Reduced Risk of Tardive Dyskinesia with 2nd-Generation Antipsychotics Re-Established

Christoph Correll, MD

In the treatment of schizophrenia, second generation antipsychotic medications are significantly less likely to cause tardive dyskinesia (TD) than first generation antipsychotics.

This finding was re-established in a recent meta-analysis which sought to reinvestigate the relationship between tardive dyskinesia and these common antipsychotic medications.

“This has been known before, although there have been recent studies that called that into question, so that’s why we wanted to re-analyze the data looking at all evidence,” Christoph Correll, MD, a professor of Psychiatry and Molecular Medicine at Hofstra Northwell School of Medicine and an investigator at the Center for Psychiatric Neuroscience at the Feinstein Institute for Medical Research, told MD Magazine®.

Recently, the long-held belief that second-generation antipsychotics reduce the risk of tardive dyskinesia was challenged by the CATIE and CUtLASS studies. However, according to Correll, one of the authors of the meta-analysis, the re-examination determined second-generation antipsychotics reduced the risk of developing tardive dyskinesia by 50%, thus supporting the original hypothesis.

“The significant TD risk reduction with SGAs found in this meta-analysis contrasts to the findings of the UK-based CUtLASS-1 study and the US-based CATIE study, which both conveyed the impression that the TD risk of FGAs and SGAs did not differ,” wrote the authors. “We confirmed our hypothesis of lower incidence rates of TD during SGA vs. FGA treatment, with a relative risk and annualized rate reduction to one third of the FGA rate and a NNT = 20.”

While the researchers were not entirely surprised with the findings in relation to first and second-generation antipsychotics, Correll said an unexpected finding showed dose moderation had no effect on first-generation antipsychotics’ association with tardive dyskinesia.

According to Correll, it was previously hypothesized that the significant difference between first and second-generation antipsychotics is driven by the fact that first generation medications are overdosed. Therefore, it was believed that if first-generation antipsychotics are administered at a low enough dose, risks of developing tardive dyskinesia may be circumvented.

“We didn’t find that,” Correll said. “Dose was not a moderation of the effect. You would not reduce this gap between first-generation antipsychotics and second-generation antipsychotics.”

In another unexpected finding, researchers determined that among second-generation antipsychotic medications, there is no medication with any significantly higher risk of developing tardive dyskinesia.

“That means that even with second-generation antipsychotic agents, there is not a particular unsafe one. But on the flip side, we found 2 that were safer than the others,” he said, specifying Abilify and Zyprexa.

With the development of new partial agonists, Correll postulated that researchers may be able to determine an even safer subgroup among second-generation antipsychotic agents. However, he qualified, the hypothesis has yet to be proven.

While second-generation antipsychotics have now been definitively proven as the safer option, researchers did not indicate that these results would lead to any wide-spread changes in terms of treatment.

“Due to the relatively low absolute annual risk of TD even during FGA treatment, the NNT to achieve a risk reduction for TD of 20 may appear too high to warrant an influence on clinical antipsychotic choice,” the study reads.

“On the other hand, the annual risk underestimates the individual lifetime risk in chronic mental illness, where antipsychotic exposure times range around 6 years in 40-year olds, being closer to 15 years in people with schizophrenia spectrum disorders. As the individual risk to develop TD is cumulative, at least during the first 5 years, the risk reduction should also be seen as a cumulative gain throughout the expected treatment period in each individual.”

The study, “Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis,” was published in World Psychiatry.