Ondansetron for the treatment of Parkinson’s disease psychosis: Rationale and literature review

Abstract Psychosis is a debilitating non-motor symptom of Parkinson’s disease that commonly manifests with illusions, presence/passage hallucinations, and well-formed visual hallucinations. Parkinson’s disease psychosis (PDP) is associated with several negative repercussions such as increased caregiver distress and high rates of nursing home placement, healthcare expenditure, and mortality. Several neurotransmitters have been implicated in the pathogenesis of PDP; these include dopamine, acetylcholine, and serotonin. Most antipsychotics have a variable degree of dopamine-blocking property that may worsen parkinsonism or result in the emergence of other drug-induced movement disorders. Therefore, atypical antipsychotics with minimal dopamine-blocking property (quetiapine, clozapine) are commonly prescribed to treat PDP. Pimavanserin, which modulates serotonergic transmission (5-HT2A inverse agonist), is the only drug approved by the US Food and Drug Administration to treat PDP; however, it is not globally available. Therefore, it is crucial to continue the search for effective pharmacotherapy of PDP. Other serotonergic targets of interest include selective 5-HT3 receptor antagonist ondansetron. Licensed for use as an antiemetic, open-label studies on ondansetron in the 1990s have shown encouraging results in the treatment of hallucinations in PD. However, ondansetron was not further studied in PDP as it was cost-prohibitive. In this article, we highlight the role of abnormal serotonergic transmission in the pathogenesis of PDP, revisit the studies that investigated the role of ondansetron in treating PDP, and discuss its potential as an effective therapeutic option for PDP.