Sex Differences and Depression: the Male-Centric Research Model’s Harmful Effects on Females
Hannah Daley
Illustrations by: Natalie Bielat
Did you know that the prevalence of depression diagnoses varies depending on sex? It might surprise you that females are twice as likely to be diagnosed with depression as males, even though treatments are largely standardized across all sexes [1]. Although depression isn’t always apparent on the surface level, chances are you know someone who has been diagnosed or affected by the disease. In fact, depression is the most common mood disorder in the US, with approximately 7.1% of adult Americans being diagnosed with a depressive episode in 2017 [1]. Despite depression’s prevalence, much remains unknown about the disease, especially in terms of its disproportionate impact on females. Uncovering the differences in depression between the sexes might be the key to developing more effective treatments, enhancing outcomes, and improving experiences for many.
Sex Vs. Gender
Before discussing sex differences in depression and treatment, it is important to first distinguish between the terms “sex” and “gender.” Sex usually refers to one’s biological genotype and the accompanying physiological processes. Gender, on the other hand, refers to an individual’s identity and does not necessarily depend on their anatomy or genetics. In medicine, the term “sex” refers to a binary system of male or female. As such, from this point on, the terms “male” and “female” will be used to refer to the sex of an individual, not their gender.
What is Depression and How is it Diagnosed?
Depression, or major depressive disorder (MDD), arises from a combination of genetic, environmental, social, and neurological factors [2]. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V) outlines nine criteria for the diagnosis of MDD. In order to be diagnosed with depression, one must experience five or more of the following symptoms in the same two week span. At least one of the symptoms must be depressed mood, loss of interest, or loss of pleasure, while others include appetite and/or weight changes, sleep difficulties, reduction of physical movement, fatigue or loss of energy, diminished ability to think or concentrate, feelings of worthlessness, and thoughts of suicide [3]. Generally, people with depression experience feelings of prolonged sadness, which affects their ability to perform daily tasks and contributes to an overall feeling of hopelessness. Since there are a wide variety of qualifiers for MDD, 227 total combinations of symptoms could result in a depression diagnosis [4]. Thus, individuals with depression can have very different symptoms and should not be classified as one and the same.
Why Does Sex Matter in Diagnoses?
It is especially important to avoid grouping all individuals with depression together when diagnosing between sexes, as symptoms are often very different. However, clinicians largely prescribe the same medication and treatments across the sexes. Current treatments for depression are not always effective, and one potential explanation for this phenomenon may be that, up until recently, studies of antidepressants have been primarily based on male subjects. In other words, because women have infrequently been studied with regard to depression treatment, there is very little research describing the effect of sex differences on treatment efficacy, or the ability of treatment to improve symptoms.
Biological differences between the sexes arise from differences in chromosomes and hormone production between males and females. Typically, males produce more of the sex hormone testosterone, while females produce more of the sex hormone estrogen, though both sex hormones are present at varying levels in all sexes. Additionally, females experience a menstrual cycle due to the fluctuation of these hormones, and its onset puts them at a higher risk for developing mood disorders [5]. One example of the impact of sex hormones on depression is demonstrated by the increased incidence of the disorder among girls who are beginning puberty and the typical decrease in depression serverity with the onset of menopause [4]. It is thought that the surge of estrogen and progesterone (another sex hormone) that occurs with the onset of menstruation is responsible for increased depression rates among girls going through puberty, and the decrease of these hormones during menopause decreases the severity of depression [6]. These findings suggest that research regarding the role of sex hormones in depression severity should be expanded. Uncovering the reasons behind these observations can lead to a better understanding of the disease and help develop more effective treatments.
Sex Differences in Biological Systems May Lead to Differential Depression Presentations
Females are approximately twice as likely to be diagnosed with depression, and two thirds of all suicides are attempted by females. Furthermore, females are more likely than males to report the depressive symptoms of chronic negative strain, low confidence in their skills, and rumination (i.e. the process of continuously thinking negative thoughts). Beyond this, females are more likely to have comorbid, or co-existing, mental health conditions along with their depression, such as anxiety-related disorders or eating disorders [4]. Moreover, the effects of depression manifest differently in males and females. Understanding the similarities and differences between males and females in the presentation and prevalence of depression can help inform diagnostic techniques and tailor treatments to increase efficacy.
