TY - JOUR T1 - A unifying theory for the pathoetiologic mechanism of tardive dyskinesia. AU - Ali,Ziad, AU - Roque,Autumn, AU - El-Mallakh,Rif S, Y1 - 2020/03/16/ PY - 2019/12/24/received PY - 2020/03/06/revised PY - 2020/03/15/accepted PY - 2020/3/23/pubmed PY - 2020/3/23/medline PY - 2020/3/23/entrez KW - Antipsychotics KW - Dopamine supersensitivity KW - Presynaptic mechanism KW - Synaptic upregulation KW - Tardive dyskinesia SP - 109682 EP - 109682 JF - Medical hypotheses JO - Med. Hypotheses VL - 140 N2 - INTRODUCTION: Chronic treatment with dopamine D2 receptor antagonists has been proposed to lead to dopamine receptor supersensitivity. Frequently, this is conceptualized as upregulation or changes in the structure or function of the post-synaptic D2 receptor. However, the measured 1.4-fold increase in D2 receptor density and the lack of actual receptor supersensitivity are probably inadequate to explain outcomes such as tardive dyskinesia (TD) and dopamine supersensitivity psychosis. HYPOTHESIS: Recent data suggest that TD may result from a combination of presynaptic, synaptic, and postsynaptic changes. DISCUSSION: Presynaptic increase in dopamine release occurs when super-therapeutic blockade of postsynaptic D2 receptors results in excess synaptic unbound dopamine which ultimately ends up being reuptaken by the presynaptic neuron through the dopamine transporter. The increased availability of recycled dopamine results in higher vesicular dopamine concentrations. Since the quantity of neurotransmitter released (known as quanta) is determined by the number of presynaptic neurotransmitter vesicles, the increase in the number (concentration) of dopamine molecules in the vesicles results in a higher concentration of synaptic dopamine with successive depolarization events. Synaptic changes such as the appearance of perforated synapses which is an early step in new synapse formation have been shown in animal models of TD. Finally, postsynaptic increases in D2 receptor expression without demonstration of increased sensitivity or potency has been demonstrated. CONCLUSION: TD likely develops due to changes across the synapse and terminology such as 'dopamine receptor supersensitivity' can be misleading. 'Synaptic upregulation' may be a more correct term. SN - 1532-2777 UR - https://www.unboundmedicine.com/medline/citation/32200182/A_unifying_theory_for_the_pathoetiologic_mechanism_of_tardive_dyskinesia L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-9877(19)31450-1 DB - PRIME DP - Unbound Medicine ER -