Parkinson's Disease Psychosis Research Articles

Assessing the risks of treatment in Parkinson disease psychosis: An in-depth analysis.

Parkinson disease (PD) psychosis (PDP) is a disabling non-motor symptom. Pharmacologic treatment is limited to pimavanserin, quetiapine, and clozapine, which do not worsen parkinsonism. A Food and Drug Administration black box warning exists for antipsychotics, suggesting increased mortality in elderly patients with dementia. However, the reasons for higher mortality are unknown. Expanding on prior work exploring mortality in treated PDP patients, we conducted a retrospective comparison to understand the links between treatment regimen, clinical characteristics, and negative outcomes. Electronic medical record data extraction included clinically diagnosed PD patients between 4/29/16-4/29/19 and excluded patients with primary psychiatric diagnoses or atypical parkinsonism. Mortality and clinical characteristics during the study period were compared between untreated patients and those receiving pimavanserin, quetiapine, or both agents (combination). Mortality analyses were adjusted for age, sex, levodopa equivalent daily dose (LEDD), and dementia. The pimavanserin group (n = 34) had lower mortality than the untreated group (n = 66) (odds ratio = 0.171, 95% confidence interval: 0.025-0.676, p = 0.026). The untreated group had similar mortality compared to the quetiapine (n = 147) and combination (n = 68) groups. All treated groups had a higher LEDD compared to the untreated group, but no other differences in demographics, hospitalizations, medical comorbidities, medications, or laboratory values were found between the untreated and treated groups. PDP patients receiving pimavanserin had lower mortality than untreated patients. We found no other clear differences in clinical characteristics to explain the mortality risk. Prospective randomized trials are needed to definitively identify the optimal PDP treatment regimen and associated risks.

Baseline free water within the visual processing system predicts future psychosis in Parkinson disease.

As psychosis is associated with decreased quality of life, increased institutionalization, and mortality in Parkinson disease (PD), it is essential to identify individuals at risk for future psychosis. This longitudinal study aimed to investigate whether diffusion tensor imaging (DTI) metrics of white matter hold independent utility for predicting future psychosis in PD, and whether they could be combined with clinical predictors to improve the prognostication of PD psychosis. This study included 123 newly diagnosed PD patients collected in the Parkinson's Progression Markers Initiative. Tract-based spatial statistics were used to compare baseline DTI metrics between PD patients who developed psychosis and those who did not during follow-up. Binary logistic regression analyses were performed to identify the clinical and white matter markers predictive of psychosis. Among DTI measures, both higher baseline whole brain (odds ratio [OR] = 1.711, p= 0.016) free water (FW) and visual processing system (OR=1.680, p< 0.001) FW were associated with an increased risk of future psychosis. Baseline FW remained a significant indicator of future psychosis in PD after controlling for clinical predictors. Moreover, the accuracy of prediction of psychosis using clinical predictors alone (area under the curve [AUC] = 0.742, 95% confidence interval [CI] = 0.655-0.816) was significantly improved by the addition of the visual processing system FW (AUC=0.856, 95% CI=0.781-0.912; Delong method, p= 0.022). Baseline FW of the visual processing system incurs an independent risk of future psychosis in PD, thus providing an opportunity for multiple-modality marker models to include a white matter marker.