Not only do males and females differ in their presentation of depression, but they also differ in the ways that their bodies process medications. The monoaminergic system, a biological system thought to be implicated in the development of depression, is known to function differently between the sexes [6]. This is a system that is often targeted by drug therapy treatments for depression. Some studies have shown that TCA (tricyclic antidepressant imipramine), one of the main drugs used as a therapeutic treatment, is more effective in males than females, though this disparity tends to disappear after menopause. However, female subjects are often given the same medication dosages as males, despite this plethora of evidence suggesting that drugs are broken down at different speeds between the sexes [7]. The fact that drug efficacy changes with the hormonal shifts of menopause further suggests an interaction of sex hormones and depression systems such as the monoaminergic system. Multiple studies also suggest that women respond preferentially to SSRIs (selective serotonin reuptake inhibitors) compared to TCAs and other antidepressants. Serotonin, the neurotransmitter involved in the use of SSRIs, is known to significantly interact with estrogen, which can cause changes in serotonin release, receptor binding, and breakdown [6]. The differential responses that females have to these common pharmaceutical treatments imply that depression may operate differently in females than in males, potentially due to interactions between estrogen and the monoaminergic system.
The Male-Centric Model
The lack of attention to sex differences in the treatment of not only depression, but also other diseases, highlights a much larger problem present in scientific research: the male-centric research model. According to one study, clinical trials for new drugs in the U.S. predominantly consisted of males up until 1988, despite females consuming 80% of all pharmaceuticals [7]. This male-centric model of research has been the standard for many years, as using females in both clinical and animal research is considered “expensive and risky.” This is likely due to research institutions’ fear of infertility as an adverse reaction that may result in lawsuits and subsequent economic turmoil. Additionally, hormonal fluctuations related to the menstrual cycle are often treated by researchers as an unavoidable confounding variable in research with female subjects. It is thought that this confounding variable will potentially prevent studies from finding any significant results, making them unable to get FDA approval to get the drug on the market. It is important to note that while female sex hormones are considered a confounding variable in drug studies, male hormones are not, even though hormonal fluctuations in males may offer similar confounding effects. Currently, less than half of the drugs approved by the FDA were tested on female subjects during clinical trials. Oftentimes, individuals assume that therapeutic responses will be the same between the sexes [7].
However, the male-centric model isn’t just ineffective for identifying inclusive treatment methods — it has also proven itself to be quite dangerous, often leaving females vulnerable to adverse drug reactions. For example, females are statistically more likely to use multiple medications simultaneously, putting them at risk for harmful drug interactions that were not otherwise investigated [8]. Additionally, the intervals between female heart beats are slightly longer due to relatively reduced levels of testosterone, which can be exacerbated by taking multiple medications at once. This phenomenon, called long QT syndrome, puts some females at higher risk for cardiac events and death. Since sex is often not accounted for when physicians write prescriptions, long QT syndrome can be overlooked. As a result, some females may experience cardiac events from routine treatments for UTIs or back pain.
The popular sleep aid, Ambien, provides another example of the massive oversight of sex in medicine efficacy. Researchers recently found that females metabolize Ambien slower than males, leaving some of the drug active in their system upon awakening. As a result, they experience extreme drowsiness the next day, putting them at increased risk for motor vehicle accidents and other dangers [8]. This oversight is just one of the many resulting from the male-centric research model, all of which could be avoided if researchers took sex into account when determining drug efficacy during clinical trials.
It is clear that sex must be considered in medical practice if treatments are to be safe and effective for everyone. In order for this to happen, major systemic changes are required in the way research is conducted. Since the Office of Research on Women’s Health at the NIH was created in 1990, inequities in clinical drug research have begun to be addressed [7]. However, there are thousands of drugs on the market, so this task is no easy undertaking. Moving forward, females need to be routinely included in clinical drug trials so that additional remedial studies do not need to take place after a drug is already approved. It would also be useful to perform clinical trials on both pre- and post-menopausal females, as it is clear that the menstrual cycle affects many body systems. In addition, medical school curriculums must be updated so that doctors are more aware of the potential of sex as a confounding factor in treatment. Surveys suggest that medical schools currently do not discuss sex in relation to treatments for most health problems, meaning that doctors are not aware of factors such as QT syndrome, or other sex related differences in their diagnoses [8]. As a whole, females have been largely ignored in clinical research and in the doctor’s office. Taking these few steps to acknowledge them is a step in right direction towards equity.
Looking Ahead
In general, our current treatment options for depression are ineffective; despite the prescription of antidepressants and other therapeutic techniques, many people continue to be affected by the disorder. However, females are affected at a disproportionate rate, as the male-centric research model has neglected to consider sex as a confounding factor for disease pathology and treatment. Research must continue to discover the specific interactions that sex-related differences have on the development of depression if more effective drug therapies are to be created. While there are many areas in modern society that require more progress towards gender equality, this pursuit is especially important in the context of scientific research, as it can have a real impact on individuals’ survival and quality of life. Sex bias in drug development should not be an additional risk factor for increased mortality for certain diseases; however, this is a problem that our society has created, and steps need to be taken to lessen this burden.
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