Abstract
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.
Highlights
No pharmacological agents are approved by the U.S Food and Drug Administration (FDA) to treat dementia-related psychosis (DRP)
Pimavanserin is being investigated (NCT03325556 and 2017-002227-13) for treating hallucinations and delusions associated with DRP across five common neurodegenerative dementias: Alzheimer’s disease (AD) dementia, Parkinson’s disease (PD) dementia, dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and vascular dementia (VaD).[4,5,6]
GABAergic interneuron or NMDA receptor dysfunction, and excess serotonin or 5-HT2A receptor upregulation in the cerebral cortex can result in sustained activation of pyramidal neurons and may lead to hyperactive glutamatergic signaling to the ventral tegmental area (VTA), resulting in excess dopamine or D2 receptor upregulation in the ventral striatum, triggering hallucinations and delusions in DRP.[55,56,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87] healthy human volunteers, psychotic symptoms that closely mimicked those observed in first-episode schizophrenic patients occur within 20 to 30 minutes of psilocybin administration
Summary
No pharmacological agents are approved by the U.S Food and Drug Administration (FDA) to treat dementia-related psychosis (DRP).
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