Clinical and neurobiological correlates of tardive dyskinesia in schizophrenia spectrum disorders and mood disorders

Abstract Tardive dyskinesia (TD) is a persistent sensorimotor syndrome associated with antipsychotic exposure in schizophrenia spectrum disorders (SSD) and mood disorders (MOD), yet its neurobiological basis remains poorly understood. We investigated whether TD represents a distinct clinical and neurobiological phenotype across SSD and MOD. In this study, we examined a bicentric cohort of 453 individuals with SSD ( n = 360) or MOD ( n = 93), including early-psychosis (EP) and multiple-episode SSD patients. TD status was defined using Schooler and Kane criteria based on the Abnormal Involuntary Movement Scale (AIMS). Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). Structural MRI data were processed using FreeSurfer (v7.4.1). Propensity score matching was applied to compare TD-positive and TD-negative patients while controlling for age, sex, illness duration, antipsychotic dose, and PANSS scores. TD prevalence was 10.6% in multiple-episode SSD ( n = 31) and 7.5% in MOD ( n = 7), whereas no EP patients met criteria for TD. Logistic regression identified male sex ( p = 0.005) and higher PANSS general psychopathology scores ( p = 0.021) as independent predictors of TD. TD-positive patients showed reduced paracentral cortical surface area in both the matched SSD sample ( n = 86; p = 0.006, corr.) and the combined transdiagnostic sample ( n = 179; p = 0.024, corr.). These alterations were absent in EP patients. In conclusion, our findings suggest that TD is a transdiagnostic phenomenon, occurring in both SSD and MOD. However, TD in SSD appears to be associated with a distinct clinical and neurobiological phenotype, marked by greater illness severity, male predominance, and focal sensorimotor cortical alterations.