Jayashri Kulkarni, PhD, MBBS, MPH

The impact of the COVID-19 pandemic on women around the world has been both troubling and illuminating. Record numbers of women have had to drop out of the workforce, and 

 There has been a 25 to 300%increase in reported cases of domestic violence against women

 Although death and hospitalization rates related to the pandemic have been higher for men than women, the COVID-19 brain health crisis (everything from depression and anxiety to neurological disorders like Alzheimer disease) has disproportionately affected women. What are the reasons underlying this inequity, known as the “The Brain Gap”? What are the impacts on children, families, communities, and future generations?

Closing the gap will require a comprehensive and systematic approach to the addressing gender equality. Getting more women in research and health care is a good first step, but it is not nearly enough. To improve women’s mental health, we must incorporate new data: namely, the perspective and experience of women. Solutions that consider the experience of women are more likely to create structural change across sectors, from neuroscience and health care to racial equality, public policy, and workplace norms.

Biological, sociocultural, and economic factors are relevant to understanding and promoting gender health, and to elucidating and reducing gender disparities. At the most fundamental level, neuroscience and clinical research have not sufficiently incorporated sex and gender-based differences into their understandings the disease development, or the subsequent treatment considerations. Accounting for sex and gender differences is a must if we want to move from a one-size-fits-all medical model towards precision medicine, where big data and artificial intelligence may enable personalized solutions.

For example, as of 2019, Alzheimer disease and other forms of dementia are the 7th leading cause of death globally, with women accounting for 

 Unfolding research demonstrates that current strategies to address the ever-growing care burden and cost of dementias have not adequately considered sex and gender differences in the molecular presentations of the illness.

 Nor have they considered the gender-specific biological and socio-cultural risk factors, rates of disease progression, or considerations for community management to ensure equity in care.

The interactions with the reproductive system are crucial for brain health and aging in women. Menopause, surgical menopause, preeclampsia, higher rates of depression, primary caregiving, and lower education levels are risk factors for developing dementia.

 These findings, however, have not changed the way we contextualize and treat these conditions. Decreasing levels of estrogen in perimenopause can contribute to issues with cognitive performance that sometimes resolve post-menopause, but have also been found to increase rates of dementia-related cognitive decline.

 Such insights can influence the way we tailor and prescribe treatments to women with Alzheimer disease.

The conversation about women’s equality must not be limited to cisgender white females. Because brain health disparities are exacerbated in racial-ethnic minorities and other underserved and marginalized groups, accounting for the impacts of interpersonal violence, racism, casteism, poverty, trans and homophobia is the only way to truly achieve gender equality and, ultimately, economic and social prosperity. For example, posttraumatic stress disorder (PTSD) was originally considered to be an illness of combat veterans, but it is much more likely to develop in women as a result of sexual assault and intimate partner violence.

 The latter is unfortunately highly prevalent in minoritized communities, and studies have shown that women of color and of lower socioeconomic status have very high rates of PTSD.

 These discrepancies exist for other mental illnesses and syndromes, including depression, anxiety, attention-deficit/hyperactivity disorder, substance use disorders, migraine, and trauma-related disorders.

 Such insights must be taken into account in next generation health care solutions for women.

Research institutions are calling for the inclusion of a more diverse array of women in preclinical development and in clinical trials, and the expansion of research design to focus on culturally relevant experiences in order to collect more 

 Furthermore, in order to translate this data into action, we must promote female leadership in health care and public health efforts. Although the majority of the long-term care workforce is female and the majority of residents in nursing homes are women, women remain underrepresented in health care leadership, underlining the lack of gendered consideration in 

Unfortunately, while the number of women employed and promoted in the workplace had been slowly trending up prior to the pandemic, COVID-19 may have halted that 

 In the United States, more than 2.2 million women have dropped out of the labor force in the 

 Women of color have been disproportionately laid off or furloughed, while others have had to tend to caregiving and primary provider responsibilities at home.

Unfortunately, these trends will have lasting consequences. For example, markers of scientific productivity decreased by 30% for women during the pandemic, whereas productivity for men 

 This could significantly set women back from professional growth for the next decade. Moreover, in the business sector, 

 found that “This is not just a ‘she-cession,’ but a devastating loss of contributions.”

