Dopamine supersensitivity psychosis: a critical evaluation of diagnostic validators

Dopamine antagonists are the cornerstone of treatment for psychotic disorders, but long-term exposure may induce dopamine supersensitivity psychosis (DSP)-a syndrome characterized by psychotic relapse upon dose reduction or discontinuation, tolerance to antipsychotic effects, and co-occurrence of tardive dyskinesia. Despite decades of clinical observation and supporting preclinical evidence, the diagnostic validity of DSP and its relationship to treatment resistance remain incompletely understood. This systematized review evaluates clinical evidence supporting DSP as a distinct diagnostic entity using the standard framework of psychiatric diagnostic validators: delineation from other disorders, predictable clinical course, predictable treatment response, reliable biomarkers, and genetic susceptibility. A systematic search of MEDLINE and Embase identified 39 eligible clinical studies comprising case series, cross-sectional studies, cohort studies, and randomized controlled trials. Methodological quality was assessed using the Murad tool for case series and Joanna Briggs Institute critical appraisal checklists for remaining designs. Data were synthesized qualitatively due to heterogeneity in study designs, diagnostic criteria, and outcome measures. Evidence suggests predictable symptom worsening following dose reduction or switching to partial agonists, and points toward possible genetic susceptibility variants. Biomarker findings remain inconclusive, and differentiation of DSP from natural illness relapse is inherently difficult. Retrospective designs, small samples, absence of control groups, and inadequate confounder control preclude definitive conclusions. Standardized diagnostic criteria and prospective, well-controlled studies integrating clinical, genetic, and biomarker assessments are urgently needed to clarify the existence, mechanisms, and optimal management of DSP.