A recent case-control study using a Japanese corporate health insurance claims database found that higher doses of antipsychotics are significantly associated with an increased risk of tardive dyskinesia, with the risk being dose-dependent.
The study, published in the Journal of Clinical Psychopharmacology, analyzed data from 2010–2020 and included 58,452 patients aged 15 to 74 years with schizophrenia, depression, or bipolar disorder who were newly prescribed antipsychotics, defined as having no prescriptions for at least 6 months after enrollment in their health insurance society.
The median daily antipsychotic dose was 75 mg/d chlorpromazine equivalent (CPZE). The researchers identified 80 cases of tardive dyskinesia (TD) within the dataset. They employed a 1:10 case-control matching design to compare newly diagnosed TD patients with matched controls. Doses were stratified into three categories: 75 mg/d or less, greater than 75 to less than 300 mg/d, and greater than 300 mg/d. The primary endpoint was the relative risk of TD associated with each dose category.
Their conditional logistic regression analysis, adjusted for age, revealed that patients who received doses that exceeded the median (greater than 75 mg/d CPZE) had a significantly higher risk of developing TD compared to those on lower doses. Higher doses showed stronger associations with TD risk, with odds ratios of 3.40 and 3.50 for doses of at least 300 mg/d compared with doses of 75 to 300 mg/d at the last prescription and maximum dose, respectively.
Even relatively low doses, as defined in the Japanese clinical context, could elevate TD risk. More than 80% of prescriptions came from medical sites with fewer than 100 beds, suggesting these findings primarily reflect outpatient treatment patterns.
The findings also suggested some difficulty in treating patients because "the proportion of patients treated with higher doses remained higher than that in the control group."
The researchers noted that dose adjustments were related to the number of prescriptions patients were on throughout the study. While 96% of patients in both groups received monotherapy at the start of the antipsychotic prescription, "the percentage of patients with 2 or more prescriptions at the maximum prescription time point was higher in the case group compared to the control group," they wrote. The percentage of monotherapy patients returned to 96% in the control group, but not in the case group. "In fact, the mean daily dose (CPZE) increased as the number of prescriptions increased."
Finally, in the case group, TD was observed in 44% of patients after they reached the maximum dose and their dose was reduced. The researchers noted that this percentage may also include covert or withdrawal dyskinesia. While "guidelines recommend dose reduction, discontinuation, or switching of antipsychotics, when TD occurs, there is insufficient evidence to support an improvement in TD with antipsychotic dose reduction," as evidenced by these and other findings from previous research.
"It is crucial to consider the potential risks of TD and to carefully monitor patients receiving antipsychotic treatment," the investigators concluded.
The study was funded by Mitsubishi Tanabe Pharma Corporation. Several authors are employees of Mitsubishi Tanabe Pharma Corporation, and the senior author reported receiving speaker's honoraria from multiple pharmaceutical companies.