 Women who voluntarily left their work reported burnout and difficulty balancing work and personal responsibilities. In the study, 70% disclosed they do most of the cooking, household shopping, and cleaning, and 80% of women who plan to reenter the workforce are concerned about limited economic opportunities and obtaining jobs that do not take full advantage of their training and skillsets. These concerns have led to a push for expanded childcare options, paid time off or medical leave; government-approved stimulus packages for childcare providers. In addition, there should be support for flexibility for employees who have multiple roles and responsibility in and out of the office. These benefits, however, are not often inclusive of the most marginalized groups, who are overrepresented in sectors that require face-to-face interactions, forcing them to choose between work and domestic care as we continue our work/study-from-home pandemic lifestyle. 

Roles for women at home range from primary caregiver for children, elderly parents and relatives, to chef, housecleaner, therapist, and educator. According to some studies, the wellbeing of women has directly correlated to the wellbeing of their families, from children, to spouses, to parents and extended community.

 A recent study showed that the state of Texas lost $2.2 billion due to untreated maternal mental health issues, not only due to effects on the mother’s productivity and health, but also due to downstream effects on the health and development of the 

 Not surprisingly, untreated mental health conditions occurred in 18.2% of Black women, and 11.4% of non-Hispanic white women, again demonstrating the importance of breaking down the data to accurately reflect the relative impact on marginalized communities.

Despite women’s central role in family wellbeing, domestic violence against women has risen during the pandemic. Prior to the crisis, 1 in 3 women around the globe experienced physical or sexual violence at least once in their 

 Since the onset of the COVID-19 pandemic, there has been a reported surge in the number of calls to violence-against-women-and-girls 

 The United Nations projected that an additional 15 million women could be affected by violence every 3 months of 

 This type of trauma decreases women’s sense of empowerment and self-worth, further burdening women with symptoms of depression, anxiety, and keeping them locked in cycles of oppression.

It is clear that women carry the major weight during times of crises, a point that is becoming even more apparent during the current brain health crises. Solutions that include women are more likely to have success and create structural change across sectors, from neuroscience and health care to racial equality, public policy, and workplace norms.

To that point, evidence indicates that women are more proactive in taking advantage of opportunities to improve, rebound, and strengthen their brain health and resilience, and translate this charge to their families, communities, and the workplace. In a recent telehealth study, women across the lifespan enrolled in the BrainHealth Project (a landmark scientific study to define, measure, and enhance brain health and performance) at 3 times the rate of men.

 The results showed comparable gains between men and women in 3 factors contributing to global brain health: 1) clarity (innovation, reasoning, optimism, compassion), 2) fortitude (emotional balance), and 3) resilience (social support, purpose). These gains were achieved at a time when so many were experiencing heightened depression, anxiety, social isolation, and brain fog. These results suggest that, while women carry the weight during times of crises, they also are ready to build brain health for themselves, their families, and their communities. Giving major attention to the pivotal role of women in boosting economic and societal resilience may help shore up the weakening foundation of our families, communities, and workforces.

To close the brain gap, we must work to identify and quantify the mental health issues facing women, with the goal of identifying data-driven levers for change. These levers can include clinical research and care, policy and process changes, as well as investing in female-identifying entrepreneurs and companies focusing on menopause, fertility, trans health, and postpartum depression. Closing the brain gap will prepare our socioeconomic systems for future shocks and will also make for stronger communities in times of peace. Doing so will require a transdisciplinary effort that is committed to building the infrastructure required to support the diversity of women in society. In order to develop successful solutions, we must work toward better understanding the underlying problems. We cannot afford to do otherwise.

is a psychiatrist with the Massachusetts General Hospital at Harvard Medical School, and co-founder and chief clinical officer of the Brainstorm Lab for Mental Health Innovation at Stanford University.

is advisor to the chief of staff and gender advisor, Office of the Secretary-General, Organisation for Economic Co-operation and Development (OECD)

is special advisor to the OECD secretary general and head of the OECD New Approaches to Economic Challenges Unit.

is an associate with the PRODEO Institute and a Thiel Fellow at Stanford University. 

is director of the Monash Alfred Psychiatry research centre and head of the Central Clinical School Department of Psychiatry at Monash University

is professor and chief director of the Center for BrainHealth at the University of Texas at Dallas and co-lead of The BrainHealth Project.

