Dr. Briana K. Chen is a neuroscientist whose work may one day change the way doctors prescribe antidepressants. As a postdoctoral researcher at Columbia University Irving Medical Center, Chen studies sex differences, stress, and psychiatric disorders with an interest in developing sex-specific treatments for mental health conditions.
Since the development of the first antidepressants in the 1950s, the subjects in clinical trials for medications to treat stress-related disorders have been primarily male. Chen says this is a problem for a number of reasons: Women are more vulnerable to these disorders and experience distinct symptoms of psychiatric disease; there are specific disorders that occur only in women; and current antidepressants exhibit sex-specific differences in treatment efficacy. Chen writes that “the antidepressants that do work in women are highly dependent on hormonal status and are often less effective in peri- or post-menopausal women.”
Moreover, she says, women are at a significantly higher risk of adverse side effects from existing antidepressants.
Her research lays the foundation for developing some of the first female-specific treatments for depression, anxiety, and post-traumatic stress disorder. In an interview with Sampan, Chen discusses her work, her background, and the future of medicine. The interview has been edited for length and clarity.
Sampan: What does a day in your life look like?
Chen: The great thing about being a scientist is that every day is different. As a postdoc, I have a wide range of responsibilities including hands-on experiments, mouse colony maintenance, data analysis, paper and grant writing, and mentorship. On a typical day, I come into the lab and spend the morning doing hands-on experiments and the afternoon doing data analysis or writing.
Sampan: What projects are you currently working on?
Chen: I am working on several projects on a variety of different topics, but the common theme is developing and testing new or repurposed pharmacological compounds in mouse models of stress. The ultimate goal of these projects is to determine whether these compounds reduce stress-induced behaviors in male and female mice as well as investigate their neurobiological effects in the brain. Overall, these data will be important for: selecting new drugs for further preclinical and clinical study (with the hope that they will be developed into novel antidepressant or anxiolytic drugs) and determining the important mechanisms of action (which may help to refine drug compounds, reduce side effects, and provide new potential biological targets for further study).
Sampan: Your work is based on sex differences and how they impact the experience and treatment of psychiatric disorders. What role do sex differences play in these disorders? For example, why might women be more prone to anxiety, whereas men seem to be more prone to substance abuse?
Chen: My research focuses heavily on what is called stress resilience. Exposure to stress is one of the greatest risk factors for developing a psychiatric disorder such as depression, anxiety, or PTSD. In fact, up to 80% of cases of depression are triggered by a major life stressor such as the death of a loved one, a natural disaster, or warfare.
Most of the population is what we call “resilient,” and can adapt to these stressors without developing a psychiatric disorder. However, a portion of individuals are susceptible, and will develop a stress-induced psychiatric disorder after exposure to trauma. Critically, women are more likely than men to be susceptible to stress. Women are two times more likely to develop depression, and three times more likely than men to develop PTSD. There are also specific depressive disorders that only occur in women, such as premenstrual dysphoric disorder (PMDD) or postpartum depression (PPD). There is also data suggesting that women are more likely to experience what we call “atypical” symptoms of depression, which include changes in weight, motivation, and sleep. Together, these data indicate that there may be biologically distinct mechanisms that contribute stress resilience and stress-related psychiatric disorders in women. If we can identify, study, and target these unique biological mechanisms, then we could potentially design more specific and effective methods of treating and preventing depression, anxiety, and PTSD in women who comprise a uniquely vulnerable portion of the population.
That said, it is still unknown exactly why we see these sex differences. In reality, as with many other concepts in neuroscience, I think a lot of the understanding behind individual variations in stress resilience boils down to nature vs. nurture. That is, our biology – genetics – interacts with our environment – our upbringing – to dictate how vulnerable or resilient we are to stress. Most of the biological research I’ve seen investigating sex differences in vulnerability/resilience to stress focuses on neuroendocrine hormones, especially estrogen.
