clozapine and pimavanserin

The current comparative efficacy, safety, and acceptability of atypical antipsychotics (AAPs) in treating Parkinson's Disease Psychosis (PDP) are not entirely understood.. To evaluate comparative efficacy, safety, and acceptability of AAPs in patients with PDP.. We conducted a systematic review and a network meta-analysis to compare the efficacy, safety, and acceptability of pimavanserin, quetiapine, olanzapine, clozapine, ziprasidone, and risperidone. We estimated relative standardized mean differences (SMDs) for continuous outcomes and odds ratios (OR) for binary outcomes, with their respective 95% confidence intervals (CIs).. We included 19 unique studies evaluating AAPs in a total of 1,242 persons with PDP. Based on Clinical Global Impression Scale for Severity, pimavanserin (SMD, -4.81; 95% CI, -5.39, -4.24) and clozapine (SMD, -4.25; 95% CI, -5.24, -3.26) significantly improved symptoms compared with placebo. Also, compared to placebo, pimavanserin (OR, 1.16; 95% CI, 1.07, 1.24) significantly improved psychotic symptoms based on Scale for Assessment of Positive Symptoms for Parkinson's Disease Psychosis/Hallucinations and Delusions scores. In comparison to placebo, clozapine (SMD, -0.69; 95% CI, -1.35, -0.02), pimavanserin (SMD, -0.01; 95% CI, -0.56, 0.53), and quetiapine (SMD, 0.00; 95% CI, -0.68, 0.69) did not impair motor function per Unified Parkinson's Disease Rating scale. Based on Mini-Mental State Examination scale, quetiapine (SMD, 0.60; 95% CI, 0.07, 1.14) significantly impaired cognition compared to placebo.. In patients with PDP, pimavanserin and clozapine demonstrated significant improvement in psychosis without affecting motor function. With quetiapine being associated with a significant decline in cognition and despite not impairing motor function, our findings suggest that it should be avoided in patients with PDP and reduced cognitive abilities.

Topics: Antipsychotic Agents; Clozapine; Humans; Network Meta-Analysis; Parkinson Disease; Psychotic Disorders; Quetiapine Fumarate

Psychosis is a common problem for people treated for Parkinson's disease. The syndrome is quite stereotypic, with hallucinations being the most common, followed by delusions. While the hallucinations are usually not very bothersome, the delusions are typically paranoid in nature. Treatment is often, but not always, required.. This article reviews the therapeutic approaches of this syndrome focusing on drug treatments used once contributory factors have been removed. This includes a review of the evidence supporting the use of clozapine and, most recently, pimavanserin, the first drug with antipsychotic efficacy that has no effect on dopamine. Treatment with second generation antipsychotic drugs and cholinesterase inhibitors are also reviewed.. Clozapine and pimavanserin have proven efficacy for Parkinson's disease psychosis (PDP), without impairing motor function. In clozapine's favor are its antipsychotic benefits seen within 1 week and its effectiveness in improving tremor in PD. However, this is counterbalanced by the need for blood monitoring, despite the extremely low doses used, and sedation. Pimanvanserin is well tolerated, without sedation or other significant side effects. Its onset of benefit, however takes 4-6 weeks. While quetiapine is also frequently used, its efficacy is not supported by double blinded, randomized trials.

Topics: Antipsychotic Agents; Clozapine; Dopamine; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Urea

To summarize and evaluate the existing literature regarding medications to treat Parkinson's disease (PD) psychosis.. MEDLINE (1946 to March 2017), EMBASE (1980 to March 2017), CINAHL (1982 to March 2017), and PsychInfo (1887 to March 2017) were searched using the following terms: Parkinson disease, Parkinson's disease, psychotic disorders, psychosis, delusions, and hallucinations.. The search was limited to randomized controlled trials (RCTs) reporting human outcomes. Data extracted included the following: study design, population, setting, intervention, control, outcomes related to psychosis and safety, and potential biases assessed using Cochrane Collaboration's Risk of Bias Assessment Tool.. After assessment, 16 of 235 studies were included; 11 articles reported comparisons between active drug and placebo, whereas 5 compared clozapine and an active comparator. Placebo-controlled trials demonstrated benefit for clozapine (n = 2) and pimavanserin (n = 2), with no firm benefits observed for quetiapine (n = 4) or olanzapine (n = 3). Comparative studies demonstrated improved efficacy in symptom scores when clozapine or comparator agent (n = 2, quetiapine; n = 1, olanzapine; n = 1, risperidone; and n = 1, ziprasidone) was assessed alone. However, no comparator data suggest that one agent is better than another, and none are yet available for pimavanserin. Overall risk of bias across all studies was moderate to high.. Despite lack of rigor in study designs, published data to date suggest that clozapine and pimavanserin should be considered drugs of choice to treat PD psychosis.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Evidence-Based Medicine; Humans; Olanzapine; Parkinson Disease; Piperazines; Piperidines; Practice Guidelines as Topic; Psychotic Disorders; Quetiapine Fumarate; Randomized Controlled Trials as Topic; Risperidone; Thiazoles; Urea

