Clinical Neuroscience

Adaptive changes to antipsychotics: How to avoid the consequences

Current Psychiatry. 2022 July;21(7):46-50,52 | doi: 10.12788/cp.0262

References

1. Stahl SM. Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: dopamine, serotonin, and glutamate. CNS Spectr. 2018;23(3):187-191.
2. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III--the final common pathway. Schizophr Bull. 2009;35(3):549-562.
3. Ginovart N, Kapur S. Role of dopamine D2 receptors for antipsychotic activity. Handb Exp Pharmacol. 2012;(212):27-52.
4. Madras BK. History of the discovery of the antipsychotic dopamine D2 receptor: a basis for the dopamine hypothesis of schizophrenia. J Hist Neurosci. 2013;22(1):62-78.
5. Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 201;63(1):182-217.
6. Martel JC, Gatti McArthur S. Dopamine receptor subtypes, physiology and pharmacology: new ligands and concepts in schizophrenia. Front Pharmacol. 2020;11:1003.
7. Monsma FJ Jr, McVittie LD, Gerfen CR, et al. Multiple D2 dopamine receptors produced by alternative RNA splicing. Nature. 1989;342(6252):926-929.
8. Seeman P, Nam D, Ulpian C, et al. New dopamine receptor, D2(Longer), with unique TG splice site, in human brain. Brain Res Mol Brain Res. 2000;76(1):132-141.
9. Khan ZU, Mrzljak L, Gutierrez A, et al. Prominence of the dopamine D2 short isoform in dopaminergic pathways. Proc Natl Acad Sci U S A. 1998;95(13):7731-7736.
10. Xu R, Hranilovic D, Fetsko LA, et al. Dopamine D2S and D2L receptors may differentially contribute to the actions of antipsychotic and psychotic agents in mice. Mol Psychiatry. 2002;7(10):1075-1082.
11. Anzalone A, Lizardi-Ortiz JE, Ramos M, et al. Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors. J Neurosci. 2012;32(26):9023-9034.
12. Ford CP. The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience. 2014;282:13-22.
13. Stroup TS, Gray N. Management of common adverse effects of antipsychotic medications. World Psychiatry. 2018;17(3):341-356.
14. El-Mallakh RS, Pant B, Caudill R, et al. Does peripheral neuropathy allow for the clinical expression of tardive dyskinesia by unmasking central nervous system changes? Med Hypotheses. 2001;57:210-215.
15. Citrome L, Saklad SR. Revisiting tardive dyskinesia: focusing on the basics of identification and treatment. J Clin Psychiatry. 2020;81(2):TV18059AH3C.
16. Carbon M, Kane JM, Leucht S, et al. Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis. World Psychiatry. 2018;17(3):330-340.
17. Samaha AN, Seeman P, Stewart J, et al. “Breakthrough” dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci. 2007;27(11):2979-2986.
18. Yin J, Barr AM, Ramos-Miguel A, et al. Antipsychotic induced dopamine supersensitivity psychosis: a comprehensive review. Curr Neuropharmacol. 2017;15(1):174-183.
19. Chouinard G, Jones BD, Annable L. Neuroleptic-induced supersensitivity psychosis. Am J Psychiatry. 1978;135(11):1409-1410.
20. Burt DR, Creese I, Snyder SH. Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science. 1977;196(4287):326-328.
21. Silvestri S, Seeman MV, Negrete JC, et al. Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study. Psychopharmacology (Berl). 2000;152(2):174-180.
22. Ali Z, Roque A, El-Mallakh RS. A unifying theory for the pathoetiologic mechanism of tardive dyskinesia. Med Hypotheses. 2020;140:109682.
23. Lieberman JA. Dopamine partial agonists: a new class of antipsychotic. CNS Drugs. 2004;18(4):251-267.
24. Mailman RB, Murthy V. Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? Curr Pharm Des. 2010;16(5):488-501.
25. Tuplin EW, Holahan MR. Aripiprazole, a drug that displays partial agonism and functional selectivity. Curr Neuropharmacol. 2017;15(8):1192-1207.
26. Hart XM, Schmitz CN, Gründer G. Molecular imaging of dopamine partial agonists in humans: implications for clinical practice. Front Psychiatry. 2022;13:832209.
27. Snyder GL, Vanover KE, Zhu H, et al. Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology (Berl). 2015;232(3):605-621.
28. Kiss B, Horváth A, Némethy Z, et al. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010;333(1):328-340.
29. Abbasian C, Power P. A case of aripiprazole and tardive dyskinesia. J Psychopharmacol. 2009;23(2):214-215.
30. Peña MS, Yaltho TC, Jankovic J. Tardive dyskinesia and other movement disorders secondary to aripiprazole. Mov Disord. 2011;26(1):147-152.
31. Tadokoro S, Okamura N, Sekine Y, et al. Chronic treatment with aripiprazole prevents development of dopamine supersensitivity and potentially supersensitivity psychosis. Schizophr Bull. 2012;38(5):1012-1020.
32. Kang NR, Kim MD. Tardive dyskinesia: treatment with aripiprazole. Clin Psychopharmacol Neurosci. 2011;9(1):1-8.
33. Frankel JS, Schwartz TL. Brexpiprazole and cariprazine: distinguishing two new atypical antipsychotics from the original dopamine stabilizer aripiprazole. Ther Adv Psychopharmacol. 2017;7(1):29-41.
34. Chan CH, Chan HY, Chen YC. Switching antipsychotic treatment to aripiprazole in psychotic patients with neuroleptic-induced tardive dyskinesia: a 24-week follow-up study. Int Clin Psychopharmacol. 2018;33(3):155-162.
35. Blair HA. Lumateperone: first approval. Drugs. 2020;80(4):417-423.
36. Calabrese JR, Durgam S, Satlin A, et al. Efficacy and safety of Lumateperone for major depressive episodes associated with bipolar I or bipolar II disorder: a phase 3 randomized placebo-controlled trial. Am J Psychiatry. 2021;178(12):1098-1106.
37. Nakai S, Hirose T, Uwahodo Y, et al. Diminished catalepsy and dopamine metabolism distinguish aripiprazole from haloperidol or risperidone. Eur J Pharmacol. 2003;472(12):89-97.
38. Vanover KE, Davis RE, Zhou Y, et al. Dopamine D2 receptor occupancy of lumateperone (ITI-007): a positron emission tomography study in patients with schizophrenia. Neuropsychopharmacology. 2019;44(3):598-605.