Estrogen is actually incredibly important for supporting the health and function of neurons, particularly in helping them form connections and communicate with neighboring neurons (a process called synaptic plasticity) as well as helping the birth and growth of new neurons in a region of the brain called the hippocampus (a process called adult hippocampal neurogenesis). Impaired synaptic plasticity and impaired adult hippocampal neurogenesis have both been implicated in psychiatric disorders, and if we genetically knock out estrogen receptors in the brain, mice show impaired social behavior as well as increased depressive- and anxiety-like behaviors. Furthermore, female mice exhibit different fear, anxiety, and depressive-like behaviors during different parts of the estrous cycle (which is equivalent to the menstrual cycle in women) when systemic levels of estrogen fluctuate, suggesting that changing levels of estrogen contribute to vulnerability to stress. I’d also like to point out, however, that there has been some research with conflicting findings.
Outside of hormones, there hasn’t been too much investigation, but I think there should be more. There was a fantastic perspective written by Dr. Becca Shansky about how sex-differences research has historically focused too much on hormones and how that has hurt health outcomes for women. I completely agree with this take. It is very likely that there are other fundamental biological processes that are different in males vs. females that may contribute to increased vulnerability in females, and we need to look outside the realm of ovarian-derived hormones to learn more.
For the environmental influences, it has been suggested that women report depression, PTSD, anxiety at higher rates because of societal expectations that lead men to not look for help. I do not quite believe this theory, as epidemiological data show that these increased rates of psychiatric disorders in women occur globally, even in cultures where men’s societal expectations are quite different, suggesting that the discrepancies we are seeing are not simply due to this. Instead, I believe that women are more likely around the globe to face an increased likelihood of trauma and higher burden of day-to-day stressors. For instance, women are almost two times more likely to experience sexual assault than men, and we know that sexual assault is more likely to result in PTSD than other types of trauma. Additionally, as women tend to shoulder the primary burden of caretaking and home chores, they often face higher rates of burnout and daily stressors. Therefore, I don’t feel that we can completely discount environmental contributions when we ask why women are more vulnerable to developing depression/anxiety/PTSD than men.
Sampan: Culturally, we appear to be moving toward a conception of sex differences as more fluid than previously or perhaps traditionally thought. How might trans, gender non-conforming, and intersex people fit into your work?
Chen: I’m so glad you brought this up. I think it is incredibly important for the research community to discuss this so that we can be as inclusive as possible, particularly since some of these populations are at a high risk of stress-induced psychiatric disorders due to the adversity they have faced.
Because my work is primarily in mice, I often use the terms “male” and “female,” but these terms are loaded when it comes to translating the future and societal potential of our work. I think an important thing to remember is that sex, just like gender, is not binary but rather bimodal; that is, the main biological factors we use to determine sex – chromosomes, hormones, and anatomy – are not binary but are actually on a scale. For example, while an individual with XY chromosomes is usually male, there are chromosomal differences that do occur, such as individuals with XXY chromosomes or XXX chromosomes. Another example might be if we look at hormones – individual variations in levels of testosterone, estradiol, and progesterone are quite common, and it is possible that someone assigned female at birth may naturally have similar testosterone levels than another individual assigned male at birth. Finally, if we look at anatomy, we know that there are a lot of individual differences there, so we can’t simply say the presence of, say breasts or genital anatomy, are defining sexual features. Therefore, because all of these different factors are not binary, we cannot say that biological sex is binary. I believe the field is moving towards more specific language and variables in scientific research – that is, rather than using “female” or “male” as a proxy label, we are moving towards specifically discussing, for instance, the effect of estradiol receptor levels on behavior or biological measures. In terms of how this fits into my own research, I think it is a reminder that we can’t over-anthropomorphize our results (i.e., female mice are very different from female people) and that we have to be very careful of the language we use in our work.
Sampan: Some of your work discusses the importance of ovarian hormones for the efficacy of certain compounds like (R,S)-ketamine in treating stress-related disorders. What insights might this offer for the treatment of disorders for peri- or post-menopausal women? Does it suggest reasons for why antidepressant use is often less effective for these populations?
Chen: As you have pointed out, many current antidepressants can become significantly less effective during menopause. A likely contributing factor may be fluctuating levels of circulating hormones – for example estradiol, progesterone – which are known to influence the efficacy of antidepressant medications. To address these concerns, I believe it is important to invest in and conduct research that is specifically aimed at increasing the representation of female subjects in biomedical research and studying the effects of menopause on the brain and behavior as well as how these changes may interact with different drugs.
