Open-label flexible-dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson's disease.

Psychosis affects at least 5% to 8% of medication-treated patients with idiopathic Parkinson's disease (PD). Treatment options include reducing medications used for the treatment of PD-related motor symptoms or introducing an atypical antipsychotic drug. Only clozapine has been demonstrated to be efficacious and tolerated in double-blind controlled trials. This study evaluated the effect of aripiprazole, an atypical antipsychotic, on psychosis in PD in an open-label pilot study. Fourteen patients meeting entry criteria were started on aripiprazole 1 mg/day and titrated up to a maximum dose of 5 mg as needed. Subjects were evaluated on the Unified Parkinson's Disease Rating Scale (UPDRS) part III for motor function, the Neuropsychiatric Inventory (NPI), and the Brief Psychiatric Rating Scale (BPRS) for psychiatric response. Statistically significant improvement in mean BPRS and positive BPRS subscales occurred with open-label aripiprazole, but eight subjects discontinued the study due to worsened Parkinsonism (three), worsened psychosis (two), worsening of both (two), and lack of efficacy (one). While some patients had a favorable response, aripiprazole was associated with an exacerbation of motor symptoms. In this small study on psychosis in PD, aripiprazole did not appear promising.     

Evidence for using pimavanserin for the treatment of Parkinson's disease psychosis

The aim of this editorial is to evaluate the evidence for using pimavanserin for the treatment of Parkinson's disease psychosis (PDP) from randomized controlled trials (RCTs). We only identified two published trials that evaluated the use of pimavanserin among individuals with PDP. Both studies found that pimavanserin improved psychotic symptoms among individuals with PDP when compared to placebo. Pimavanserin was fairly well tolerated in both studies and did not appear to cause significant sedation or worsen motor symptoms among individuals with PDP. However, given the limited data, additional confirmatory studies are required before pimavanserin can be considered as a first line agent for the treatment of psychotic symptoms among individuals with PD.     

Treatment of psychosis in Parkinson's disease and dementia with Lewy Bodies: A review

There is a considerable overlap between Parkinson's Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB). They present a challenge therapeutically, with regard to morbidity and mortality risk. In particular, symptoms of psychosis in these conditions augur a considerably increased burden.To date, there has been a myriad of prospective, retrospective and case studies examining the use of neuroleptics in the treatment of psychotic symptoms in PDD/DLB. Clozapine has the most robust evidence base however its use is limited by agranulocytosis risk and the associated need for frequent blood count monitoring. Quetiapine is more readily used, however, it has a more equivocal evidence base, in terms of efficacy. Other neuroleptics have thus far demonstrated mixed results with increased risk of extrapyramidal worsening. In addition to the atypical agents, the introduction of pimavanserin has provided another treatment option for Parkinson's Disease Psychosis (PDP), decreasing concern for deterioration in motor function. We await further research to confidently demonstrate its efficacy and safety in DLB psychosis. Cholinesterase inhibitors likely have a limited role in treating milder psychosis symptomatology in DLB and perhaps PDD.After review of the current literature for antipsychotic therapy in both PDD and DLB, we provide a logical framework for addressing psychotic symptoms in each condition.     

Long-term safety and efficacy of apomorphine infusion in Parkinson's disease patients with persistent motor fluctuations: Results of the open-label phase of the TOLEDO study

IntroductionThe randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP).MethodsAll patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry. The primary objective was the evaluation of long-term safety of APO.ResultsEighty-four patients entered the OLP (40 previously on APO, 44 on placebo) and 59 patients (70.2%) completed the study. The safety profile of APO was consistent with experience from extensive clinical use. Common treatment-related adverse events (AEs) were mild or moderate infusion site nodules, somnolence and nausea. Fourteen (16.7%) patients discontinued the OLP due to AEs, those involving >1 patient were infusion site reactions (n = 4) and fatigue (n = 2); hemolytic anemia occurred in one case. Reduction in daily OFF time and improvement in ON time without troublesome dyskinesia were sustained for up to 64 weeks. Pooled data for week 64 (n = 55) showed a mean (SD) change from DBP baseline in daily OFF time of −3.66 (2.72) hours and in ON time without troublesome dyskinesia of 3.31 (3.12) hours. Mean (±SD) daily levodopa-equivalent dose decreased from DBP baseline to week 64 by 543 mg (±674) and levodopa dose by 273 mg (±515).ConclusionsThe safety and efficacy of APO infusion were demonstrated with long-term use for persistent motor fluctuations, allowing substantial reductions in oral PD medication.     

