Phelan-McDermid syndrome is a rare genetic disorder characterized by various neurodevelopmental, medical, and psychiatric issues. Although bipolar disorder-like presentations and catatonia are particularly common, psychosis has also been reported but is less well described. As such, this systematic review sought to characterize the phenomenology of psychosis in Phelan-McDermid syndrome, clarify the association of psychotic symptoms with other neuropsychiatric features of the disorder, and describe antipsychotic treatment response.

A literature search was completed in July 2024 using PubMed and Scopus. Only English-language articles that reported the occurrence of psychotic symptoms in Phelan-McDermid syndrome were eligible for inclusion. 18 articles describing 35 individuals were included in the main analyses. Three additional articles of relevance are discussed separately, as they either provided limited clinical information or did not present data in a patient-specific manner.

The average age of psychosis onset was ∼17 years, and 65% of individuals developed symptoms at or before age 15. ∼69% of individuals also experienced catatonia, ∼81% experienced mood symptoms, and 50% experienced both. Visual hallucinations were the most commonly reported psychotic symptom. Where reported, ∼76% (13/17) of individuals exhibited at least a partial and/or temporary response to antipsychotic therapy.

Psychotic presentations in Phelan-McDermid syndrome may qualitatively differ from schizophrenia. Although numerous antipsychotics may be efficacious in the treatment of Phelan-McDermid syndrome-associated psychosis, this review most importantly highlights the paucity of available high-quality evidence to guide treatment decisions in this respect, and as such indicates the need for more reports to be published.