piperidines and Psychotic-Disorders

Dementia due to Parkinson's disease and Alzheimer's disease are associated with behavioural and psychological symptoms, including psychosis. Long-term management presents a challenge for health care providers and caregivers. Symptoms of psychosis include hallucinations and delusions; if untreated, these can lead to institutionalisation, decreased quality of life, and significant patient and caregiver distress. A critical step in the effective management of dementia-related psychosis (DRP) is the identification and diagnosis of affected patients. The lack of a standardised diagnostic approach presents a barrier to treatment and there are no consensus guidelines for DRP. Furthermore, there are no approved therapies for the treatment of DRP. Antipsychotic medications are often prescribed off-label, even though some are associated with an increased risk of adverse events or mortality. We present currently available screening tools and guidelines for the diagnosis and treatment of Parkinson's disease psychosis and DRP in the context of what is needed for effective management of psychosis.KEY POINTSWe present currently available screening tools and guidelines for Parkinson's disease psychosis and dementia-related psychosis, and discuss the unmet need for simple clinical diagnostic tools and treatment guidelines.The identification of psychosis is variable across different settings and specialties, without a unified approach to screening, definition, or diagnosis.Currently used tools for defining and assessing psychosis in a research setting are usually too cumbersome for everyday clinical practice.The development of a standardised set of diagnostic criteria would provide clinicians the opportunity to improve the detection, treatment, and quality of life of patients and their caregivers.

Topics: Alzheimer Disease; Antipsychotic Agents; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Quality of Life; Urea

Dementia-related psychosis (DRP) is prevalent across dementias and typically manifests as delusions and/or hallucinations. The mechanisms underlying psychosis in dementia are unknown; however, neurobiological and pharmacological evidence has implicated multiple signaling pathways and brain regions. Despite differences in dementia pathology, the neurobiology underlying psychosis appears to involve dysregulation of a cortical and limbic pathway involving serotonergic, gamma-aminobutyric acid ergic, glutamatergic, and dopaminergic signaling. Thus, an imbalance in cortical and mesolimbic excitatory tone may drive symptoms of psychosis. Delusions and hallucinations may result from (1) hyperactivation of pyramidal neurons within the visual cortex, causing visual hallucinations and (2) hyperactivation of the mesolimbic pathway, causing both delusions and hallucinations. Modulation of the 5-HT2A receptor may mitigate hyperactivity at both psychosis-associated pathways. Pimavanserin, an atypical antipsychotic, is a selective serotonin inverse agonist/antagonist at 5-HT2A receptors. Pimavanserin may prove beneficial in treating the hallucinations and delusions of DRP without worsening cognitive or motor function.

Topics: Dementia; Hallucinations; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

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.

Topics: Antipsychotic Agents; Humans; Lewy Body Disease; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Behavioral and psychological symptoms of dementia are symptoms of disturbed perception, mood, behavior, and thought content that occurred frequently. These symptoms, which include apathy, depression, anxiety, psychosis, agitation, and aggression, can serve as predictors of and early clinical diagnostic markers for Alzheimer's disease (AD) and are common precipitants of institutional care. Agitation and psychosis are associated with accelerated disease progression and increased tau phosphorylation in patients with AD. Current guidelines recommend the use of second-generation antipsychotics for the treatment of agitation and psychosis in AD, but only after first-line non-pharmacological interventions and for no longer than 12 weeks because long-term use of these drugs is associated with an increased risk of mortality and an increased frequency of cerebrovascular events. Therefore, new antipsychotic drugs with improved efficacy and safety are needed as an alternative to current antipsychotic drugs. In this report, we discuss some of the most relevant advances in the field of agitation and psychosis in AD and focus on the recent positive clinical evidence observed with two new antipsychotics drugs: brexpiprazole and pimavanserin. Brexpiprazole is a receptor partial agonist (D2, D3, 5-HT1A), receptor antagonist (5-HT2A/B, α1B/α2C) according to the neuroscience-based nomenclature. Two recent phase III clinical trials have shown that brexpiprazole 2 mg/day is effective for the treatment of agitation in patients with AD and has an improved tolerability and safety profile compared with currently available second-generation antipsychotics. Pimavanserin is a receptor antagonist (5-HT2A, 5-HT2C) that has been given market authorization for psychosis occurring in Parkinson's disease. Recent phase II studies suggest that this drug is effective in AD patients with more severe psychosis, although further long-term studies are needed to better define the efficacy and long-term safety profile of pimavanserin for the treatment of psychosis in AD.

Topics: Alzheimer Disease; Antipsychotic Agents; Anxiety; Humans; Piperidines; Psychotic Disorders; Quinolones; Thiophenes; Urea

Topics: Animals; Antipsychotic Agents; Delusions; Hallucinations; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

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.

Topics: Clinical Trials as Topic; Humans; Numbers Needed To Treat; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Urea

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-HT

Topics: Antipsychotic Agents; Delusions; Hallucinations; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Urea

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

Psychosis is common across dementia types with a prevalence of 20% to 70%. Currently, no pharmacologic treatment is approved for dementia-related psychosis. Atypical antipsychotics are frequently used to treat these disorders, despite significant safety concerns. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved in the U.S. for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Patients in the pimavanserin group experienced a significant (p=0.001) improvement in Scale for the Assessment of Positive Symptoms - Parkinson's disease (SAPS-PD) scores vs. placebo. In a subgroup analysis of patients with cognitive impairment (MMSE score ≥21 but ≤24), the observed improvement on the SAPS-PD with pimavanserin (N=50) was also significant (p=0.002) and larger than in the overall study population without an adverse effect on cognition. In a Phase 2 study with pimavanserin in Alzheimer's disease psychosis, pimavanserin significantly (p=0.045) improved psychosis at Week 6 vs. placebo on the NPI-NH Psychosis Score (PS). In a prespecified subgroup of patients with a baseline NPI-NH PS ≥12, a substantively larger treatment effect (p=0.011) was observed vs. participants with NPI-NH PS <12. The results of these studies in cognitively impaired patients with PDP provided the scientific foundation for an ongoing study of pimavanserin for treating patients with dementia-related psychosis associated with the most common neurodegenerative disorders. The study uses a relapse-prevention design with the endpoint of time-to-relapse of psychosis to evaluate the long-term efficacy and safety of pimavanserin as a potential treatment for hallucinations and delusions of dementia-related psychosis.

Topics: Alzheimer Disease; Clinical Trials as Topic; Dementia; Humans; Mental Status and Dementia Tests; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Severity of Illness Index; Treatment Outcome; Urea

Patients with Parkinson's disease psychosis (PDP) are often treated with an atypical antipsychotic, especially quetiapine or clozapine, but side effects, lack of sufficient efficacy, or both may motivate a switch to pimavanserin, the first medication approved for management of PDP. How best to implement a switch to pimavanserin has not been clear, as there are no controlled trials or case series in the literature to provide guidance. An abrupt switch may interrupt partially effective treatment or potentially trigger rebound effects from antipsychotic withdrawal, whereas cross-taper involves potential drug interactions. A panel of experts drew from published data, their experience treating PDP, lessons from switching antipsychotic drugs in other populations, and the pharmacology of the relevant drugs, to establish consensus recommendations. The panel concluded that patients with PDP can be safely and effectively switched from atypical antipsychotics used off label in PDP to the recently approved pimavanserin by considering each agent's pharmacokinetics and pharmacodynamics, receptor interactions, and the clinical reason for switching (efficacy or adverse events). Final recommendations are that such a switch should aim to maintain adequate 5-HT2A antagonism during the switch, thus providing a stable transition so that efficacy is maintained. Specifically, the consensus recommendation is to add pimavanserin at the full recommended daily dose (34 mg) for 2-6 weeks in most patients before beginning to taper and discontinue quetiapine or clozapine over several days to weeks. Further details are provided for this recommendation, as well as for special clinical circumstances where switching may need to proceed more rapidly.

Topics: Antiparkinson Agents; Antipsychotic Agents; Consensus; Drug Substitution; Humans; Off-Label Use; Parkinson Disease; Piperidines; Practice Guidelines as Topic; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Urea

To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of pimavanserin for the treatment of hallucinations and delusions of Parkinson's disease psychosis (PDP).. A comprehensive PubMed search (1966 to January 2017) was conducted using the search terms Parkinson's disease psychosis, hallucinations, delusions, pimavanserin, and ACP-103. Additional data were obtained from references of identified articles, governmental sources, manufacturer product labeling and website, and Clinicaltrials.gov.. All English-language trials evaluating pimavanserin in PDP were included. Data from review articles were included if relevant to clinical practice. One phase II and 3 phase III trials are discussed.. Pimavanserin was approved in April 2016 for the treatment of delusions and hallucinations of PDP. One phase II and 2 phase III trials reported no difference for primary outcomes when pimavanserin was compared with placebo. The pivotal phase III ACP-103-020 trial adapted a scale to target more specific symptoms prevalent in PDP and showed that least-squares mean differences of the total PD-adapted Scale for the Assessment of Positive Symptoms score were significantly improved for pimavanserin-treated patients as compared with placebo-treated patients (difference = -3.06; 95% CI [-4.91 to -1.20]; P = 0.0014]). Pimavanserin's adverse effect profile includes urinary tract infections, falls, peripheral edema, hallucinations, confusion, nausea, and headaches.. Pimavanserin is a novel 5-HT

Topics: Antiparkinson Agents; Antipsychotic Agents; Delusions; Hallucinations; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; 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

A panel of experts drawn from neurology, psychiatry, geropsychiatry, geriatrics, and pharmacy representatives of 3 health plans convened in New York City on July 30, 2016, with the objective of sharing opinions, ideas, and information regarding the optimal management of Parkinson's disease psychosis (PDP). Three key points emerged from the discussion: (1) Because of the nature of Parkinson's disease and PDP, finding appropriate treatment can prove challenging; (2) emerging therapies may present an opportunity for effective disease management; and (3) moving forward, provider and patient education regarding PDP and available treatment options is essential for well-managed symptoms and better quality of life. The panel reviewed current practices and formulated recommendations on moving forward in the treatment of PDP.. This project and manuscript was funded by ACADIA Pharmaceuticals and developed by Magellan Rx Management. Lopes and Farnum are employees of Magellan Rx Management. Kremens has received consulting/speaker fees from Teva Pharmaceuticals, UCB, Sunovion, Impax, Lundbeck, ACADIA, USWorldMeds, Merz, Acorda, Kyowa, Neurocrine, and GE Healthcare. Pagan reports consulting/speaker fees from Teva Nanoscience, AbbVie, Impax, ACADIA, Medtronic, USWorldMeds, Merz, and Cynapsus and research and educational grants from USWorldMeds, Teva, and Medtronic. Patel has received consultant/speaker fees from ACADIA, Allergen, and Avanir. Alva reports research support from Accera, Allergan, Axovant, Eisai, Neurotrope, Genentech, Intra Cellular, Janssen, Lundbeck, Neurim, Novartis, Otsuka, Roche, Suven, and Trans Tech and consultant/speaker fees from ACADIA, Alkermes, Allergan, Avanir, Janssen, Lundbeck, Merck, Nestle, Otsuka, Sunovion, Takeda, and Vanda. The other authors report no potential conflicts of interest, financial or otherwise.

Topics: Animals; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Quality of Life; Urea

Parkinson's disease (PD) is a progressive neurodegenerative disease associated with a decrease in the neurotransmitter dopamine and characterized by the cardinal motor hallmarks of resting tremor, rigidity, bradykinesia/akinesia, and postural instability. Lesser-known features of PD revolve around nonmotor concerns including psychosis, dementia, sleep disturbances, autonomic dysfunction, and sensory abnormalities. Parkinson's disease psychosis (PDP) contributes significantly to morbidity, mortality, nursing home placement, and quality of life (QOL). PDP management suffers from a lack of safe, effective pharmacological agents and the opposing nature of atypical antipsychotics and dopaminergic therapies. Pimavanserin, the only atypical antipsychotic currently approved by the FDA for treating PDP-related hallucinations and delusions, has no appreciable affinity for dopaminergic receptors, and a controlled clinical study demonstrated its efficacy in treating PDP-associated hallucinations and delusions without affecting motor function. A recent analysis of all health resource utilization (HRU) and total costs attributable to PD and PDP found that mean 12-month HRU services per patient were 2.3 times higher and costs were 2.1 times higher in the PDP cases, while falls were 3.4 times higher and fractures 2.3 times higher, respectively. Products or services that prevent, delay, or lessen the severity of PDP may contribute to reduced healthcare system costs and improve the QOL of patients with PDP and of their caregivers.

Topics: Antipsychotic Agents; Cost of Illness; Health Care Costs; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Parkinson's disease psychosis (PDP) may develop in up to 60% of Parkinson's patients and is associated with increased morbidity and mortality. It also correlates with depression and dementia, and can contribute to caregiver stress and burnout. Pimavanserin is the first FDA approved drug for the treatment of hallucinations and delusions associated with PDP. Areas covered: For this review, a MEDLINE literature search (via PubMed) and information provided by ACADIA Pharmaceuticals were used. This review will discuss the pathophysiology and current management of PDP. In addition, this review will focus on the rationales behind the development of pimavanserin, mechanism of action, pharmacokinetics, pharmacodynamics, and the clinical trials evaluating the efficacy and safety of pimavanserin. Last, the review will address the drug's package insert warning. Expert commentary: Pimavanserin, a 5HT2A receptor inverse agonist, is the first FDA approved drug for the treatment of PDP which has been shown to reduce psychosis in PD through its unique mechanism of action. Pimavanserin, does not worsen PD motor symptoms and has an acceptable safety profile. The development of pimavanserin as an antipsychotic opened a new therapeutic avenue in the treatment of PDP as well as targeting psychosis in other disorders such as Alzheimer's disease.

Topics: Antipsychotic Agents; Delusions; Drug Inverse Agonism; Hallucinations; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Urea

Alzheimer's disease (AD) is a progressive condition that affects cognition, function, and behavior. Approximately 60-90% of patients with AD develop neuropsychiatric symptoms (NPS) such as hallucinations, delusions, agitation/aggression, dysphoria/depression, anxiety, irritability, disinhibition, euphoria, apathy, aberrant motor behavior, sleep disturbances, appetite and eating changes, or altered sexual behavior. These noncognitive behavior changes are thought to result from anatomical and biochemical changes within the brain, and have been linked, in part, to cholinergic deficiency. Cholinesterase inhibitors may reduce the emergence of NPS and have a role in their treatment. These agents may delay initiation of, or reduce the need for, other drugs such as antipsychotics. This article summarizes the effects of donepezil, a cholinesterase inhibitor, on the NPS of dementia with emphasis on AD and dementia with Lewy bodies.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Lewy Body Disease; Piperidines; Psychotic Disorders

Acetylcholinesterase inhibitors (AceI) and memantine might prove useful in bipolar disorder (BD) given their neuroprotective and pro-cognitive effects, as highlighted by several case reports. We aimed to systematically review the efficacy and safety of AceI and memantine across multiple outcome dimensions in BD.. Systematic PubMed and SCOPUS search until 04/17/2015 without language restrictions. Included were randomized controlled trials (RCTs), open label studies and case series of AceI or memantine in BD patients reporting quantitative data on depression, mania, psychotic symptoms, global functioning, or cognitive performance. We summarized results using a best-evidence based synthesis.. Out of 214 hits, 12 studies (RCTs=5, other designs=7, total n=422) were included. Donepezil (studies=5; treated=102 vs. placebo=21): there was strong evidence for no effect on mania and psychotic symptoms; low evidence indicating no effect on depression. Galantamine (studies=3; treated=21 vs. controls=20) (placebo=10, healthy subjects=10): there was strong evidence for no effect on mania; moderate evidence for no effect on depression; low evidence for no effect on global functioning. Memantine (studies=4; treated=152 vs. placebo=88): there was conflicting evidence regarding efficacy for mania, depression and global functioning.. Paucity of RCTs; small sample size studies; heterogeneous design, outcome and patient characteristics.. There is limited but converging evidence of no effect of AceI in BD, and conflicting evidence about memantine in BD. Too few studies of mostly medium/low quality and lacking sufficient numbers of patients in specific mood states, especially mania, contributed data, focusing solely on short-term/medium-term treatment, necessitating additional high-quality research to yield more definite results.

Topics: Adult; Bipolar Disorder; Case-Control Studies; Cholinesterase Inhibitors; Clinical Trials as Topic; Depression; Depressive Disorder; Donepezil; Evidence-Based Medicine; Excitatory Amino Acid Antagonists; Female; Galantamine; Humans; Indans; Male; Memantine; Middle Aged; Piperidines; Psychotic Disorders; Randomized Controlled Trials as Topic; Treatment Outcome

Parkinson´s disease (PD) is a synucleinopathy that affects millions of people worldwide and leads to progressive disability. Psychosis is highly prevalent in PD patients and is associated with poor prognosis. Until April 2016, there were no licensed drugs available in the United States of America (USA) for the treatment of PD psychosis (PDP). Pimavanserin is the first Food and Drug Administration approved medicine for the treatment of hallucinations and delusions associated with PDP.. A MEDLINE literature search, publicly available information provided by ACADIA Pharmaceuticals, and expert opinion were used for this review. A review of PDP, its current treatment and limitations is followed by the rationale for development of pimavanserin. The mechanism of action, preclinical data, pharmacokinetics, pharmacodynamics, and clinical data supporting the efficacy and safety of pimavanserin in PDP are reviewed. We also describe the potential benefits of pimavanserin in other contexts such as schizophrenia and sleep disorders.. Pimavanserin is an antipsychotic with a unique mechanism of action (5-HT2A receptor inverse agonist) and no measurable dopaminergic activity; it has been demonstrated to be efficacious, well tolerated and safe for the treatment of PDP. The development of pimavanserin as an antipsychotic represents a major breakthrough in the pharmacotherapy of psychotic symptoms associated with PD.