Treatment of drug-induced psychosis in Parkinson's disease with ziprasidone can induce severe dose-dependent off-periods and pathological laughing

"Atypical anti-psychotics" are substances of choice in treating drug-induced psychosis (DP) in Parkinson's disease (PD). We report on four patients with DP who received treatment with ziprasidone after previously applied clozapine and quetiapine had failed. Three patients showed a significant improvement of DP, without deterioration of motor function. In one case, ziprasidone considerably increased decline in off-periods. Two patients developed pathological laughing as a possible side-effect of ziprasidone. Ziprasidone may serve as an additional "atypical anti-psychotic" for the treatment of DP in PD but can also induce deterioration of motor function.     

A trial of buspirone for anxiety in Parkinson's disease: Safety and tolerability

IntroductionIn Parkinson's disease (PD), anxiety is common, associated with lower health-related quality of life, and undertreated. The primary objective of this study was to determine the tolerability of buspirone for the treatment of anxiety in PD.MethodsIndividuals with PD and clinically significant anxiety were randomized 4:1 to flexible dosage buspirone or placebo for 12 weeks. Treatment was initiated at 7.5 mg twice daily and titrated based on response and tolerability to an optimal dosage (maximum 30 mg twice daily). The primary outcome was the proportion of participants who failed to complete the study on study drug. Secondary outcomes included adverse events, dosage reductions, motor function, dyskinesias, and anxiety.ResultsA total of 21 participants enrolled, 4 were randomized to placebo and 17 to buspirone (mean (SD) age 65.5 (9.8), 76.5% male, 88% on concomitant antidepressant or anxiolytic). In the buspirone group, 7 (41%) failed to complete the study on drug, 5 due to intolerability. The median buspirone dosage was 7.5 mg twice daily. No serious adverse events occurred. A total of 9 (53%) buspirone participants experienced adverse events consistent with worsened motor function. In the buspirone group, mean (SD) improvement from baseline to week 12 in Hamilton Anxiety Rating Scale was −3.9 (3.8) and Parkinson Anxiety Scale −7.1 (6.4).ConclusionTolerability concerns do not support moving immediately forward with a large-scale efficacy trial. However, concomitant anxiolytics may have affected tolerability and a signal of efficacy was seen suggesting that future studies of buspirone monotherapy be considered.     

Domain‐specific cognitive impairment in non‐demented Parkinson's disease psychosis

Introduction

In Parkinson's disease (PD), psychosis is associated with cognitive impairment that may be more profound in particular cognitive domains. Our goal was to determine whether psychosis in non‐demented PD participants is associated with domain‐specific cognitive impairment on the Mini‐Mental State Exam (MMSE).

Methods

The Morris K. Udall Parkinson's Disease Research Center of Excellence Longitudinal Study at Johns Hopkins is a prospective study that was initiated in 1998. Clinical assessments are conducted at two‐year intervals at the Johns Hopkins Hospital. We analyzed data from 137 enrolled participants with idiopathic PD. Psychosis diagnoses were established by psychiatrist interview per DSM‐IV criteria. An incident dementia diagnosis resulted in exclusion from analysis for that evaluation and any future evaluations in that participant. We used logistic regression with generalized estimated equations (GEE) to model the time‐varying relationship between MMSE subscale scores and psychosis, adjusting for potential confounding variables identified through univariable analysis.

Results

Thirty‐one unique psychosis cases were recorded among non‐demented participants. Fifty total evaluations with psychosis present were analyzed. In multivariable regressions, psychosis was associated with lower scores on the orientation (relative odds ratio, rOR: 0.73; 95% CI: 0.58–0.93; p = 0.011), language (rOR: 0.64; 95% CI: 0.48–0.86; p = 0.003), and intersecting pentagon (rOR: 0.43; 95% CI: 0.20–0.92 p = 0.030) subscales of the MMSE.

Conclusions

In PD, executive dysfunction, disorientation, and impaired language comprehension may be associated with psychosis. Our findings suggest that the corresponding MMSE subscales may be useful in identifying participants with a higher likelihood of developing psychosis. Copyright © 2017 John Wiley & Sons, Ltd.     