1218 GREY MATTER VOLUME AND NEUROTRANSMITTER RECEPTORS ABNORMALITIES IN PARKINSON’S DISEASE PSYCHOSIS: A META-ANALYSIS

Abstract Introduction Recent evidence suggests extensive grey matter abnormalities in Parkinson’s Disease Psychosis (PDP), as well as dysfunction of dopaminergic and serotonergic receptors. However, findings remain unclear. This meta-analysis aimed to identify neuroanatomical correlates of PDP and to examine the relationship between grey matter and key candidate receptors. Method Peak coordinates were extracted from structural magnetic resonance imaging (MRI) studies (identified through systematic searches on PubMed, Web of Science, and Embase) for PDP patients and Parkinson's Disease patients without psychosis (PDnP) and were analysed using Seed-based d mapping with permutation of subject images (SDM-PSI). Gene expression data for dopaminergic (D1/D2) and serotonergic (5-HT2a/5-HT1a) receptors were extracted from the Allen Human Brain Atlas, probe-to-gene re-annotation data were downloaded from Arnatkevic̆iūtė et al. (Neuroimage, 2019;189:353-67) and parcellated on 78 regions of the Desikan-Killiany brain atlas. Effect-size estimates, extracted from the SDM-PSI analysis for these 78 regions as a measure of grey matter in PDP patients, were entered in multiple regression models. Results 10 studies were included in the meta-analysis (PDP, n= 211; mean age = 69.01 years, 52.1% males; PDnP, n = 298, mean age = 67.34 years, 41.9 % males). Reduction in grey matter was observed in parieto-temporo-occipital regions in PDP patients (uncorrected, p &amp;lt; 0.05). When controlling for PD medications, expressed in Levodopa equivalent daily dose (LEDD), results remained significant (uncorrected, p &amp;lt; 0.05). 5-HT2a and 5-HT1a gene receptor expressions were associated with estimates of grey matter volume (5-HT2a, b=-0.20, p=0.01, adjusted for LEDD, b=-0.18, p=0.03; 5-HT1a, b=0.11, p=0.02, adjusted for LEDD, b=0.12, p=0.01). Conclusion We observed lower cortical volume in parieto-temporo-occipital areas, which are involved in information processing, integration, and attention in PDP compared to PDnP patients. We also reported an association between regional brain expression of serotonergic receptors and grey matter volume suggesting a role of serotonin in PDP.

Comparison of Pimavanserin Versus Quetiapine for Hospitalization and Mortality Risk Among Medicare Beneficiaries with Parkinson's Disease Psychosis.

Pimavanserin is currently the only antipsychotic approved for Parkinson's disease (PD) psychosis, yet its relative safety compared with treatment alternatives has not been thoroughly assessed. This study aimed to compare hospitalization and mortality risk in Medicare beneficiaries with PD receiving new prescriptions of pimavanserin or quetiapine for PD psychosis. The study identified new users of pimavanserin and quetiapine from a 15% national sample of Medicare fee-for-service claims collected between May 1, 2016, and December 30, 2018. All-cause hospitalization and mortality were assessed in time-to-event regression models. Standardized mortality ratio weighting balanced pimavanserin and quetiapine users on baseline characteristics. Follow-up was censored at discontinuation, switch, disenrollment, or the end of the study period. There were 844 new pimavanserin users and 2505 new quetiapine users. The adjusted hazard ratios (95% confidence intervals [CIs]) for hospitalization at 30, 90, 180, and 365 days for pimavanserin versus quetiapine users were 0.59 (0.43-0.81), 0.56 (0.44-0.72), 0.63 (0.52-0.77), and 0.70 (0.60-0.83). The most common reasons for hospitalization were traumatic injury and sepsis. Hospitalizations for heart-related issues were higher with pimavanserin (P< 0.05). The adjusted hazard ratios (95% CIs) for all-cause mortality at 90, 180, and 365 days for pimavanserin versus quetiapine users were 0.73 (0.48-1.13), 0.80 (0.58-1.10), and 0.94 (0.74-1.19). Risk of hospitalization was lower in pimavanserin users compared with quetiapine, and no difference in mortality was observed between pimavanserin and quetiapine. An active comparator analyses with treatment alternatives provided the most clinically relevant information for patients and physicians.

Mortality in Patients with Parkinson's Disease-Related Psychosis Treated with Pimavanserin Compared with Other Atypical Antipsychotics: A Cohort Study.

Pimavanserin is approved in the USA to treat hallucinations and delusions associated with Parkinson's disease psychosis (PDP). We evaluated mortality in patients with PDP after initiation of pimavanserin or comparator atypical antipsychotics, overall, over time, and across subgroups. A cohort of patients aged ≥65years in the USA with PDP newly initiating pimavanserin or a comparator atypical antipsychotic (clozapine, quetiapine, risperidone, olanzapine, aripiprazole, brexpiprazole) was identified in 2016-2019 Medicare claims data. All-cause mortality in the propensity score-matched treatment groups was compared with hazard ratios (HRs) and 95% confidence intervals (CIs) estimated with Cox-proportional hazards models. Cumulative incidence curves and time period-specific models evaluated risk over time. Subgroup and sensitivity analyses were performed, including a sub-cohort of long-term care (LTC) or skilled nursing facility (SNF) residents. We identified 2892 pimavanserin initiators and 19,083 comparator initiators (overall 47% female, mean age=80.9years, LTC/SNF residents=30%). Before matching, pimavanserin users had fewer severe comorbidities and more anti-Parkinson medication use than comparators. Matching resulted in 2891 patients in both groups, and all covariates were well balanced. In the matched cohort, the HR for mortality for pimavanserin versus comparator was 0.78 (95% CI 0.67-0.91), with the lowest time period-specific HRs in the first 180days. Hazard ratios were similar across sensitivity analyses and subgroups. In LTC/SNF residents, the HR was 0.78 (95% CI 0.60-1.01). The observed mortality rates were lower among patients treated with pimavanserin compared with those treated with other atypical antipsychotics. European Union Post-authorization Study (EU PAS) register number 46331.

