Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis

Carbon, Maren; Kane, John M.; Leucht, Stefan; Correll, Christoph U.

doi:10.1002/wps.20579

Cited by 214Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorTreatment of Major Depression

Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis

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Carbon, Maren, Kane, John M., Leucht, Stefan, Correll, Christoph U.·2018·World Psychiatry

DOI 10.1002/wps.20579PMC PMC6127753

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Abstract

Tardive dyskinesia (TD) risk with D2/serotonin receptor antagonists or D2 receptor partial agonists (second-generation antipsychotics, SGAs) is considered significantly lower than with D2 antagonists (first-generation antipsychotics, FGAs). As some reports questioned this notion, we meta-analyzed randomized controlled studies (RCTs) to estimate the risk ratio (RR) and annualized rate ratio (RaR) of TD comparing SGAs vs. FGAs and SGAs vs. SGAs. Additionally, we calculated raw and annualized pooled TD rates for each antipsychotic. Data from 57 head-to-head RCTs, including 32 FGA and 86 SGA arms, were meta-analyzed, yielding 32 FGA-SGA pairs and 35 SGA-SGA pairs. The annualized TD incidence across FGA arms was 6.5% (95% CI: 5.3-7.8%) vs. 2.6% (95% CI: 2.0-3.1%) across SGA arms. TD risk and annualized rates were lower with SGAs vs. FGAs (RR=0.47, 95% CI: 0.39-0.57, p<0.0001, k=28; RaR=0.35, 95% CI: 0.28-0.45, p<0.0001, number-needed-to-treat, NNT=20). Meta-regression showed no FGA dose effect on FGA-SGA comparisons (Z=-1.03, p=0.30). FGA-SGA TD RaRs differed by SGA comparator (Q=21.8, df=7, p=0.003), with a significant advantage of olanzapine and aripiprazole over other non-clozapine SGAs in exploratory pairwise comparisons. SGA-SGA comparisons confirmed the olanzapine advantage vs. non-clozapine SGAs (RaR=0.66, 95% CI: 0.49-0.88, p=0.006, k=17, NNT=100). This meta-analysis confirms a clinically meaningfully lower TD risk with SGAs vs. FGAs, which is not driven by high dose FGA comparators, and documents significant differences with respect to this risk between individual SGAs.

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Drugs like aripiprazole that are partial agonists at the D2 receptor are less likely to induce dopaminergic hypersensitivity (as evidenced by very low rates of TD) and therefore may be less likely to cause a relapse on discontinuation, as supported by animal data, but this has not yet been examined in clinical studies.
“There is recent evidence that drugs like aripiprazole that are partial agonists at the D2 receptor are less likely to induce dopaminergic hypersensitivity (as evidenced by very low rates of TD)106 and, therefore, may be less likely to cause a relapse on discontinuation as supported by animal data,107 but this has not yet been examined in clinical studies.”
From A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse (2021) · cites this paper as [106]
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The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness
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Revisiting Amantadine as A Treatment for Drug-Induced Movement Disorders
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130. Meta-Analysis of Tardive Dyskinesia Rates in Randomized Controlled Studies Comparing First- to Second-Generation Antipsychotics
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SU1. Tardive Dyskinesia Prevalence in the Period of Second-Generation Antipsychotic Use: A Meta-Analysis
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Authors: Carbon, M., Kane, J. M., Leucht, S., & Correll, C. U.
Affiliations: Zucker Hillside Hospital (US)
Feinstein Institute for Medical Research (US)
TUM Klinikum (DE)
ORCID: Kane, John M.
Leucht, Stefan
Correll, Christoph U.
Venue: World Psychiatry
Publisher: Wiley
Published: 2018-09-07
Volume: 17
Issue: 3
Pages: 330-340
ISSN: 1723-8617 (ISSN-L)
2051-5545
DOI: 10.1002/wps.20579
PMC: PMC6127753
OpenAlex: W2889881994
Cited by: 214
References: 87
Citations by year: 2026: 30 · 2025: 25 · 2024: 32 · 2023: 22 · 2022: 32 · 2021: 22 · 2020: 28 · 2019: 22 · 2018: 1
FWCI: 14.26
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: World Psychiatry (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords: tardive dyskinesia, antipsychotic drugs, atypical antipsychotics, typical antipsychotics, dopamine D2 receptor antagonists, olanzapine, aripiprazole, clozapine, antipsychotic dosing, adverse drug reactions, schizophrenia treatment, bipolar disorder

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Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis

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