Antidepressant use in treatment of psychosis with comorbid depression in Parkinson's disease

The authors report an improvement in delusions and hallucinations after antidepressant treatment (Clomipramine) in a parkinsonian patient with psychosis and comorbid depression. Their findings, which support a previous case treated with Citalopram, highlight the possible effectiveness of antidepressant therapy on psychotic symptoms in parkinsonian patients.     

Psychotic and compulsive symptoms in Parkinson's disease

The objective of this study is to evaluate psychiatric symptoms in Parkinson's disease (PD) patients and to assess their relation with other clinical aspects of PD. Psychotic symptoms (PS) and compulsive symptoms (CS) as well as other nonmotor and motor features were evaluated in 353 PD patients. Psychotic and compulsive symptom scores did not correlate significantly. PS occurred in 65% of patients, with item frequencies ranging from 10% (paranoid ideation) to 55% (altered dream phenomena). Regression analysis showed that autonomic impairment accounted for 20% of the 32% explained variance of PS, whereas cognitive problems, depression, daytime sleepiness, and dopamine agonist (DA) dose explained the rest. CS occurred in 19%, with item frequencies of 10% for both sexual preoccupation and compulsive shopping/gambling. Patients with more severe CS (score ≥ 2 on one or both items) were significantly more often men, had a younger age at onset, a higher DA dose and experienced more motor fluctuations compared to the other patients. PS and CS are common but unrelated psychiatric symptoms in PD. The relations found between PS and cognitive problems, depression, daytime sleepiness, and autonomic impairment suggests a resemblance with Dementia with Lewy Bodies. The prominent association between PS and autonomic impairment may be explained by a shared underlying mechanism. Our results confirm previous reports on the profile of patients developing CS, and mechanisms underlying motor fluctuations may also play a role in the development of CS in PD. © 2009 Movement Disorder Society     

Visual symptoms in Parkinson's disease and Parkinson's disease dementia

Visual symptoms are common in PD and PD dementia and include difficulty reading, double vision, illusions, feelings of presence and passage, and complex visual hallucinations. Despite the established prognostic implications of complex visual hallucinations, the interaction between cognitive decline, visual impairment, and other visual symptoms remains poorly understood. Our aim was to characterize the spectrum of visual symptomatology in PD and examine clinical predictors for their occurrence. Sixty-four subjects with PD, 26 with PD dementia, and 32 age-matched controls were assessed for visual symptoms, cognitive impairment, and ocular pathology. Complex visual hallucinations were common in PD (17%) and PD dementia (89%). Dementia subjects reported illusions (65%) and presence (62%) more frequently than PD or control subjects, but the frequency of passage hallucinations in PD and PD dementia groups was equivalent (48% versus 69%, respectively; P = 0.102). Visual acuity and contrast sensitivity was impaired in parkinsonian subjects, with disease severity and age emerging as the key predictors. Regression analysis identified a variety of factors independently predictive of complex visual hallucinations (e.g., dementia, visual acuity, and depression), illusions (e.g., excessive daytime somnolence and disease severity), and presence (e.g., rapid eye movement sleep behavior disorder and excessive daytime somnolence). Our results demonstrate that different "hallucinatory" experiences in PD do not necessarily share common disease predictors and may, therefore, be driven by different pathophysiological mechanisms. If confirmed, such a finding will have important implications for future studies of visual symptoms and cognitive decline in PD and PD dementia.     

Efficacy and safety of atypical antipsychotics for psychosis in Parkinson's disease: A systematic review and Bayesian network meta-analysis