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-HT

Topics: Antipsychotic Agents; Cholinesterase Inhibitors; Clozapine; Humans; Molecular Targeted Therapy; Neurotransmitter Agents; Parkinson Disease; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Urea

Psychosis is a major psychiatric problem that often occurs at the interface of psychiatry and the neurological specialty of movement disorders. Psychotic syndromes are common in treated movement disorder patients, and almost all antipsychotic drugs produce movement disorders. There is little published data on psychosis in movement disorders aside from Parkinson's disease (PD).. In this review, we focus primarily on PD, in which about 30% of treated patients have visual hallucinations and 5-10% have paranoid delusions; dementia with Lewy bodies, a variant of PD in which dementia occurs early and psychotic symptoms are common; Huntington's disease (HD), an inherited disorder that causes behavioral problems, frequently including psychosis; and tardive dyskinesia (TD), a group of movement disorder syndromes caused by antipsychotic drugs. All articles were reviewed in each of the more common movement disorders and indexed in PubMed with keywords including psychosis, psychotic symptoms, antipsychotics, hallucinations and delusions.. Although there are no approved drugs for treating psychotic symptoms in any of the movement disorders, pimavanserin, a 5-HT2A inverse agonist, is thought likely to gain approval in 2015 for treating PD psychosis. We present evidence that clozapine is currently the drug of choice for treating psychosis in patients with parkinsonism; however, blood monitoring requirements make it difficult to use. The choice of treatment of hyperkinetic disorders such as HD and the TD disorders depends on the clinical scenario.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Movement Disorders; Piperidines; Psychotic Disorders; Treatment Outcome; Urea

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.

Topics: Antipsychotic Agents; Clozapine; Female; Humans; Male; Parkinson Disease; Psychotic Disorders

Dementia with Lewy bodies (DLB) is characterized by neurocognitive disorders associated with core clinical features including hallucinations. There is currently no cure but a combination of symptomatic treatments: clozapine is commonly used in DLB-related psychosis. Pimavanserin is a serotonin 5HT-2A receptor inverse agonist that has recently been shown to reduce psychosis related to dementia. Trazodone is a serotonin reuptake inhibitor and a 5-HT2 receptor antagonist: it is effective in the treatment of the frontal syndrome and is commonly used in frontotemporal degeneration.. We describe three patients with DLB, hospitalized in the cognitive-behavioral unit of the University Hospitals of Strasbourg, who presented with major visual hallucinations, delusion, and an orbitofrontal syndrome including disinhibition, agitation, and irritability. The 3 patients were intolerant of low-dose Clozapine (neutropenia for one, somnolence for the other and Pisa syndrome and falls for the last one). We evaluated the Neuropsychiatric Inventory (NPI) before and after the introduction of both treatments.. Given their psychotic and frontal symptoms, we used Pimavanserin and Trazodone simultaneously. After 4 to 6 weeks of treatment, a marked improvement was observed in all 3 patients, with a decrease of the NPI scores from a mean of 88 to 38.. To our knowledge, there is no previously described combination of these two treatments in DLB. A clinical trial combining these two molecules against pervasive behavioral disorders in DLB would be interesting in view of these preliminary results.

Topics: Clozapine; Dementia; Drug Inverse Agonism; Hallucinations; Humans; Lewy Body Disease; Trazodone

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.. 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).. 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.. 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.

