Tardive dyskinesia is caused by maladaptive synaptic plasticity: A hypothesis

Abstract

It has been 50 years since the first patients with tardive dyskinesia (TD) were described, but the pathophysiology is only partially understood and effective treatments have remained elusive. Newer atypical antipsychotics with less nonspecific activity at dopamine receptors have not heralded the end of tardive dyskinesia and merely highlight the incomplete understanding of the disorder. We present an overview of the existing pathophysiology of the disorder and incorporate recent developments in genetics and the study of human synaptic plasticity in other hyperkinetic movement disorders. We propose a hypothesis that dopamine-receptor sensitization and altered function of the N-methyl-D-aspartate receptor produces maladaptive synaptic plasticity, which allows the encoding of abnormal motor programs, and propose studies that would falsify or support this hypothesis. In conclusion, a maladaptive synaptic plasticity" hypothesis goes some way toward filling in the gaps of existing theories of TD with the pathophysiology of other hyperkinetic movement disorders. © 2012 Movement Disorder Society.

A Case of Tardive Dyskinesia in the Last Weeks of Life

“…Twelve to forty-three percent of patients who have taken neuroleptics and other dopamine blockers are estimated to develop TD in the course of their lifetimes. 8 Risk factors include total duration of neuroleptic exposure, decreased functional reserve (older age, intellectual disability, substance abuse, traumatic brain injury), female gender, mood disorder, and African American ethnicity. 4,14,15 These factors are generally believed to predict risk for rapid development, severity, and irreversibility of TD.…”

“…4 Paradoxically, the dopamine-blocking neuroleptic agents that lead to this denervation supersensitivity can also further block the dopamine receptors and suppress the movements at least temporarily 4,8,9 ; conversely, TD will often only manifest after the neuroleptic-induced dopamine blockade is withdrawn, so-called withdrawal-emergent dyskinesia. 8,10 Restarting or increasing neuroleptic dose is generally an inadvisable management strategy, though, as it only suppresses movements for a limited period of time and worsens the problem in the long run. 9,11 However, at the end of life when expected survival is limited, this may occasionally be a viable strategy.…”

Identification and management of tardive dyskinesia: A case series and literature review

“…These observations have pointed to the possibility of environmental and genetic vulnerability in TD [8][9][10].…”

Antipsychotikainduzierte tardive Syndrome

“…Kleinere Studien deuten auf die Beteiligung von Genen hin, die die Neurotransmission und die synaptische Plastizität regulieren. Diese synaptische Plastizität könnte maladaptiv sein [34].…”