Emerging drugs for antipsychotic-induced tardive dyskinesia: investigational drugs in Phase II and Phase III clinical trials

Introduction: Antipsychotic drugs (APs) represent the mainstay of treatment for schizophrenia and other forms of psychosis. Tardive dyskinesia (TD) is a motor disorder associated with the ongoing use of APs and is characterized by involuntary, repetitive movements that are potentially irreversible. Current treatment is wanting, due in part to our limited understanding of the mechanisms underlying TD. Areas covered: Risk of TD associated with APs appears linked to continuous blockade of dopamine D-2 receptors in the basal ganglia. Proposed mechanisms include increased dopamine activation of D-2 receptors caused by supersensitivity and neurodegeneration of dopamine-producing neurons due to biochemical changes incurred by ongoing AP exposure. Existing treatments are designed to reverse or prevent the neurochemical/biological changes caused by dopamine D-2 receptor blockade and include vesicular monoamine transporter (VMAT) inhibitors, antioxidants, compounds with serotonin receptor agonisnn as well as antagonism, GABA agonists and cholinergic agents. Randomized, controlled trials in Phase II and Phase Ill (Clinical-Trials.org/ClinicalTrialsRegister.eu) are summarized and discussed. Expert opinion: Effective adjunctive treatment for the symptoms of TD will depend on gaining a better understanding of the neurological changes induced by chronic dopamine D-2 receptor antagonism from APs.