Topics: Antipsychotic Agents; Clozapine; Humans; Parkinson Disease; Quetiapine Fumarate; Receptors, Dopamine; Receptors, Serotonin; Retrospective Studies

BACKGROUND Antidopaminergic medications, including antipsychotics, are known to worsen motor and neuropsychiatric symptoms, including cognition and psychosis, in patients with dementia with Lewy body (DLB). The intensity of worsened clinical symptoms may vary and can result in mortality in certain situations. There have been some reports supporting clozapine, quetiapine and pimavanserin use in psychosis control in this population. CASE REPORT We describe the case of 75-year-old man with diagnosis of DLB and the post-treatment outcome with olanzapine for psychosis during hospitalization. He experienced worsened cognitive and motor functions. Discontinuation of olanzapine resulted in resolution of the clinical worsening. Further, re-initiation of Pimavanserin helped treat his hallucinations. He returned back to his baseline during a follow-up visit in the clinic at 1 month after discharge. Further, we incorporated the use of Best Practice Alert (BPA) as a part of the electronic health record (EHR) system to help providers identify patients prone to neuroleptic sensitivity and help select appropriate medications to treat psychosis in this patient population. CONCLUSIONS Administration of antipsychotics in patients with parkinsonism, especially DLB, requires close clinical monitoring and judicious use. Awareness of morbidity and mortality associated with such use is of importance, especially during hospitalization. From our experience, we incorporated use of BPA, which can help providers make judicious choices while treating this patient population. Pimavanserin, which is FDA-approved for psychosis in Parkinson's disease, could be a potential safe and effective treatment option in this patient population.

Topics: Aged; Antipsychotic Agents; Clozapine; Humans; Inpatients; Lewy Body Disease; Male; Olanzapine; Quetiapine Fumarate

Clozapine was the widely accepted gold standard treatment for treatment resistant psychotic symptoms. Clozapine has efficacy of about 50% and some responding patients have to discontinue it due to serious adverse effects. The search for novel agents to use for clozapine-non-responders continues. One such possible agent is the non-dopaminergic antipsychotic pimavanserin, an inverse agonist of serotonin 5-HT2A receptors which was recently approved for the hallucinations and delusions of Parkinson's Disease Psychosis. We report here the successful results of using pimavanserin in patients with refractory hallucinations and delusions who failed to respond to clozapine. We also report similar results in refractory psychosis patients who did not receive clozapine.. We present ten cases of patients with schizophrenia and schizoaffective disorder with refractory hallucinations and delusions who received a trial of pimavanserin when clozapine or multiple antipsychotics failed. Six of ten patients had not responded to a clozapine trial. The subjects' ages ranged between 21 and 77 years and were followed up for several months.. All 10 patients with refractory hallucinations and delusions showed marked response to pimavanserin 34 mg/day within 4-8 weeks, with continuation of the response for several months of follow-up. Improvements in negative symptoms and social functioning were also observed in several patients.. This series of 10 cases of patients with refractory psychosis who responded to pimavanserin is an important new finding that has never been reported before. Controlled studies comparing clozapine and pimavanserin in refractory schizophrenia are warranted to confirm these clinical observations.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Delusions; Drug Resistance; Female; Hallucinations; Humans; Male; Middle Aged; Piperidines; Psychotic Disorders; Retrospective Studies; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Urea; Young Adult

Psychotic disorders in Parkinson's disease (PDPD) are common and significantly influence the quality of life and disability level. The pathogenesis of PDPD is complex and not yet fully understood. Taking into consideration the features of the Parkinson's disease (usually older patients with a risk of cognitive decline), and the pharmacodynamics of the antiparkinsonian and traditional antipsychotic drugs, the management of PDPD is a challenging issue of clinical neurology and psychiatry. In this systematic review, scientific publications for the period 2014-2016 were analyzed within two bibliographic databases: MEDLINE/PubMed and eLIBRARY.RU. Additionally, the guidelines of the International Parkinson and Movement Disorders Society, American Academy of Neurology and European Academy of Neurology were included in the analysis. Clozapine is recommended to use in the treatment of PDPD, quetiapine is possible to use, pimavanserin will probably become a remedy of choice. Nonpharmacological approaches have positive effects on the general condition of the patients with PDPD, however the efficacy of such approaches to treat psychosis is unclear.. Психотические расстройства при болезни Паркинсона (ПРБП) отмечаются у большого числа пациентов. Они оказывают значительное влияние на качество жизни и уровень инвалидизации. Патогенез ПРБП является сложным и до конца не изученным. Принимая во внимание специфику БП (как правило, пациенты пожилого возраста с риском появления когнитивных нарушений), а также фармакодинамические особенности антипаркинсонических и классических антипсихотических средств, лечение ПРБП требует особого внимания неврологов и психиатров. Представлен систематический обзор, в котором обобщены результаты научных публикаций за период 2014-2016 гг. в двух библиографических базах данных: MEDLINE/PubMed и eLIBRARY.RU, а также клинических рекомендаций Международного общества болезни Паркинсона и нарушений движения, Американской и Европейской академий неврологии. Из антипсихотических средств клозапин является препаратом, рекомендованным к применению, кветиапин - препарат, который признается возможным к применению, пимавансерин, вероятно, станет одним из препаратов выбора в терапии ПРБП. Нефармакологические методы лечения оказывают положительный эффект в плане улучшения общего состояния пациентов с ПРБП, однако их эффективность по лечению собственно ПРБП остается неясной.