Topics: Antipsychotic Agents; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Urea

Dopamine depletion is one of the most important features of Parkinson's Disease (PD). However, insufficient response to dopaminergic replacement therapy suggests the involvement of other neurotransmitter systems in the pathophysiology of PD. Cholinergic degeneration contributes to gait impairments, cognitive impairment, psychosis, and REM-sleep disturbances, among other symptoms. Areas covered: In this review, we explore the idea that enhancing cholinergic tone by pharmacological or neurosurgical procedures could be a first-line therapeutic strategy for the treatment of symptoms derived from cholinergic degeneration in PD. Expert opinion: Rivastigmine, a drug that increases cholinergic tone by inhibiting the enzyme cholinesterase, is effective for dementia, whereas the use of Donepezil is still in the realm of investigation. Interesting results suggest the efficacy of these drugs in the treatment of gait dysfunction. Evidence on the clinical effects of these drugs for psychosis and REM-sleep disturbances is still weak. Stimulation of the pedunculo-pontine tegmental nuclei (which provide cholinergic innervation to the brain stem and subcortical nuclei) has also been used with some success for the treatment of gait dysfunction. Anticholinergic drugs should be used with caution in PD, as they may aggravate cholinergic symptoms. Notwithstanding, in some patients they might help control parkinsonian motor symptoms.

Topics: Animals; Cholinergic Agents; Cholinergic Neurons; Clinical Trials as Topic; Cognition Disorders; Dementia; Donepezil; Gait; Humans; Indans; Nerve Degeneration; Parkinson Disease; Piperidines; Psychotic Disorders

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

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.

Topics: Animals; Clinical Trials as Topic; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Urea

Parkinson's disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson's patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT2A receptor inverse agonist, selectivity for 5-HT2A over 5-HT2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician's clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson's disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.

Topics: Drug Discovery; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; 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

Insufficient treatment of psychosis often manifests as violent and aggressive behaviors that are dangerous to the patient and others, and that warrant treatment strategies which are not considered first-line, evidence-based practices. Such treatment strategies include both antipsychotic polypharmacy (simultaneous use of 2 antipsychotics) and high-dose antipsychotic monotherapy. Here we discuss the hypothesized neurobiological substrates of various types of violence and aggression, as well as providing arguments for the use of antipsychotic polypharmacy and high-dose monotherapy to target dysfunctional neurocircuitry in the subpopulation of patients that is treatment-resistant, violent, and aggressive. In this review, we focus primarily on the data supporting the use of second-generation, atypical antipsychotics both at high doses and in combination with other antipsychotics.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Brain; Clozapine; Dibenzocycloheptenes; Drug Therapy, Combination; Heterocyclic Compounds, 4 or More Rings; Humans; Impulsive Behavior; Isoxazoles; Lurasidone Hydrochloride; Olanzapine; Paliperidone Palmitate; Piperazines; Piperidines; Polypharmacy; Psychotic Disorders; Quetiapine Fumarate; Receptors, Dopamine D2; Risperidone; Thiazoles; Violence

Parkinson's disease (PD) is a neurobehavioral disorder defined by its motor features. Its treatment is frequently complicated by the presence of psychotic symptoms, most prominently hallucinations and delusions. These cause major distress and are the primary cause for nursing home placement. Current treatment requires either a reduction in medications for mobility or the addition of atypical antipsychotics, none of which are approved in the United States, and which are associated with major potential drawbacks.. Information from extensive personal experience, a Pubmed literature search plus a direct request to Acadia Pharmaceuticals was used for this review. A brief review of the clinical problem and its current state of treatment will be followed by a discussion of pimavanserin and its potential role in treating PD psychosis (PDP). Several observations have implicated serotonin in the physiology of psychotic symptoms. Lysergic acid diethylamide, phencyclidine, and similar drugs that activate 5HT2A serotonin receptors produce psychotic syndromes, and almost all antipsychotic neuroleptics share the property of blocking the 5HT2A receptor as well as the dopamine D2 receptor. The reduced motor side effects of the second-generation antipsychotics have been ascribed to these drugs having greater 5HT2A antagonism than the first generation. Studies in animal models of psychosis have suggested benefits from drugs blocking the 5HT2A receptor alone without the motor side effects seen with D2 receptor antagonism.. Pimavanserin, a 5HT2A inverse agonist, has no motor side effects, and a remarkable safety profile that is comparable to placebo. Its antipsychotic effects coupled with its lack of motor side effects could make it an ideal drug for treating psychotic symptoms in PD, a major unmet need. One Phase III trial in PDP has demonstrated excellent tolerability and significant benefit. The FDA agreed to the filing of a planned new drug approval (NDA) for an indication in the treatment of PDP.

Topics: Animals; Antiparkinson Agents; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Treatment Outcome; Urea

Antipsychotic medication remains the mainstay of treatment for schizophrenia and has been in use for a long time. As evidenced by ongoing research and partial effectiveness of the antipsychotics on cognitive and negative symptoms, the search is on for drugs that may improve these domains of functioning for someone suffering from schizophrenia. Acetylcholinesterase inhibitors have long been in use for treating cognitive symptoms of dementia.. The aim of the review was to evaluate the clinical effects, safety and cost effectiveness of acetylcholinesterase inhibitors for treating people with schizophrenia. We searched the Cochrane Schizophrenia Group's Register (February 2009), and inspected the references of all identified studies for further trials.. We included all clinical randomised trials comparing acetylcholinesterase inhibitors with antipsychotics or placebo either alone, or in combination, for schizophrenia and schizophrenia-like psychoses.. We extracted data independently. For dichotomous data, we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat (ITT) basis based on a random-effects model. For continuous data, we calculated mean differences (MD), again based on a random-effects model.. The acetylcholinesterase inhibitor plus antipsychotic showed benefit over antipsychotic and placebo in the following outcomes.1. Mental state - PANSS negative symptoms average end point score (2 RCTs, n = 31, MD -1.69 95% CI -2.80 to -0.57), PANSS General Psychopathology average end point score (2 RCTs, n = 31, MD -3.86 95% CI -5.40 to -2.32), and improvement in depressive symptoms showed at least by one short-term study as measured by CDSS scale (data skewed).2. Cognitive domains - attention, (1 RCT, n = 73, MD 1.20 95% CI 0.14 to 2.26), visual memory (2 RCTs, n = 48 , MD 1.90 95% CI 0.52 to 3.28), verbal memory and language (3 RCTs, n = 42, MD 3.46 95% CI 0.67 to 6.26) and executive functioning (1 RCT, n = 24, MD 17.10 95% CI 0.70 to 33.50).3. Tolerability - EPSE: AIMS, (1 RCT, n = 35, MD 1.50 95% CI 1.04 to 1.96).No difference was noted between the two arms in other outcomes. The overall rate of participants leaving studies early was low (13.6 %) and showed no clear difference between the two groups.. The results seem to favour the use of acetylcholinesterase inhibitors in combination with antipsychotics on a few domains of mental state and cognition, but because of the various limitations in the studies as mentioned in the main text, the evidence is weak. This review highlights the need for large, independent, well designed, conducted and reported pragmatic randomised studies.

Topics: Antipsychotic Agents; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Psychotic Disorders; Randomized Controlled Trials as Topic; Rivastigmine; Schizophrenia; Schizophrenic Psychology

Akathisa is one of the most common and distressing neuroleptic-induced extrapyramidal side effects. Although it is well recognized in the context of conventional antipsychotic medications, there have been recent concerns raised by clinicians and researchers that this syndrome is overlooked in relation to second-generation or atypical antipsychotics. This review examines the recent literature relevant to second-generation antipsychotic (SGA)-induced akathisia.. Recent studies using large databases clearly indicate that extrapyramidal side effects, in particular akathisia, do occur with the SGAs, although the frequency is not as high as with the conventional antipsychotics. Risk factors include use of high doses, high potency SGAs, or combinations of SGAs with other psychotropic drugs, bipolar depression, palliative care settings, and comorbid substance abuse in psychosis. The dopamine hypothesis remains plausible for understanding the pathophysiology of akathisia. There is emerging evidence that mirtazapine may be useful in the treatment of acute akathisia.. Even though akathisia is less prevalent with SGAs than with the first-generation drugs, it remains clinically important and all clinicians should be conversant with its recognition and management.

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Isoxazoles; Olanzapine; Piperazines; Piperidines; Prevalence; Psychomotor Agitation; Psychotic Disorders; Quetiapine Fumarate; Quinolones; Risk Factors; Risperidone; Sulpiride; Thiazoles

Iloperidone, a mixed D2/5-HT2 antagonist, is currently in clinical development for the treatment of schizophrenia. This article assesses the short-term safety of iloperidone using a pooled analysis of 3 phase 2, short-term acute schizophrenia studies conducted between 1998 and 2002 (N = 1943). Patients exposed to 3 dose ranges of iloperidone, another antipsychotic, or placebo were compared on rates of serious adverse events (SAEs), adverse events (AEs), extrapyramidal symptoms, akathisia, prolactin, weight and metabolic parameters, QTc, and other standard safety parameters. The most common treatment-related AEs observed with iloperidone were dizziness, headache, dry mouth, nausea, and insomnia. Discontinuation due to AEs was 4.8% for iloperidone, 7.6% for haloperidol, 6.2% for risperidone, and 4.8% for placebo. Iloperidone groups showed better overall performance on the Extrapyramidal Symptom Rating Scale and Barnes Akathisia Scale than risperidone or haloperidol groups. Patients taking iloperidone experienced a mild weight increase (range, 1.5-2.1 kg) similar to that of risperidone (1.5 kg), whereas those on haloperidol and placebo showed mean weight loss (-0.1 kg and -0.3 kg, respectively). QTc interval significantly increased across all iloperidone groups (least squares mean change from baseline to end point, 2.9-9.1 msec) and for haloperidol (5.0 msec). No significant QTc changes occurred in the risperidone or placebo groups. Iloperidone was associated with no change from baseline in total cholesterol, mild elevation in serum glucose, and slight decrease in triglycerides. Prolactin levels decreased with iloperidone and increased significantly with risperidone and haloperidol. These short-term trials suggest that iloperidone has a reassuring safety profile in many of the areas that are of potential concern, including relatively low dropout rates because of AEs, low extrapyramidal symptoms, akathisia, and prolactin elevation, and a modest short-term effect on weight gain.

Topics: Adolescent; Adult; Aged; Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Double-Blind Method; Female; Humans; Isoxazoles; Long QT Syndrome; Male; Middle Aged; Patient Dropouts; Piperidines; Prospective Studies; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia; Weight Gain

The early demonstration of chlorpromazine efficacy in schizophrenia and its subsequent identification as a dopamine receptor antagonist, established the only known mechanism for antipsychotic development to date. By extension, it is easy to hypothesize that any mechanism shown to reduce dopamine-mediated transmission in brain will have antipsychotic properties. The evaluation of partial dopamine agonists for antipsychotic efficacy and their application in the treatment of psychosis has derived from this background. Partial dopamine agonists at the D2 dopamine receptor, have high affinity for that receptor, but reduced intrinsic activity. These agonists have higher affinity for the presynaptic autoreceptor than for the postsynaptic receptor. Hence, these compounds reduce dopamine synthesis and release through an agonist action at the dopamine autoreceptor. Moreover, the agonists have lower intrinsic activity at the postsynaptic receptor than its natural ligand dopamine. Therefore, they diminish the dopaminergic signal at postsynaptic sites as well through delivering a reduced message; this component of drug action becomes more prominent the lower the intrinsic activity of the drug. Several partial dopamine agonists have been evaluated in schizophrenia. One of them, aripiprazole, is nearing approval for marketing. With partial dopamine agonist treatment, advantages should accrue to schizophrenia treatment in the areas of affect control and cognitive performance.

Topics: Animals; Dopamine Agonists; Humans; Piperidines; Psychotic Disorders; Receptors, Dopamine; Schizophrenia

The discovery and characterization of dopamine in the mammalian brain earned Dr. Arvid Carlsson the Nobel Prize in 2000. Along with his many insights about dopamine pharmacology, came his proposal of the existence and critical role of dopamine autoreceptors in the overall regulation of dopamine-mediated neurotransmission. In this paper, the rationale, the putative mechanisms, and pertinent clinical data are reviewed to support the idea of the clinical relevance of dopamine agonists, especially partial agonists, in the treatment of psychosis. Evidence was gathered for the usefulness of this strategy in schizophrenia in early trials with apomorphine and N-propylnoraporphine (NPA). But clinical relevance was not a reality before the application of (-)-3PPP. These clinical results are presented. Moreover, now a partial dopamine agonist, aripiprazole, has been developed and will likely be marketed by BMS and Otsuka for the treatment of psychosis and will be the first drug in this class to be commercially available. Partial dopamine agonists represent the next new class of antipsychotic drugs, effective in treating schizophrenia.

Topics: Animals; Apomorphine; Autoreceptors; Brain; Dopamine Agonists; Humans; Piperidines; Psychotic Disorders; Receptors, Dopamine

Topics: Antiparkinson Agents; Basal Ganglia Diseases; Butyrophenones; Chlorpromazine; Drug Therapy, Combination; Humans; Iatrogenic Disease; Parasympatholytics; Piperazines; Piperidines; Psychotic Disorders; Time Factors

Topics: Adolescent; Adult; Aged; Alcoholism; Antisocial Personality Disorder; Child; Dementia; Epilepsy; Female; Humans; Intellectual Disability; Male; Mental Disorders; Middle Aged; Neurotic Disorders; Nitriles; Paranoid Disorders; Personality Disorders; Phenothiazines; Piperidines; Psychotic Disorders; Schizophrenia; Tranquilizing Agents

This was an open-label extension (OLE) study in patients previously completing one of three double-blind, placebo-controlled (Core) studies. All patients received pimavanserin 34 mg once daily. Efficacy assessments included the Scale for the Assessment of Positive Symptoms (SAPS) PD and H + D scales, Clinical Global Impression (CGI) Improvement and Severity scales and Caregiver Burden Scale (CBS), through 4 weeks in the OLE. Safety assessments were conducted at each visit.. Of 459 patients, 424 (92.4%) had a Week 4 efficacy assessment. At Week 4 (10 weeks total treatment), SAPS-PD mean (standard deviation) change from OLE baseline was -1.8 (5.5) and for SAPS-H + D was -2.1 (6.2) with pimavanserin 34 mg. Patients receiving placebo during the Core studies had greater improvements (SAPS-PD -2.9 [5.6]; SAPS-H + D -3.5 [6.3]) during the OLE. For participants treated with pimavanserin 8.5 or 17 mg during the Core studies, further improvement was observed during the OLE with pimavanserin 34 mg. The mean change from Core Study baseline for SAPS-PD score was similar among prior pimavanserin 34 mg and prior placebo-treated participants (-7.1 vs. -7.0). The CGI-I response rate (score of 1 or 2) at Week 4 was 51.4%. Adverse events were reported by 215 (46.8%) patients during the first 4 weeks of OLE. The most common AEs were fall (5.9%), hallucination (3.7%), urinary tract infection (2.8%), insomnia (2.4%), and peripheral edema (2.2%) CONCLUSIONS: Patients previously on pimavanserin 34 mg during three blinded core studies had durability of efficacy during the subsequent 4 week OLE SAPS-PD assessment. Patients previously on blinded placebo improved after 4 weeks of OL pimavanserin treatment. These results in over 400 patients from 14 countries support the efficacy of pimavanserin for treating PDP.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Patients with dementia due to neurodegenerative disease can have dementia-related psychosis. The effects of the oral 5-HT. We conducted a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia. Patients received open-label pimavanserin for 12 weeks. Those who had a reduction from baseline of at least 30% in the score on the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D, with higher scores indicating greater psychosis) and a Clinical Global Impression-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) at weeks 8 and 12 were randomly assigned in a 1:1 ratio to continue receiving pimavanserin or to receive placebo for up to 26 weeks. The primary end point, assessed in a time-to-event analysis, was a relapse of psychosis as defined by any of the following: an increase of at least 30% in the SAPS-H+D score and a CGI-I score of 6 (much worse) or 7 (very much worse), hospitalization for dementia-related psychosis, stopping of the trial regimen or withdrawal from the trial for lack of efficacy, or use of antipsychotic agents for dementia-related psychosis.. Of the 392 patients in the open-label phase, 41 were withdrawn for administrative reasons because the trial was stopped for efficacy; of the remaining 351 patients, 217 (61.8%) had a sustained response, of whom 105 were assigned to receive pimavanserin and 112 to receive placebo. A relapse occurred in 12 of 95 patients (13%) in the pimavanserin group and in 28 of 99 (28%) in the placebo group (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.73; P = 0.005). During the double-blind phase, adverse events occurred in 43 of 105 patients (41.0%) in the pimavanserin group and in 41 of 112 (36.6%) in the placebo group. Headache, constipation, urinary tract infection, and asymptomatic QT prolongation occurred with pimavanserin.. In a trial that was stopped early for efficacy, patients with dementia-related psychosis who had a response to pimavanserin had a lower risk of relapse with continuation of the drug than with discontinuation. Longer and larger trials are required to determine the effects of pimavanserin in dementia-related psychosis. (Funded by Acadia Pharmaceuticals; HARMONY ClinicalTrials.gov number, NCT03325556.).

