Treatment Of Parkinson's Disease Psychosis Research Articles

Risk of long-term care admissions among Medicare beneficiaries treated with pimavanserin or quetiapine for Parkinson's disease psychosis in USA: a retrospective administrative claims database analysis.

Aim: Risk of long-term care (LTC) admission (LTCA) associated with atypical antipsychotic (AAP) use among patients with Parkinson's disease psychosis (PDP) is a major concern. However, no comparative studies have examined the differences in risk of LTC admissions between pimavanserin (PIM), the only FDA-approved AAP for PDP, and other off-label AAPs including quetiapine (QUE). Objective: To examine all-cause LTCA rates and risk among PDP patients treated with AAPs such as QUE or PIM. Methods: Analysis of Parts A, Band D claims (100% Medicare sample; 2013-2019) of Medicare beneficiaries with PDP that initiate ≥12-month continuous PIM or QUE monotherapy from 1 January 2014 to31 December 2018 (i.e., index date) without any AAP use in the 12-month pre-index period was conducted. Outcome assessments among 1:1 propensity score-matched (31 variables - age, sex, race, region and 27 Elixhauser comorbidities) beneficiaries on PIM versus QUE included risk of all-cause skilled nursing facility stays (SNF-stays), LTC-stays, and overall LTCA (i.e., SNF-stays or LTC-stays). All-cause LTCA rates and LTCA risk were compared using logistic regression and cox proportional hazards models, respectively, controlling for demographics, comorbidities and co-existing-dementia or insomnia. Results: Of the matched sample (n=842 for each group) from total sample (n=9652), overall all-cause LTCA and SNF-stay rates were 23.2 and 20.2% for PIM versus 33.8 and 31.4% for QUE, respectively (p<0.05, for each). Hazard ratio (95% CI) for risk of SNF-stay and overall LTCA was 0.78 (0.61, 0.98) and 0.80 (0.66, 0.97), respectively, for PIM versus QUE beneficiaries (p<0.05, for each). Conclusion: The 20% lower risk of LTCA (i.e., greater delay) with PIM versus QUE in this analysis may suggest that PIM should be started early for the treatment of PDP.

Ulotaront, a Trace Amine-Associated Receptor 1/Serotonin 5-HT1A Agonist, in Patients With Parkinson Disease Psychosis: A Pilot Study.

Ulotaront (SEP-363856) is a trace amine-associated receptor 1 agonist with 5-HT1A receptor agonist activity currently in phase 3 clinical development for the treatment of schizophrenia. In this exploratory, flexibly dosed study, ulotaront was evaluated for the treatment of Parkinson disease psychosis (PDP). Patients with PDP requiring antipsychotic therapy were randomized, double-blind to ulotaront (25, 50, or 75 mg/d) or placebo. Mixed Model for Repeated Measures was used to assess change from baseline in the Scale for the Assessment of Positive Symptoms for Parkinson Disease (SAPS-PD) at 6 weeks (primary end point). The efficacy analysis sample comprised 38 patients (ulotaront, n = 24; placebo, n = 14). SAPS-PD total scores were numerically reduced in ulotaront-treated vs placebo-treated patients from week 1 to week 6: Least squares mean (95% confidence interval) difference in change from baseline at week 6 was -1.1 (-6.5, 4.3, p = 0.681). PDP symptom complete remission (≥100% improvement [reduction] from baseline in SAPS-PD total score) was observed in 25% of ulotaront-treated vs 0% of placebo-treated patients. SAPS-PD and Neuropsychiatric Inventory hallucinations subscales were numerically reduced vs placebo, and SAPS-PD total scores were reduced in patients with greater cognitive impairment (baseline Mini-Mental State Examination [MMSE] scores ≤24). Ulotaront improved Scales for Outcomes in Parkinson Disease Sleep Scale - Daytime Sleepiness scores (p = 0.022). There was no worsening of Unified Parkinson Disease Rating Scale Part III motor score, MMSE, or vital signs. Adverse events (≥10%) with ulotaront vs placebo included hallucinations (24% vs 14%), confusional state (20% vs 14%), dizziness (16% vs 7%), nausea (12% vs 7%), and falls (12% vs 21%). In this exploratory pilot study, ulotaront may decrease PDP symptoms without worsening motor function, particularly in patients with cognitive impairment. ClinicalTrials.gov identifier: NCT02969369; submitted: November 17, 2016; study start date: December 31, 2016. This Class II study was an exploratory pilot study that was underpowered to detect a statistically significant difference between ulotaront and placebo in the treatment of patients with Parkinson disease psychosis without worsening motor function.

