Pimavanserin: A Novel Antipsychotic for Parkinson’s Disease Psychosis

Bozymski, Kevin M; Lowe, Denise; Pasternak, Kiersten M; Gatesman, Travis L; Crouse, Ericka L. Breden

doi:10.1177/1060028017693029

Cited by 31 publications

(20 citation statements)

References 22 publications

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“…Likewise, serotonin has long been implicated in salience attribution (especially aversive salience) and psychosis. 5-HT (serotonin) receptors are targeted by multiple antipsychotics, and the specific 5-HT2A antagonist pimavanserin has recently been approved for the treatment of psychosis in parkinsonian patients ( Bozymski et al, 2017 ; Kianirad and Simuni, 2017 ; Sahli and Tarazi, 2018 ).…”

Section: Limitations and Challenges Of Harnessing The Hippocampus→nacmentioning

confidence: 99%

Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia

et al. 2020

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The development of current neuroleptics was largely aiming to decrease excessive dopaminergic signaling in the striatum. However, the notion that abnormal dopamine creates psychotic symptoms by causing an aberrant assignment of salience that drives maladaptive learning chronically during disease development suggests a therapeutic value of early interventions that correct salience-related neural processing. The mesolimbic dopaminergic output is modulated by several interconnected brain-wide circuits centrally involving the hippocampus and key relays like the ventral and associative striatum, ventral pallidum, amygdala, bed nucleus of the stria terminalis, nucleus reuniens, lateral and medial septum, prefrontal and cingulate cortex, among others. Unraveling the causal relationships between these circuits using modern neuroscience techniques holds promise for identifying novel cellular—and ultimately molecular—treatment targets for reducing transition to psychosis and symptoms of schizophrenia. Imaging studies in humans have implicated a hyperactivity of the hippocampus as a robust and early endophenotype in schizophrenia. Experiments in rodents, in turn, suggested that the activity of its output region—the ventral subiculum—may modulate dopamine release from ventral tegmental area (VTA) neurons in the ventral striatum. Even though these observations suggested a novel circuit-level target for anti-psychotic action, no therapy has yet been developed along this rationale. Recently evaluated treatment strategies—at least in part—target excess glutamatergic activity, e.g. N-acetyl-cysteine (NAC), levetiracetam, and mGluR2/3 modulators. We here review the evidence for the central implication of the hippocampus-VTA axis in schizophrenia-related pathology, discuss its symptom-related implications with a particular focus on aberrant assignment of salience, and evaluate some of its short-comings and prospects for drug discovery.

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Section: Limitations and Challenges Of Harnessing The Hippocampus→nacmentioning

confidence: 99%

Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia

et al. 2020

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“…It is beneficial in psychosis in PD patients with PD, however this effect was not significant for visual hallucinations 8. A large augmentation study in patients with chronic schizophrenia showed improvement on total Positive and Negative Symptom Scale (PANSS) score for pimavanserin combined with risperidone, but not for pimavanserin added to haloperidol 9…”

Section: Discussionmentioning

confidence: 99%

Successful treatment of intractable visual hallucinations with 5-HT_{_2A}antagonist ketanserin

Sommer¹,

Kleijer

Visser

et al. 2018

BMJ Case Reports

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Hallucinations, visual, auditory or in another sensory modality, often respond well to treatment in patients with schizophrenia. Some, however, do not and can be very chronic and debilitating. We present a patient with schizophrenia with intractable hallucinations despite state of the art care, including high-dose clozapine and transcranial magnetic stimulation. Based on the possible role of the 5-HT receptor in hallucinations, we treated her with the antihypertensive drug ketanserin, a 5-HT receptor antagonist.This significantly reduced her visual but not her auditory hallucinations, suggesting a possible role of the 5HT receptor in the pathophysiology of specifically visual hallucinations. This is the first time ketanserin has been described to successfully reduce visual hallucinations in a patient with schizophrenia.

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“…This observation led to the hypothesis that a serotonin receptor inverse agonist, which binds to the serotonin receptor and decreases its intrinsic activity, may be useful in treating psychosis. Pimavanserin is a novel serotonin receptor inverse agonist that lacks activity at dopamine, muscarinic, adrenergic, and histamine receptors [64], and has recently been approved for PDP, as it reduced hallucinations and delusions in patients with PDP [65].…”

Section: Pimavanserinmentioning

confidence: 99%

Clozapine as a Model for Antipsychotic Development

Mihaljević²,

et al. 2017

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Schizophrenia is a devastating illness that affects up to 1% of the population; it is characterized by a combination of positive symptoms, negative symptoms, and cognitive impairment. Currently, treatment consists of one class of medications known as antipsychotics, which include typical (first-generation) and atypical (second-generation) agents. Unfortunately, antipsychotic medications have limited efficacy, with up to a third of patients lacking a full response. Clozapine, the first atypical antipsychotic developed, is the only medication shown to be superior to all other antipsychotics. However, owing to several life-threatening side effects and required enrollment in a registry with routine blood monitoring, clozapine is greatly underutilized in the US. Developing a medication as efficacious as clozapine with limited side effects would likely become the first-line therapy for schizophrenia and related disorders. In this review, we discuss the history of clozapine, landmark studies, and its clinical advantages and disadvantages. We further discuss the hypotheses for clozapine's superior efficacy based on neuroreceptor binding, and the limitations of a receptor-based approach to antipsychotic development. We highlight some of the advances from pharmacogenetic studies on clozapine and then focus on studies of clozapine using unbiased approaches such as pharmacogenomics and gene expression profiling. Finally, we examine how these approaches could provide insights into clozapine's mechanism of action and side-effect profile, and lead to novel and improved therapeutics.

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Pimavanserin: A Novel Antipsychotic for Parkinson’s Disease Psychosis

Abstract: Pimavanserin is a novel 5-HT inverse agonist that has shown promising results for managing hallucinations and delusions in patients with PDP without worsening motor effects or orthostasis. Yet its high cost and specialty pharmacy access may limit use in clinical practice.

Cited by 31 publications

References 22 publications

Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia

Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia

Successful treatment of intractable visual hallucinations with 5-HT_{_2A}antagonist ketanserin

Clozapine as a Model for Antipsychotic Development

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Pimavanserin: A Novel Antipsychotic for Parkinson’s Disease Psychosis

Abstract: Pimavanserin is a novel 5-HT inverse agonist that has shown promising results for managing hallucinations and delusions in patients with PDP without worsening motor effects or orthostasis. Yet its high cost and specialty pharmacy access may limit use in clinical practice.

Cited by 31 publications

References 22 publications

Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia

Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia

Successful treatment of intractable visual hallucinations with 5-HT2Aantagonist ketanserin

Clozapine as a Model for Antipsychotic Development

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Product

Resources

About

Successful treatment of intractable visual hallucinations with 5-HT_{_2A}antagonist ketanserin