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Departments of Obstetrics and Gynecology, Weill Cornell Medicine, New York, New YorkDepartment of Psychiatry, Weill Cornell Medicine, New York, New York
The role of the ego in melancholia is sadistic, or, rather, the ego allows the conscience (superego) to torture it because of the guilty withdrawal to narcissistic isolation. The outer world is given up. Love objects are lost and recreated in the ego, and then treated by the ego in a sadistic way.—Arnold Palmer and Stephen Sherman, 1938
In 1907, the superintendent of the Government Hospital for the Insane, William A. White, ranked the most prevalent forms of insanity in U.S. hospitals: manic depressive psychosis, dementia praecox, and involutional melancholia (
). Manic depression and dementia praecox, now referred to as bipolar disorder and schizophrenia, are among the most common conditions treated by psychiatrists today. Involutional melancholia, once a catch-all diagnosis for depressive symptoms that seemed to occur most commonly in mid-life women, has vanished. What exactly caused involutional melancholia was a point of contention between the prominent psychoanalytically oriented community and the burgeoning field of biologically inclined psychiatrists.
The name, involutional melancholia, was itself a psychoanalytic formulation. Psychoanalysts posited that some women had medical conditions or personality traits that predisposed them toward depression. These included a “stormy menstrual history,” “heterosexual maladaptation,” and conflicts relating to an “intolerant, puritanical conscience.” Involutional melancholia could result from the reemergence of anal tendencies, which occurs when the uterus involutes, fertility declines, and women’s societal value diminishes (
Biologically inclined psychiatrists (few though they may have been at the time) were skeptical. August Werner and his colleagues at the St. Louis School of Medicine noted that fertility was linked to hormones and suspected that mood might be, too. To test their hypothesis, they injected an unspecified number of women with a preparation of estrogen and monitored their moods. After 6 weeks, nearly 90% of participants reportedly improved. In 1937, Werner and his associates suggested that involutional melancholia was a severe symptom of menopause and asserted that “estrogenic substances should prove a boon to these women, a relief to their families, and an economic benefit to the nation” (
Werner’s results were never replicated, but that hardly detracted from the appeal of a potential wonder drug. In 1966, outspoken Brooklyn gynecologist Robert A. Wilson, in his best-selling book Feminine Forever, claimed that menopause diminished a woman’s worth by robbing her of some of her most fundamental qualities: youthfulness, femininity, and sexuality (
). As devastating as this was for women, what made menopause truly calamitous was the havoc it wreaked on the men who were left to contend with their “decaying” wives. Salvation from this “supreme tragedy,” Wilson said, came in the form of estrogen replacement therapy (
Not everyone bought into Wilson’s blatantly misogynist perspective, but a lot of people bought estrogen. In fact, by 1975, it was the fifth most frequently prescribed drug in the United States. Estrogen can relieve certain menopausal symptoms, but it cannot “save” women from a normal part of aging. Fortunately, some scientists weren’t satisfied with the status quo.
Nancy Woods and Ellen Mitchell, renowned researchers in menopause from the University of Washington, noticed that something important was missing from the sensational stories about estrogen: input from women. With the aim of “illuminat[ing] women’s experiences of symptoms during the menopausal transition,” Woods and Mitchell launched the Seattle Midlife Women’s Health Study (SMWHS). Enrolling more than 500 participants between 1990 and 2013, SMWHS became one of the largest longitudinal studies of perimenopausal and menopausal women. In addition to biological measures, they gathered data from health diaries, annual questionnaires, and interviews (
). In a review of open-ended interviews with 230 SMWHS participants, Mitchell and Woods discovered that physical changes were not the singular concern among women. Rather, nearly two thirds (62%) of interviewees described an undesirable change in memory in the preceding years (
). This study was significant not just because of its finding but also because it amplified women’s voices and set the stage for systematic study into estrogen’s effects on the brain.
Results from the SMWHS caught the attention of C. Neill Epperson, a pioneer in women’s health. At the time, she and her colleagues were experimenting with proton magnetic resonance spectroscopy (H-MRS), a noninvasive means of measuring brain chemistry in vivo. Using H-MRS in the occipital cortex, they observed a phenomenon that had only been seen in animal studies: Fluctuations in levels of 17β-estradiol, the most potent and ovarian-specific estrogen, were associated with changes in levels of important neurotransmitters throughout the menstrual cycle (
Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: A proton magnetic resonance spectroscopy study.