CEO of the Women’s Brain Project and head of stakeholder liaison (Alzheimer disease) for Biogen.

is a fourth-year psychiatry resident at Yale Department of Psychiatry. She is the chief resident of digital psychiatry and the chief resident of quality improvement, and she is also the co-founder of the Women’s Mental Health Conference, the first academic and trainee-led conference on women’s wellbeing in the country.

is co-founder of the PRODEO Institute, co-lead of the OECD Neuroscience-Inspired Policy Initiative, president of PRODEO, adjunct associate professor with the Institute for Mental Health and Physical Health and Clinical Translation at Deakin University, instructor in brain health diplomacy and entrepreneurship at the Global Brain Health Institute (University of California, San Francisco and Trinity College Dublin).

Disclosures: Dr Chadha is currently an employee of Biogen International; her involvement in the Women’s Brain Project that she cofounded is pro-bono. Dr Aragam is a scientific advisor at BetterUp and has consulted for HealthyGamer, Tik Tok, and TASF. The opinions expressed in this manuscript are that of the authors and may not reflect the views of the organizations with which they are affiliated.

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Highlighting Brain-Based Inequalities for Women: From Bedside and Boardroom to Policy

Emil Kraepelin proposed links between dementia praecox (schizophrenia) and hormones in 1892. Other early researchers, such as Hoskins, studied endocrine changes in people with schizophrenia at postmortem. The discovery of insulin further stimulated interest in the interaction between behavior and metabolism. Between 1940 and 1970, there was considerable interest in the psychoendocrinology of schizophrenia. Mason (1975) demonstrated the mimicking of psychotic symptoms by administering high doses of steroid hormones. Brambilla and Penati (1978) reviewed the evidence for malfunctioning of the adrenal, pituitary and thyroid glands and of the gonads in people with schizophrenia. Endocrinopathies were only rarely present, thus suggesting that endocrine abnormalities in these patients are not the cause of schizophrenia. As the role of neurotransmitters in the regulation of pituitary hormone release via hypothalamic hormones becomes clearer, neuroendocrine studies in people with schizophrenia aim to use the pituitary gland as the "window to the brain." This involves using probes to modify the secretion of anterior pituitary hormones to detect abnormalities in tubero-infundibular pituitary function reflecting similar abnormalities in the mesolimbic system. Lieberman and Koreen (1993) concluded in a large review that the hypothalamic-pituitary-thyroid axis, in general, has not been shown to manifest disturbances in schizophrenia. Nevertheless, studies of growth hormone have tended to show a response to a wide variety of pharmacological probes (e.g., apomorphine [Uprima], tryptophan, fenfluramine [Pondimin], baclofen [Liofen, Lioresal], clonidine [Catapres], methylphenidate [Ritalin] and bromocriptine [Parlodel]), suggestive of enhanced noradrenergic activity in patients with schizophrenia compared with controls. A clear omission from the neuroendocrine studies described to date is the study of hormonal profiles in women with schizophrenia. Researchers have often excluded women because of a putative inability to control the variable fluctuating monthly hormonal cycles. In considering the relationship between gonadotrophin and other gonadal steroids and mental state in patients with schizophrenia, there are very few studies examining the female patient. Riecher-Rossler and colleagues (1994) studied 32 acutely psychotic women and found a significant excess of admissions in the premenstrual and menstruation phases with an inverse relationship between serum estradiol and severity of psychotic symptoms. 

Pioneering researchers in the area of gender differences in the onset, treatment and outcome of schizophrenia have proposed that, in women, estrogen may confer protection against the early onset of severe schizophrenia (Lewine, 1988; Seeman and Lang, 1990). These researchers have suggested that women are vulnerable to relapses of schizophrenia, or their first episode of illness, in the perimenopausal period when estrogen production diminishes. As articulated by Hafner and colleagues (1998), the hypothesis also encompasses early estrogen effects on the developing brain such that a structural effect of estrogen acting during brain maturation causes the delay of first onset schizophrenia in females. From puberty, this putative structural effect is reinforced by a functional effect. Fading estrogen secretion around menopause causes women predisposed for schizophrenia (but who until then had been protected by estrogens) to fall ill with late-onset schizophrenia. Essentially, the estrogen protection hypothesis is based on three broad lines of work: epidemiological studies, biological or basic science studies in animal models, and clinical studies (Hafner et al., 1998).

A gender difference in the age at first admission, with women being older than men, was noted by Kraepelin (1913-1915). The finding was largely ignored until the late 1980s when Angermeyer and Kuhn (1988) confirmed the age difference at first admission in 50 out of 53 international studies. It is now widely accepted that males presenting with their first episode of schizophrenia are usually between the ages of 16 and 19 years, while women are up to five to 10 years older at first presentation. 