Health care resource utilization patterns among patients with Parkinson’s disease psychosis: analysis of Medicare beneficiaries treated with pimavanserin or other-atypical antipsychotics

Background Pimavanserin (PIM) is the only FDA-approved atypical antipsychotic (AAP) for hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). Comparative real-world analyses demonstrating its benefits are needed. Objectives To evaluate health care resource utilization (HCRU) outcomes among PDP patients treated with PIM vs. other-AAPs. Methods Retrospective cohort analysis of Parts A, B, and D claims from 100% Medicare sample from 01 January 2013–31 December 2019 was conducted. PDP Patients initiating (i.e. index date) continuous monotherapy (PIM vs. other-AAPs) for ≥12-months during 01 January 2014–31 December 2018 without 12-months pre-index AAP use were selected after 1:1 propensity score matching (PSM) on 31 variables (sex, race, region, age, and 27 Elixhauser comorbidities). HCRU outcomes included: annual all-cause and psychiatric hospitalization (short-term stay, long-term stay, and SNF-stay [skilled nursing facility]) rates, annual all-cause and psychiatric-ER visit rates, mean per-patient-per-year (PPPY) hospitalizations, and average length of stay (ALOS). PIM and other-AAPs were compared using generalized linear models (GLM) controlled for demographic characteristics, comorbidities, coexisting-dementia, and coexisting insomnia. Results Of 12,164 PDP patients, 48.41% (n = 5,889) were female, and mean age was 77 (±8.14) years. Among 1:1 matched patients (n = 842 in each), 37.8% (n = 319) on PIM vs. 49.8% (n = 420) on other-AAPs (p < .05) reported ≥1 all-cause hospitalizations, respectively. Specifically, short-term and SNF-stay among PIM patients vs. other-AAPs were: 34% (n = 286) vs. 46.2% (n = 389) and 20.2% (n = 170) vs. 31.8% (n = 267) (p < .05), respectively. Similarly, 9.6% (n = 81) of PIM vs. 14.6% (n = 123) of other-AAPs patients had ≥1 psychiatric hospitalization (p < .05). Furthermore, ≥1 all-cause and psychiatric ER visit among PIM vs. other-AAPs were 61.6% (n = 519) vs. 69.4% (n = 584) and 5.2% (n = 43) vs. 10.2% (n = 86) (p < .05), respectively. PIM also had significantly lower ALOS, and mean PPPY short-term hospitalization and SNF-stays. Conclusions In this analysis of PDP patients, PIM monotherapy resulted in nearly 12% and 7% lower all-cause hospitalizations and ER visits vs. other-AAPs.

Motor- and cognition-related safety of pimavanserin in patients with Parkinson's disease psychosis.