Repurposing Pimavanserin, an Anti-Parkinson Drug for Pancreatic Cancer Therapy

Despite major advances in cancer treatment, pancreatic cancer is still incurable and the treatment outcomes are limited. The aggressive and therapy-resistant nature of pancreatic cancer warrants the need for novel treatment options for pancreatic cancer management. Drug repurposing is emerging as an effectual strategy in the treatment of various diseases, including cancer. In the present study, we evaluated the anticancer effects of pimavanserin tartrate (PVT), an antipsychotic drug used for the treatment of Parkinson disease psychosis. PVT significantly suppressed the proliferation and induced apoptosis in various pancreatic cancer cells and gemcitabine-resistant cells with minimal effects on normal pancreatic epithelial cells and lung fibroblasts. Growth-suppressive and apoptotic effects of PVT were mediated by the inhibition of the Akt/Gli1 signaling axis. The oral administration of PVT suppressed subcutaneous and orthotopic pancreatic tumor xenografts by 51%–77%. The chronic administration of PVT did not demonstrate any general signs of toxicity or change in behavioral activity of mice. Our results indicate that pancreatic tumor growth suppression by PVT was orchestrated by the inhibition of Akt/Gli1 signaling. Since PVT is already available in the clinic with an established safety profile, our results will accelerate its clinical development for the treatment of patients with pancreatic cancer.

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.

Advances in Management of Psychosis in Neurodegenerative Diseases.

Psychosis is broadly defined as a disengagement from reality. It describes syndromes that impair both thought content and thought process. Psychosis negatively impacts an individual's quality of life, in addition to the families caring for them. Psychosis with different types of hallucinations and delusions occurs in the context of delirium. Neuropsychiatric symptoms (NPS) are almost universal in the course of common neurodegenerative disorders (NDD) like Alzheimer's disease (AD) or Parkinson's disease (PD). In this paper, the authors took an effort to characterize AD and PD psychosis with a special focus on the most diagnostically reliable features. Effectiveness and limitations of pharmacological interventions are discussed. Consensus diagnostic criteria have evolved for psychosis secondary to AD as well as psychosis in PD. Psychotropic medications can be effective in the treatment of NPS in NDD; however, clinicians must be mindful of the side effects. There is a consensus on benefit of initiating any acetylcholinesterase inhibitor (ACHI: donepezil, rivastigmine, and galantamine) as a first line of treatment for psychosis in AD, as it may reduce and/or avoid the need for the use antipsychotics. Pimavanserin, a selective-serotonin inverse agonist that preferentially targets 5-HT2A receptors, while avoiding activity at dopamine and other receptors commonly targeted by antipsychotics had recently been approved by FDA to treat hallucinations and delusions in PD. Quetiapine is widely prescribed for the treatment of psychosis in different NDD, but the data remains equivocal. Psychosis with different types of hallucinations and delusions may occur in the context of delirium and is almost universal as a neuropsychiatric symptom in the course of PD and AD. Currently, pimavanserin remains the only pharmacologic agent approved for treatment of psychosis in PD. In cases of other NPS in other than Parkinson's diseases, atypical antipsychotics are commonly used off-label. More research is greatly needed to advance this field and address NPS especially psychosis in geriatric population.

Can pimavanserin help patients with Parkinson disease psychosis?

Pimavanserin is a first-in-class selective serotonin 5-HT2A receptor inverse agonist approved for the treatment of Parkinson disease psychosis. This article discusses pimavanserin's mechanism of action, which patients are appropriate candidates for therapy, adverse reactions, and appropriate dosing.

Mortality in patients with Parkinson disease psychosis receiving pimavanserin and quetiapine.

