Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 1: pathophysiology and mechanisms of induction.
OBJECTIVE
Tardive dyskinesia (TD) is the principal adverse effect of long-term treatment with conventional antipsychotic agents. Several mechanisms may exist for this phenomenon. Mechanisms for the lower incidence of TD with atypical antipsychotics also remain to be fully understood. We undertook to explore and better understand these mechanisms.


METHODS
We conducted a comprehensive review of TD pathophysiology literature from January 1, 1965, to January 31, 2004, using the terms tardive dyskinesia, neuroleptics, antipsychotics, pathophysiology, and mechanisms. Additional articles were obtained by searching the bibliographies of relevant references. Articles were considered if they contributed to the current understanding of the pathophysiology of TD.


RESULTS
Current TD vulnerability models include genetic vulnerability, disease-related vulnerability, and decreased functional reserve. Mechanisms of TD induction include prolonged blockade of postsynaptic dopamine receptors, postsynaptic dopamine hypersensitivity, damage to striatal GABA interneurons, and damage of striatal cholinergic interneurons. Atypical antipsychotics may cause less TD because they have less impact on the basal ganglia and are less likely to cause postsynaptic dopamine hypersensitivity.


CONCLUSIONS
Although the ultimate model for TD is not yet understood, it is plausible that several of these vulnerabilities and mechanisms act together to produce TD. The lower incidence of TD with atypical antipsychotics has helped to elucidate the,mechanisms of TD.
Margolese
Howard C
HC
Department of Psychiatry, McGill University, Montreal, Quebec. psychopharm.unit@mcgill.ca
Chouinard
Guy
G
Kolivakis
Theodore T
TT
Beauclair
Linda
L
Miller
Robert
R
D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002799:Cholinergic Fibers / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000209:etiology* / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006801:Humans; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy*; D012701:Serotonin / Q000378:metabolism
D014150:Antipsychotic Agents; D018079:Receptors, GABA; D012701:Serotonin; D004298:Dopamine