Women are more likely to experience a variety of mental illnesses than men. Women also face greater challenges receiving adequate and effective care for those illnesses. The roots of these twin issues extend into the history of psychiatry, gender-based differences in socioemotional expectations and experiences in daily life, and standard practice in modern research and clinical practice. Moving toward more equitable mental health care must involve incorporating sex differences — neurobiological, hormonal, and social — into the design and implementation of clinical trials. This article provides an overview of the role of biological sex-based differences in both the etiology of mental illness and the efficacy of pharmacological treatments and outlines suggestions for improving mental health care for women through the design of more inclusive and rigorous clinical trials.
Sex-Specific Neurobiological and Hormonal Predictors of Depression and Anxiety
Women face a disproportionately higher risk of developing certain mental illnesses than men, including anxiety and depression.1 The National Institute of Mental Health estimates that the 1-year prevalence of major depressive disorder is 10.3% among women and 6.2% among men.2 Women are also more likely to seek psychosocial treatment options when experiencing depression than are men.3 In addition to depression, women experience higher rates of anxiety — 19%, compared with 11.9% of men, had experienced clinically significant anxiety symptoms in the past two weeks when surveyed by the Centers for Disease Control and Prevention (CDC)4 — and are more likely than men to seek treatment for anxiety disorders.5
These differences in prevalence and treatment seeking are the result of complex interplay between biological and social factors. Women experience higher rates of mental illness due to exposure to more environmental stressors (i.e., pregnancy, birth, and childcare; employment insecurity; sleep disturbances; greater likelihood of victimization through rape and domestic violence),11,12,16 and research suggests that neurobiological and hormonal factors unique to people assigned female at birth predict risk of developing mood and anxiety disorders in the absence of — or as a result of — stress triggers.
Over the past decade, neurobiological research has uncovered countless sex differences in etiology, course, and outcomes of depression, anxiety, and other mental illness. Human-subjects biomarker research suggests that the severity of depressive symptoms among women are uniquely linked to inflammatory, serotonergic, and neurotrophic markers.6 Preclinical modeling of major depressive disorder (MDD) and anxiety in rodents has revealed sex differences in neurotransmitter response to stressors, specifically highlighting differential responses to oxytocin following social stress, with oxytocin protective for males and anxiogenic for females. among a variety of neurobiological differences in depression and anxiety onset and course across sexes.8 In humans, sex differences in stress response have also been linked to differences in hypothalamic–pituitary–adrenal (HPA) axis structure and cortisol responsivity.12
Recent research has also revealed the crucial role of hormone levels in producing depression and anxiety and highlighted interactions between sex and hormonal factors. Among women, steroid hormone fluctuation across the life span is associated with hippocampal neurogenesis, a predictor of disease trajectories of depression and Alzheimer disease.7 Rodent studies suggest that lower estrogen and higher estradiol levels among premenopausal females are associated with lower hippocampal dendritic density — a predictor of depression and anxiety — whereas an inverse association between hormone level and symptomatology was found in older and postmenopausal females.10 Human-subjects research has further implicated reproductive life stage as a predictor of depression specific to women.11 These results indicate not only a unique predictive value of hormone levels for psychopathology among women but a key role of sex–age interaction in explaining the association between hormones and disease etiology and course.
Given this evidence for sex-based biomarkers of risk and course of the most common mental illnesses, the myriad socioenvironmental factors predisposing women to mental illness, and growing preclinical and theoretical consideration of sex as a predictor of mental health etiology and outcome,9 it is high time for clinical trial methodology to become more gender inclusive.
Why Women Aren’t Included: Active and Passive Mechanisms
Despite movement to include sex in preclinical research on mental illness, applying that research to clinical trial methodology has historically been overlooked13 and remains uniquely challenging. Many pharmacological treatments that pass clinical trials carry significant risk of causing birth defects and are associated with health risks in nursing children, leaving pregnant and post-partum patients with uni- and bipolar depression and anxiety without a crucial component of their treatment plan.14 Patients using hormonal birth control are often excluded from clinical trials owing to risk of drug interactions confounding results or causing harm to the patient but severely limits inclusion of female participants and thus reduces generalizability.15
Beyond unique health and drug interaction risks among women in clinical trials, recruiting women poses additional challenges. Women typically bear a greater burden of childcare17 and may thus be less able to take time away from home to participate in clinical trials or risk side effects of experimental treatments than men. Social norms regarding women’s role in society — what makes a “good” woman — often include sacrificing one’s own wellbeing in service of caring for others and may decrease the appeal of participation in trials aimed at personal wellbeing and quality-of-life improvement. Practically, this might look like a mother using sick days or paid leave days from work for instances in which her children need her, rather than to care for herself.18
However, exclusion of women from clinical trials, neglect to control for sex in analyses, and reporting of sex-specific results remain the norm even when health risks and recruitment challenges are not considered by researchers. As of 2016, meta-analysis of phase III clinical trials revealed that 43% of trials overrepresented men, and only 22% of studies analyzed sex differences in outcome. Of the studies that included sex in analyses, none included sex differences in their discussion sections.19
The past decade has seen significant development in guidelines for inclusion criteria and study design geared specifically toward inclusion of women and other minority populations in clinical trials, but such efforts have been ongoing since the 1990s, when the guideline to exclude women from phase I and II clinical trials was first lifted by the FDA.20 This year, the FDA released a follow-up to the original 1993 guideline change detailing it’s implications for Institutional Review Board (IRB) decisions about clinical trial safety,20 highlighting the limited progress made over the past 30 years.24
How to Design Better Clinical Trials
The National Institutes of Health (NIH) requires that women — including women of childbearing age — be included in clinical trials conducted under their perview,22 but not all psychiatric clinical trials use NIH funding and thus avoid the requirement. Even when trial protocols specify that women will be included, recruitment and retention remain challenging. Several organizations have released guidelines and recommendations for conducting more inclusive clinical trials. Suggestions include:
Offering assistance with childcare18,21 and transportation.21
Designing better recruitment materials and advertising protocols:21,22 one-size-fits-all recruitment materials and advertising modalities may inadvertently target non-representative samples, possibly catering specifically to prospective male participants when materials are designed by male team members.