Parkinson disease (PD) is a complex neurodegenerative disorder. Cognitive dysfunction and psychosis are leading contributors to nursing home placement.1 Psychosis onset is associated with cognitive decline, levodopa supplementation, and visual dysfunction.2 Treatment of PD psychosis (PDP) centers on levodopa dose adjustment, use of second-generation antipsychotics (SGAs), and cholinesterase inhibitors. SGAs function via serotonergic modulation and dopamine receptors blockade. Quetiapine, a structural analogue to clozapine, is often used to treat PDP, although evidence of its efficacy is mixed in randomized controlled trials.3 Furthermore, there is a concern for increased morbidity and mortality with use of quetiapine and other SGAs in patients with dementia or those with PD, prompting a black box warning by the Food and Drug Administration (FDA).4

Pimavanserin use in a movement disorders clinic: a single-center experience.

Parkinson's disease psychosis (PDP) is a disabling non-motor symptom of Parkinson's disease (PD) that is challenging to treat. Dopamine receptor blockers (DRB) are used to treat PDP, though these may be associated with adverse effects, including worsening of Parkinsonism. Pimavanserin, a selective 5-HT2A receptor inverse agonist, was recently FDA-approved for treatment of PDP; however, there is limited information on its long-term use in PDP patients. A retrospective chart review of patients prescribed pimavanserin was performed in August, 2017. Data on demographics, psychotic features, sleep, and adverse effects was collected using a semi-structured telephone interview with patients or caregivers. Hallucination severity (HS) was quantified as mild (< 1 episode/week), moderate (1/week to < 1/day), or severe (daily/continuous). Seventeen patients consented to participate in the study; 16 were diagnosed with PDP, 1 with Lewy body dementia. Fourteen had co-morbid cognitive impairment/dementia. The mean duration of Parkinsonism was 11.8 ± 8.0years, with 2.6 ± 1.9years of psychosis. Eleven of the seventeen patients reported improvement of hallucinations of which 5/8 were initiated on pimavanserin monotherapy, and 6/9 reported improvement of HS with combination of DRB. Six of nine patients prescribed DRB were able to discontinue this medication after introduction of pimavanserin. Four patients discontinued medications (2, no benefit; 1, spontaneous resolution; 1, cost). No major side effects were reported, and two patients noted subjective improvement of sleep. In our series based on a small sample size, pimavanserin is well-tolerated and effective as both monotherapy and adjuvant treatment for moderate to severe. This medication can facilitate reduction or cessation of DRB medication.

Treating Hallucinations and Delusions Associated With Parkinson's Disease Psychosis.

We discuss features of Parkinson's disease psychosis (PDP) including symptomology and pathophysiology. Treatment options, including non-pharmacologic strategies, dose reduction of offending agents, and the addition of non-dopaminergic antipsychotics, are addressed. The efficacy of second-generation antipsychotics and novel agents is examined. Pimavanserin, a 5-HT2A/C receptor inverse agonist with no other receptor activity, has shown efficacy and tolerability and is now FDA approved for PDP treatment. Research into novel targets is ongoing. PDP is a morbid complication of Parkinson's disease with complex incompletely understood mechanisms. Treatment is directed towards mitigation of psychosis without worsening of motor features.

Pimavanserin for the treatment of Parkinson's disease psychosis: number needed to treat, number needed to harm, and likelihood to be helped or harmed.

Our aim was to describe the efficacy and tolerability of pimavanserin, a highly selective serotonin 5-HT2A receptor inverse agonist/antagonist indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (PDP), using the metrics of number needed to treat (NNT) and number needed to harm (NNH). Categorical efficacy and tolerability data were extracted from the clinical trial databases of the double-blind placebo-controlled studies of pimavanserin in persons with PDP. NNT and NNH values were calculated with their respective 95% confidence intervals. The likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response versus discontinuation because of an adverse event. NNT values for pimavanserin 34 mg/d versus placebo for several definitions of clinical response are 10, and/or are not statistically significant, and/or show an advantage for pimavanserin over placebo (such as for postural hypotension). In terms of LHH, pimavanserin 34 mg/d is about five times more likely to result in clinical response (as measured by a ≥3 point decrease from baseline on the Scale for the Assessment of Positive Symptoms adapted for Parkinson's disease) versus discontinuation due to an adverse event. Using the metrics of NNT, NNH, and LHH, pimavanserin 34 mg/d for the treatment of PDP appears to have a compelling benefit/risk profile.