IntroductionWe performed a systematic review and Bayesian network meta-analysis to clarify the relative efficacy and safety of pimavanserin compared to atypical antipsychotics for psychosis in Parkinson's disease (PD).MethodsPubMed, Embase, Cochrane Central Register of Controlled Trials, and Japana Centra Revuo Medicina Web were searched for relevant articles until October 31, 2019. Eligible randomized controlled trials were synthesized for efficacy (Brief Psychiatry Rating Scale [BPRS] and Clinical Global Impression Scale [CGI-S]) and safety (Unified Parkinson's Disease Rating Scale part III [UPDRS-III] and dropouts due to adverse events). The mean differences (BPRS, CGI-S, and UPDRS-III) or odds ratios (dropouts due to adverse events) between each active drug and placebo were estimated and summarized as means and 95% credible intervals, respectively.ResultsWe identified 17 relevant trials. Clozapine showed significant efficacy (BPRS, −5.6 [−8.4 to −2.7] and CGI-S, −1.2 [−1.7 to −0.7]), with low impact on motor functions (UPDRS-III, −1.1 [−3.8 to 1.5]), but an increase in dropouts due to adverse events (2.9 [0.9 to 9.6]) as compared to placebo. Pimavanserin also showed significant efficacy (CGI-S, −0.5 [−0.9 to −0.2]) and similar impact on motor functions (UPDRS-III, 0.2 [−1.4 to 1.9]), but a tendency of increase in dropouts due to adverse events (2.2 [0.5 to 12.4]) as compared to placebo.ConclusionsClozapine showed an efficacy with low impact on motor functions that was consistent with previous reports. Although the efficacy of pimavanserin may be inferior to that of clozapine, it had a favorable profile for the treatment of psychosis in PD.     

Quetiapine improves psychotic symptoms and cognition in Parkinson's disease.

Twenty-nine elderly patients who failed treatment with clozapine, risperidone, or olanzapine entered this 24-week, single-center, open-label trial to assess the efficacy of quetiapine (12.5-400 mg/day) for psychosis in patients with Parkinson's disease (PD). Psychiatric, motor, and cognitive assessments were administered at baseline and at periodic intervals for 24 weeks. These included the Brief Psychiatric Rating Scale (BPRS), Neuropsychiatric Inventory (NPI), Unified Parkinson's Disease Rating Scale (UPDRS) and tests of intellectual functioning, attention, and memory. Repeated measures statistical analysis was used to assess change from baseline. The results revealed significant improvements in the 24-week BPRS total score and NPI psychosis subscale scores, with no decline in UPDRS total or motor subscale scores. There was also significant improvement in recall scores on cognitive measures. These results indicate that quetiapine may treat psychotic symptoms and improve cognition without worsening motor function in patients with PD, suggesting that quetiapine is an effective and well-tolerated antipsychotic in this population.     

Neuropsychiatric co-morbidities in non-demented Parkinson's disease

Objective:

To evaluate neuropsychiatric co-morbidities (depression, psychosis and anxiety) in non-demented patients with Parkinson''s disease (PD).

Background:

Non-motor symptoms like neuropsychiatric co-morbidities are common in Parkinson''s disease and may predate motor symptoms. Currently there is scarcity of data regarding neuropsychiatry manifestations in Indian patients with PD.

Methods:

In this cross-sectional study consecutive 126 non-demented patients with PD (MMSE ≥25) were enrolled. They were assessed using Unified Parkinson''s disease rating scale (UPDRS), Hoehn & Yahr (H&Y) stage, Schwab and England (S&E) scale of activity of daily life. Mini-international neuropsychiatric interview (MINI) was used for diagnosis of depression, psychosis and anxiety. Beck''s depression inventory (BDI), Brief psychiatric rating scale (BSRS) and Hamilton rating scale for anxiety (HAM-A) scales were used for assessment of severity of depression, psychosis and anxiety respectively.

Results:

Mean age and duration of disease was 57.9 ± 10.9 years and 7.3 ± 3.6 years respectively. At least one of the neuropsychiatric co-morbidity was present in 64% patients. Depression, suicidal risk, psychosis and anxiety were present in 43.7%, 31%, 23.8% and 35.7% respectively. Visual hallucinations (20.6%) were most frequent, followed by tactile (13.5%), auditory (7.2%) and olfactory hallucinations (1.6%). Patients with depression had higher motor disability (UPDRS-motor score 33.1 ± 14.0 vs 27.3 ± 13.3; and UPDRS-total 50.7 ± 21.8 vs 41.0 ± 20.3, all p values <0.05). Patients with psychosis were older (63.6 ± 8.0 years vs 56.1 ± 11.1 years, p < 0.05) and had longer duration of illness (8.6 ± 3.4 years vs 6.9 ± 3.5, p < 0.05).

Conclusions:

About two third patients with Parkinson''s disease have associated neuropsychiatric co-morbidities. Depression was more frequent in patients with higher disability and psychosis with longer duration of disease and older age. These co-morbidities need to be addressed during management of patients with PD.