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Dementia; Double-Blind Method; Female; Hallucinations; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Parkinson Disease; Piperidines; Proportional Hazards Models; Psychotic Disorders; Recurrence; Urea

Parkinson's disease psychosis (PDP) is a common nonmotor symptom that affects up to 60% of patients. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, is approved for treating hallucinations and delusions associated with PDP.. Evaluate the efficacy and tolerability of pimavanserin in an open-label extension (OLE) study.. Patients completing a pivotal 6-week placebo-controlled trial (Core Study) could enroll in the OLE. All patients pimavanserin 34 mg once daily, blinded to previous treatment allocation. Prespecified blinded assessments at Week 4 were the Scale for the Assessment of Positive Symptoms (SAPS) PD version and SAPS H + D scales, Caregiver Burden Scale (CBS), and Clinical Global Impression (CGI) Improvement and Severity scales.. Of 171 who entered the OLE, 148 (87%) completed Week 4. Among patients who received placebo in the Core Study, mean (SD) change from OLE baseline to OLE Week 4 for the SAPS-PD was - 3.4 (6.3); p < 0.0001. Mean change from Core Study baseline to OLE Week 4 for SAPS-PD was similar among prior pimavanserin- and placebo-treated patients (-6.9 vs. -6.3). Improvement was similar with CGI-I, CGI-S, CBS, and SAPS-H + D in patients previously treated with placebo. Adverse events occurred in 92 (53.8%) patients during the 4-week OLE.. Improvements at OLE Week 4 from pretreatment baseline were similar with placebo and pimavanserin in the Core Study. The beneficial effects observed with pimavanserin in the 6-week Core Study were maintained for 4 weeks in the blinded OLE, supporting the durability of response with pimavanserin 34 mg for PDP over 10 weeks.

Topics: Aged; Aged, 80 and over; Double-Blind Method; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Urea

Patients with Alzheimer's disease psychosis (ADP) commonly experience concomitant agitation and aggression. We investigated whether a reduction in ADP following pimavanserin treatment conferred a reduction in associated agitation and aggression.. ACP-103-019 was a 12-week, randomized, double-blind, placebo-controlled study that evaluated the efficacy of pimavanserin (34 mg) in reducing psychotic symptoms in patients with ADP. The primary endpoint was change from baseline in Neuropsychiatric Inventory-Nursing Home Version-Psychosis Score (NPI-NH-PS) at week six. A post hoc analysis examined whether there was a greater reduction in agitation and aggression (NPI-NH domain C [agitation/aggression] and Cohen-Mansfield Agitation Inventory-Short Form [CMAI-SF]) in pimavanserin-treated patients who experienced a reduction of hallucinations and delusions (psychosis responders defined as ≥50% reduction from baseline in NPI-NH-PS, week six) when compared with those who did not (nonresponders).. Pimavanserin-treated patients with ≥50% response in psychotic symptoms (n = 44) showed a greater improvement in agitation and aggression symptoms on the NPI-NH domain C (week six, least squares mean [LSM] difference = -3.64, t = -4.69, P < .0001) and the CMAI-SF (week six, LSM difference = -3.71, t = -2.01, P = .0483) than nonresponders (n = 32). Differences between psychosis responders and nonresponders were also observed in patients with more severe agitation and aggression at baseline on the NPI-NH domain C (responders, n = 26; nonresponders, n = 13; week six, LSM difference = -3.03, t = -2.44, P = .019).. Patients with ADP, who show improvement in psychotic symptoms after pimavanserin treatment, also experience an improvement in concomitant agitation and aggression.

Topics: Aggression; Alzheimer Disease; Double-Blind Method; Humans; Piperidines; Psychomotor Agitation; Psychotic Disorders; Treatment Outcome; Urea

Dopamine supersensitivity psychosis (DSP) is a key factor contributing to the development of antipsychotic treatment-resistant schizophrenia. We examined the efficacy and safety of blonanserin (BNS) and olanzapine (OLZ) as adjuncts to prior antipsychotic treatment in patients with schizophrenia and DSP in a 24-week, multicenter (17 sites), randomized, rater-blinded study with two parallel groups (BNS and OLZ add-on treatments) in patients with schizophrenia and DSP: the ROADS Study. The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 24. Secondary outcomes were changes in the PANSS subscale scores, Clinical Global Impressions, and Extrapyramidal Symptom Rating Scale (ESRS), and changes in antipsychotic doses. The 61 assessed patients were allocated into a BNS group (n = 26) and an OLZ group (n = 29). The PANSS total scores were reduced in both groups (mean ± SD: -14.8 ± 24.0, p = 0.0042; -10.5 ± 12.9, p = 0.0003; respectively) with no significant between-group difference (mean, -4.3, 95 %CI 15.1-6.4, p = 0.42). The BNS group showed significant reductions from week 4; the OLZ group showed significant reductions from week 8. The ESRS scores were reduced in the BNS group and the others were reduced in both groups. The antipsychotic monotherapy rates at the endpoint were 26.3 % (n = 6) for BNS and 23.8 % (n = 5) for OLZ. The concomitant antipsychotic doses were reduced in both groups with good tolerability. Our results suggest that augmentations with BNS and OLZ are antipsychotic treatment options for DSP patients, and BNS may be favorable for DSP based on the relatively quick responses to BNS observed herein.

Topics: Antipsychotic Agents; Benzodiazepines; Dopamine; Humans; Olanzapine; Piperazines; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Treatment Outcome

Pimavanserin is a 5-HT2A receptor inverse agonist/antagonist and is approved in the United States for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis.. Evaluate the efficacy of pimavanserin on symptoms of psychosis in patients with Alzheimer's disease (AD).. Randomized, double-blind, placebo-controlled trial.. Nursing home residents.. Patients with AD psychosis.. Pimavanserin 34 mg or placebo daily for 12 weeks.. The primary endpoint was mean change from baseline at Week 6 on the Neuropsychiatric Inventory-Nursing Home Version psychosis score (NPI-NH-PS). In the prespecified subgroup analysis, the mean change in NPI-NH-PS and the responder rates among those with baseline NPI-NH-PS ≥12 were evaluated.. Of 181 patients randomized (n=90 pimavanserin; n=91 placebo), 57 had baseline NPI-NH-PS ≥12 (n=27 pimavanserin; n=30 placebo). In this severe subgroup, large treatment effects were observed (delta=-4.43, Cohen's d=-0.73, p=0.011), and ≥30% improvement was 88.9% vs. 43.3% (p<0.001) and ≥50% improvement was 77.8% vs. 43.3% (p=0.008) for pimavanserin and placebo, respectively. The rate of adverse events (AEs) in the severe subgroup was similar between treatment groups, and urinary tract infection, fall, and agitation were most frequent. Serious AEs was similar with pimavanserin (17.9%) and placebo (16.7%) with fewer discontinuations due to AEs with pimavanserin (7.1%) compared to placebo (10.0%). Minimal change from baseline occurred for the mean MMSE score over 12 weeks.. Pimavanserin demonstrated significant efficacy in AD psychosis in patients with higher baseline severity of psychotic symptoms (NPI-NH-PS ≥12). Treatment with pimavanserin showed an acceptable tolerability profile.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Nursing Homes; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome; Urea

Pimavanserin is a selective 5-HT. We did a phase 2, randomised, double-blind, placebo-controlled, single-centre (with multiple affiliated nursing home sites across the UK) study. We included participants of either sex who were aged 50 years or older with possible or probable Alzheimer's disease and psychotic symptoms including visual or auditory hallucinations, delusions, or both. Participants were randomly assigned (1:1) to 12 weeks of oral treatment with either pimavanserin (two 17 mg tablets daily) or placebo, with use of permuted block sizes of four and stratified by baseline Mini-Mental State Examination (MMSE) total score (<6 or ≥6) and Neuropsychiatric Inventory-Nursing Home version (NPI-NH) psychosis score (<12 or ≥12). Participants, caregivers, the study sponsor, and study personnel at the clinic site were masked to treatment assignment. The primary endpoint was mean change from baseline to week 6 in the NPI-NH psychosis score for pimavanserin versus placebo in the modified intention-to-treat population. Sustained benefit and safety of pimavanserin were assessed through week 12. This study is registered at ClinicalTrials.gov, number NCT02035553.. Between Jan 16, 2014, and Oct 27, 2016, 345 participants across 133 nursing homes were screened, of whom 181 were randomly assigned treatment (n=90 pimavanserin and n=91 placebo). 178 participants were included in the modified intention-to-treat population. Mean total baseline NPI-NH psychosis scores were 9·5 (SD 4·8) for the pimavanserin group and 10·0 (5·6) for the placebo group. Mean change in the NPI-NH psychosis score at week 6 was -3·76 points (SE 0·65) for pimavanserin and -1·93 points (0·63) for placebo (mean difference -1·84 [95% CI -3·64 to -0·04], Cohen's d=-0·32; p=0·045). By week 12, no significant advantage for pimavanserin versus placebo was observed for the overall study population (treatment difference -0·51 [95% CI -2·23 to 1·21]; p=0·561). Common adverse events were falls (21 [23%] of 90 participants in the pimavanserin group vs 21 [23%] of 91 in the placebo group), urinary tract infections (20 [22%] vs 25 [28%]), and agitation (19 [21%] vs 13 [14%]). Eight (9%) participants on pimavanserin and 11 (12%) on placebo discontinued treatment because of adverse events. No detrimental effect was observed on cognition or motor function in either group.. Pimavanserin showed efficacy in patients with Alzheimer's disease psychosis at the primary endpoint (week 6) with an acceptable tolerability profile and without negative effect on cognition. Further follow-up to week 12 did not show significant advantage for pimavanserin versus placebo.. ACADIA Pharmaceuticals.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Nursing Homes; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Treatment Outcome; Urea

PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms.. To evaluate the differential effect of the antipsychotic pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive-enhancing medications.. Data from the pivotal randomized clinical trial of pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21-24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive-enhancing medications. The primary outcome measure was change in the PD-adapted Scale for the Assessment of Positive Symptoms.. Mean (pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; -6.62 vs. -0.91; P = 0.002) versus the cognitively unimpaired (n = 135; -5.50 vs. -3.23; p = 0.046) group. The comparable change was -6.04 versus -2.18 (P = 0.012) and -5.66 versus -3.15 (P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive-enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive-enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors.. The antipsychotic effect of pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive-enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Cognition Disorders; Double-Blind Method; Female; Humans; Male; Mental Status Schedule; Middle Aged; Nootropic Agents; Parkinson Disease; Piperidines; Psychotic Disorders; Treatment Outcome; Urea

To establish the mortality risk and adverse events associated with the use of atypical antipsychotic medications in people with Parkinson disease psychosis (PDP) in a clinically defined trial cohort.. Post hoc analysis of data from a multicenter, open-label extension study of pimavanserin comparing people taking and not taking current antipsychotics.. Primary and secondary care medical centers in the United States, Canada, Europe, and India.. A total of 459 people with PDP enrolled in the extension study. Participants were between ages 30 and 80 years, and had an established diagnosis of idiopathic Parkinson disease and moderate to severe psychosis.. Participants were categorized into 2 groups: those receiving concomitant antipsychotic medications ("concurrent APD") and those who did not take antipsychotic medications at any time during the study ("no APD"). Participants were receiving 40 mg pimavanserin daily in addition to concurrent antipsychotics and Parkinson disease medications.. Safety assessments at 2 weeks; 1, 3, 6, 9, and 12 months; and every 6 months thereafter, including evaluation of adverse events (AEs), vital signs, weight, physical examinations, 12-lead electrocardiograms, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS-II+III, activities of daily living and motor impairment, respectively). Differences between participants taking and not taking current antipsychotics were evaluated using incidence rate ratios (IRRs) with 95% confidence intervals (CIs).. There was significant increase in the mortality rate for participants taking concurrent antipsychotics compared with the group not taking antipsychotic medications (IRR 4.20, 95% CI 2.13-7.96). Participants who received a concurrent antipsychotic were also significantly more likely to experience overall a serious AE (IRR 2.95, 95% CI 2.02-4.24), any antipsychotic-related event (IRR 1.66, 95% CI 1.18-2.29), cognition-related events (IRR 2.70, 95% CI 1.19-5.58), infections (IRR 1.97, 95% CI 1.17-3.16), and edema (IRR 2.61, 95% CI 1.09-5.59). The risk of falls, stroke, sedation, orthostatic hypotension, and thromboembolic events was also increased in these individuals but this was not significant.. This study highlights a significant risk of mortality, and severe AEs in patients with Parkinson disease receiving atypical antipsychotics. This is similar to or greater than the risks seen in people with Alzheimer disease, although with a less clear-cut risk of stroke and a longer delay to increased mortality.

Topics: Accidental Falls; Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Antipsychotic Agents; Drug Therapy, Combination; Edema; Female; Humans; Hypotension, Orthostatic; Infections; Male; Middle Aged; Parkinson Disease; Piperidines; Psychotic Disorders; Stroke; Thromboembolism; Urea

Parkinson's disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinson's disease. We aimed to assess safety and efficacy of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population.. In our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinson's disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01174004.. Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a -5·79 decrease in SAPS-PD scores compared with -2·73 for placebo (difference -3·06, 95% CI -4·91 to -1·20; p=0·001; Cohen's d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function.. Pimavanserin may benefit patients with Parkinson's disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease.. ACADIA Pharmaceuticals.

Topics: Aged; Analysis of Variance; Antiparkinson Agents; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Treatment Outcome; Urea

Blonanserin is a relatively new atypical antipsychotic drug, and has been used in Korea and Japan for 1 and 3 years, respectively. Therefore, the clinical characteristics of blonanserin remain unclear. In this study, to clarify the features of blonanserin, we performed prospective and long-term comparative investigations of patients treated with blonanserin.. We followed 10 psychiatric patients who were switched to blonanserin from other antipsychotics for 1 year (schizophrenia: 8; mental retardation: 2). In the light of quality of life, we focused on adverse effects of patients during the follow-up.. In the long-term follow-up, (i) hyperprolactinemia is more frequently in risperidone than in blonanserin; however, it is more often in blonanserin than in olanzapine; and (ii) weight gain is more common in olanzapine than in blonanserin.. We switched to blonanserin from other antipsychotic drugs within the same case, and then followed the case for 1 year. We consider that long-term observations within the same case lead to obvious comparisons among drugs. On the basis of our findings, we conclude that blonanserin may be useful for the maintenance treatment of schizophrenia without inducing hyperprolactinemia and weight gain.

Topics: Adult; Antipsychotic Agents; Female; Follow-Up Studies; Humans; Piperazines; Piperidines; Prolactin; Psychotic Disorders; Quality of Life; Schizophrenia

The efficacy and tolerability characteristics of an antipsychotic are difficult to determine from a single registration study. We thus conducted an analysis that assessed key efficacy and tolerability outcomes post hoc from four pooled short-term (4-6 weeks) phase III studies that evaluated iloperidone versus placebo in patients with schizophrenia or schizoaffective disorder.. Patient-level data were pooled from four prospective, randomized, double-blind, placebo-controlled and active-controlled, multicenter trials of iloperidone in patients with schizophrenia or schizoaffective disorder aged 18-65 years. Iloperidone 4-8, 10-16, and 20-24 mg/day (all dosed twice daily) were compared with placebo. Active controls used for assay sensitivity included risperidone 4-8 mg/day, haloperidol 15 mg/day, and ziprasidone 160 mg/day. Outcomes of interest were change from baseline to endpoint in the Brief Psychiatric Rating Scale (derived) (BPRSd), Positive and Negative Syndrome Scale (PANSS)-total (PANSS-T) score, and PANSS-positive (PANSS-P) and PANSS-negative (PANSS-N) subscale scores. An analysis of covariance (with treatment and study as factors, baseline as a covariate) was performed to compare changes between the iloperidone treatment groups versus placebo, on the basis of a last-observation-carried-forward approach for the intent-to-treat (ITT) populations. Tolerability outcomes were obtained from spontaneously reported adverse events (AEs), and number needed to harm was calculated for each antipsychotic versus placebo for the total population.. The ITT population included both schizoaffective and schizophrenia patients (N = 2401): n = 370, n = 494, and n = 424 for iloperidone 4-8, 10-16, and 20-24 mg/day, respectively; n = 294 for risperidone; n = 114 for haloperidol; n = 144 for ziprasidone; and n = 561 for placebo. Treatment with iloperidone 10-16 mg/day or 20-24 mg/day was associated with significantly improved BPRSd, PANSS-T, PANSS-P, and PANSS-N scores versus treatment with placebo. When only patients with schizophrenia were included (n = 1941), the pattern of results was essentially unchanged. The active controls confirmed assay sensitivity. Across all iloperidone dose groups, the incidences of extrapyramidal disorders and akathisia were similar to those observed with placebo. AEs for which the frequency was greater for iloperidone than placebo and for which the 95% confidence interval for number needed to harm did not contain infinity were dizziness, dry mouth, somnolence, nasal congestion, fatigue, sedation, and tachycardia; in general, for these AEs, frequency was higher with higher doses, resulting in a lower number needed to harm.. Consistent with product labeling, iloperidone 10-16 mg/day or 20-24 mg/day demonstrated significant improvement over placebo on BPRSd and PANSS-T scores, as well as on PANSS-P and PANSS-N subscale scores over 6 weeks of treatment in patients with schizophrenia and in the ITT population, which includes patients with schizoaffective disorder. Iloperidone did not differ from placebo in terms of extrapyramidal disorders and akathisia.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Labeling; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperazines; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Thiazoles; Treatment Outcome; Young Adult

To observe the effects of remifentanil or esmolol on the stress responses during electric shock therapy in psychiatric patients.. Upon the approval of institutional Ethics Committee, Eighty psychiatric patients requiring electric shock therapy were randomly divided into 2 groups:esmolol group (Group E) and remifentanil group (Group R) (n = 40 each). The patients in Groups E and R were injected with esmolol 1 mg/kg or remifentanil 2 µg/kg respectively before induction of anesthesia. Electric shock therapy was performed after a disappearance of fasciculation. MAP (mean arterial pressure) and HR (heart rate) were recorded at the following time points:prior to anesthesia (T0), prior to electric shock therapy (T1) and at 1 min (T2), 3 min (T3) & 5 min (T4) after electric shock therapy. Venous blood samples were collected at (T0) and (T4). The plasma levels of cortisol and norepinephrine were determined by enzyme-linked immunosorbent assay.. The levels of MAP and HR at T2, T3 were significantly higher than those at T0 in Group E (P < 0.05). And the levels of cortisol and norepinephrine at T4 were significantly higher than those at T0 in 2 groups (P < 0.05). However, their levels were significantly higher in Group E than those in Group R (P > 0.05).. In modified electric convulsive treatment, remifentanil is superior to esmolol in maintaining the stabilization of cardiovascular system and effectively inhibiting the stress responses.