Treatment of psychotic symptoms in patients with Parkinson disease.

Persistent psychotic symptoms will develop in up to 60% of patients with Parkinson disease (PD). The initial approach to the management of PD psychosis (PDP) begins with addressing concurrent systemic conditions associated with psychotic behavior, such as delirium, medical conditions (eg, infections), psychiatric disorders (eg, major depression with psychotic symptoms, mania, schizophrenia), and substance misuse or withdrawal. A review of current medications is recommended, and medications that may trigger psychotic symptoms should be eliminated. If possible, antiparkinson medications should be reduced to the minimum therapeutic dose or discontinued in a sequential manner. Generally, dose reduction or discontinuation of anticholinergics is attempted first, followed by that of monoamine oxidase B inhibitors, amantadine, dopamine agonists, catechol-O-methyltransferase inhibitors, and lastly carbidopa/levodopa. The aim of antiparkinson medication dose reduction is to achieve a balance between improving drug-related psychotic symptoms and not significantly worsening the motor symptoms of PD. If additional measures are needed for chronic PDP treatment, the use of second-generation antipsychotics, such as clozapine, pimavanserin, or quetiapine, must be considered. The first-generation antipsychotics (eg, fluphenazine, haloperidol) are not recommended. In the patient with comorbid dementia, the addition of a cholinesterase inhibitor might also be beneficial for PDP. The choice of agent is based on patient-specific parameters, potential benefit, and side effects.

Pimavanserin (Nuplazid™) for the treatment of Parkinson disease psychosis: A review of the literature.

Introduction:Pimavanserin (Nuplazid™) is an atypical antipsychotic currently indicated for the treatment of hallucinations and delusions associated with Parkinson disease psychosis. The antipsychotic effects of this new agent are believed to occur via selective inverse agonist activity at serotonin 5-HT2a receptors.Methods:Study authors completed a literature review of 2 published randomized controlled trials of pimavanserin for the treatment of Parkinson disease psychosis. The Food and Drug Administration Briefing Document by the Psychopharmacologic Drugs Advisory Committee for the review of pimavanserin dated March 29, 2016, was reviewed for additional information on 2 unpublished trials.Results:Pimavanserin has demonstrated no worsening of motor symptoms of Parkinson disease, but only 1 of 4 trials has shown consistent statistically significant improvements in psychotic symptoms compared with placebo.Discussion:Options for the treatment of Parkinson disease psychosis are limited. The selective receptor profile of pimavanserin offers advantages for tolerability. Further studies are warranted to better provide clinicians and patients with information regarding the clinical utility of this agent.

A Retrospective Study of Pimavanserin Use in a Movement Disorders Clinic.

Pimavanserin, a 5-HT2A inverse agonist, was commercially released in the United States in April 2016 for the treatment of Parkinson disease psychosis. No "naturalistic" treatment results have yet been published. Charts from the movement disorders clinic were reviewed for all patients who received this drug as treatment for psychosis associated with primary parkinsonism due to α-synucleinopathies. Data of 10 patients with idiopathic Parkinson disease, including 1 with a long history of schizophrenia, 4 with dementia with Lewy bodies, and 1 with multiple-system atrophy, were reviewed. There were no adverse events reported. Ten patients improved and continue on the drug, whereas 5 stopped because of lack of benefit.

Pimavanserin: A novel therapeutic option for Parkinson disease psychosis.

In April 2016, the Food and Drug Administration (FDA) approved a first-in-class atypical antipsychotic medication called pimavanserin for the treatment of Parkinson disease psychosis (PDP). We aim to inform readers about its indications, effectiveness, and safety profile. Pimavanserin acts as an inverse agonist at serotonin 5-HT2A receptors and has negligible effects on other receptors, thereby avoiding the D2 receptor antagonism that can potentially worsen motor symptoms. Its FDA approval was based primarily on the results of a single randomized, placebo-controlled phase 3 trial. While pimavanserin appears to be a safe, effective, and well-tolerated therapeutic option for PDP, additional clinical trials and open-label extension studies are needed to determine the long-term safety and efficacy of this promising therapy. In the meantime, prescribers need to be aware of the possible adverse effects of pimavanserin including QT interval prolongation and a potential to cause a paradoxical worsening of symptoms.

