“MANAGING THE MENAGERIE IN MY HOME”, SUCCESSFUL CLOZAPINE TITRATION FOR “PIMAVANSERIN-RESISTANT” PARKINSON'S DISEASE PSYCHOSIS

Introduction The umbrella term “synucleinopathies” includes Parkinson's disease (PD), Dementia with Lewy bodies (DLB), Parkinson's disease-dementia (PDD), and Multiple System Atrophy (MSA), all of which share a similar pathogenesis, clinical presentation, and treatment plan. The shared clinical features include neurocognitive decline, autonomic dysfunction, parkinsonian motor features, and neuropsychiatric symptoms including depression, anxiety, and psychosis. Parkinson's Disease Psychosis (PDPsy) is best characterized by visual hallucinations. These psychotic symptoms can lead to impairments in activities of daily living, earlier nursing home placement, and caregiver burnout. The initial treatment plan for PDPsy usually involves a dose reduction of dopaminergic agents. If an acceptable reduction of psychotic symptoms is not achieved with this strategy, the use of an antipsychotic medication is often considered – usually clozapine, quetiapine, and now pimavanserin (a novel 5-HT2A inverse agonist). All of these agents share a minimal propensity to worsen parkinsonian motor symptoms. At present, there are no trials directly comparing clozapine and pimavanserin (the two agents with the best evidence base for PDPsy), making the choice of antipsychotic somewhat arbitrary. Methods Presented here is a case of PDPsy, wherein the patient's psychosis improved after a cross-titration from a dual-antipsychotic regimen of pimavanserin and quetiapine to a monotherapy regimen of clozapine. A review of the literature was gathered through October 2019 MEDLINE, EMBASE, and PsycINFO. Further studies found through this process were reviewed to identify additional reports. Results Mrs. KJ is a 62-year-old, married female with a medical history limited to idiopathic PD diagnosed in 2011. When first diagnosed, she developed an acute adjustment disorder and was treated with escitalopram. In January 2019, she was referred to our clinic for management of PDPsy that had begun in 2016. She described her psychosis as a “circus-menagerie” of animals living in her house as well as significant delusions of marital infidelity. Prior to our involvement, carbidopa-levodopa and ropinirole had been decreased, quetiapine had been initiated, and pimavanserin had been added, all with minimal resolution of psychosis. After discontinuing escitalopram and increasing the dose of quetiapine without benefit, a decision had to be made whether to abandon pimavanserin and try clozapine. The barriers to starting clozapine, including side effects, were weighed against its unknown comparative efficacy to pimavanserin. An eventual decision was made to initiate clozapine followed by the discontinuation of quetiapine and then pimavanserin. The “circus of animals” greatly decreased, and she gained insight into her delusions. The accompanying review resulted in 16 articles from MEDLINE, 29 from EMBASE and 4 from PsycINFO. While the literature supports clozapine's efficacy, there are frequent references to barriers to its initiation, including the need for frequent blood draws and the high potential side effect burden (though one of these potentially problematic side effects – its anticholinergic properties, may result in a reduced need for dopaminergic agents). There are no trials (open-label or otherwise) or case reports directly comparing clozapine to pimavanserin for PDPsy. Conclusions This is the first report of a successful titration from pimavanserin to clozapine for PDPsy. As access to pimavanserin increases, its use will expectedly increase, and it may become a first-line treatment for PSDsy. This case describes a potentially useful treatment strategy for the “pimavanserin-resistant” patient by demonstrating that a trial of clozapine after sub-optimal response to pimavanserin can lead to further symptom improvement. The decision to use antipsychotics for PDPsy should take a shared, patient-centered approach. For clozapine, this includes a discussion of its potential life-threatening side effects, the need for enrollment in a national REMS program, and its blood monitoring requirements. To date, there have been no head-to-head comparisons of clozapine with pimavanserin making the step-wise plan of when to initiate and/or abandon quetiapine, clozapine, or pimavanserin for PDPsy an unknown. This case adds to the shared decision-making process by providing evidence of the potential benefits of switching to clozapine when psychosis persists. Additional, large scale studies are needed to compare pimavanserin with other atypical antipsychotics, particularly clozapine. This research was funded by: Not applicable