Topics: Adult; Blood Pressure; Electroconvulsive Therapy; Female; Heart Rate; Humans; Male; Middle Aged; Piperidines; Propanolamines; Psychotic Disorders; Remifentanil; Stress, Physiological; Young Adult

Psychotic symptoms occur in up to 40% of patients with Parkinson's disease (PD). Clozapine and quetiapine, two atypical antipsychotic drugs, at doses markedly lower than those effective in schizophrenia, which, nevertheless, still cause sedation, hypotension, and other side effects, are widely used to treat psychotic symptoms in patients with PD psychosis (PDP), although quetiapine has never been shown to be effective in a placebo-controlled study. The demonstrated efficacy of clozapine in PDP has been attributed to serotonin (5-HT(2A)) receptor blockade. We postulated that pimavanserin (ACP-103), a highly selective 5-HT(2A) inverse agonist, would attenuate psychosis in patients with PDP, but avoid motoric worsening and non-motoric side effects. In this double-blind, randomized multicenter 28-day study, the tolerability and efficacy of pimavanserin was compared with placebo in 60 patients with L-DOPA or dopamine (DA) agonist-induced PDP. Motor function was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III. Antipsychotic efficacy was evaluated using multiple measures from the Scale for the Assessment of Positive Symptoms (SAPS) and a UPDRS Part I psychosis-relevant item. Pimavanserin did not differentiate from placebo with regard to motor impairment, sedation, hypotension, or other side effects. The principal measures of efficacy of antipsychotic response to pimavanserin, the SAPS total domain score, only showed a trend. However, the pimavanserin-treated patients showed significantly greater improvement in some but not all measures of psychosis, including SAPS global measures of hallucinations and delusions, persecutory delusions, and the UPDRS measure of delusions and hallucinations. Pimavanserin showed significantly greater improvement in psychosis in patients with PDP at a dose which did not impair motor function, or cause sedation or hypotension Thus, pimavanserin may represent a novel treatment for PDP. Furthermore, these results support the hypothesis that attenuation of psychosis secondary to DA receptor stimulation in PDP may be achieved through selective 5-HT(2A) receptor antagonism.

Topics: Aged; Analysis of Variance; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Motor Activity; Parkinson Disease; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists; Severity of Illness Index; Urea

Altered expression of central muscarinic and nicotinic acetylcholine receptors in hippocampal and cortical regions may contribute to the cognitive impairment exhibited in patients with schizophrenia. Increasing cholinergic activity through the use of a cholinesterase inhibitor (ChEI) therefore represents a possible strategy for cognitive augmentation in schizophrenia. We examined the efficacy and safety of the ChEI donepezil as cotreatment for mild to moderate cognitive impairment in schizophrenia or schizoaffective disorder in a prospective, 12-week, placebo-controlled, double-blind, parallel-group study. In total, 250 patients (18-55 years) with schizophrenia or schizoaffective disorder who were clinically stabilized on risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole, alone or in combination, were enrolled at 38 outpatient psychiatric clinics in the United States. Patients were randomized to donepezil 5 mg q.d. for 6 weeks then 10 mg q.d. for 6 weeks, or placebo administered as oral tablets. The primary outcome measure was the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) neurocognitive battery composite score. In the intent-to-treat sample (donepezil, n=121; placebo, n=124), both treatments showed improvement in the composite score from baseline to week 12. At week 12, cognitive improvement with donepezil was similar to that with placebo (last-observation-carried-forward effect size, 0.277 vs 0.411; p=0.1182) and statistically significantly inferior for the observed-cases analysis (0.257 vs 0.450; p=0.044). There was statistically significant improvement in the Positive and Negative Syndrome Assessment Scale negative symptoms score for placebo compared with donepezil, while total and positive symptom scores were similar between both treatments. Statistically significant improvements in positive symptoms score and Clinical Global Impression-Improvement for donepezil compared with placebo were noted at Week 6. Treatment-emergent adverse events (AEs) were observed for 54.5% of donepezil- and 61.3% of placebo-treated patients; most AEs were rated as mild to moderate in severity. Donepezil was safe and well-tolerated but was not effective compared with placebo as a cotreatment for the improvement of cognitive impairment in this patient population. A significant and surprisingly large placebo/practice effect was observed among placebo-treated patients, and is a serious consideration in future clinical trial study desig

Topics: Adult; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Placebo Effect; Practice, Psychological; Prospective Studies; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Time Factors

Thirteen outpatients with chronic but stable schizophrenia received donepezil and placebo augmentation of their maintenance antipsychotic medication regimen. Each subject received in a randomized, counterbalanced order 1) donepezil 5 mg for 6 weeks then donepezil 10 mg for six weeks and 2) placebo donepezil for 12 weeks. Serial ratings of the Positive and Negative Symptom Scale (PANSS) [Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13(2): 261-276] were performed by a trained rater blind to the donepezil order and condition: at baseline, 12 weeks and 24 weeks. On donepezil as compared to baseline or placebo, there was a significant improvement in PANSS negative scores (p=.018, n=13). These results are discussed with respect to other studies using cholinesterase inhibitors as an augmentation strategy in schizophrenia.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Cholinesterase Inhibitors; Clozapine; Cross-Over Studies; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Nootropic Agents; Olanzapine; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

To assess the efficacy and tolerability of quetiapine for agitation or psychosis in patients with dementia and parkinsonism.. Multicenter randomized, double-blind, placebo-controlled parallel groups clinical trial involving 40 patients with dementia with Lewy bodies (n = 23), Parkinson disease (PD) with dementia (n = 9), or Alzheimer disease with parkinsonian features (n = 8). The main outcome measure for efficacy was change in the Brief Psychiatric Rating Scale (BPRS) from baseline to 10 weeks of therapy. For tolerability it was change in the Unified PD Rating Scale (UPDRS) motor section over the same time period. The trial was confounded by the need for a design change and incomplete recruitment.. No significant differences in the primary or secondary outcome measures of efficacy were observed. An unexpectedly large placebo effect, inadequate dosage (mean 120 mg/day), and inadequate power may have contributed to lack of demonstrable benefit. Quetiapine was generally well-tolerated and did not worsen parkinsonism, but was associated with a trend toward a decline on a measure of daily functioning.. Quetiapine was well-tolerated and did not worsen parkinsonism. Although conclusions about efficacy may be limited, the drug in the dosages used did not show demonstrable benefit for treating agitation or psychosis in patients with dementia and parkinsonism. These findings are in keeping with prior studies reporting limited efficacy of various medications for reducing behavioral problems in demented patients.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Antiparkinson Agents; Antipsychotic Agents; Cholinesterase Inhibitors; Confounding Factors, Epidemiologic; Dementia; Dibenzothiazepines; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Lewy Body Disease; Male; Neuropsychological Tests; Parkinson Disease; Patient Selection; Piperidines; Placebo Effect; Psychomotor Agitation; Psychotic Disorders; Quetiapine Fumarate; Research Design; Severity of Illness Index; Treatment Failure

Topics: Adolescent; Adult; Antipsychotic Agents; Biological Availability; Cross-Over Studies; Fasting; Food-Drug Interactions; Half-Life; Humans; Male; Middle Aged; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Tablets; Therapeutic Equivalency; Urea

Donepezil, 5 mg/d for 6 wk then 10 mg/d for 6 wk, and placebo daily for 12 wk in a double-blind cross-over paradigm, was added to the therapeutic regimen of 13 patients with schizophrenia or schizoaffective disorders, clinically stable on atypical antipsychotic medications. Patients had varying degrees of depressive symptoms, ranging from no depression to clinically significant depression. There was no worsening or induction of depression in individual patients or the group as a whole. In addition there was a statistically significant antidepressant effect in the group as a whole during the donepezil condition and a clinically significant antidepressant effect in the patients with clinically significant depressive symptoms, although there were not enough depressed patients in the group to conclude that donepezil may have antidepressant effects. Thus, in this study, donepezil did not induce or worsen depressive symptoms in schizophrenic and schizoaffective disorder patients.

Topics: Adult; Affect; Analysis of Variance; Cross-Over Studies; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Four studies using identical protocols evaluated the safety and efficacy of four novel, evidence-based targets for antipsychotic agents: a neurokinin (NK(3)) antagonist (SR142801), a serotonin 2A/2C (5-HT(2A/2C)) antagonist (SR46349B), a central cannabinoid (CB(1)) antagonist (SR141716), and a neurotensin (NTS(1)) antagonist (SR48692).. Adults with schizophrenia or schizoaffective disorder (N=481) were randomly assigned in a 3:1:1 ratio to receive fixed doses of investigational drug, placebo, or haloperidol for 6 weeks. Primary efficacy variables included changes from baseline in total score on the Positive and Negative Syndrome Scale, severity of illness score on the Clinical Global Impression (CGI), and total score and psychosis cluster score on the Brief Psychiatric Rating Scale (BPRS).. Significantly greater improvement in all primary efficacy variables was seen in the group receiving haloperidol than in the group receiving placebo at 6 weeks (endpoint analyses), indicating the validity of the study. The group receiving the NK(3) antagonist showed significantly greater improvement over baseline than the group receiving placebo as measured by Positive and Negative Syndrome Scale total score, CGI severity of illness score, and BPRS psychosis cluster score. Reductions in the Positive and Negative Syndrome Scale total and negative scores in the group receiving the 5-HT(2A/2C) antagonist were significantly larger than those in the group receiving placebo. The improvements in psychopathology produced by the NK(3) and 5-HT(2A/2C) antagonists were smaller than those produced by haloperidol, although the response to the NK(3) antagonist was positively correlated with plasma levels. The groups receiving the CB(1) and NTS(1) antagonists did not differ from the group receiving placebo on any outcome measure. All investigational drugs were well tolerated.. The novel design used in this study permitted the use of a smaller number of patients receiving placebo to test the efficacy of the four novel compounds. The NK(3) and 5-HT(2A/2C) antagonists showed evidence of efficacy in the treatment of schizophrenia and schizoaffective disorder. Study limitations preclude a definitive conclusion on the efficacy of CB(1) and NTS(1) antagonists in the treatment of schizophrenia. Further study of these two promising nondopaminergic mechanisms to treat schizophrenia and schizoaffective disorder appears indicated.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Cannabinoids; Double-Blind Method; Drugs, Investigational; Female; Haloperidol; Humans; Male; Middle Aged; Neurotensin; Peptide Fragments; Piperidines; Placebos; Psychotic Disorders; Pyrazoles; Pyrrolidonecarboxylic Acid; Receptors, Neurokinin-3; Research Design; Rimonabant; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome

We used L-(quinoxalin-6-ylcarbonyl)piperidine (CX516) (a modulator of the alpha-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA) receptor) as a sole agent in a double blind placebo-controlled design in a small series of patients with schizophrenia who were partially refractory to treatment with traditional neuroleptics. The study entailed weekly increments in doses of CX516, from 300 mg tid for week 1 up to 900 mg tid on week 4. Patients were followed with clinical ratings, neuropsychological testing, and were monitored for adverse events. Four patients received 2 to 4 weeks of CX516, two received placebo and two withdrew during the placebo phase. Adverse events associated with drug administration were transient and included leukopenia in one patient and elevation in liver enzymes in another. No clear improvement in psychosis or in cognition was observed over the course of the study. CX516 at the doses tested did not appear to yield dramatic effects as a sole agent, but inference from this study is limited.

Topics: Adult; Antipsychotic Agents; Dioxoles; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Psychotic Disorders; Schizophrenia

Until recently, conventional antipsychotics were the standard pharmacotherapy for psychosis and behavioral disturbances associated with dementia. This double-blind, placebo-controlled study compared the acute efficacy of the selective serotonin reuptake inhibitor citalopram and the neuroleptic perphenazine with placebo for the treatment of psychosis and behavioral disturbances in nondepressed patients with dementia.. Eighty-five hospitalized patients with at least one moderate to severe target symptom (aggression, agitation, hostility, suspiciousness, hallucinations, or delusions) were randomly assigned to receive either citalopram, perphenazine, or placebo under double-blind conditions for up to 17 days.. Patients treated with citalopram or perphenazine showed statistically significant improvement on several Neurobehavioral Rating Scale factor scores. Compared to those receiving placebo, only patients treated with citalopram showed significantly greater improvement in their total Neurobehavioral Rating Scale score as well as in the scores for the agitation/aggression and lability/tension factors. Side effect scores were similar among the three treatment groups.. Citalopram was found to be more efficacious than placebo in the short-term hospital treatment of psychotic symptoms and behavioral disturbances in nondepressed, demented patients.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Behavioral Symptoms; Citalopram; Dementia; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Hospitalization; Humans; Indans; Male; Perphenazine; Piperidines; Placebos; Psychotic Disorders; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

Cognitive impairment in multiple domains is common in patients with schizophrenia and may be a powerful determinant of poor functional ability and quality of life. We report a double-blind, placebo-controlled, cross-over study of donepezil augmentation in a schizoaffective disorder patient stabilized on olanzapine pharmacotherapy. The patient showed significant improvements in several cognitive measures and increased activation of prefrontal cortex and basal ganglia on functional MRI during the donepezil augmentation. In addition, the donepezil augmentation resulted in a reduction of depressive symptoms and in significant improvements in functional abilities and quality of life. Further studies of donepezil augmentation of neuroleptics in schizophrenia are warranted.

Topics: Adult; Basal Ganglia; Benzodiazepines; Brain; Brain Mapping; Cognition Disorders; Cross-Over Studies; Donepezil; Double-Blind Method; Drug Therapy, Combination; Humans; Indans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Olanzapine; Piperidines; Pirenzepine; Prefrontal Cortex; Psychiatric Status Rating Scales; Psychotic Disorders; Quality of Life

Risperidone and remoxipride are recently introduced atypical antipsychotics, with clinical efficacy comparable to that of classical antipsychotics but lower propensity to induce extrapyramidal side effects (EPS). It is unclear whether these properties relate to weak dopamine D2 receptor blockade in vivo, as has been suggested for the archetypal atypical antipsychotic clozapine. We have used 123I-IBZM single photon emission tomography (SPET) to characterize the patterns of striatal D2 receptor binding in vivo in DSMIII-R-diagnosed schizophrenic and schizo-affective patients treated with either risperidone (n = 6) or remoxipride (n = 4) but predominantly EPS free. These groups were compared to age- and BPRS- matched subjects from a previously reported D2 receptor binding database of patients treated with clozapine (n = 10) and classical antipsychotics (n = 10). Patients on risperidone and remoxipride had high levels of D2 receptor blockade, comparable to those of patients on classical antipsychotics, and significantly greater than those obtained with clozapine-treated patients (risperidone versus clozapine, P < 0.005; remoxipride versus clozapine, P < 0.025). These results suggest high levels of striatal D2 receptor occupancy in association with remoxipride and risperidone treatment and argue against modest D2 antagonism as the explanation for the low incidence of EPS associated with these drugs.

Topics: Adult; Antipsychotic Agents; Basal Ganglia; Benzamides; Cerebral Cortex; Dopamine D2 Receptor Antagonists; Female; Humans; Image Processing, Computer-Assisted; Iodine Radioisotopes; Isoxazoles; Male; Middle Aged; Neostriatum; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Pyrrolidines; Remoxipride; Risperidone; Schizophrenia; Tomography, Emission-Computed, Single-Photon

A double-blind eight-week study was carried out to compare the efficacy and safety of risperidone in relation to haloperidol. Sixty-two inpatients suffering from acute schizophrenic or schizoaffective psychoses diagnosed according to ICD-9 were treated with risperidone 2-20 mg daily or haloperidol 2-20 mg daily. The mean total BPRS scores were reduced from 45.5 to 32.4 in the risperidone group and from 43.1 to 28.5 in haloperidol group. There were no significant differences between the two treated groups with regard to the total BPRS score and the percentage of remissions achieved. No statistically significant difference was found between the groups in any of the factors or items except guilt feeling (p < 0.02), anxiety (p < 0.005), and factor I--anxiety/depression--(p < 0.02) in favour of haloperidol. Risperidone had the benefit of a lower incidence of extrapyramidal side-effects.