Psychosis in Parkinson Disease: A Review of Etiology, Phenomenology, and Management.

Parkinson disease psychosis (PDP) is a common phenomenon in Parkinson disease (PD) patients treated with dopaminergic drugs, and is associated with high morbidity and mortality. It also correlates with depression and dementia, and can contribute to considerable caregiver stress and burnout. While symptoms can be relieved by decreasing doses or number of anti-PD medications, this may lead to an unacceptable worsening of motor function. When general medical or psychiatric conditions have been ruled out, and decreasing dopaminergic agents is not effective in treating psychosis, therapies include atypical antipsychotics, primarily clozapine and quetiapine. Of these, clozapine is effective but is associated with a poor side-effect profile and the necessity for frequent blood draws. Clinicians prefer quetiapine for its theoretically better safety profile, although there is no evidence for efficacy in treating psychosis. All atypical antipsychotics are associated with increased mortality in this patient population. Cholinesterase inhibitors can ameliorate psychosis symptoms. The serotonin 5-HT2A receptor inverse agonist pimavanserin was recently approved by the US FDA for the treatment of PDP and may prove to be a more targeted therapy without the downsides of atypical antipsychotics.

Current Understanding of Psychosis in Parkinson's Disease.

Psychosis in Parkinson's disease (PD) is one of the greatest determinants of nursing home placement and caregiver stress. Traditionally associated with medications with dopaminergic effect, it has now been linked to other medications and other stressors e.g. systemic illnesses. The development of hallucinations in a PD patient can herald the onset of dementia and usually predicts increased mortality risk. Medication reduction in PD psychosis usually reduces the symptoms; however, this comes at the cost of worsening motor function. If gradually decreasing the patient's medications does not resolve the psychosis, the treatment of choice is an atypical antipychotic. Though only clozapine has level A recommendation for this indication, other atypicals like quetiapine continue to get used for this purpose on account of the logistics involved with clozapine use. Cholinesterase inhibitors are also increasingly being used for PD psychosis on account of the association with dementia. The treatment of PD psychosis is an unmet need in PD management and search for suitable agents constitutes an active area of research in PD.

Affective Correlates of Psychosis in Parkinson's Disease.

To examine the nature of the association between affective disorders and psychosis in Parkinson's disease (PD). In PD, psychosis and affective disorders are common and independently impact quality of life and mortality. Both depression and psychosis are correlated with the occurrence of cognitive dysfunction, suggesting that they may share neurobiological substrates. Anxiety has not been examined as a correlate of psychosis. 144 PD subjects were evaluated with the Schedule for Assessment of Positive Symptoms to assess psychotic features, while depression and anxiety were examined by the Structured Clinical Interview for DSM-IV-TR (SCID) and self-assessment scales Beck Depression Inventory II (BDI-II) and Beck Anxiety Inventory (BAI). Correlational analyses assessed associations between hallucinations and delusions with depression and anxiety. A diagnosis of anxiety (SCID) was significantly (p=.015) associated with hallucinations (OR=4.81, CI=1.36-16.99). Severity of anxiety (BAI) significantly predicted (p=.03) the presence of hallucinations (OR=1.08, CI=1.01-1.15) and delusions (OR=1.09, CR=1.01-1.17). Current depression (SCID) was significantly (p=.001) associated with the presence of hallucinations (OR=6.12, CI=2.04-18.39) and delusions (OR=7.14, CI=2.23-22.93). Multiple linear regressions revealed that severity of anxiety remained an independent predictor (p<.05) of both the number of types of hallucinations (t=3.06, p=.003) and delusions (t=2.87, p=.005). Severity of depression was a significant predictor of the total number of delusions (t=2.28, p=.024). This study demonstrates an association between depression and psychosis and, for the first time, an association between anxiety and psychosis. These associations may have implications on pathophysiology and treatment of psychosis in PD.

Serotonin 2A Receptor Inverse Agonist as a Treatment for Parkinson's Disease Psychosis: A Systematic Review and Meta-analysis of Serotonin 2A Receptor Negative Modulators.

