To What Extent Do Sex Differences Matter When Prescribing?

Do women and men respond differently to psychoactive medications? Should a patient’s sex influence the choice and dose of psychiatric medications?

Some recent animal research suggests that hormonal and other differences between males and females may affect how men and women are differentially impacted by stress, experience psychiatric disorders, and respond to common psychiatric medications.

This research, still in its nascent phase, has yet to be incorporated into human studies of psychiatric medication let alone into clinical practice where—with a few exceptions—clinicians do not make prescribing decisions based on gender-related differences. This topic was the focus of a recent review article in the Journal of Psychopharmacology.

“Recent guidelines have addressed sex differences by considering guidance for the perinatal period but general evidence from translational research that does not refer to pregnancy or breastfeeding has yet to reach the clinician,” wrote Blanca Bolea-Alamanac, M.D., of the Centre for Addiction and Mental Health at the University of Toronto and colleagues. “The development of a branch of psychopharmacology focused on sex differences will help to structure the evidence and increase knowledge translation between preclinical researchers and clinical professionals until these findings are fully integrated in everyday medical practice.”

In comments to Psychiatric News, Bolea-Alamanac noted while most clinicians are used to adjusting medications around pregnancy, it is rare for medication decisions to be based on sex alone.

“Most clinicians make medication and dose choice according to the medication’s side-effect profile, and sometimes according to a patient’s history or other personal factors such as body weight, but we do not know if this works well for both sexes,” she said.

Preclinical research has in the past tended to use only male animals, a trend that is beginning to change. “We are just starting to understand how hormones and neurosteroids affect the brains of men and women differentially,” she said.

In the review article, Bolea-Alamanac and colleagues summarized animal research showing that different biological mechanisms may underlie sex differences in response to stress. For instance, in female rats, rapid changes in circulating progesterone levels are associated with exaggerated behavioral responses to mild stress and blunted responses to benzodiazepines. Acute treatment with fluoxetine appears to blunt those responses.

“A change in progesterone secretion during the menstrual cycle can clearly have a significant influence on brain function and behavior in females, [and] may also be a factor, together with actions and interactions with other gonadal hormones, that influences drug effects,” Bolea-Alamanac and colleagues wrote. “For example, anxiolytic effects of a benzodiazepine seen in the early stages of the estrous cycle in female rats were not evoked when the drug was given in the late diestrus phase. These findings highlight the importance of taking into account female hormonal status when working towards developing a sex-specific pharmacology.”

Bolea-Alamanac and colleagues suggested potential lines of future research that may be pursued based on observed differences in humans. For instance, they noted that the neuropeptide oxytocin shows sex-specific effects in a range of social behaviors and may act as a biomarker in posttraumatic stress disorder where sex differences are evident. “Studies in women using hormonal contraception show that some of these oxytocin-mediated effects are likely influenced by sex hormones,” they wrote.

Jennifer Payne, M.D., director of the Women’s Mood Disorders Center at Johns Hopkins University School of Medicine, who reviewed the paper for Psychiatric News, said the subject of sex differences in psychopharmacology is a ripe one for further research and for consideration by clinicians. “Women undergo regular hormonal shifts that can profoundly influence mood, metabolism of medications, and influence risk for particular psychiatric illnesses,” she told Psychiatric News.

Payne, deputy representative from the Caucus of Women Psychiatrists in the APA Assembly, was instrumental in advocating for the creation of a new Council on Women’s Mental Health, which was approved by the Assembly in November 2017.

A 2016 paper in Dialogues in Clinical Neuroscience summarized research on sex differences in response to antidepressants and found mixed evidence and uncertain clinical implications.

“Clearer data exists regarding sex differences in antidepressant metabolism, related to absorption, distribution, and elimination,” co-author John J. Sramek, Pharm.D., and colleagues wrote. “A better understanding of the interactions between these many complex systems is probably required to understand sex differences in depression prevalence and treatment response. At the present time, no specific guidelines can be offered, thus the clinician must remain vigilant to the possibility of sex effects either on the levels of exposure achieved with therapeutic dosing or on the clinical efficacy when treating depressed patients.”

Bolea-Alamanc and colleagues argued for better representation of women in clinical trials and reporting of effects by sex in published studies of medication trials. In 2010, the Institute of Medicine released a report brief titled “Women’s Health Research: Progress, Pitfalls and Promise,” which found that while the number of women participating in clinical trials had increased over the previous two decades, they were still underrepresented. Even when women are included in these trials the results are often not analyzed separately by sex, the report found.

In December 2017, the National Institutes of Health (NIH) amended its inclusion policy to enhance the public reporting of sex/gender and race/ethnicity inclusion data. “With backing from the 21st Century Cures Act, this amendment specifically requires reporting the results of ‘valid analyses’ on sex/gender and race/ethnicity to ClinicalTrials.gov after completing an applicable NIH-defined phase 3 clinical trial,” a representative of the NIH Office of Extramural Research told Psychiatric News by email. “NIH expects this policy to increase the transparency and availability of data about how treatments work among different sex/gender and race/ethnicity groups.”

The NIH Office of Research on Women’s Health was established in September 1990 to strengthen and enhance research related to diseases, disorders, and conditions that affect women; ensure that women are appropriately represented in biomedical and biobehavioral research studies supported by the NIH; and develop opportunities and support for recruitment, retention, reentry, and advancement of women in biomedical careers.

This month the office is sponsoring a seminar on “Sex Differences in Vaccine Response.” The 2015-2016 “Report of the Advisory Committee on Research on Women’s Health” describes progress promoting preclinical and clinical research on sex differences in health and disease and medication response.

“As more studies are published it is likely that gender would be a factor to consider in prescribing, and this may change how we practice in the next decade,” Bolea-Alamanac told Psychiatric News. ■