BackgroundPimavanserin, a selective 5-HT2A inverse agonist/antagonist, is the only treatment approved by the US Food and Drug Administration for hallucinations and delusions associated with Parkinson's disease (PD) psychosis.AimWe aimed to evaluate motor- and cognition-related safety in pimavanserin-treated patients with PD psychosis.MethodsThis analysis included patients with PD psychosis treated with pimavanserin 34 mg from a pooled analysis of 3 randomized, double-blind, placebo-controlled, 6-week studies [NCT00477672 (study ACP-103-012), NCT00658567 (study ACP-103-014), and NCT01174004 (study ACP-103-020)] and a subgroup of patients with PD dementia with psychosis from HARMONY (NCT03325556), a randomized discontinuation study that included a 12-week open-label period followed by a randomized double-blind period of up to 26 weeks. Motor- and cognition-related safety were examined.ResultsThe pooled analysis included 433 randomized patients (pimavanserin, 202; placebo, 231). Least squares mean (standard error [SE]) change from baseline to week 6 Unified Parkinson's Disease Rating Scale (UPDRS) II + III score was similar for pimavanserin [−2.4 (0.69)] and placebo [−2.3 (0.60)] (95% Confidence Interval [CI]:−1.9, 1.6). The change from baseline to week 6 for UPDRS II and UPDRS III scores was similar between groups. In the HARMONY open-label period, 49 patients with PD dementia with psychosis were treated with pimavanserin 34 mg, 36 of whom were randomized in the double-blind period (pimavanserin, 16; placebo, 20). In the open-label period, the mean (SE) change from baseline to week 12 (n = 39) Extra-Pyramidal Symptom Rating Scale (ESRS-A) score was −1.7 (0.74); in the double-blind period, the results were generally comparable between the pimavanserin and placebo arms. The change from baseline in Mini-Mental State Examination (MMSE) score was also comparable between pimavanserin- and placebo-treated patients in HARMONY [open-label (n = 37): mean (SE) change from baseline to week 12, 0.3 (0.66)]. Rates of motor- and cognition-related adverse events were similar between pimavanserin and placebo in both analyses.ConclusionsPimavanserin 34 mg was well tolerated and did not yield a negative impact on motor- or cognition-related function in patients with PD psychosis.

Pimavanserin and Parkinson's Disease Psychosis: A Narrative Review.

Pimavanserin (PMV) is the first approved drug for treating hallucinations and delusions in Parkinson’s disease (PD) psychosis. Psychosis is one of the leading causes of nursing home placement in people with PD. Furthermore, hallucinations are a more frequent cause of institutionalization than motor disability or dementia related to PD. The management of PD psychosis involves antipsychotic medications. Most of the drugs in this class directly block dopamine D2 receptors, leading to significantly worsening motor symptoms in patients with PD. The most commonly used medications for managing PD psychosis are quetiapine, clozapine, and PMV. This literature review aims to study pimavanserin’s history, mechanism, clinical trials, and post-marketing experience. PMV is a potent 5-HT2A receptor antagonist/inverse agonist. Moreover, this drug can interact with 5-HT2C receptors. We calculated some physicochemical descriptors and pharmacokinetic properties of PMV. Eight clinical trials of PMV and PD psychosis are registered on ClinicalTrials.gov. Only four of them have complete results already published. Meta-analytic results showed that PMV efficacy is inferior to clozapine. However, PMV has a significantly lower number of side-effects for managing psychosis in PD. Medicare database assessment revealed 35% lower mortality with PMV compared to other atypical antipsychotics. Moreover, sensitive statistical analysis demonstrated that PMV is a protective factor for the risk of falls in individuals with PD.

Emerging role of psychosis in Parkinson's disease: From clinical relevance to molecular mechanisms.

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Psychosis is one of the common psychiatric presentations in the natural course of PD. PD psychosis is an important non-motor symptom, which is strongly correlated with a poor prognosis. Increasing attention is being given to PD psychosis. In this opinion review, we summarized and analyzed the identification, screening, epidemiology, mechanisms, risk factors, and therapeutic approaches of PD psychosis based on the current clinical evidence. PD psychosis tends to have a negative effect on patients' quality of life and increases the burden of family caregiving. Screening and identification in the early stage of disease is crucial for establishing tailored therapeutic strategies and predicting the long-term outcome. Development of PD psychosis is believed to involve a combination of exogenous and endogenous mechanisms including imbalance of neurotransmitters, structural and network changes, genetic profiles, cognitive impairment, and antiparkinsonian medications. The therapeutic strategy for PD psychosis includes reducing or ceasing the use of dopaminergic drug, antipsychotics, cholinesterase inhibitors, and non-pharmacological interventions. Ongoing clinical trials are expected to provide new insights for tailoring therapy for PD psychosis. Future research based on novel biomarkers and genetic factors may help inform individualized therapeutic strategies.

Atypical antipsychotic use and mortality risk in Parkinson disease

IntroductionDopamine 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. MethodsWe 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). ResultsWe 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. ConclusionMortality 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.

Management of Parkinson's Disease Psychosis.

