Aetiology
The single most important aetiological factor in the emergence of TD is exposure to dopamine receptor-blocking agents.[11][12] While antipsychotics (particularly typical antipsychotics) are the usual causative agents, several other drugs may also result in TD.[5] For example, chronic use of prokinetic agents (e.g., metoclopramide), selective serotonin-reuptake inhibitors (e.g., citalopram) and serotonin-noradrenaline reuptake inhibitors (e.g., duloxetine), tricyclic antidepressants (e.g., amitriptyline), lithium, and cinnarizine (an antihistamine/calcium antagonist).[5][4][13] TD caused by antipsychotics and other classes of drugs are often clinically indistinguishable. While it is well established that the typical antipsychotics have a higher propensity to cause TD because of their higher affinity to D2 receptors, it remains unclear why only some patients taking these drugs develop TD and not others, and why there is heterogeneity in the dose of these drugs and duration of exposure that is associated with the emergence of TD.
Pathophysiology
The pathophysiology of TD is incompletely understood. The most accepted theory is that chronic blockade of D2 receptors results in upregulation of D1 receptor-mediated striatopallidal output that is responsible for the emergence of TD. As typical antipsychotics have a higher affinity than atypical antipsychotics for D2 receptors, the risk of emergence of TD is much higher with typical antipsychotics.[5][14]
Atypical antipsychotics not only have a lower affinity for D2 receptors but also dissociate from them rapidly, and thereby carry a relatively lower risk for TD.[5][15]
Post-synaptic D2 receptor hypersensitivity could also play a role in TD.[5][16] Hypersensitisation of these receptors disinhibits the projection to cortex, resulting in TD. This theory is supported by the observation that a very high dose of dopamine receptor-blocking agents can temporarily ameliorate symptoms of TD.[5] The major criticism for this theory comes from the observation that symptoms of TD persist for months or years even after discontinuing the causative drugs.[5][6] D2 receptors are abundant in the medium spiny interneurons in the striatum in the indirect pathway.
There is some evidence suggesting a potential role of abnormal gamma-aminobutyric acid (GABA) transmission in the pathogenesis of TD. Animal studies have reported reduced GABAergic transmission after chronic treatment with antipsychotics.[17] It is possible that genetic susceptibility and synaptic plasticity also play a role in the pathogenesis of TD.[14]
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