Topics: Adult; Antiparkinson Agents; Antipsychotic Agents; Basal Ganglia Diseases; Double-Blind Method; Female; Haloperidol; Humans; Isoxazoles; Male; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology

Sixty-one adult psychotic patients were treated for four weeks in an open dose-finding study with the new combined serotonin-dopamine antagonist risperidone (R 64 766). Risperidone had a rapid onset of action; a highly significant decrease in the total score on the Brief Psychiatric Rating Scale (BPRS) was already noticed after the first week of treatment. There was also a significant decrease in score for individual BPRS items related to positive, negative, and affective symptoms. In spite of the withdrawal of antiparkinson medication at selection, a significant decrease in extra-pyramidal symptoms (EPS) was observed, as assessed on the Simpson and Angus Scale. The Clinical Global Impression of therapeutic effect was consistent with the BPRS scores, showing a constant improvement throughout the study. The mean daily dose of risperidone at the end of the study was 3.7 mg. Tolerance was excellent and only mild side-effects were reported. Vital signs, ECG-parameters, and laboratory values remained within normal limits. This study demonstrates that risperidone has great potential as an effective and well-tolerated alternative for the treatment of chronically psychotic patients. It has potent antipsychotic effects, a low EPS-inducing profile, and, at the same time, it improves the negative and affective symptoms of schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Brief Psychiatric Rating Scale; Drug Evaluation; Female; Humans; Isoxazoles; Male; Middle Aged; Pilot Projects; Piperidines; Psychotic Disorders; Risperidone

Penfluridol is a diphenylbutylpiperdine derivative with a half-life of sixty-six (66) hours. The present study was designed to determine its efficacy for the maintenance of schizophrenia. In a 52 week double-blind study, once weekly doses of penfluridol were compared with once daily doses of chlorpromazine in 56 schizophrenic patients receiving maintenance treatment on an outpatient basis. Both drugs were similar in their clinical effectiveness; no major side effects occurred with either drug.

Topics: Adult; Chlorpromazine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation; Female; Humans; Male; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia

Topics: Aged; Biperiden; Clinical Trials as Topic; Clozapine; Dibenzazepines; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Male; Parkinson Disease, Secondary; Piperidines; Psychotic Disorders; Thioridazine

Topics: Adolescent; Adult; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Intellectual Disability; Male; Middle Aged; Penfluridol; Piperidines; Psychotic Disorders; Schizophrenia; Tablets; Time Factors

Topics: Administration, Oral; Adult; Behavior; Benztropine; Clinical Trials as Topic; Drug Evaluation; Drug Tolerance; Electrocardiography; Eye; Humans; Hydrocarbons, Halogenated; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Time Factors; Toluene; Tranquilizing Agents

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Clinical Trials as Topic; Female; Humans; Male; Methotrimeprazine; Middle Aged; Palmitic Acids; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Sex Factors; Sulfonamides

Topics: Administration, Oral; Adult; Antiparkinson Agents; Antipsychotic Agents; Basal Ganglia Diseases; Benzyl Compounds; Delayed-Action Preparations; Drug Evaluation; Humans; Injections, Intramuscular; Male; Middle Aged; Palmitic Acids; Phenothiazines; Piperidines; Piperidones; Placebos; Psychotic Disorders; Remission, Spontaneous; Sulfonamides

Topics: Acute Disease; Adolescent; Adult; Aggression; Chlorpromazine; Clinical Trials as Topic; Emotions; Evaluation Studies as Topic; Female; Humans; Injections, Intramuscular; Male; Mental Disorders; Middle Aged; Neurotic Disorders; Nitriles; Phenothiazines; Piperidines; Psychotic Disorders; Tranquilizing Agents

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Nitriles; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Thioridazine; Tranquilizing Agents

Topics: Benzimidazoles; Clinical Trials as Topic; Humans; Piperidines; Psychotic Disorders; Schizophrenia; Tranquilizing Agents

A controlled study was made of penfluridol medication consisting of a single weekly oral dose of 30 mg in 30 patients with acute psychoses of varying type and origin. This medication was found to be effective. No significant side effects occurred.Several long-acting neuroleptics for injection are now available. The development of an oral compound of this type is an asset because of the manageability of the oral drug in the hands of family doctors and social psychiatrists.

Topics: Acute Disease; Administration, Oral; Adult; Aged; Chlorpromazine; Clinical Trials as Topic; Delusions; Female; Hallucinations; Humans; Hydrocarbons, Halogenated; Male; Middle Aged; Paranoid Disorders; Piperidines; Psychomotor Disorders; Psychotic Disorders; Time Factors; Tranquilizing Agents

Topics: Administration, Oral; Adult; Antiparkinson Agents; Basal Ganglia Diseases; Benztropine; Benzyl Compounds; Clinical Trials as Topic; Delayed-Action Preparations; Evaluation Studies as Topic; Haloperidol; Humans; Injections, Intramuscular; Intraocular Pressure; Male; Middle Aged; Movement Disorders; Parasympatholytics; Piperidines; Piperidones; Placebos; Psychotic Disorders; Tropanes

Topics: Adolescent; Adult; Age Factors; Aged; Child; Extrapyramidal Tracts; Female; Humans; Male; Middle Aged; Movement Disorders; Parasympatholytics; Parkinson Disease; Parkinson Disease, Secondary; Piperidines; Placebos; Psychotic Disorders; Sex Factors; Time Factors; Tranquilizing Agents; Trihexyphenidyl

Topics: Adult; Aged; Clinical Trials as Topic; Delayed-Action Preparations; Electroencephalography; Female; Haloperidol; Humans; Male; Middle Aged; Piperidines; Psychotic Disorders; Time Factors; Tranquilizing Agents

Topics: Dementia; Humans; Piperidines; Psychotic Disorders; Urea

Topics: Bipolar Disorder; Humans; Piperidines; Psychotic Disorders; Urea

Pimavanserin, a serotonin 5-HT. This was a retrospective new-user cohort study of Medicare beneficiaries with Parkinson's disease initiating pimavanserin (N=3,227) or atypical antipsychotics (N=18,442) from April 2016 to March 2019. All-cause mortality hazard ratios and 95% confidence intervals were estimated for pimavanserin compared with atypical antipsychotics, using segmented proportional hazards regression over 1-180 and 181+ days of treatment. Potential confounding was addressed through inverse probability of treatment weighting (IPTW).. Pimavanserin users had a mean age of approximately 78 years, and 45% were female. Before IPTW, some comorbidities were more prevalent in atypical antipsychotic users; after IPTW, comorbidities were well balanced between groups. In the first 180 days of treatment, mortality was approximately 35% lower with pimavanserin than with atypical antipsychotics (hazard ratio=0.65, 95% CI=0.53, 0.79), with approximately one excess death per 30 atypical antipsychotic-treated patients; however, during treatment beyond 180 days, there was no additional mortality advantage with pimavanserin (hazard ratio=1.05, 95% CI=0.82, 1.33). Pimavanserin showed no mortality advantage in nursing home patients.. Pimavanserin use was associated with lower mortality than atypical antipsychotic use during the first 180 days of treatment, but only in community-dwelling patients, not nursing home residents.

Topics: Aged; Antipsychotic Agents; Cohort Studies; Female; Humans; Male; Medicare; Parkinson Disease; Piperidines; Psychotic Disorders; Retrospective Studies; United States; Urea

Topics: Hallucinogens; Humans; Piperidines; Psychotic Disorders; Urea

Topics: Antipsychotic Agents; Dementia; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Starting from a screening hit, a set of analogs was synthesized based on a 4-(2-aminoethyl)piperidine core not associated previously with trace amine-associated receptor 1 (TAAR1) modulation in the literature. Several structure-activity relationship generalizations have been drawn from the observed data, some of which were corroborated by molecular modeling against the crystal structure of TAAR1. The four most active compounds (EC

Topics: Animals; Dopamine; Dopamine Plasma Membrane Transport Proteins; Piperidines; Psychotic Disorders; Rats; Receptors, G-Protein-Coupled

Topics: Dementia; Humans; Piperidines; Psychotic Disorders; Urea

High doses of the Cannabis constituent Δ9-tetrahydrocannabinol (THC) increase the risk of psychosis in humans. Highly accessible animal models are needed to address underlying mechanisms. Using zebrafish with a conserved endocannabinoid system, this study investigates the acute effects of THC on adult zebrafish behavior and the mechanisms involved. A concentration-dependent THC-induced behavioral stereotypy akin to THC's effect in rats and the psychotropics phencyclidine and ketamine in zebrafish was established. Distinctive circular swimming during THC-exposure was measured using a novel analytical method that we developed, which detected an elevated Repetition Index (RI) compared to vehicle controls. This was reduced upon co-administration of N-methyl-D-aspartate (NMDA) receptor agonist NMDA, suggesting that THC exerts its effects via biochemical or neurobiological mechanisms associated with NMDA receptor antagonism. Co-treatment of γ-aminobutyric acid receptor antagonist pentylenetetrazol also showed signs of reducing the RI. Since THC-induced repetitive behavior remained in co-administrations with cannabinoid receptor 1 inverse agonist AM251, the phenotype may be cannabinoid receptor 1-independent. Conversely, the inverse cannabinoid receptor 2 agonist AM630 significantly reduced THC-induced behavioral stereotypy, indicating cannabinoid receptor 2 as a possible mediator. A significant reduction of the THC-RI was also observed by the antipsychotic sulpiride. Together, these findings highlight this model's potential for elucidating the mechanistic relationship between Cannabis and psychosis.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Dronabinol; N-Methylaspartate; Piperidines; Psychotic Disorders; Psychotropic Drugs; Pyrazoles; Receptor, Cannabinoid, CB1; Stereotyped Behavior; Zebrafish

Topics: Aged; Hospitalization; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

To determine the risk of hospitalization and death associated with pimavanserin use.. We conducted a retrospective cohort study of adults 65 years and older with Parkinson disease between November 1, 2015, and December 31, 2018, using an administrative dataset on residents of Medicare-certified long-term care facilities and linked Medicare claims data. Propensity score-based inverse probability of treatment weighting (IPTW) was used to balance pimavanserin users and nonusers on 24 baseline characteristics. Fine-Gray competing risk and Cox proportional hazards regression models were used to estimate the risk of hospitalization and death up to 1 year, respectively.. The study cohort included 2,186 pimavanserin users and 18,212 nonusers. There was a higher risk of 30-day hospitalization with pimavanserin use vs nonuse (IPTW-adjusted hazard ratio [aHR] 1.24, 95% confidence intervals [CI] 1.06-1.43). There was no association of pimavanserin use with 90-day hospitalization (aHR 1.10, CI 0.99-1.24) or with 30-day mortality (aHR 0.76, CI 0.56-1.03). Pimavanserin use vs nonuse was associated with increased 90-day mortality (aHR 1.20, CI 1.02-1.41) that persisted after 180 days (aHR 1.28, CI 1.13-1.45) and 1 year (aHR 1.56, CI 1.42-1.72).. Pimavanserin use vs nonuse in older adults was associated with an increased risk of hospitalization at 1 month of initiation and a higher risk of death for up to 1 year following initiation. These findings, in a large real-world cohort within long-term care facilities, may help to inform decisions regarding its risk/benefit balance among patients with Parkinson disease.. This study provides Class II evidence that in patients with Parkinson disease who are 65 or older and residing in Medicare-certified long-term care facilities, pimavanserin is associated with an increased risk of 30-day hospitalization and higher 90-, 180-, and 365-day mortality.

Topics: Aged; Hospitalization; Humans; Medicare; Parkinson Disease; Piperidines; Psychotic Disorders; Retrospective Studies; United States; Urea

Topics: Clinical Trials as Topic; Dementia; Humans; Piperidines; Psychotic Disorders; Urea

Topics: Cross-Sectional Studies; Genotype; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Sleep; Urea

Topics: Brain; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Piperidines; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin 5-HT2 Receptor Agonists; Urea

This was an open-label extension (OLE) study in patients previously completing a double-blind, placebo-controlled study or a previous OLE study. Safety was evaluated from adverse events (AEs), clinical laboratory results, motor symptoms, electrocardiograms (ECG), and mortality. Durability of response was assessed from the Clinical Global Impression-Severity (CGI-S) scale and Caregiver Burden Scale (CBS).. Of 459 participants treated in this OLE study (average age 71.2 years), the median duration of treatment was 454 days. Over the entire study period (approximately 11 years), ≥1 AE occurred in 392 (85.4%) patients; the majority were of mild to moderate intensity, with fall (32.0%), urinary tract infection (19.0%), and hallucination (13.7%) most common. Serious AEs occurred in 188 (41.0%) patients, and an AE leading to study termination or dose discontinuation occurred in 133 (29.0%) patients. Sixty-one patients died, 59 (12.9%) during treatment or within 30 days after the last dose of study drug; the observed mortality rate was 6.45 per 100 patient-years of exposure. Mean scores for the CGI-S scale and CBS generally remained stable for up to 192 weeks (>3.5 years).. Long-term treatment with pimavanserin 34 mg once daily demonstrated a favorable benefit/risk profile with no unexpected safety concerns. Mortality rates suggested no increased risk following long-term treatment.

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Female; Hallucinations; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Topics: Antipsychotic Agents; Death, Sudden; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Psychosis is common among patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Limited data exist on the most effective therapies.. Retrospective cohort study comparing patients with PD or DLB initiated on quetiapine or pimavanserin for psychosis. Primary outcome was time to discontinuation of pimavanserin or quetiapine using Kaplan-Meier survival analysis. We hypothesized the rate of antipsychotic discontinuation would be lower in the pimavanserin group. Subjects were included if the indication for treatment was psychosis and excluded if there was a history of major mental illness or no follow up data were available.. Forty-seven patients were included in the quetiapine cohort and 45 in the pimavanserin cohort. Patients in the pimavanserin cohort were more likely to have a diagnosis of DLB (33% vs. 11%, P = 0.01) and to have been prescribed an antipsychotic previously (62% vs. 6%, P < 0.01); otherwise, the groups were similar. Time to discontinuation analysis, which accounts for efficacy, safety and tolerability, revealed a lower early pimavanserin discontinuation rate and a higher late pimavanserin discontinuation rate (HR < 1 before day 43, HR > 1 after day 43; P = 0.04). There was no difference in mortality in the pimavanserin group compared to the quetiapine group (HR 0.37, 95% CI 0.06 to 2.45; P = 0.88). More individuals had a documented secondary indication for taking quetiapine than pimavanserin (38% vs. 4%; P = 0.001).. Accounting for efficacy, safety and tolerability, pimavanserin may be more clinically useful for promptly managing psychosis, while quetiapine may confer additional secondary benefits long-term.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Cohort Studies; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Urea

Topics: Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

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.

Topics: Antipsychotic Agents; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Urea

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

Psychosis is common in Parkinson's disease-related disorders and is associated with significant morbidity. Pimavanserin is a newly approved treatment for Parkinson's disease psychosis, but real-world experience with pimavanserin has been limited by small sample sizes and limited assessment of longitudinal outcomes.. The aim was to summarize the clinical experience with pimavanserin in a large cohort of patients with Parkinson's disease-related psychosis.. We conducted a retrospective chart review of patients who were prescribed pimavanserin at Vanderbilt University Medical Center in the southeast United States between May 2016 and July 2018. We used Chi-squared analyses to compare efficacy and tolerability of pimavanserin, considering patient diagnosis, presence of dementia or delusions, use of deep brain stimulation, and prior antipsychotic failure. Additionally, we compared the clinical characteristics of patients who started treatment and those who did not, to evaluate safety outcomes.. We identified 107 patients prescribed pimavanserin, and 91 began treatment. Clinical improvement in psychosis was documented in 76% of patients (69/91) and did not differ based on diagnosis, presence of dementia, delusions, use of deep brain stimulation, or prior antipsychotic failure. Adverse effects were reported in 20 patients (22%), the most common of which was worsening gait instability (5/91, 5%). Side effects led to cessation of therapy in 11 of the 91 patients (12%). At current follow-up, 50 (65%) of 77 living patients remain on treatment, with a mean treatment duration of 14.6 months. Although most of these patients are on pimavanserin monotherapy (33/50, 66%), 17 patients (34%) are on a dual-antipsychotic regimen. The living patients no longer on treatment stopped pimavanserin primarily because of a lack of perceived benefit (11/77, 14%), side effects (9/77, 12%), or both (1/77, 1%), though six patients (8%) stopped for reasons unrelated to medication effects, including the desire to reduce overall medication burden and negative media reporting on pimavanserin.. Study results emphasize long-term efficacy and tolerability of pimavanserin for psychosis in Parkinson's disease-related disorders, including patients with dementia, delusions, deep brain stimulation use, or prior antipsychotic failure.

Topics: Aged; Antiparkinson Agents; Antipsychotic Agents; Female; Humans; Male; Parkinson Disease; Piperidines; Psychotic Disorders; Retrospective Studies; Urea

Topics: Antiparkinson Agents; Antipsychotic Agents; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Topics: Alzheimer Disease; Double-Blind Method; Humans; Piperidines; Psychotic Disorders; Urea

Topics: Antipsychotic Agents; Drug Approval; Humans; Off-Label Use; Parkinson Disease; Piperidines; Psychotic Disorders; United States; United States Food and Drug Administration; Urea

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

Topics: Antipsychotic Agents; Clinical Trials as Topic; Drug Approval; Humans; Outcome Assessment, Health Care; Parkinson Disease; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Urea

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Female; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Survival Analysis; Treatment Outcome; Urea

Pimavanserin is not curative, but can improve the quality of life remaining for the person with Parkinson's disease who typically has been suffering from this relentless neurodegenerative disease for years. Using pimavanserin effectively requires knowledge not only about the product itself, but also about the treatments pimavanserin is replacing.