Collaborating with female scientist and hiring female staff to conduct trials:22,23 female participants are more likely to trust trials with gender-representative leadership and staff.
Designing trials based on feedback from previous female participants.22
Communicating sex-specific risks posed by study participation and allowing sufficient time for participants to review study information and consent documents.22
Providing flexible clinic hours and at-home follow-up:22,24 beyond providing childcare and transportation options, this intervention may make participation easier and more appealing for women who work and are primary caregivers to children.
Reimbursing participants (beyond the potential benefits of the medications being tested):22 a generally beneficial practice for collecting a larger and more representative sample across demographics.
Continuously updating recruitment strategies:23 studies that assess and appropriately update their recruitment methods based on success or failure of initial methods to recruit gender representative samples and more likely to ultimately enroll gender-representative samples.
Most of these recommendations require relatively little effort and cost to implement. Perhaps the most challenging suggestion is to include gender-representative researchers and staff. Across disciplines in psychological science — and particularly in clinical psychology and psychiatry — women are still underrepresented. Until research is designed by women, with women in mind, progress toward representative clinical trials may remain stilted.
The Role of Pharma’s Drive for Productivity
The pharmaceutical industry — a major source of funding for most clinical trials — prioritizes fast results from clinical trials and trial success over improvements in trial design and representative sampling. Each year, roughly 90% of clinical trials fail. As a result, clinical researchers are encouraged to conduct trials as quickly as possible.25 Following the COVID-19 pandemic, pharmaceutical R&D has boomed in the U.K. and India, largely due to the drive to develop and improve vaccinations. Initiatives and policy changes originally intended to fast-track vaccine development have remained in place, allowing poorly designed clinical trials across the board to be approved.26,27
Until the incentives given to researchers conducting clinical trials by their funders include conducting more representative science, little improvement in gender-inclusive trial design is likely to take place. The pharma industry has an important role to play in driving change, yet its role is consistently overlooked in recommendations for improvement of trial design, leaving researchers interested in conducting more inclusive — and thereby more conclusive — clinical trials between a rock and a hard place. Changing industry incentives is just as important as designing better trials in driving change toward more inclusive clinical research.
Conclusions
Women bear a greater burden of mental illness — particularly depression and anxiety, the most common forms of mental illness — than men. Preclinical research in the past decade has revealed numerous sex-specific risk and etiological factors, mechanisms of maintenance, and lifetime disease course. Yet clinical trials routinely recruit a greater percentage of men, ultimately drawing conclusions about drug safety and efficacy that do not account for these known sex-specific factors. Clinical trials that do include women often exclude women who are able to become pregnant, a significant percentage of the female population. Women who are on birth control typically meet inclusion criteria but may not be asked what form of birth control they use. Because hormonal birth control may interact with experimental drugs, these women are put at additional — and potentially undisclosed — risk of harm.
Two steps that can be taken to include more women in clinical trials for psychopharmacological treatments are improved trial design and quality-over-quantity incentives from funding agencies in the pharmaceutical industry. Until researchers are incentivized to improve recruitment and retention procedures, make accommodations such that participation is possible for women, and collect and analyze for sex-specific results, little change will be possible.
Once the correct incentives are in place — and restrictive, counterproductive incentives are removed — there are many measures that can be incorporated into study design to make participation easier and more appealing to women. By providing childcare and transportation, clear risk and benefit documentation (and, importantly, sufficient time for participants to review them), flexible clinic hours, and collaborating with gender-representative researchers and staff — to name just a few of many recommendations for more inclusive science — the gender gap in pharmacological psychotherapies, and possibly the gap in mental health burden overall, may one day be closed.
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