Risk of Tardive Dyskinesia Higher in Women

Patients taking antidopaminergic agents are at risk of developing tardive dyskinesia (TD), a disorder characterized by abnormal, involuntary movements of the face, trunk, and limbs. However, women may face a higher risk than men.

“Women, especially in older age groups, are disproportionately affected compared to men,” noted Mohsin Raza, MD, MSc, of Universal Health Services’ Dover Behavioral Health System in Delaware, and colleagues in StatPearls.

This disparity is also recognized by practice guidelines from the American Psychiatric Association for treating schizophrenia, which list female sex as a key factor associated with a greater vulnerability for developing TD.

Higher Prevalence in Women

Meta-analyses have indicated that the average prevalence of TD is approximately 20% to 25% among antipsychotic-treated individuals, Raza’s team noted. The incidence among women is estimated to be around 30% following 1 year of cumulative exposure to antipsychotics, according to a review by Elyse Cornett, PhD, of Louisiana State University Health in Shreveport, and colleagues.

An older literature review, which analyzed data on nearly 40,000 patients from 76 studies, also reported that women tended to have more severe cases of TD than men.

“Overall, the TD prevalence seemed to reach its peak in the 50 to 70-year-old age group in men and continued to rise after age 70 in women,” Ramzy Yassa, MD, of Douglas Hospital Centre in Montreal, Canada, and Dilip Jeste, MD, of the University of California San Diego, wrote.

Drivers of Sex Disparities

“Several hypotheses have been put forward to explain the discrepancy in the TD prevalence between men and women,” they added. “Some investigators reported that women tended to have more chronic illness and longer hospitalizations than men.”

Of note, older age is another risk factor for TD, which may disproportionately impact women due to their longer lifespans, Yassa and Jeste said.

“A third possibility is that psychosis may develop later in life in women than in men,” the duo explained. “Some studies have indicated this finding. TD was found to develop with a shorter period of neuroleptic treatment and in a more severe form when neuroleptics were given later in life than when neuroleptics were started earlier in life.”

Higher antipsychotic doses also tend to carry a greater risk of TD compared with lower doses. With that in mind, some data have suggested that women respond to antipsychotic drugs at lower doses versus men. “This means that, in many cases, standard doses are too high for women and cause unnecessary adverse effects,” Mary Seeman, MD, of the University of Toronto, pointed out in a 2021 review.

“The sexes differ with respect to absorption, distribution, metabolism, and elimination of most drugs,” she continued. “Men and women, on average, differ in levels of gastric acidity, degree of intestinal motility, body weight and distribution of adipose tissue, blood volume, liver enzymes — mainly the cytochrome P450 series — and renal excretion rates, each of these factors affecting plasma drug levels in separate ways.”

“Gastric acidity is lower in women than in men and gastric emptying time is slower. Intestinal transit time is also slower. The solubility of drugs can be affected by the composition of bile acid, which also differs between men and women,” Seeman added. “When these effects are taken together, women tend to absorb drugs more thoroughly than men.”

However, she noted that other factors such as genetics and age probably determine drug response and tolerability to a greater degree than biological sex or gender social roles.

Potential Role of Estrogen

While women face a higher TD risk than men, that risk also appears to fluctuate throughout a woman’s life, increasing after menopause. In addition to aging, declining estrogen levels after menopause may drive some of the heightened risk for TD in older women.

“Evidence suggests that estrogen modulates dopamine-mediated behaviors and can exhibit an antioxidant effect, which could protect against TD,” noted Cornett and co-authors in their review.

This was also demonstrated in a small study that found that postmenopausal women with TD who were taking estrogen replacement had a 38% reduction in mean Abnormal Involuntary Movement Scale (AIMS) score after 3 weeks of treatment compared with a 9% reduction in patients receiving placebo (P<0.10). Another small study reported varying degrees of TD symptom improvement when daily estrogen was administered.