Objectives To discuss therapeutic management of Parkinson's disease psychosis (PDP) and the burdens associated with it. Parkinson's disease (PD) is an incurable, progressive, and devastating neurodegenerative disease. The prolonged use of dopamine agonists to improve the motor symptoms of PD may result in nonmotor complications such as psychosis. These complications are as devastating as the motor symptoms that accompany PD. PDP is associated with financial burden for patients and health care organizations. Data Sources PubMed search using the phrases Parkinson's disease, Parkinson's disease psychosis, clozapine, quetiapine, and "pimavanserin." Conclusion Pimavanserin is the only US Food and Drug Administration approved drug for the management of hallucinations and delusions associated with PD psychosis. The off-label use of clozapine and quetiapine has demonstrated clinical utility; however, there is still a need for the development of novel therapeutic molecules to avoid side effects associated with current therapeutic options and reduce the burdens of patients, caregivers, and health care institutions.

Screening, Diagnosis, and Management of Parkinson's Disease Psychosis: Recommendations From an Expert Panel.

IntroductionHallucinations and delusions present with psychosis are debilitating non-motor symptoms of Parkinson’s disease, with a prevalence of up to 50–70% at some point during the course of the disease. Often patients and caregivers do not report the presence of hallucinations or delusions unless specifically questioned. A panel of experts in neurology and geriatric psychiatry convened to develop a simple screening tool and guidance on diagnosis and treatment of Parkinson’s disease psychosis (PDP).MethodsThe working group reviewed literature for existing PDP guidelines on diagnosis and management and identified gaps in recommendations. The group discussed and developed a screening tool and treatment guidance that addressed the gaps in existing methodology based on their clinical experience.ResultsThe proposed screening tool consists of two parts: (1) a brief pre-visit screening portion to be completed by the patient and caregiver, and (2) a clinician portion to be completed via clinical interview of the patient and caregiver. If psychotic symptoms are present, an appropriate treatment plan is developed for PDP based on evaluation.ConclusionsThis simple screening tool and treatment guidance offers a practical clinical approach for clinicians in the diagnosis and management of PDP.

Plasma Neurofilament Light and p-tau181 and Risk of Psychosis in Parkinson's Disease.

Neuropsychiatric symptoms are common and important to people with Parkinson's disease (PD), but their etiology is poorly understood. Plasma neurofilament light (NfL) and p-tau181 are biomarkers of neuro-axonal degeneration and tau pathology respectively, which have yet to be explored in association with the affective and psychotic symptoms in PD. To investigate the relationship between plasma NfL and p-tau181 with the affective and psychotic symptoms in PD. We assessed the baseline concentration of plasma NfL and p-tau181 in a cohort of 108 patients with PD and 38 healthy controls. A subgroup of patients (n = 63) were assessed annually with clinical measures for up to 7 years. Psychotic symptoms were assessed using the Non-Motor Symptom Scale and affective symptoms were measured in the Hospital Anxiety and Depression Scale. Baseline plasma NfL was a significant predictor of psychotic symptoms longitudinally across the study adjusted for age, Hoehn and Yahr stage, duration of follow up, duration of disease, baseline levodopa and dopamine agonist medication, and baseline cognition: (OR 8.15 [95% CI 1.40-47.4], p = 0.020). There was no association between NfL concentration and the cumulative prevalence of affective symptoms. Plasma p-tau181 concentration was not associated with psychotic or affective symptoms. These findings suggest psychotic symptoms are associated with greater neurodegeneration in PD. Further studies are needed to explore NfL as a potential biomarker for psychosis in PD.

Obstructive Sleep Apnea and Other Vascular Risk factors' Impact on Non-Motor Symptoms in Parkinson's Disease.

Previous studies revealed an association between vascular comorbidities and obstructive sleep apnea (OSA) and the severity of motor and cognitive symptoms in Parkinson's disease (PD). However, there is a lack of studies assessing the entire spectrum of non-motor symptoms (NMS). To investigate the relationship between vascular comorbidities and NMS in PD patients. Patients were assessed at baseline and 4 years later with the Non-Motor Symptom Assessment Scale, Parkinson's Psychosis Questionnaire, Unified Parkinson's Disease Rating Scale (UPDRS), Montreal Cognitive Assessment, and Apathy scale. After tetrachoric correlation matrix, we conducted linear regression models (adjusted for age, gender, disease duration, and UPDRS-III) to investigate the relationship between vascular comorbidities and NMS. In 73 PD patients, (mean disease duration 7.1 [5.3]), 57% had hypertension, 44% body mass index >25, 44% elevated cholesterol, 15% diabetes mellitus, 15% OSA, 14% cigarette-smoking history, 8% prior stroke, and 8% coronary disease. Cognition, psychotic symptoms, apathy, urinary function, and miscellaneous domains significantly worsened at the 4-year follow-up. OSA was significantly associated with higher severity of hallucinations/illusions at baseline and with a more severe deterioration of attention/memory, psychotic symptoms, and apathetic mood at the 4-year follow-up. At baseline, but not at follow-up, hypertension was negatively associated with miscellaneous domain scores and coronary disease with autonomic function scores (gastrointestinal tract and urinary function domains). Among PD-associated comorbidities, OSA was the main factor of decline. In addition to cognitive impairment, OSA might also potentially worsen psychotic symptoms and apathy. Treatment of OSA could be a strategy to improve these important NMS.

