitive symptoms of PDD. Psychotic symptoms of PDD are best managed with pimavanserin, which was recently investigated and approved in the USA. Caution is needed in prescribing practices, including treatment of motor symptoms, to avoid iatrogenic worsening of nonmotor symptoms.Palliative care should be integrated into the management of PDD. [ABSTRACT FROM AUTHOR]

Introduction: Dopamine receptor blocking atypical antipsychotic (DRB-AAP) use has previously been associated with increased adverse effects and mortality risk among persons with Parkinson disease (PD). Pimavanserin, the only AAP indicated for PD psychosis in the U.S., is a serotonin receptor inverse agonist/antagonist with no known DRB activity. Early observational data have reported inconsistent findings regarding mortality risk associated with pimavanserin. The objective of this study was to estimate all-cause mortality risks of pimavanserin as compared to DRB-AAPs.Methods: We conducted a retrospective cohort study using a large U.S. commercial insurance database. Cox proportional hazards models were used to compare all-cause mortality risks between propensity score-matched groups of PD patients who were new users of pimavanserin or a DRB-AAP, further dividing DRB-AAPs into preferred (quetiapine, clozapine) and non-preferred (other remaining AAPs).Results: We identified 775, 4,563, and 1,297 individuals on pimavanserin, preferred, and non-preferred DRB-AAPs, respectively. There was no difference in mortality risk for pimavanserin vs. preferred DRB-AAPs [adjusted hazard ratio (aHR) 0.99, 95% CI: 0.81-1.20], or pimavanserin vs. non-preferred DRB-AAPs (aHR 0.98, 95% CI: 0.79-1.22) in intention-to-treat analyses.Conclusion: Mortality risk among PD patients using AAPs did not differ by antipsychotic drug categorization based on mechanism of action. Research on the comparative efficacy and morbidity of AAPs, and the mortality associated with psychosis itself is needed to guide clinical decision-making in the PD population. [ABSTRACT FROM AUTHOR]

Abstract Background Antipsychotics are used in Parkinson disease (PD) to treat psychosis, mood, and behavioral disturbances. Commonly used antipsychotics differ substantially in their potential to worsen motor symptoms through dopaminergic receptor blockade. Recent real-world data on the use and continuation of antipsychotic therapy in PD are lacking. The objectives of this study are to (1) examine the continuation of overall and initial antipsychotic therapy in individuals with PD and (2) determine whether continuation varies by drug dopamine receptor blocking activity. Methods We conducted a retrospective cohort study using U.S. commercially insured individuals in Optum 2001–2019. Adults aged 40 years or older with PD initiating antipsychotic therapy, with continuous insurance coverage for at least 6 months following drug initiation, were included. Exposure to pimavanserin, quetiapine, clozapine, aripiprazole, risperidone, or olanzapine was identified based on pharmacy claims. Six-month continuation of overall and initial antipsychotic therapy was estimated by time to complete discontinuation or switching to a different antipsychotic. Cox proportional hazards models evaluated factors associated with discontinuation. Results Overall, 38.6% of 3566 PD patients in our sample discontinued antipsychotic therapy after the first prescription, 61.4% continued with overall treatment within 6 months of initiation. Clozapine use was too rare to include in statistical analyses. Overall therapy discontinuation was more likely for those who initiated medications with known dopamine-receptor blocking activity (adjusted hazard ratios 1.76 [95% confidence interval 1.40–2.20] for quetiapine, 2.15 [1.61–2.86] for aripiprazole, 2.12 [1.66–2.72] for risperidone, and 2.07 [1.60–2.67] for olanzapine), compared with serotonin receptor-specific pimavanserin. Initial antipsychotic therapy discontinuation also associated with greater dopamine-receptor blocking activity medication use – adjusted hazard ratios 1.57 (1.28–1.94), 1.88 (1.43–2.46), 2.00 (1.59–2.52) and 2.03 (1.60–2.58) for quetiapine, aripiprazole, risperidone, and olanzapine, respectively, compared with pimavanserin. Similar results were observed in sensitivity analyses. Conclusions Over one-third of individuals with PD discontinued antipsychotic therapy, especially if the initial drug has greater dopamine-receptor blocking activity. Understanding the drivers of antipsychotic discontinuation, including ineffectiveness, potentially inappropriate use, clinician inertia, patient adherence and adverse effects, is needed to inform clinical management of psychosis in PD and appropriate antipsychotic use in this population.

