clinical topic updates

Antipsychotic Switching Strategies in Tardive Dyskinesia

by Andrew J. Cutler, MD

Overview

Given the differing risk profiles of the available dopamine receptor–blocking agents (DRBAs) for tardive dyskinesia (TD), DRBA switching strategies continue to be of interest. However, data to support specific DRBA switching strategies as treatments for TD are currently limited.

Expert Commentary

Andrew J. Cutler, MD

Clinical Associate Professor of Psychiatry
SUNY Upstate Medical University
Lakewood Ranch, FL
Chief Medical Officer
Neuroscience Education Institute
Carlsbad, CA

“Strategies to manage TD risk through DRBA switching or dose adjustments were largely developed prior to 2017, before we had the US Food and Drug Administration–approved vesicular monoamine transporter 2 inhibitors for TD.”

Andrew J. Cutler, MD

Strategies to manage TD risk through DRBA switching or dose adjustments were largely developed prior to 2017, before we had the US Food and Drug Administration–approved vesicular monoamine transporter 2 inhibitors for TD. Historically, the guidance on TD risk reduction has focused on reducing the use of DRBAs, if possible, or reducing the dose of the DRBA. There was also evidence that higher-potency D2-blocking agents (eg, first-generation antipsychotics) and higher doses of these DRBAs might increase TD risk compared with second-generation agents.

Based on these data, consideration may be given to switching from a first-generation antipsychotic to a second-generation antipsychotic, or to selecting a second-generation agent with a lower D2 receptor affinity. In the past, switching patients with schizophrenia to the second-generation agent clozapine was frequently attempted in the setting of TD. This was not always effective, but it would occasionally result in some improvement.

There are various estimates of the prevalence of TD, but a large meta-analysis by Carbon and colleagues showed a prevalence that ranges from approximately 7% to 30%. In this meta-analysis, the lifetime prevalence of TD with first-generation agents was 30%. The rate in patients currently taking second-generation agents was 20.7%, which is lower, but most studies in the analysis did not control for previous first-generation antipsychotic exposure. An analysis of the subset of studies in patients who had only ever taken a second-generation agent and were confirmed to have never previously been exposed to a first-generation antipsychotic reported a TD prevalence of approximately 7%, which is lower but still significant.

Even among different second-generation agents, however, I think that the risk of TD is likely to vary. For instance, those with an especially low affinity for D2 receptors (eg, clozapine, quetiapine, and, one of the newest agents, lumateperone) might have a lower TD risk. In addition to lower D2 receptor occupancy, it has been suggested that serotonin receptor modulation may play a role in the risk for TD. 5-HT2A receptors are widely distributed in the caudate and putamen of the dorsal striatum, and via complex interplay with D2 receptors may contribute to the regulation of motor activity. The partial D2 agonism of some of the atypical antipsychotics has been theorized to decrease the risk of drug-induced movement disorders; however, TD certainly occurs with the D2 partial agonists, such as aripiprazole.

In conclusion, the propensity of a DRBA to cause TD may be a consideration when choosing an initial treatment. Once TD has already emerged, specific second-generation DRBA switching strategies might be considered, but they simply do not have robust data showing a decrease in TD symptoms at this point.

References

Bergman H, Rathbone J, Agarwal V, Soares-Weiser K; Cochrane Schizophrenia Group. Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia. Cochrane Database Syst Rev. 2018;2018(2):CD000459. doi:10.1002/14651858.CD000459.pub3

Carbon M, Hsieh C-H, Kane JM, Correll CU. Tardive dyskinesia prevalence in the period of second-generation antipsychotic use: a meta-analysis. J Clin Psychiatry. 2017;78(3):e264-e278. doi:10.4088/JCP.16r10832

Carbon M, Kane JM, Leucht S, Correll CU. Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis. World Psychiatry. 2018;17(3):330-340. doi:10.1002/wps.20579

Pardis P, Remington G, Panda R, Lemez M, Agid O. Clozapine and tardive dyskinesia in patients with schizophrenia: a systematic review. J Psychopharmacol. 2019;33(10):1187-1198. doi:10.1177/0269881119862535

Pozhidaev IV, Paderina DZ, Fedorenko OY, et al. 5-hydroxytryptamine receptors and tardive dyskinesia in schizophrenia. Front Mol Neurosci. 2020;13:63. doi:10.3389/fnmol.2020.00063

Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002;47(1):27-38.

Teo JT, Edwards MJ, Bhatia K. Tardive dyskinesia is caused by maladaptive synaptic plasticity: a hypothesis. Mov Disord. 2012;27(10):1205-1215. doi:10.1002/mds.25107

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