Topics: Antipsychotic Agents; Consensus; Humans; Neurodegenerative Diseases; Off-Label Use; Parkinson Disease; Piperidines; Psychotic Disorders; Quality of Life; Urea

Parkinson's disease psychosis (PDP) occurs commonly and can comprise the most troubling symptoms among the many that occur with this illness. Prior treatment options for PDP have been limited and unsatisfactory due to uneven efficacy data, burdensome monitoring, and lack of a specific FDA indication coupled with warnings of increased mortality. Pimavanserin, approved for the treatment of PDP by the FDA in 2016, overcomes some of these obstacles, with data proven efficacy and without the frequent monitoring required for clozapine. This presents an opportunity to transition patients with PDP to pimavanserin from older therapies. Black and colleagues provide their thoughtful recommendations on how to achieve this transition to pimavanserin while maintaining symptom control and minimizing disruptions that might occur with a medication change.

Topics: Antipsychotic Agents; Consensus; Humans; Off-Label Use; Parkinson Disease; Piperidines; Psychotic Disorders; Urea

Parkinson's disease psychosis (PDP) is a frequent complication of idiopathic Parkinson's disease (iPD) with significant impact on quality of life and association with poorer outcomes. Atypical antipsychotic drugs (APDs) are often used for the treatment of PDP; however, their use is often complicated by adverse drug reactions (ADRs). In this study, we present patients with PDP who were treated with the most commonly used atypical antipsychotic agents and review their respective ADRs.. A retrospective study was carried out to include a total of 45 patients with iPD who visited a movement disorders clinic between 2006 and 2015. All PDP patients treated with atypical APDs were included in the analysis for their specific ADRs.. Forty-five iPD patients (mean age of onset: 62.67 ± 9.86 years) were included, of those 10 patients had psychosis (mean age of onset: 76.80 ± 4.61 years). Of the 45 patients, 22.2% were found to have psychotic symptoms, of whom 70% had hallucinations, 20% had delusions, and 10% illusions. Seventy percent of psychotic symptoms occurred after ten or more years from diagnosis of iPD. PDP patients were treated with quetiapine, olanzapine, and risperidone separately or in combination, all of which were found to have certain ADRs.. This study was limited by its retrospective study design and small sample size and with likely selection bias.. The prevalence of PDP is relatively high in older patients with iPD. The uses of the currently available atypical APDs in this patient population are often complicated by ADRs. The selective 5-HT

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Olanzapine; Outcome and Process Assessment, Health Care; Parkinson Disease; Piperidines; Psychological Techniques; Psychotic Disorders; Quality of Life; Retrospective Studies; Urea

Parkinson's disease (PD) is a progressive neurodegenerative disorder with prominent motor and non-motor symptoms. Psychosis develops in over 40% of PD patients and it is one of the most distressing symptoms for patients and caregivers alike. Until recently, atypical antipsychotics, clozapine and quetiapine were used to treat psychotic symptoms, but treatment was associated with substantial concerns for side-effects of clozapine and unfounded efficacy for quetiapine. Extensive research has shown that the antipsychotic effect of these drugs could be attributed to serotonin 2a receptor (5-HT2A) triggered mechanisms. A selective 5-HT2A inverse agonist, pimavanserin, has been developed, investigated and has gained approval in April 2016 in the US for the treatment of hallucinations and delusions in PD. In this review we primarily focus on psychosis in PD, the current treatment possibilities and the new, emerging therapy, pimavanserin, a selective 5-HT2A inverse agonist. All articles were reviewed in this topic and indexed in PubMed with keywords: Parkinson's disease psychosis, serotonin 2a receptor inverse agonist, clozapine, quetiapine, pimavanserin.

Topics: Animals; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Agonists; Urea

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

The aim was to evaluate the clinical profile and effectiveness of ECT in women. A retrospective chart review was carried out to identify female patients who had received ECT during the period September 2013-February 2015. Details regarding their sociodemographic, clinical, and treatment data were extracted from these records for the present study. The total number of patients, admitted to our psychiatry inpatient clinic during the survey period, was 802. During this period, 26 (3.24 %) female patients received ECT. Patients who received ECT were mostly in age group of 25-44 years (76.9 %). Twenty percent of patients were in the postpartum period. Psychotic disorders (46.1 %) was the most common diagnosis for which ECT was used, followed by bipolar affective disorder, current episode manic (19.2 %). At the end of ECT courses, 70 % of the patients showed good response with a CGI-I of 1 or 2, and 30 % showed minimal response with a CGI-I score of 3. The most common side effects were post-ECT confusion (15.4 %) and prolonged seizure (11.5 %). This rate of prolonged seizure was higher the rates reported in the literature. The bronchospasm related with remifentanil, post-ECT bradycardia, hypertensive crisis and oligohydramnios were also reported in one case each. ECT is a safe and effective treatment option in women with severe psychiatric disorders and disorders in the perinatal/postpartum period are a major area of ECT use. The female gender may be a contributing factor for the higher rates of prolonged seizure.

Topics: Adult; Aged; Anesthetics, Intravenous; Bipolar Disorder; Bradycardia; Bronchial Spasm; Depression, Postpartum; Depressive Disorder; Electroconvulsive Therapy; Female; Hospitals, Psychiatric; Humans; Hypertension; Middle Aged; Oligohydramnios; Piperidines; Pregnancy; Pregnancy Complications; Psychotic Disorders; Puerperal Disorders; Remifentanil; Retrospective Studies; Treatment Outcome; Turkey; Young Adult

Parkinson's disease psychosis (PDP) is a common and often very disturbing component of Parkinson's disease (PD). PDP consists of hallucinations that are mainly visual and delusions that are often of a paranoid nature. These symptoms can be the most troubling and disruptive of all the manifestations of Parkinson's disease. Current treatment methods include the reduction of anti-Parkinson's medications, a strategy that may worsen the motor problems the medications are prescribed to alleviate, and the introduction of selected antipsychotic medications that carry with them the potential for troubling side effects and serious consequences. Pimavanserin has been developed and studied in clinical trials to specifically address Parkinson's disease psychosis and has been submitted to the U.S. Food and Drug Administration for its approval for this purpose. If this is granted, we believe the evidence of Pimavanserin efficacy, safety and tolerability will position this medication as the first choice for treatment of Parkinson's disease psychosis.

Topics: Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Tartrates

Approximately all clinically useful antipsychotic drugs have known activity as dopamine receptor antagonists, but many of these drugs also are inverse agonists at the serotonin-2A (5HT2A) receptor. Pimavanserin is an inverse agonist at the 5HT2A receptor, with a lower binding affinity at the serotonin-2C receptor and sigma 1 receptor, but no significant binding to dopamine or other receptors. Because of its unique pharmacology, pimavanserin was approved for the treatment of psychosis associated with Parkinson's disease, and it has a low risk for exacerbating motor symptoms compared to standard antipsychotic medications. Whether pimavanserin can treat psychotic symptoms in schizophrenia, psychotic depression, psychotic mania, delirium, or drug-induced psychosis, is not known. Based on its inverse agonist effect at 5HT2A receptors, pimavanserin may have potential for treating symptoms associated with the use of hallucinogen drugs and for treating akathisia associated with antipsychotic medications. [Journal of Psychosocial Nursing and Mental Health Services, 54 (6), 21-24.].

Topics: Female; Humans; Male; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Urea

Topics: Antiparkinson Agents; Antipsychotic Agents; Drug Administration Schedule; Drug Costs; Drug Interactions; Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Treatment Outcome; Urea

Pimavanserin, a novel agent approved for the treatment of Parkinson's disease psychosis, has potent actions as an antagonist/inverse agonist at serotonin 5HT2A receptors and less potent antagonist/inverse agonist actions at 5HT2C receptors.

Topics: Humans; Parkinson Disease; Piperidines; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Urea

Parkinson's disease psychosis (PDP) is theoretically a serotonin-dopamine imbalance syndrome due to disruption of the normal balance between the serotonergic and dopaminergic neurotransmitter systems in key brain circuits.

Topics: Antiparkinson Agents; Antipsychotic Agents; Brain; Dopamine; Humans; Levodopa; Lewy Bodies; Parkinson Disease; Piperidines; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Serotonin; Urea

Topics: Antiparkinson Agents; Antipsychotic Agents; Female; Humans; Male; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Urea

Topics: Antidepressive Agents; Depressive Disorder, Major; Female; Humans; Hyponatremia; Middle Aged; Piperazines; Piperidines; Psychotic Disorders

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

Topics: Antiparkinson Agents; Antipsychotic Agents; Female; Humans; Male; Parkinson Disease; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Agonists; Urea

In this work we investigated the ability of AM251 to reverse schizophrenia-like symptoms produced by a neurodevelopmental animal model based on a social isolation procedure. First, we assessed the validity of our isolation-rearing protocol and, as expected, isolation-reared rats showed hyperlocomotion in a novel environment, cognitive impairment in the novel object recognition (NOR) test and a significant increase in the number of aggressive behaviours in the social interaction test compared to group-housed controls. This behavioural picture was associated with a reduction in CB₁ receptor/G protein coupling in specific brain areas as well as reduced c-Fos immunoreactivity in the prefrontal cortex and caudate putamen. In this model, chronic but not acute treatment with the CB₁ receptor antagonist AM251 counteracted isolation-induced cognitive impairment in the NOR test and aggressive behaviours in the social interaction test. This behavioural recovery was accompanied by the rescue of CB₁ receptor functionality and c-Fos levels in all brain regions altered in isolation-reared rats. Moreover, chronic AM251 also increased c-Fos immunoreactivity in the nucleus accumbens, as previously demonstrated for antipsychotic drugs. Interestingly, the behavioural recovery due to chronic AM251 administration persisted until 10 d after discontinuing the treatment, indicating a long-lasting effect of the cannabinoid antagonist on psychotic-like symptoms.

Topics: Acute Disease; Animals; Antipsychotic Agents; Cannabinoids; Interpersonal Relations; Male; Piperidines; Psychotic Disorders; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Recovery of Function; Social Isolation; Treatment Outcome

The 5-hydroxytryptamine7 (5-HT7) receptor is a G-protein coupled receptor for serotonin that has been implicated in the pathophysiology of psychiatric and neurological disorders including anxiety, depression and schizophrenia. A number of studies have attempted to evaluate the potential role of the 5-HT7 receptor in schizophrenia by utilising genetic or pharmacological tools but to date these have provided conflicting results. Here we investigate the effect of a selective 5-HT7 receptor antagonist, SB-269970, in in vivo psychosis and cognition models and relate efficacy to brain exposures of the compound. SB-269970 significantly attenuated amphetamine-induced rearing and circling in rats. A similar effect was observed in an N-methyl d-aspartic acid (NMDA) receptor antagonist driven psychosis model, where SB-269970 significantly reversed phencyclidine-induced hyperlocomotion, rearing and circling; although the effect was not as robust as with the 5-HT2a receptor antagonist positive control, MDL100,907. SB-269970 also attenuated a temporal deficit in novel object recognition (NOR), indicative of an improvement in recognition memory. Pharmacokinetic analysis of plasma and brain samples taken after behavioural testing confirmed that efficacy was achieved at doses and pre-treatment times where receptor occupancy was substantial. These findings highlight the anti-psychotic and pro-cognitive potential of 5-HT7 receptor antagonists and warrant further studies to explore their therapeutic potential in schizophrenia.

Topics: Amphetamine; Animals; Animals, Outbred Strains; Cognition; Disease Models, Animal; Fluorobenzenes; Locomotion; Male; Phencyclidine; Phenols; Piperidines; Psychotic Disorders; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Recognition, Psychology; Serotonin Antagonists; Sulfonamides

Patients suffering from amphetamine-induced psychosis display repetitive behaviors, partially alleviated by antipsychotics, which are reminiscent of rodent stereotypies. Due to recent evidence implicating endocannabinoid involvement in brain disorders, including psychosis, we studied the effects of endocannabinoid signaling on neuronal oscillations of rats exhibiting methamphetamine stereotypy. Neuronal network oscillations were recorded with multiple single electrode arrays aimed at the nucleus accumbens of freely-moving rats. During the experiments, animals were dosed intravenously with the CB1 receptor antagonist rimonabant (0.3 mg/kg) or vehicle followed by an ascending dose regimen of methamphetamine (0.01, 0.1, 1, and 3 mg/kg; cumulative dosing). The effects of drug administration on stereotypy and local gamma oscillations were evaluated. Methamphetamine treatment significantly increased high frequency gamma oscillations (∼80 Hz). Entrainment of a subpopulation of nucleus accumbens neurons to high frequency gamma was associated with stereotypy encoding in putative fast-spiking interneurons, but not in putative medium spiny neurons. The observed ability of methamphetamine to induce both stereotypy and high frequency gamma power was potently disrupted following CB1 receptor blockade. The present data suggest that CB1 receptor-dependent mechanisms are recruited by methamphetamine to modify striatal interneuron oscillations that accompany changes in psychomotor state, further supporting the link between endocannabinoids and schizophrenia spectrum disorders.

Topics: Animals; Brain Waves; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Central Nervous System Stimulants; Disease Models, Animal; Dose-Response Relationship, Drug; Interneurons; Male; Methamphetamine; Nerve Tissue Proteins; Neurotoxicity Syndromes; Nucleus Accumbens; Piperidines; Psychomotor Performance; Psychotic Disorders; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, Cannabinoid; Rimonabant

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration in cognitive functioning. Overall, 25-50% of patients with AD also show symptoms of psychosis including hallucinations and delusions. As all available antipsychotic drugs have a 'black-box' warning for use in these patients because of increased mortality, no appropriate treatment for psychotic symptoms in AD currently exists. In the present study, we examined whether selective antagonism of 5-HT(2A) serotonin receptors has antipsychotic-like activity in an animal model of AD. Mice receiving an intracerebroventricular infusion of the amyloid β(25-35) peptide fragment showed AD-like histopathology and a psychosis-related behavioral phenotype with enhanced responses to the psychostimulants 2,5-dimethoxy-4-iodoamphetamine hydrochloride and amphetamine as well as disrupted prepulse inhibition. Treatment with pimavanserin, a selective serotonin 5-HT(2A) receptor inverse agonist, prevented 2,5-dimethoxy-4-iodoamphetamine hydrochloride-induced head twitches, reversed the augmented locomotor response to amphetamine, and normalized prepulse inhibition in mice with amyloid pathology. These data suggest that an infusion of amyloid β might induce alterations in serotonergic function that underlie a psychosis-like phenotype that can be normalized by treatment with a 5-HT(2A) inverse agonist. This in turn suggests that 5-HT(2A) inverse agonists, such as pimavanserin, might have therapeutic benefits in the treatment of psychosis in AD patients.

Topics: Alzheimer Disease; Amphetamine; Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Disease Models, Animal; Drug Inverse Agonism; Male; Mice; Piperidines; Psychotic Disorders; Serotonin 5-HT2 Receptor Antagonists; Urea

Both severe hypokalemia and persistent hypertension are clinical symptoms of hyperaldosteronism. Hyperaldosteronism may occur as a primary or secondary syndrome. Excess ACTH produced ectopically by tumors may induce hyperaldosteronism through the mineralocorticoid activity of glucocorticoids that are upregulated by ACTH. Licorice, with the active ingredient glycyrrhiza, is also a well-known inducer of hyperaldosteronism under specific conditions. In this report, we describe a case of severe hypokalemia caused by ectopic ACTH syndrome (EAS) elicited by an intrathoracic carcinoid tumor, which had transformed to produce ACTH during the 6-year clinical course, and was modulated by licorice ingestion. Hypokalemia was not clearly recognized preoperatively but became obvious within 3 h of general anesthesia with epidural blockade. At the end of anesthesia, arterial blood gas analysis indicated severe hypokalemia ([K(+)] = 1.7 mEq/l) and metabolic alkalosis (pH 7.56, PaCO(2) = 54.9 mmHg, HCO(3)(-) = 44.5 mmol/l, BE = 21.8 mmol/l), without any typical symptoms such as muscle weakness or ECG abnormalities. The hypokalemia was resistant to potassium supplementation and persisted for 4 days. Perioperative imbalance between the administration and elimination of potassium and surgical stress might contribute to the rapid exacerbation and induce the clinical manifestation of EAS.

Topics: ACTH Syndrome, Ectopic; Adjuvants, Anesthesia; Anesthesia; Anesthetics, Intravenous; Blood Gas Analysis; Blood Pressure; Carcinoid Tumor; Fentanyl; Heart Rate; Hormones; Humans; Hypertension; Hypokalemia; Male; Middle Aged; Nicardipine; Perioperative Period; Piperidines; Pneumonia, Pneumocystis; Psychotic Disorders; Remifentanil; Thoracic Neoplasms; Tomography, X-Ray Computed

Parkinson's disease psychosis (PDP) is a condition for which a safe, tolerated, and effective therapy is lacking. Treatment with typical or atypical antipsychotics may be contraindicated in patients with PDP because of the potential for aggravating motor symptoms. This study used a novel animal model with features of both Parkinson's disease (PD) and psychosis to examine a potential mechanism for reversing PDP. Animals with bilateral 6-hydroxydopamine lesions of the substantia nigra displayed motoric impairments characteristic of humans with PD. In addition, they displayed augmented head twitches, augmented amphetamine-induced locomotor activity, and disrupted prepulse inhibition compared with sham controls, behavioral indices frequently used to assess antipsychotic activity in animal models. Pimavanserin, a selective 5-HT2A antagonist/inverse agonist, reversed the psychotic-like behavioral deficits, suggesting that nigrostriatal (6-hydroxydopamine) lesions induced alterations in 5-HT2A-mediated signaling. The selective 5-HT2A inverse agonist M100907, but not the selective 5-HT2C inverse agonist SB 252084 paralleled the effects of pimavanserin. Of note, the reversal of psychotic-like behaviors produced by 5-HT2A inverse agonists occurred without disrupting motor behaviors in lesioned subjects, suggesting that 5HT2A antagonism/inverse agonism may be beneficial in the treatment of PDP.