Topics: Antiparkinson Agents; Antipsychotic Agents; Clozapine; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Quality of Life; Quetiapine Fumarate; Urea

No safe, tolerated, and effective treatment for Parkinson's disease psychosis (PDP) is available; however, clozapine and quetiapine are often used off-label. An ideal PDP drug should have a therapeutic window that alleviates psychotic symptoms at doses that allow for maintained motor control and do not cause sedation. The present study determined the effective doses of quetiapine, clozapine, and the nondopaminergic, selective 5-HT2A inverse agonist/antagonist, pimavanserin, in an animal model of PDP and compared them with the doses that caused dopamine blockade and sedation. Augmented amphetamine-induced locomotion in rats with bilateral substantia nigra lesions was used to assess antipsychotic efficacy, whereas blockade of apomorphine-induced rotations in rats with unilateral 6-hydroxydopamine lesions was used to assess antidopaminergic action and reduction in spontaneous locomotion was used to assess sedation. The estimated therapeutic ratios for clozapine and quetiapine varied between 0.81 and 3.3. In contrast, the estimated therapeutic ratios for pimavanserin were at or above 170. These results suggest that a selective 5-HT2A inverse agonist/antagonist, such as pimavanserin, may provide distinct advantages compared with clozapine or quetiapine as a therapy for PDP.

Topics: Amphetamine; Animals; Antiparkinson Agents; Antipsychotic Agents; Apomorphine; Clozapine; Dopamine; Dose-Response Relationship, Drug; Male; Parkinsonian Disorders; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Urea

The in vitro and in vivo pharmacological properties of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103) are presented. A potent 5-hydroxytryptamine (5-HT)(2A) receptor inverse agonist ACP-103 competitively antagonized the binding of [(3)H]ketanserin to heterologously expressed human 5-HT(2A) receptors with a mean pK(i) of 9.3 in membranes and 9.70 in whole cells. ACP-103 displayed potent inverse agonist activity in the cell-based functional assay receptor selection and amplification technology (R-SAT), with a mean pIC(50) of 8.7. ACP-103 demonstrated lesser affinity (mean pK(i) of 8.80 in membranes and 8.00 in whole cells, as determined by radioligand binding) and potency as an inverse agonist (mean pIC(50) 7.1 in R-SAT) at human 5-HT(2C) receptors, and lacked affinity and functional activity at 5-HT(2B) receptors, dopamine D(2) receptors, and other human monoaminergic receptors. Behaviorally, ACP-103 attenuated head-twitch behavior (3 mg/kg p.o.), and prepulse inhibition deficits (1-10 mg/kg s.c.) induced by the 5-HT(2A) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride in rats and reduced the hyperactivity induced in mice by the N-methyl-d-aspartate receptor noncompetitive antagonist 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate; MK-801) (0.1 and 0.3 mg/kg s.c.; 3 mg/kg p.o.), consistent with a 5-HT(2A) receptor mechanism of action in vivo and antipsychotic-like efficacy. ACP-103 demonstrated >42.6% oral bioavailability in rats. Thus, ACP-103 is a potent, efficacious, orally active 5-HT(2A) receptor inverse agonist with a behavioral pharmacological profile consistent with utility as an antipsychotic agent.

Topics: Animals; Behavior, Animal; Biological Availability; Cloning, Molecular; Humans; Male; Mice; NIH 3T3 Cells; Piperidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Urea