CO10 Association of Pimavanserin with Mortality Compared to Quetiapine for Parkinson's Disease Psychosis in Medicare Beneficiaries: 2016-2018

Pimavanserin is the only antipsychotic approved for Parkinson’s disease psychosis (PDP). Like other antipsychotics, it carries a warning for increased mortality risk but the relative safety of treatment alternatives has not been assessed. The objective of this analysis was to compare mortality risk among new users of pimavanserin versus quetiapine for PDP in Medicare beneficiaries in long-term care (LTC) and community-dwelling settings.

Psychosis in Parkinson’s Disease: A Lesson from Genetics

Psychosis in Parkinson’s disease (PDP) represents a common and debilitating condition that complicates Parkinson’s disease (PD), mainly in the later stages. The spectrum of psychotic symptoms are heterogeneous, ranging from minor phenomena of mild illusions, passage hallucinations and sense of presence to severe psychosis consisting of visual hallucinations (and rarely, auditory and tactile or gustatory) and paranoid delusions. PDP is associated with increased caregiver stress, poorer quality of life for patients and carers, reduced survival and risk of institutionalization with a significant burden on the healthcare system. Although several risk factors for PDP development have been identified, such as aging, sleep disturbances, long history of PD, cognitive impairment, depression and visual disorders, the pathophysiology of psychosis in PD is complex and still insufficiently clarified. Additionally, several drugs used to treat PD can aggravate or even precipitate PDP. Herein, we reviewed and critically analyzed recent studies exploring the genetic architecture of psychosis in PD in order to further understand the pathophysiology of PDP, the risk factors as well as the most suitable therapeutic strategies.

Clozapine Use in a Movement Disorder Clinic.

Clozapine is an effective antipsychotic for Parkinson's disease (PD) that does not worsen motor function and can improve tremor. It is approved for PD psychosis in Europe and Australia. The aim of this study was to report on the use of clozapine in a movement disorder clinic. We report on patients monitored during the COVID-19 pandemic in clinic over a 7-month period. Sixty-five patients were seen, of whom 50 had PD. Thirty-one were treated for psychosis, 18 for refractory tremor and 1 for levodopa dyskinesias. The remainder had psychotic symptoms with dementia with Lewy bodies (n = 2) or other movement disorders. Four had clozapine discontinued because of sedation and 1 for agranulocytosis. Three had clozapine temporarily halted because of granulocytopenia but were rechallenged successfully. When comparing clozapine use in this clinic as compared with others, we deduce that clozapine is likely significantly underutilized in the United States.

Incidence, Prevalence, and Mortality of Psychosis Associated with Parkinson's Disease (1991-2010).

Parkinson's disease (PD)-associated psychosis is a well-known non-motor complication, occurring years after diagnosis of PD. Incidence data vary across different studies highlighting a need for long-term observation and clinical definition. To determine the incidence of psychosis in patients with PD and to investigate their survival in an incident cohort study from 1991-2010 in Olmsted County, MN. We used the Rochester Epidemiology Project to define an incident-cohort study of parkinsonism (1991-2010) in Olmsted County, MN. A movement-disorder specialist reviewed the electronic medical records and applied diagnosis criteria to PD. Psychosis was diagnosed using of NINDS/NIMH unified criteria. We identified 669 cases of parkinsonism; 297 patients were clinically diagnosed with PD. 114/297 (38.4%) patients had evidence of psychosis (60% male); the median onset age of psychosis was 79.4 years. The incidence of Parkinson's disease psychosis (PDP) was 4.28/100 person-years. PDP patients had a 71% increased risk of death compared to PD patients. In PD patients without psychosis, men had 73.4% increased risk of death compared to women, whereas no significant sex difference was observed among PDP men vs. women. Of 114 patients diagnosed with psychosis, 59 were treated with antipsychotics. There was no significant difference in survival between treated and untreated patients. PDP increased the odds of death compared to PD patients. Men with PD without psychosis had greater odds of death compared to women; however, in PD with psychosis the odds of death were comparable among sexes. Lastly, treatment with anti-psychotics did not significantly affect survival.