There is uncertainty about the efficacy and tolerability of serotonin 2A (5-HT2A) receptor negative modulators for Parkinson's disease psychosis (PDP). This is the first meta-analysis of randomized placebo-controlled trials (RCTs) testing negative modulators of the 5-HT2A receptor as a treatment for PDP. The primary outcome was the Scale for Assessment of Positive Symptoms (SAPS)-hallucinations (H) and -delusions (D) scores (SAPS-H+D). Other outcome measures were SAPS-H, SAPS-D, the Unified Parkinson's Disease Rating Scale Part II and III (UPDRS-II+III), discontinuation rates, and individual adverse events. Four RCTs were identified that met inclusion criteria, all assessing the 5-HT2A inverse agonist pimavanserin (including 417 drug-treated and 263 placebo-treated PDP patients). Pimavanserin significantly decreased SAPS-H+D scores compared to placebo [weighted mean differences (WMD) = -2.26, 95% confidence interval (95% CI) = -3.86 to -0.67, p = 0.005, I2 = 30% , N = 4 studies, n = 502 patients]. Moreover, pimavanserin was superior to placebo for reducing SAPS-H (WMD = -2.15, 95% CI = -3.45 to -0.86, p = 0.001, I2 = 0% , N = 2, n = 237) and SAPS-D scores (WMD = -1.32, 95% CI = -2.32 to -0.32, p = 0.010, I2 = 0% , N = 2, n = 237). Pimavanserin was associated with less orthostatic hypotension than placebo (risk ratio = 0.33, 95% CI = 0.15-0.75, p = 0.008, I2 = 0% , number needed to harm = 17, p = 0.01, N = 3, n = 476). There were no significant differences in rates of all-cause discontinuation, adverse events, and death, UPDRS-II+III scores, and incidences of individual adverse events (other than orthostatic hypotension) between pimavanserin and placebo groups. Pooled RCT results suggest that pimavanserin is beneficial for the treatment of PDP and is well tolerated. We did not identify other negative modulators of the 5-HT2A receptor for the treatment of PDP.

Parkinson's disease and psychoses

Psychotic symptoms are common in Parkinson's disease (PD) and are associated with increased disability, worsened quality of life, and poor long-term prognosis. In this article, clinical features, hypotheses on pathogenesis, and current treatment strategies for Parkinson's disease psychosis (PDP) are reviewed. According to epidemiological studies, the prevalence of PDP is between 20 to 40%. Complex visual hallucinations are the most common psychotic symptoms and are present in 17-72% of the patients. Other sensory disturbances encompass tactile hallucinations and minor hallucinatory phenomena, such as sense of presence and visual illusions. Hallucinations are often accompanied by delusions, whose most frequent themes are persecution and jealousy. The pathophysiology of PDP remains unclear. Different factors have been implicated, including Levo-dopa and dopaminergic medications, neurotransmitter imbalances, neuroanatomic alterations, abnormal visuospatial processes, and genetic predisposition. The first-line strategy in the treatment of persistent and problematic PDP is represented by reduction in anti-PD medications. Second-generation antipsychotics are the treatment of choice, with clozapine being demonstrated as the most effective and tolerable drug for PD patients.

Pimavanserin.

Pimavanserin (ACP-103) is a selective inverse agonist of the 5-hydroxytryptamine 2A (5-HT2A) receptor intended to treat patients with Parkinson's disease psychosis (PDP). Currently there are no FDA-approved medications in the United States for the treatment of PDP, although on September 2, 2014, the United States Food and Drug Administration granted breakthrough therapy status to pimavanserin, highlighting the unmet need for therapeutics in this class. Most antipsychotic medications worsen motor dysfunction due to dopamine antagonism, and all carry a black box warning for an increased risk of mortality in elderly patients with dementia-related psychosis. Data from phase II and phase III clinical trials suggest that pimavanserin is a safe and effective treatment option for PDP. Trial results indicate a significant reduction in hallucinations and delusions in patients with PDP without worsening motor symptoms. Additional studies are ongoing for the treatment of Alzheimer's psychosis, schizophrenia and insomnia. Such promising outcomes warrant a review of the available literature regarding pimavanserin and its use in the treatment of PDP symptoms.