Take-home points

Adaptive upregulation of dopamine neurotransmission underlies acute adverse effects such as parkinsonism and is also key for delayed consequences such as TD, and possibly the development of treatment resistance. Adaptive upregulation results from an increase in postsynaptic dopamine receptors, numbers of synapses, and dopamine release. The latter has been demonstrated to be greatest with full antagonists, less with partial agonists, and not present with lumateperone, which is a postsynaptic antagonist but a presynaptic partial agonist (Figure²⁷). Reducing adaptive upregulation can reduce both acute and long-term consequences of dopamine blockade. Early use of agents that minimize these adaptive changes, such as a postsynaptic partial agonist (aripiprazole, brexpiprazole, or cariprazine) or a presynaptic partial agonist (lumateperone), appears to be a reasonable clinical option.

Bottom Line

Chronic dopamine D2 receptor blockade with antipsychotics induces adaptive changes that can contribute to both acute and chronic adverse effects. The most severe of these are tardive dyskinesia (TD) and dopamine supersensitivity psychosis (DSP). The use of agents that mitigate these changes, such as the partial D2 agonists aripiprazole, brexpiprazole, and cariprazine and the postsynaptic antagonist/presynaptic partial agonist lumateperone, can potentially reduce these adaptive changes and reduce the likelihood of TD and DSP.

Related Resources

Citrome L. Aripiprazole, brexpiprazole, and cariprazine: not all the same. Current Psychiatry. 2018;17(4):24-33,43.
Meyer JM. Lumateperone for schizophrenia. Current Psychiatry. 2020;19(2):33-39.

Drug Brand Names

Aripiprazole • Abilify
Brexpiprazole • Rexulti
Cariprazine • Vraylar
Haloperidol • Haldol
Lumateperone • Caplyta
Methamphetamine • Desoxyn
Risperidone • Risperdal