Delusions and hallucinations correlates in Parkinson's disease psychosis

<h3>Introduction</h3> Patients with Parkinson disease (PD) can experience hallucinations (spontaneous aberrant perceptions) and illusions (misinterpretations of real perceptual stimuli). Of such phenomena, visual hallucinations and illusions are the most frequently encountered, although auditory, olfactory and tactile hallucinations can also occur. Hallucinations can have substantial psychosocial effects and, historically, were the main reason for placing patients in nursing homes. Concomitant or overlapping mechanisms are probably active during visual hallucinations, and these include the following: central dopaminergic over-activity and an imbalance with cholinergic neurotransmission; dysfunction of the visual pathways, alterations of brainstem sleep-wake and dream regulation; and impaired attention focus.The aim of this is to present epidemiological, genetic and pathophysiological aspects of psychosis in PD. <h3>Methods</h3> Pacific Northwest Udall Center (PANUC) was analyzed. MOCA was used to assess cognition and the NPI to examine neuropsychological symptoms including psychosis. Patients with PD without hallucinations or delusions served as controls Comparing characteristics of the PD cohort according to having either no psychosis or delusions with or without hallucinations (using the 10-item Neuropsychiatric Inventory (NPI).Chi-square test was applied to compare categorical variables; Fisher's exact test was applied to compare categorical variables when cell frequency is less than 5. Categorical factors were presented as frequencies (percentages). Unavailable logistic regression models were employed to assess association between predictors and outcome.All tests was two-tailed and performed at a significance level of 0.05. R version 3.5.1 (The R Foundation for Statistical Computing, Vienna, Austria) was used for all analyses. <h3>Results</h3> 129 persons (11% of analyzed sample) were included to the study. Of the entire patient's who reported psychotic symptoms: (84%) experienced hallucinations without delusions, (36%) had symptoms dominated by delusions. Severity and/or number of hallucination subtypes were significantly correlated with lower scores in language, memory, attention, executive functioning, and visuospatial ability. Correlations with delusions were non-significant. Tests of differences in the size of the correlations between groups revealed a significant relationship between language and visuospatial performance with hallucinations. Results suggested a significant association between APOE4 status and hallucinations. Compared to APOE4 non-carrier, APOE carrier patients have 4.509 times of odds to develop hallucinations. <h3>Conclusions</h3> Genetic and cognitive correlates of hallucinations and delusions appear to be different in PD, suggesting distinct pathogenic mechanisms and possibly anatomical substrates. Hence, delusions may not share the same associations with dementia as hallucinations

Improving the treatment of Parkinson's disease: Structure-based development of novel 5-HT2A receptor antagonists/inverse agonists

Pimavanserin is a selective 5-HT2A receptor antagonist and inverse agonist approved by the FDA in 2016, which is used to treat patients with Parkinson's disease psychosis (PDP). But pimavanserin has potential risk with increasing mortality in elderly patients and also increasing the risk of QT interval prolongation in patients. Therefore, searching for new drugs with high efficacy and low toxicity is urgently needed. Based on the docking study of pimavanserin, a series of novel pimavanserin derivatives (7–1∼7–37) were designed and synthesized. The biological activities were evaluated by cell assays and compound 7–16 exhibited 50-fold higher 5-HT2A receptor antagonist activity (IC50 = 0.54 vs 27.3 nM) and 23-fold higher inverse agonist activity (IC50 = 2.1 vs 50 nM) than pimavanserin. Moreover, 7–16 showed increased potency window between the 5-HT2A and hERG activities than pimavanserin. Furthermore, compound 7–16 demonstrated excellent in vitro and in vivo pharmacokinetics, 4-fold more improvement in functional activity in vivo, and good safety profile. Therefore, compound 7–16 represents a potentially promising candidate as a novel anti-PDP agent that warrants further investigation.