Silent action of dopamine receptor antagonist in synaptic remodelling: Molecular basis of tardive dyskinesia due to chronic antipsychotic exposure.

Dopamine receptor antagonists are still a mainstay treatment for schizophrenia, bipolar disorder, psychotic depression and many other neuropsychiatric disorders, resulting in widespread and often lifelong exposure to agents that mainly exert their therapeutic effects through dopamine D2 receptor blockade. Due to their clinical efficacy, prolonged treatment exposes patients to the delayed phenomenon of tardive dyskinesia (TD), a potential source of permanent and debilitating hyperkinetic movement disorder that can develop late in the course of treatment, frequently remaining clinically quiescent during its earliest phases. There is evidence that TD is not simply a consequence of dopamine receptor super-sensitivity, but the endpoint of progressive neurobiological adaptations activated by chronic D2 receptor antagonism. Long-term receptor blockade has been proposed to initiate multiple downstream neuroadaptive processes supported by varying levels of clinical and experimental evidence i.e. neuroadaptive hypofunction leading to receptor upregulation, suboptimal synaptic plasticity resulting from long-range ROS-signalling, mitochondrial dysfunction and neuroinflammatory responses, neurotransmitter dysregulation within the dopaminergic, glutamatergic, GABAergic and cholinergic systems that may contribute to structural and functional alterations in motor circuits. Such changes superimpose progressive neuroadaptive processes, initially transiently compensatory, on an eventual stable pathological network state which accounts for the late-onset nature and chronicity of TD. This study aims to integrate the molecular, structural and clinical manifestations of TD with sustained D₂ receptor antagonism into a framework and interpreting TD as a disorder of pathological neuroplasticity and circuit dysregulation affords a more informative context about its pathogenesis and underscores an urgent unmet therapeutic need for early biomarkers, and safer antipsychotic therapies that can maintain psychiatric efficacy while preventing long-term neurological sequelae.