Sampan: As you point out on your website, we have historically used predominantly male subjects in psychiatric research. How can we give incentives for researchers to be more inclusive?
Chen: In 2016, the National Institutes of Health implemented its Sex as a Biological Variable (SABV) policy, which mandated researchers to factor sex into the design, analysis, and reporting of research studies. This was an incredibly important policy that standardized what many (but not all) researchers had already been doing, which was to use both male and female test subjects, disaggregate research results by sex, and report these results in a transparent manner. By requiring these practices in all grant submissions, the NIH did a great job in placing priority on studies to address longstanding inequities in biomedical research. Since the implementation of this policy, there has been a lot of new research coming out on sex differences particularly in neuroscience research. I think the effects of this policy make it clear that financial investment is a driving factor in scientific research. Establishing more investments in research that benefit the heath of women and individuals assigned female at birth (e.g., grant mechanisms that prioritize issues in women’s health or requirements for SABV in grant applications or journal articles) are important for addressing inequities in healthcare related to sex and gender.
Sampan: Do you see a future in which individualized medicine responds to cultural differences as well as sex differences? How might psychiatric drugs and treatments change not only with regard to sex differences but also cultural differences, including cultural differences in gender and sex expression?
Chen: I absolutely think that psychiatry as a field is moving towards more personalized and individualized medicine. One of the larger goals of our research is to prevent psychiatric disorders before they occur by developing drugs to enhance resilience to stress. However, I do not see a future where we broadly administer these drugs to everyone. Rather, I envision the possibility of identifying vulnerable individuals and selectively intervening during or after a stressor to prevent psychiatric disease. I bring this up because while it is not the focus of our research, it will be important to develop screening tools to identify those most at risk, and I believe it will be critical for those very screening tools to consider an individual holistically – that is, how that individual’s sex, biology, family history, and cultural background may come together to influence how the person responds to stress. There are many labs currently that use clinical data and data science approaches to investigate and develop such screening tools, and I think it is important to acknowledge their hard work and expertise.
SAMPAN: You have talked about your parents, first-generation immigrants from China and Malaysia, in previous interviews. You point out that “there are lots of other immigrants who struggle. And it’s very interesting to see what the combination of factors is behind that, how changes and different environments interact with intrinsic biological properties to do with resilience and adaptation.” Can you speak more to this? As we discover more about the biological properties underlying resilience and adaptation, what changes do you think we will see medically and perhaps socially?
Chen: Thank you so much for bringing this up – I’m incredibly grateful to my parents and their hard work, and so many of the opportunities I’ve had in life have been due to their sacrifices.
When my parents came to the U.S., they struggled financially and because they were a long ways away from the life they knew. However, they were lucky to have an education, and they worked hard to use that education to develop a better life for themselves. I want to acknowledge that privilege, because a lot of immigrants do not have that.
Immigrating to a new country is a huge stressor that has the potential to impact future generations of a family. I think that any immigrant or a child of immigrants can attest to this fact. Dealing with the adversity of adjusting to a new life, a new culture, and a new language while also losing close contact with family and friends has an incredible impact on a person. Furthermore, especially in this day and age, many migrants have the added burden of potentially fleeing from conflict in their home country, being exposed to violence, and encountering adversity in their new country. This trauma is likely to influence current and future rates of depression, anxiety, and PTSD around the globe as well as affect generations to come; indeed, studies have shown that trauma is transmissible to future offspring through a variety of mechanisms, including epigenetic changes. However, will these changes lead to higher resilience or more vulnerability to psychiatric disease in future generations? Could the same trauma that makes one individual vulnerable to PTSD or depression make another individual resilient and able to adapt to changing circumstances? What are the environmental and biological factors that empower some people to build a better life while others struggle? These are the types of questions that fascinate me and, I believe, speak so much to the immigrant experience.
While I do not have the answers to these questions, I hope that we can improve attitudes towards immigrants. Immigrants bring new perspectives, cultures, and customs that can improve society as a whole. Scientific research, in particular, is only made better by the hard work of immigrant scientists who sacrifice so much to contribute their expertise and hard work to improve the field. I would love to see more support from institutions to help immigrant scientists with visas and related immigration paperwork, more funding opportunities for immigrant scientists, and support for scientists who do not speak English as a first language.