Background: Antipsychotics are used in Parkinson disease (PD) to treat psychosis, mood, and behavioral disturbances. Commonly used antipsychotics differ substantially in their potential to worsen motor symptoms through dopaminergic receptor blockade. Recent real-world data on the use and continuation of antipsychotic therapy in PD are lacking. The objectives of this study are to (1) examine the continuation of overall and initial antipsychotic therapy in individuals with PD and (2) determine whether continuation varies by drug dopamine receptor blocking activity.Methods: We conducted a retrospective cohort study using U.S. commercially insured individuals in Optum 2001-2019. Adults aged 40 years or older with PD initiating antipsychotic therapy, with continuous insurance coverage for at least 6 months following drug initiation, were included. Exposure to pimavanserin, quetiapine, clozapine, aripiprazole, risperidone, or olanzapine was identified based on pharmacy claims. Six-month continuation of overall and initial antipsychotic therapy was estimated by time to complete discontinuation or switching to a different antipsychotic. Cox proportional hazards models evaluated factors associated with discontinuation.Results: Overall, 38.6% of 3566 PD patients in our sample discontinued antipsychotic therapy after the first prescription, 61.4% continued with overall treatment within 6 months of initiation. Clozapine use was too rare to include in statistical analyses. Overall therapy discontinuation was more likely for those who initiated medications with known dopamine-receptor blocking activity (adjusted hazard ratios 1.76 [95% confidence interval 1.40-2.20] for quetiapine, 2.15 [1.61-2.86] for aripiprazole, 2.12 [1.66-2.72] for risperidone, and 2.07 [1.60-2.67] for olanzapine), compared with serotonin receptor-specific pimavanserin. Initial antipsychotic therapy discontinuation also associated with greater dopamine-receptor blocking activity medication use - adjusted hazard ratios 1.57 (1.28-1.94), 1.88 (1.43-2.46), 2.00 (1.59-2.52) and 2.03 (1.60-2.58) for quetiapine, aripiprazole, risperidone, and olanzapine, respectively, compared with pimavanserin. Similar results were observed in sensitivity analyses.Conclusions: Over one-third of individuals with PD discontinued antipsychotic therapy, especially if the initial drug has greater dopamine-receptor blocking activity. Understanding the drivers of antipsychotic discontinuation, including ineffectiveness, potentially inappropriate use, clinician inertia, patient adherence and adverse effects, is needed to inform clinical management of psychosis in PD and appropriate antipsychotic use in this population. [ABSTRACT FROM AUTHOR]

In 2016, pimavanserin, a 5-hydroxytryptamine 2A inverse agonist, became the first U.S. Food and Drug Administration (FDA) approved medication for Parkinson disease psychosis (PDP) after demonstrating modest clinical improvement in a single positive trial as assessed by a novel PDP scale, the Scale for the Assessment of Positive Symptoms for Parkinson's Disease Psychosis (SAPS-PD). This followed three trials that demonstrated negative findings on established measures of psychosis widely used in PDP research, including the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, the Parkinson Psychosis Rating Scale, and the Clinical Global Impression-Severity Scale. This review article provides an overview of the scale construction of the SAPS-PD, a measure which has yet to be established as valid, reliable, or sensitive to change in PDP. Furthermore, this article reviews analyses completed by an FDA statistical reviewer that call into question whether pimavanserin demonstrated a clinically significant difference from placebo on the SAPS-PD. These findings underscore concerns regarding the clinical efficacy of pimavanserin. [ABSTRACT FROM AUTHOR]

Pimavanserin is an antipsychotic that is approved for use in Parkinson's disease psychosis. Working as a serotonin 2A inverse agonist, pimavanserin allows patients to improve their psychotic symptoms without worsening the motor symptoms of Parkinson's. This mechanism is mediated via serotonin receptors and may allow for pimavanserin to be considered for use in other disease processes that present with psychosis. Here, the authors describe the case of a 75-year-old man with Lewy Body Dementia (LBD) who was started on pimavanserin. The response of the patient to the medication was measured over a six-week time course using the Scales for the Assessment of Positive Symptoms of Schizophrenia (SAPS). Overall, pimavanserin was shown to be effective in this patient with LBD. The authors also provide a review of the sparse literature attesting to other off-label uses for this unique antipsychotic., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Baker et al.)

Pimavanserin is the only approved drug for Parkinson's disease psychosis (PDP) and is an increasingly used therapy where available. Clozapine has proven efficacy for PDP but is much less commonly used secondary to frequent blood tests to monitor for agranulocytopenia. We identified 27 patients with PDP (72 ± 7.3 years, 11 (41%) female), with an inadequate response to pimavanserin, who subsequently started clozapine. The final mean daily dose of clozapine was 49.5 mg [range 25–100] at night, and mean duration of follow-up was 17 months [range: 2–50 months]. Patients reported clozapine to be markedly effective in 11 (41%), moderately effective in 6 (22%), somewhat effective in 5 (18%). No patient reported that it was ineffective, but 5 (19%) had inadequate follow-up. Clozapine should be considered in pimavanserin refractory psychosis. [ABSTRACT FROM AUTHOR]