Topics: Amphetamine; Amphetamines; Animals; Antipsychotic Agents; Behavior, Animal; Central Nervous System Stimulants; Disease Models, Animal; Dyskinesias; Fenfluramine; Fluorobenzenes; Hyperkinesis; Male; Motor Activity; Oxidopamine; Parkinson Disease; Piperidines; Psychotic Disorders; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Sensory Gating; Serotonin 5-HT2 Receptor Antagonists; Serotonin Agents; Serotonin Receptor Agonists; Substantia Nigra; Tyrosine 3-Monooxygenase; Urea

Topics: Antipsychotic Agents; Cyclooxygenase 2 Inhibitors; Dibenzocycloheptenes; Evidence-Based Medicine; Heterocyclic Compounds, 4 or More Rings; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Isoindoles; Isoxazoles; Lactones; Lurasidone Hydrochloride; Piperidines; Psychotic Disorders; Pyridines; Serotonin Receptor Agonists; Sulfones; Thiazoles

Pharmacovigilance has revealed hundreds of reports of neuropsychiatric disorders and several deaths by suicide.

Topics: Cannabinoid Receptor Antagonists; Clinical Trials as Topic; Depression; Drug-Related Side Effects and Adverse Reactions; Europe; Humans; Movement Disorders; Piperidines; Psychotic Disorders; Pyrazoles; Suicide

The role of fibroblast growth factor receptors (FGFR) in normal brain development has been well-documented in transgenic and knock-out mouse models. Changes in FGF and its receptors have also been observed in schizophrenia and related developmental disorders. The current study examines a transgenic th(tk-)/th(tk-) mouse model with FGF receptor signaling disruption targeted to dopamine (DA) neurons, resulting in neurodevelopmental, anatomical, and biochemical alterations similar to those observed in human schizophrenia. We show in th(tk-)/th(tk-) mice that hypoplastic development of DA systems induces serotonergic hyperinnervation of midbrain DA nuclei, demonstrating the co-developmental relationship between DA and 5-HT systems. Behaviorally, th(tk-)/th(tk-) mice displayed impaired sensory gaiting and reduced social interactions correctable by atypical antipsychotics (AAPD) and a specific 5-HT2A antagonist, M100907. The adult onset of neurochemical and behavioral deficits was consistent with the postpubertal time course of psychotic symptoms in schizophrenia and related disorders. The spectrum of abnormalities observed in th(tk-)/th(tk-) mice and the ability of AAPD to correct the behavioral deficits consistent with human psychosis suggests that midbrain 5-HT2A-controlling systems are important loci of therapeutic action. These results may provide further insight into the complex multi-neurotransmitter etiology of neurodevelopmental diseases such autism, bipolar disorder, Asperger's Syndrome and schizophrenia.

Topics: Animals; Animals, Newborn; Antipsychotic Agents; Behavior, Animal; Disease Models, Animal; Exploratory Behavior; Female; Fluorobenzenes; Gait Disorders, Neurologic; Grooming; Hydroxyindoleacetic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neural Inhibition; Piperidines; Protein-Tyrosine Kinases; Psychotic Disorders; Rats; Receptors, Fibroblast Growth Factor; Reflex, Startle; Serotonin; Serotonin Antagonists; Social Behavior

Iloperidone is an atypical antipsychotic in development for the treatment of schizophrenia. This report examines efficacy results from three 6-week, randomized, double-blind, placebo- and active comparator-controlled studies in patients with schizophrenia or schizoaffective disorder. Multiple doses of iloperidone were studied. Active comparators (haloperidol 15 mg/d, or risperidone 4-8 mg/d) were included to confirm trial validity. The primary protocol-defined efficacy variable in Study 1 was change from baseline to end point in Positive and Negative Syndrome Scale total scores; in Studies 2 and 3, it was change in the Positive and Negative Syndrome Scale-derived Brief Psychiatric Rating Scale scores. Results were assessed through analysis of covariance using last observation carried forward in the intent-to-treat population. In total, 1943 patients were randomized. At least 1 iloperidone dosing group in each study demonstrated significantly better efficacy than placebo (Study 1, iloperidone 12 mg/d [P = 0.047]; Study 2, 4-8 mg/d [P = 0.012] and 10-16 mg/d [P = 0.001]; and Study 3, 20-24 mg/d [P = 0.010]). Active controls were also significantly more effective than placebo in each trial, thus validating the trials. Additional analysis in patients who received active treatment for at least 2 weeks indicated comparable efficacy score reductions at 6 weeks for patients receiving iloperidone 20 to 24 mg/d versus those receiving haloperidol or risperidone. Risk for motor-related adverse events (eg, akathisia and extrapyramidal symptoms) was lower with iloperidone than with risperidone and haloperidol and was generally similar to placebo. These trials indicate that iloperidone is effective for the treatment of schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Endpoint Determination; Female; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia

Neuropsychiatric behaviours in Alzheimer's disease (AD) patients have been associated with neocortical alterations of presynaptic cholinergic and muscarinic M2 receptor markers. In contrast, it is unclear whether non-M2 muscarinic receptors have a role to play in AD behavioural symptoms.. To correlate the alterations of neocortical postsynaptic muscarinic receptors with clinical features of AD.. [(3)H]4-DAMP were used in binding assays with lysates of Chinese hamster ovary (CHO) cells stably transfected with M1-M5 receptors. [(3)H]4-DAMP was further used to measure muscarinic receptors in the postmortem orbitofrontal cortex of aged controls and AD patients longitudinally assessed for cognitive decline and behavioural symptoms.. [(3)H]4-DAMP binds to human postmortem brain homogenates and M1-, M3-, M4- and M5-transfected CHO lysates with subnanomolar affinity. Compared to the controls, the [(3)H]4-DAMP binding density is reduced only in AD patients with significant psychotic symptoms. The association between reduced [(3)H]4-DAMP binding and psychosis is independent of the effects of dementia severity or neurofibrillary tangle burden.. This study suggests that the loss of non-M2 muscarinic receptors in the orbitofrontal cortex may be a neurochemical substrate of psychosis in AD and provides a rationale for further development of muscarinic receptor ligands in AD pharmacotherapy.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Animals; CHO Cells; Cohort Studies; Cricetinae; Cricetulus; Female; Humans; Longitudinal Studies; Male; Muscarinic Antagonists; Neocortex; Neurofibrillary Tangles; Neuropsychological Tests; Piperidines; Psychotic Disorders; Radioligand Assay; Receptor, Muscarinic M2; Receptors, Muscarinic; Synapses; Transfection

Although the Van Rossum hypothesis of dopamine receptor overactivity in schizophrenia is supported by the antagonism of, or reduced dopamine neurotransmission at, dopamine D2 receptors by antipsychotics, it has been claimed that the antipsychotic (-)-OSU6162 has a very low affinity for the dopamine D2 receptor, and has only autoreceptor dopamine D2 receptor-stimulating action, and, therefore, in order to explain its clinical action, the drug must stimulate dopamine D2 receptors that are defective or underactive in schizophrenia. Because the mode of action of (-)-OSU6162 is critical in determining whether psychosis is associated with dopamine D2 receptor overactivity or deficit activity, we measured the potency of (-)-OSU6162 on the binding of [3H]domperidone and on the incorporation of [35S]-GTP-gamma-S into human cloned dopamine D2 receptor-containing cells. We found that (-)-OSU6162 had a dissociation constant of 35 nM at the functional high-affinity site of the dopamine D2 receptor, stimulated the incorporation of [35S]-GTP-gamma-S above 100 nM, and inhibited the incorporating action of 1 microM dopamine with an inhibitory dissociation constant, Ki, of 27 nM, all being properties of a dopamine partial agonist. While not excluding the possibility that dopamine underactivity may exist in the mesocortical system in psychosis, the antipsychotic action of (-)-OSU6162 is consistent with dopamine overactivity in psychosis.

Topics: Animals; Antipsychotic Agents; CHO Cells; Clone Cells; Cricetinae; Cricetulus; Dopamine; Dopamine Agonists; Humans; Hyperkinesis; Kinetics; Piperidines; Psychotic Disorders; Receptors, Dopamine D2

The effect of LSD in humans has been described as occurring in two temporal phases. The behavioral effects in rats also occur in two temporal phases: an initial suppression of exploration followed by increased locomotor activity.. We decided to investigate this phenomenon from the perspective that the pharmacology might have relevance to the neurochemical mechanisms underlying psychosis.. Twenty-five male Sprague-Dawley rats were trained to discriminate LSD (186 nmol/kg, 0.08 mg/kg, i.p.) with a 30-min preinjection time (LSD-30, N=12) and LSD (372 nmol/kg, 0.16 mg/kg, i.p.) with a 90-min preinjection time (LSD-90, N=13) from saline, using a two-lever, food-reinforced operant conditioning task.. LSD (186 or 372 nmol/kg, 0.08 or 0.16 mg/kg) given 30 min prior to training produced a cue that was completely antagonized by 5-HT2A antagonists and lasted no longer than 1 h. LSD (372 nmol/kg, 0.16 mg/kg) injected 90 min before training produced a cue that was not fully blocked by 5-HT2A antagonists, but instead was significantly inhibited by haloperidol. In these rats, substitution no longer occurred with the 5-HT2 agonists DOI or LSD (30 min preinjection), but full substitution was obtained with the D2 agonists apomorphine, N-propyldihydrexidine, and quinelorane.. The discriminative stimulus effect of LSD in rats occurs in two phases, and these studies provide evidence that the later temporal phase is mediated by D2 dopamine receptor stimulation. A second temporal phase that involves dopaminergic pathways would be consistent with the widespread belief that excessive dopaminergic activity may be an underlying cause of paranoid psychosis.

Topics: Amphetamine; Amphetamines; Animals; Apomorphine; Behavior, Animal; Cues; Discrimination Learning; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Fluorobenzenes; Hallucinogens; Haloperidol; Indans; Injections, Intraperitoneal; Lysergic Acid Diethylamide; Male; Piperidines; Psychotic Disorders; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors

Topics: Animals; Antipsychotic Agents; Drug Tolerance; Humans; Mice; Piperazines; Piperidines; Psychotic Disorders

Topics: Adult; Aged; Antipsychotic Agents; Cholinesterase Inhibitors; Donepezil; Drug Administration Schedule; Dyskinesia, Drug-Induced; Humans; Indans; Male; Middle Aged; Piperidines; Psychotic Disorders; Schizophrenia; Treatment Outcome

A new diaryl-methylene piperidine derivative, 2, displayed an atypical antipsychotic profile both in vitro and in vivo. The main pharmacological characteristics of this compound appears to reside in a more potent antagonism of the 5-HT2 serotonergic receptor than of the D2 dopaminergic receptor. This confirms that molecules displaying a D2/5-HT2 binding ratio < 1 possess clozapine-like antipsychotic activity.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Mice; Piperidines; Protein Binding; Psychomotor Agitation; Psychotic Disorders; Receptors, Dopamine D2; Receptors, Serotonin; Serotonin Antagonists

Tardive dyskinesia (TD) remains a significant clinical problem for which there is no uniformly effective treatment. Earlier trials with acetylcholine precursors may have been disappointing because of underlying damage to striatal cholinergic neurons in patients with TD. In contrast, new cholinesterase inhibitors, developed for the treatment of dementia, may improve TD by directly increasing cholinergic synaptic transmission.. We conducted an 8-week open-label trial of donepezil in the treatment of TD. Ten patients with schizophrenia or schizoaffective disorder who received stable doses of antipsychotics and met DSM-IV criteria for TD were treated with donepezil, 5 to 10 mg/day, for 6 weeks after a 2-week baseline period. Changes in total Abnormal Involuntary Movement Scale (AIMS) scores measured every 2 weeks were assessed for significance. Patients were also assessed using the Brief Psychiatric Rating Scale, the Mini-Mental State Examination, the Barnes Akathisia Scale, and the Simpson-Angus Scale.. Total AIMS scores decreased significantly (p = .0009), with no changes in other measures. Nine patients showed a positive response. Improvement was greatest in orofacial and upper extremity movements. No significant interactions were noted between the total AIMS scores and age (p > .29), duration of TD (p > .38), or duration of antipsychotic treatment (p > .14).. Donepezil appeared to be effective in suppressing TD in this pilot study. However, placebo-controlled, double-blind studies are necessary before donepezil can be recommended as a treatment for TD.

Topics: Adult; Aged; Antipsychotic Agents; Donepezil; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Neurologic Examination; Pilot Projects; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia

Topics: Aged; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Lewy Body Disease; Male; Piperidines; Psychotic Disorders

The goal of this study was to develop a suitable kinetic analysis method for quantification of 5-HT2A receptor parameters with [11C]MDL 100,907. Twelve control studies and four preblocking studies (400 nmol/kg unlabeled MDL 100,907) were performed in isoflurane-anesthetized rhesus monkeys. The plasma input function was determined from arterial blood samples with metabolite measurements by extraction in ethyl acetate. The preblocking studies showed that a two-tissue compartment model was necessary to fit the time activity curves of all brain regions including the cerebellum--in other words, the need for two compartments is not proof of specific binding. Therefore, a three-tissue compartment model was used to analyze the control studies, with three parameters fixed based on the preblocking data. Reliable fits of control data could be obtained only if no more than three parameters were allowed to vary. For routine use of [11C]MDL 100,907, several simplified methods were evaluated. A two-tissue (2T') compartment with one fixed parameter was the most reliable compartmental approach; a one-compartment model failed to fit the data adequately. The Logan graphical approach was also tested and produced comparable results to the 2T' model. However, a simulation study showed that Logan analysis produced a larger bias at higher noise levels. Thus, the 2T' model is the best choice for analysis of [11C]MDL 100,907 studies.

Topics: Animals; Blood Pressure; Brain; Carbon Radioisotopes; Depression; Fluorobenzenes; Heart Rate; Ligands; Macaca mulatta; Models, Biological; Piperidines; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Tomography, Emission-Computed

Previous studies have shown D2-like dopamine receptor involvement in the regulation of phospholipid methylation (PLM), while others have documented impaired methionine and folate metabolism in schizophrenia. Utilizing [14C]formate labeling in cultured neuroblastoma cell lines, we now show that D4 dopamine receptors (D4R) mediate the stimulatory effect of dopamine (DA) on PLM. The effect of DA was potently blocked by highly D4R-selective antagonists and stimulated by the D4R-selective agonist CP-226269. DA-stimulated PLM was dependent upon the activity of methionine cycle enzymes, but DA failed to increase PLM in [3H]methionine labeling studies, indicating that a methionine residue in the D4R might be involved in mediating PLM. A direct role for MET313, located on transmembrane helix No. 6 immediately adjacent to phospholipid headgroups, was further suggested from adenosylation, site-directed mutagenesis and GTP-binding results. A comparison of PLM in lymphocytes from schizophrenia patients vs control samples showed a four-fold lower activity in the schizophrenia group. These findings reveal a novel mechanism by which the D4R can regulate membrane composition. Abnormalities in D4R-mediated PLM may be important in psychiatric illnesses such as schizophrenia.

