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

Abstract

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 D₂ receptors in the basal ganglia. Proposed mechanisms include increased dopamine activation of D₂ 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 D₂ receptor blockade and include vesicular monoamine transporter (VMAT) inhibitors, antioxidants, compounds with serotonin receptor agonism as well as antagonism, GABA agonists and cholinergic agents. Randomized, controlled trials in Phase II and Phase III (ClinicalTrials.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 D₂ receptor antagonism from APs.

Keywords:

• antipsychotic side effects
• investigational drugs
• pharmacotherapy
• Phase II
• Phase III
• tardive dyskinesia

Declaration of interest

G Remington has received consultant fees from Neurocrine Biosciences, Medicure, Synchroneuron and Roche as well as research support and speaker’s fees from Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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