Andrea Fagiolini, Paolo Barone, Antonello Bellomo, Emi Bondi, Carlo Colosimo, Giovanni Fabbrini, Giuseppe Maina, Maurizio Pompili, Michele Tinazzi, Antonio Vita, Alessandro Cuomo

Tardive dyskinesia (TD) is a chronic, often disabling hyperkinetic movement disorder associated with prolonged use of dopamine receptor blocking agents (DRBAs), particularly antipsychotics (APs) for psychiatric disorders such as schizophrenia and bipolar disorder. It manifests as abnormal, involuntary movements, often involving the orofacial region, extremities, or trunk, and is associated with significant physical and psychosocial impairment. TD is primarily linked to dopamine receptor hypersensitivity, oxidative stress, and genetic susceptibility, with a higher prevalence in patients treated with first-generation APs. However, second-generation APs (SGAs) have not eliminated the risk entirely, particularly in older adults and those with prolonged exposure. Diagnosis relies on clinical assessments such as the Abnormal Involuntary Movement Scale (AIMS) and comprehensive neurological evaluations. Treatment guidelines emphasize early detection, prevention through minimal effective doses of APs, and the use of VMAT2 inhibitors (vesicular monoamine transporter 2 inhibitors) as a first-line therapy in moderate-to-severe cases. VMAT2 inhibitors reduce dopamine signaling dysregulation without directly blocking D2 receptors, effectively managing symptoms in many patients. For treatment-resistant cases, deep brain stimulation and other non-pharmacological interventions offer promising alternatives. Current research underscores the complexity of TD’s pathophysiology and the need for personalized approaches. Future directions include developing biomarkers for risk stratification, refining therapeutic strategies, and optimizing long-term outcomes through multidisciplinary care.