Topics: Amino Acid Sequence; Aminopyridines; Animals; Benzazepines; Binding Sites; Carbon Radioisotopes; CHO Cells; Clozapine; Cricetinae; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Formates; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Methionine; Mutagenesis, Site-Directed; Neuroblastoma; Phospholipids; Phosphorylation; Piperidines; Psychotic Disorders; Pyridines; Pyrroles; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D4; Recombinant Proteins; S-Adenosylmethionine; Salicylamides; Schizophrenia; Transfection; Tumor Cells, Cultured

Topics: Adult; Antipsychotic Agents; Humans; Isoxazoles; Male; Piperidines; Priapism; Psychotic Disorders; Risperidone

While effective as a single agent in a significant proportion of treatment refractory patients, clozapine is often used in combination with other medications, including classical neuroleptics (1), mood stabilizers and antidepressants (2), benzodiazepines (3) and lithium (4). In Denmark, where clozapine has been in near continuous use since 1975, up to 60% of clozapine patients receive additional medication (4). Classical neuroleptics, often at antipsychotic levels, are the medications most frequently added, and are used in 30-35% of patients receiving clozapine (4,5). Clozapine, due to its low D2-blocking effect, may be therapeutically insufficient to contain symptoms and additional agents may be required (4). In controlled clinical trials risperidone has been shown to be superior to haloperidol (6), but has not yet been rigorously compared to clozapine. In light of its established efficacy and pharmacological profile (7) risperidone may be reasonably construed to be a medication with efficacy somewhere between clozapine and classical neuroleptics. As such, it may be especially well suited for use with clozapine as a part of an augmentation strategy. There are no reports in the literature describing the concurrent use of risperidone and clozapine. We present two cases demonstrating augmentation of clozapine's effects through combined use with clozapine.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Humans; Isoxazoles; Male; Piperidines; Psychotic Disorders; Risperidone; Schizophrenia, Paranoid; Schizophrenic Psychology

Topics: Adult; Antipsychotic Agents; Female; Humans; Isoxazoles; Neuroleptic Malignant Syndrome; Piperidines; Primidone; Psychotic Disorders; Risperidone; Tremor

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Humans; Isoxazoles; Male; Piperidines; Psychotic Disorders; Risperidone

The present study has shown that a subthreshold dose of the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801, combined with a subthreshold dose of LSD, produces marked locomotor stimulation in monoamine-depleted mice. Likewise, MK-801, as well as the muscarine receptor antagonist atropine and the alpha-adrenoceptor agonist clonidine, were found to interact synergistically with the putative 5-HT2 receptor agonist UH-232 to produce locomotor activation in monoamine-depleted mice. All these responses were effectively blocked by the highly selective 5-HT2A receptor antagonist MDL 100,907. On the other hand, MDL 100,907 did not antagonize the hyperactivity response produced by clonidine given in combination with MK-801 or atropine in monoamine-depleted mice, nor the response produced by the mixed DA receptor agonist apomorphine, underlining the selectivity in the antagonistic action of MDL 100,907. Furthermore, MDL 100,907 attenuated the hyperactivity produced in intact mice by such disparate agents as MK-801, atropine or the DA uptake inhibitor GBR 12,909. A putative "permissive" role of the 5-HT2 receptor in the context of psychomotor activation is discussed, as well as its possible importance as target for antipsychotic therapy.

Topics: Animals; Biogenic Monoamines; Disease Models, Animal; Dizocilpine Maleate; Dopamine Uptake Inhibitors; Excitatory Amino Acid Antagonists; Fluorobenzenes; Glutamic Acid; Hallucinogens; Lysergic Acid Diethylamide; Male; Mice; Mice, Inbred Strains; Neurotransmitter Agents; Piperazines; Piperidines; Psychomotor Performance; Psychotic Disorders; Receptor, Serotonin, 5-HT2A; Receptors, Muscarinic; Receptors, Serotonin; Serotonin; Serotonin Antagonists

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Clozapine; Drug Costs; Humans; Isoxazoles; Nursing Homes; Piperidines; Psychotic Disorders; Research; United States

Topics: Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Psychotic Disorders; Risperidone

Topics: Antipsychotic Agents; Humans; Isoxazoles; Parkinson Disease; Piperidines; Psychotic Disorders; Risperidone

Topics: Adolescent; Antipsychotic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hospitalization; Humans; Isoxazoles; Male; Piperidines; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology

The author presents some comments of an open study on clinical evaluation of risperidone. Except for the diminuation of the manifest psychotic symptoms sedative and extrapyramidal side-effects appeared, which decreased during further medication, as well as the tachycardia. The exclusion of the restless patient at the very beginning of the study was the negative result of the wash-out interval. As a maintenance therapy 1-2 mg daily dose of respiridone was enough. Further follow-up is useful after one year medication to study the longterm effect of the therapy. The main purpose of the paper is to state ten practical problems which should be taken into consideration.

Topics: Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Psychotic Disorders; Risperidone

Topics: Antipsychotic Agents; Humans; Piperidines; Psychotic Disorders; Receptors, Opioid; Receptors, sigma

In vitro receptor-binding profiles and in vivo pharmacological studies have shown risperidone to be a potent mixed serotonin-S2 dopamine-D2-like receptor antagonist. While anti-D2 activity may relate to the antipsychotic potency of neuroleptic drugs, an antidepressive efficacy of substances with anti-S2 activity has been suggested. In an open pilot-study, ten patients with schizodepressive disorders or a DSM-III-R diagnosis of psychotic major depressive episodes were treated with risperidone (2-10 mg/d) for six weeks. Weekly psychopathological evaluation was performed, including BPRS, SANS, SAPS, VAS scales, and AIMS and UKU for the assessment of side-effects. Generally, the psychotic syndrome (BPRS, SANS and SAPS) decreased markedly in all patients; seven patients also showed a clinically significant improvement of depressive symptoms (BPRS). Except for two patients who needed biperiden because of extrapyramidal side-effects, the tolerance of risperidone was good. The antipsychotic and antidepressive properties of risperidone shown in our pilot study are promising enough to merit full double-blind controlled trials for further evaluation of its therapeutic value in this broad spectrum of psychiatric disorders.

Topics: Adult; Aged; Antipsychotic Agents; Depressive Disorder; Female; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Syndrome

Risperidone (R 64766) was administered during 4 weeks in increasing doses to 17 psychotic patients, to evaluate the hematological and cardiovascular safety, the therapeutic effect, side effects, effects upon endocrinological parameters and the pharmacokinetic profile. Following a placebo wash-out period of 1 week, the initial dose was 10 mg daily, increasing with 5 mg per week until the maximal dose of 25 mg daily was reached during the 4th week of treatment. Doses up to 20 mg daily resulted in a significant improvement of the total BPRS score and of the different BPRS factor scores; with higher doses, no further clinical benefit was achieved except for the hostility and anxiety-depression factor, while sedation became more prominent. No increase of extrapyramidal symptoms was noticed. Except for the sedation observed with higher doses, risperidone was well tolerated. No clinically relevant effects on cardiovascular and ECG parameters were noticed, and except for a slight increase of aspartate aminotransferase and alanine aminotransferase in one patient, no laboratory abnormalities were observed. Prolactin showed an expected increase, while the other endocrinological parameters revealed no changes. Risperidone had a linear pharmacokinetic profile.

Topics: Adult; Aged; Antipsychotic Agents; Blood Pressure; Electrocardiography; Female; Hormones; Humans; Isoxazoles; Male; Middle Aged; Oxazoles; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone

Topics: Adult; Biperiden; Female; Haloperidol; Humans; Infant, Newborn; Male; Maternal-Fetal Exchange; Milk, Human; Piperidines; Pregnancy; Pregnancy Complications; Psychotic Disorders

Topics: Adult; Basal Ganglia Diseases; Delusions; Haloperidol; Humans; Male; Neuroleptic Malignant Syndrome; Parasympatholytics; Piperidines; Psychotic Disorders

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Biperiden; Double-Blind Method; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Parkinson Disease, Secondary; Piperidines; Psychotic Disorders; Valproic Acid

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Anxiety Disorders; Butyrophenones; Female; Humans; Male; Middle Aged; Piperidines; Psychotic Disorders; Schizophrenia

Thirty female patients were studied while taking penfluridol, continuous neuroleptic antipsychotic medication given orally. These patients were hospitalized making observation and control adequate in 73.3% of the cases. Colateral effects that we observed were minimum and variable in nearly all the patients, and many of these effects are of little significance as they are observed with other neuroleptics.

Topics: Adult; Drug Evaluation; Female; Humans; Penfluridol; Piperidines; Psychotic Disorders

Topics: Acute Disease; Adult; Antipsychotic Agents; Female; Fluphenazine; Humans; Male; Middle Aged; Piperidines; Psychotic Disorders; Sulfonamides; Time Factors; Tranquilizing Agents

Topics: Administration, Oral; Adolescent; Adult; Aged; Delayed-Action Preparations; Female; Humans; Hydrocarbons, Halogenated; Male; Middle Aged; Piperidines; Psychotic Disorders; Toluene; Tranquilizing Agents

Topics: Alcoholism; Antipsychotic Agents; Chronic Disease; Delayed-Action Preparations; Female; Fluphenazine; Hallucinations; Humans; Male; Palmitic Acids; Paranoid Disorders; Piperidines; Psychotic Disorders; Schizophrenia; Sulfonamides

Topics: Adult; Attention; Delayed-Action Preparations; Female; Humans; Hydrocarbons, Halogenated; Male; Middle Aged; Perception; Piperidines; Psychological Tests; Psychotic Disorders; Time Factors; Toluene; Tranquilizing Agents; Writing

Topics: Adolescent; Adult; Aged; Delusions; Female; Humans; Injections, Intramuscular; Male; Mental Disorders; Middle Aged; Neurotic Disorders; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenia, Disorganized; Schizophrenia, Paranoid; Spiro Compounds; Tranquilizing Agents

Topics: Anxiety; Benzimidazoles; Chronic Disease; Hallucinations; Humans; Ketones; Mental Disorders; Piperidines; Psychotic Disorders; Schizophrenia; Schizophrenia, Disorganized; Tranquilizing Agents

Topics: 1-Propanol; Adolescent; Adult; Antiparkinson Agents; Basal Ganglia Diseases; Biperiden; Catatonia; Delayed-Action Preparations; Extrapyramidal Tracts; Humans; Male; Middle Aged; Paranoid Disorders; Piperidines; Psychotic Disorders; Schizophrenia; Schizophrenia, Disorganized; Tranquilizing Agents; Tremor

Topics: Adult; Benzimidazoles; Female; Humans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Tranquilizing Agents

Topics: Benzimidazoles; Humans; Male; Paranoid Disorders; Piperidines; Psychotic Disorders; Schizophrenia

Topics: Animals; Drug Combinations; Drug Tolerance; Humans; Mental Disorders; Piperidines; Psychotic Disorders; Rats; Schizophrenia; Tranquilizing Agents

Topics: Benzimidazoles; Humans; Piperidines; Psychotic Disorders; Tranquilizing Agents

Topics: Acute Disease; Adolescent; Adult; Chronic Disease; Delayed-Action Preparations; Drug Tolerance; Esters; Humans; Middle Aged; Phenothiazines; Piperidines; Psychotic Disorders; Undecylenic Acids

Topics: Adolescent; Adult; Aged; Anxiety Disorders; Female; Humans; Middle Aged; Phenothiazines; Piperidines; Psychotic Disorders; Tranquilizing Agents

Topics: Adolescent; Adult; Aged; Benzimidazoles; Chemical Phenomena; Chemistry; Drug Tolerance; Female; Humans; Middle Aged; Piperidines; Psychotic Disorders; Tranquilizing Agents

Topics: Benzimidazoles; Chemical Phenomena; Chemistry; Dibenzazepines; Humans; Piperidines; Psychotic Disorders; Spiro Compounds; Tranquilizing Agents

Topics: Butyrophenones; Drug Synergism; Drug Tolerance; Haloperidol; Humans; Phenothiazines; Piperazines; Piperidines; Psychopharmacology; Psychotherapy; Psychotic Disorders; Thioridazine; Thiothixene; Tranquilizing Agents; Triflupromazine; Xanthenes

Topics: 1-Propanol; Adult; Age Factors; Aged; Bipolar Disorder; Follow-Up Studies; Humans; Middle Aged; Neurologic Manifestations; Parkinson Disease; Piperidines; Psychotic Disorders; Schizophrenia; Tranquilizing Agents

Topics: Adolescent; Adult; Aged; Female; Humans; Hypnotics and Sedatives; Male; Methaqualone; Middle Aged; Neurotic Disorders; Piperidines; Psychotic Disorders; Sleep Initiation and Maintenance Disorders

Topics: Adolescent; Antidepressive Agents; Aspartate Aminotransferases; Attention; Brain Damage, Chronic; Butyrophenones; Child; Child Behavior Disorders; Child, Preschool; Fluorine; Humans; Piperidines; Psychotic Disorders; Schizophrenia, Childhood; Trifluperidol

Topics: Antidepressive Agents; Butyrophenones; Fluorine; Haloperidol; Humans; Piperidines; Psychotic Disorders; Trifluperidol

Topics: Adult; Aged; Hallucinations; Humans; Male; Mental Disorders; Middle Aged; Paranoid Disorders; Piperidines; Psychotic Disorders; Schizophrenia

Topics: Antidepressive Agents; Butyrophenones; Chlorpromazine; Extrapyramidal Tracts; Female; Fluorine; Humans; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Tranquilizing Agents; Trifluoperazine; Trifluperidol

Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Nervous System Diseases; Neurotic Disorders; Nitriles; Phenothiazines; Piperidines; Psychotic Disorders; Tranquilizing Agents

Topics: Adolescent; Adult; Aged; Female; Humans; Intellectual Disability; Middle Aged; Nitriles; Phenothiazines; Piperidines; Psychotic Disorders; Schizophrenia; Tranquilizing Agents

Topics: Adult; Butyrophenones; Depression; Female; Fluphenazine; Humans; Male; Piperidines; Psychotic Disorders; Schizophrenia; Thioridazine

Topics: Adult; Female; Humans; Piperidines; Psychotic Disorders

Topics: Antisocial Personality Disorder; Bipolar Disorder; Depression; Drug Combinations; Glycolates; Hallucinogens; Mental Disorders; Piperidines; Psychotic Disorders; Pyrrolidines; Schizophrenia; Toxicology

Topics: Biomedical Research; Drug Combinations; Glycolates; Hallucinogens; Humans; Piperidines; Psychopharmacology; Psychotic Disorders; Pyrrolidines

Topics: Antisocial Personality Disorder; Anxiety; Anxiety Disorders; Atropine; Bipolar Disorder; Depression; Drug Combinations; Drug Therapy; Electroencephalography; Glycolates; Hallucinogens; Mental Disorders; Piperidines; Psychoses, Alcoholic; Psychotic Disorders; Pyrrolidines; Schizophrenia; Toxicology

Topics: Bipolar Disorder; Butyrophenones; Hallucinations; Humans; Hypnotics and Sedatives; Intellectual Disability; Mental Disorders; Paranoid Disorders; Paresis; Parkinsonian Disorders; Piperidines; Psychomotor Agitation; Psychotic Disorders; Schizophrenia

Topics: Bipolar Disorder; Butyrophenones; Chorea; Drug Therapy; Electromyography; Haloperidol; Humans; Huntington Disease; Mental Disorders; Movement Disorders; Piperidines; Psychotic Disorders; Temperament

Topics: Anesthetics; Diagnosis, Differential; Hallucinogens; Humans; Neurotic Disorders; Phencyclidine; Piperidines; Psychopharmacology; Psychotic Disorders

Topics: Anesthetics; Brain Chemistry; Pharmacology; Phencyclidine; Piperidines; Psychoses, Substance-Induced; Psychotic Disorders; Toxicology

Topics: Mental Disorders; Phenothiazines; Piperidines; Psychotic Disorders; Tranquilizing Agents

Topics: Chlorpromazine; Dementia; Humans; Mental Disorders; Opium; Piperidines; Psychopharmacology; Psychotic Disorders; Reserpine

Topics: Electroconvulsive Therapy; Haloperidol; Piperidines; Psychotherapy; Psychotic Disorders

Topics: Humans; Medical Records; Piperidines; Psychoses, Alcoholic; Psychotic Disorders; Schizophrenia

Topics: Electroconvulsive Therapy; Piperidines; Psychosurgery; Psychotherapy; Psychotic Disorders

Topics: Mental Disorders; Phenothiazines; Piperidines; Promazine; Psychotic Disorders

Topics: Disease; Mental Disorders; Piperidines; Psychosurgery; Psychotic Disorders; Veterans

Topics: Dementia; Double-Blind Method; Humans; Mental Disorders; Piperidines; Psychotic Disorders

Topics: Chlorpromazine; Lysergic Acid Diethylamide; Mental Disorders; Piperidines; Psychotic Disorders

Topics: Electroconvulsive Therapy; Piperidines; Psychotherapy; Psychotic Disorders

Topics: Central Nervous System; Central Nervous System Stimulants; Humans; Mental Disorders; Nervous System; Piperidines; Psychotic Disorders

Topics: Electroconvulsive Therapy; Mental Disorders; Piperidines; Psychotic Disorders

Topics: Mental Disorders; Piperidines; Psychosurgery; Psychotic Disorders

Topics: Bipolar Disorder; Chlorpromazine; Depression; Depressive Disorder, Major; Methylphenidate; Piperidines; Psychotic Disorders

Topics: Electroconvulsive Therapy; Piperidines; Psychiatry; Psychosurgery; Psychotic Disorders

Topics: Electroconvulsive Therapy; Piperidines; Psychosurgery; Psychotic Disorders

Topics: Anti-Allergic Agents; Autonomic Agents; Biphenyl Compounds; Histamine H1 Antagonists; Humans; Phenothiazines; Piperidines; Psychotic Disorders; Syndrome

Topics: Delusions; Electroconvulsive Therapy; Hallucinations; Humans; Piperidines; Psychosurgery; Psychotherapy; Psychotic Disorders

Topics: Chlorpromazine; Electroconvulsive Therapy; Mental Disorders; Piperidines; Psychotic Disorders; Reserpine; Secologanin Tryptamine Alkaloids

Topics: Delusions; Electroconvulsive Therapy; Hallucinations; Humans; Piperidines; Psychosurgery; Psychotherapy; Psychotic Disorders

Topics: Chlorpromazine; Hospitalization; Humans; Mental Disorders; Piperidines; Psychosurgery; Psychotic Disorders; Reserpine; Secologanin Tryptamine Alkaloids

Topics: Bridged-Ring Compounds; Hallucinations; Humans; Mental Disorders; Piperidines; Psychotic Disorders; Syndrome; Urea

Topics: Electroconvulsive Therapy; Humans; Piperidines; Psychosurgery; Psychotic Disorders

Topics: Electroconvulsive Therapy; Mental Disorders; Piperidines; Psychotherapy; Psychotic Disorders

Topics: Mental Disorders; Piperidines; Psychotic Disorders; Schizophrenia