). Identifying this association paved the way for research into other regions of the human brain.
Jacobs and D’Esposito from the University of California at Berkeley were long curious about estrogen and the role it might play in working memory in the prefrontal cortex (PFC). Previous research had shown that the relationship between dopamine in the PFC and working memory resembled the Goldilocks Effect: optimal dopamine levels maximized working memory; too much or too little dopamine impeded it (Figure 1). Jacobs and D’Esposito wondered whether estradiol might affect working memory through a dopaminergic mechanism. To study this, they looked at the COMT gene, which is involved in the breakdown of dopamine in the PFC. By dividing participants by COMT genotype and measuring their working memory across the menstrual cycle, the researchers found that working memory varied according to estrogen levels and participants’ specific genotypes (
). In essence, estrogen affects dopamine, and this effect varies among individuals.
Figure 1In the proposed model, the optimal concentration of dopamine maximizes working memory performance in the prefrontal cortex, while suboptimal and supraoptimal concentrations impair cognition. Genetics contribute to baseline dopamine concentration, whereas estrogen increases dopamine concentration and shifts performance to the right. For menstruating women with the COMT val/val genotype, dopamine is readily degraded, establishing a lower baseline concentration of dopamine in the prefrontal cortex. The addition of estrogen enhances working memory. In individuals with the met/met genotype, dopamine is at optimal concentrations at baseline and the addition of estrogen worsens working memory. During menopause, fluctuating levels of estrogen (and thus lower prefrontal cortex dopamine) are associated with cognitive changes; symptoms can be relieved with estrogen treatment. Directly enhancing dopamine concentrations via the stimulant lisdexamphetamine (LDX) in postmenopausal women has also shown promise in addressing cognitive changes (
To further investigate the mechanism behind this dopamine–estrogen interaction, Epperson and her colleagues sought to stimulate the PFC by directly modulating dopamine. The most obvious candidate drugs were stimulants. In a 2015 study of perimenopausal women, the group showed that lisdexamphetamine (LDX) significantly improved participants’ cognition (
). To examine the underlying mechanism more finely, the group later performed a multimodal imaging study using H-MRS, functional magnetic resonance imaging, and cognitive function tests on a subset of the original participants. The results indicated that LDX activated the PFC and improved working memory by optimizing the concentrations of dopamine and other neurotransmitters (
). Although these studies did not directly examine LDX response in light of COMT genotype, they do show that we may need to consider LDX response in the context of both underlying genetic variability and estrogen status.
At this point, research has identified a key relationship between estrogen and dopamine, described its impact on cognition, and demonstrated a successful treatment. Nevertheless, despite decades of work, one of the most common symptoms that women complain of—cognitive difficulty—is still largely ignored.
The path forward is simple. It begins by listening to women’s concerns and taking them seriously. It also involves consistently screening for all common symptoms of menopause. When cognition is a significant concern, psychiatrists should address it using a full biopsychosocial treatment plan, including consideration of stimulants. Meanwhile, additional studies that recruit diverse study populations are needed to expand on the LDX work, explore the interplay between psychostimulants and genotype, and develop evidence-based treatment protocols. Crucially, such protocols may require precision approaches that account for the different ways in which a common underlying etiology may present in different people.
When Mitchell and Woods surveyed women about their experiences during the menopausal transition, the participants didn’t describe a “supreme tragedy” or ask to be rescued. They described real concerns about real symptoms. It’s time we appreciated that the real “boon to these women” would be a listening ear, a helping hand, and evidence-based therapies.
Acknowledgments and Disclosures
Clinical Commentaries are produced in collaboration with the National Neuroscience Curriculum Initiative (NNCI). DAR, in his dual roles as Executive Director of the NNCI and as Education Editor of Biological Psychiatry, manages the development of these commentaries but plays no role in the decision to publish each commentary. The NNCI is funded in part by the Deeda Blair Research Initiative Fund for Disorders of the Brain through support to the Foundation for the National Institutes of Health.
Supported by National Institute of Mental Health Grant Nos. 2T32MH019112-29A1 (to EBB), 5R37MH121564-03 (to NL), and K23MH110607 (to LMO). DAR receives support from the Alberta Health Services Chair in Mental Health Research.
The authors report no biomedical financial interests or potential conflicts of interest.
References
White W.A.
Outlines of Psychiatry.
Nervous and Mental Disease Publishing Co,
New York1907
Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: A proton magnetic resonance spectroscopy study.
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