Behrens and colleagues (1992) showed that estrogen has a complex action on the dopamine system in animals, but were able to conclude from a series of studies that estrogen downregulates dopamine transmission. This finding has been replicated in animals (Clopton and Gordon, 1986; Ferretti et al., 1992; Perry et al., 1981). More recently, Fink and colleagues (1999, 1998) have shown that estrogen induces a significant increase in 5-HT

 receptors and the serotonin transporter (SERT) in regions of the rat forebrain that are concerned with mental state mood, cognition, memory, emotion and neuroendocrine control in humans. The precise mechanism of the estrogen serotonin interaction is not yet clear. The net effect of the action of estrogen on 5-HT

  receptors and SERT dopamine in general could be thought to mimic so-called atypical or newer antipsychotic medications. The significance of these findings for schizophrenia suggests that in fact the effect of estrogen in the brain on key neurotransmitter systems involved in the production of psychotic symptoms accounts for the estrogen protection hypothesis. 

Clinically, there have been case reports of psychotic symptoms occurring cyclically in women with schizophrenia during the late luteal phase when estrogen levels are at their lowest (Endo et al., 1978; Riecher-Rossler et al., 1992). Seeman (1983) reported that neuroleptic dose requirements in women who are psychotic rise as they approach menopause and described premenopausal women as "already neuroleptized by their antidopaminergic estrogens." The psychiatric literature contains case reports of women suffering from psychotic symptoms around the time of menopause (Berlin et al., 1982). There are also reports of improvement in psychotic symptoms with the addition of a combined estrogen-progesterone oral contraceptive (Dennerstein et al.,1983; Felthous et al., 1980). Following these clues, it appears that estrogen has inherent protective aspects that may prove to be clinically important in considering hormone treatments for women with schizophrenia. As a clinical trial, my colleagues and I conducted an open-label pilot study in which 11 women of childbearing age with schizophrenia were given 0.02 mg oral ethynyl estradiol as an adjunct to antipsychotic drug treatment for eight weeks. Their progress was compared to a similar group who received antipsychotic drugs only (Kulkarni et al., 1996). The group receiving estrogen made a significantly more rapid recovery from acute psychosis symptoms. Subsequently, we conducted a dose-finding study for the optimal use of estradiol in women with 

 schizophrenia (Kulkarni et al., 2001). In this three-arm, double-blind, placebo-controlled, 28-day study, 12 women received 50 mcg transdermal estradiol plus antipsychotic medication; 12 women received 100 mcg transdermal estradiol plus antipsychotic medication; and 12 women received transdermal placebo plus antipsychotic medication. The main finding was that the women who received 100 mcg estradiol adjunct made a more rapid and greater recovery in their psychotic symptoms (positive, negative and general symptoms as measured by the Positive and Negative Syndrome Scale [PANSS]). To confirm this finding, we are continuing a two-arm, 28-day, double-blind, placebo-controlled study comparing symptom resolution in women with schizophrenia receiving transdermal 100 mcg estradiol plus antipsychotic medication, with women receiving transdermal placebo plus antipsychotic medication. This is an ongoing study, and interim data are included below.

The sample size reported here is 36 (18 women in each group). Women were excluded if they were taking any synthetic steroids (including the oral contraceptive) or illicit drugs; they were also excluded if they were pregnant, lactating or postmenopausal. All patients gave written informed consent, and the Alfred Hospital Ethics Committee approved the study. Each subject was enrolled for 28 days (one menstrual cycle) and received baseline psychopathology and hormone assessment, followed by assessments at days 4, 7, 14, 21 and 28. Psychopathology was measured with PANSS. Hormone assays for serum estrogen, progesterone, prolactin, luteinizing hormone, follicle stimulating hormone and testosterone were performed.

There were no statistically significant differences between the women receiving the 100 mcg transdermal estradiol adjunct and the women who received the placebo adjunct, in terms of age, menstrual cycle phase, race, illness duration, diagnosis or antipsychotic drug dose. The mean baseline PANSS was 86.3±12.3 for the estrogen group and 73.3±12.3 for the placebo group. The difference is statistically significant (p

Women with schizophrenia may benefit from hormone replacement therapy. A new study measured the efficacy of estrogen, progesterone, Prolactin, luteinizing hormone, follicle stimulating hormone and testosterone on women with the disorder.

Jayashri Kulkarni, PhD, MBBS, MPH

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Highlighting Brain-Based Inequalities for Women: From Bedside and Boardroom to Policy

Hormonal Treatments for Women With Schizophrenia