Depression is different for women. One-size-fits-all drugs aren’t helping.
The trauma of an accident, an assault, abuse, or even simply losing someone we love can have long-term effects. For some, it can trigger mental illnesses. But what if, in the hours after the experience, you could take a pill that made you less likely to fall ill? And what if there were such a pill tailored specifically for women? That’s the goal Briana K. Chen ’16, a postdoctoral neuroscientist at Columbia University, spends her days nudging us closer to.
To grasp the problem she’s working toward solving, it’s useful to understand the perverse situation we face now: women are roughly twice as likely as men to experience depression, yet antidepressants were predominantly tested on male subjects. Moreover, while certain antidepressants seem to work better in men and others in women, that usually isn’t reflected in how they’re prescribed. Women are also more likely to experience adverse side effects with antidepressant use. Likewise, women face a higher risk of developing PTSD and anxiety, and again, the drugs used to treat these conditions were tested mainly on men. This means millions of women around the world suffer unnecessarily.
Chen’s research suggests it doesn’t have to be that way. She investigates the interaction between sex differences, stress, and mental illnesses, and her work could lead to some of the first female-specific treatments for depression, PTSD, and anxiety.
Chen finds it baffling that women and men receive the same medical treatments for psychiatric disorders when the differences between them are so significant—not only biologically, but also in terms of howthey experience the same illnesses. Women, for example, are more likely to have anxiety alongside depression. In men, on the other hand, depression is likelier to coincide with substance abuse disorders.
Part of Chen’s frustration with the status quo can be traced back to her upbringing. She went to all-girls schools from second grade through high school. The process of emerging from an insulated, all-female environment into the wider world was eye-opening for her. “One thing that was really striking, in the transition from high school to college, was the realization that the default is not female. The default is male. That was a bit of a shock to me,” she says.
Chen credits her abrupt exit from that nurturing environment with giving her a more clear-eyed view of current societal issues. “Injustices and inequalities exist, and you’re better poised to be able to see them and therefore address them,” she says.
Early results suggest that one dose of the drug is enough to prevent a whole range of fearful, depressive, and anxiety-like behaviors in female mice—and it appears to have very long-lasting effects.
When she arrived at MIT in the fall of 2012, Chen knew she wanted to major in brain and cognitive sciences. Through the Undergraduate Research Opportunities Program (UROP), she got a chance to delve into neuroscience research in several MIT labs, including that of Nobel Prize winner Susumu Tonegawa, whose team had just identified brain cells involved in encoding memories. Soon her interest in mental health more broadly was piqued.
“This whole journey began at MIT,” she says—referring both to her studies and to her deepening personal interest in the topic. The school “has a really big focus on mental health, especially for undergrads,” she adds. “Maybe it has something to do with the stressful, high-achieving environment.”
Chen says her parents inadvertently played a role in getting her interested in stress and resilience. They are first-generation immigrants—her mother from China and her father from Malaysia—who met in the UK while studying chemistry. Both went to the US for graduate school and then, in her mother’s case, postdoctoral training. “They are immigrants who did really well, but 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,” she says.
In 2014, the summer before her junior year, Chen got a summer UROP working for Steve Ramirez, PhD ’15, who was then a doctoral student in Tonegawa’s lab, studying how we form memories and how optogenetics—a technique that uses light to control the activity of specific neurons—can be used to reactivate positive memories in the brain as a treatment for PTSD and depression. (Ramirez is now a professor of neuroscience at Boston University.)
The work was a revelation for Chen, who realized while working with Ramirez that she wanted to focus on studying stress-related disorders. In 2016 she applied to the doctoral program at Columbia University and got in. She landed in the lab of neuroscientist Christine Ann Denny, where she focused on developing sex-specific drugs that can enhance stress resilience and prevent stress-induced mental illnesses. Today Chen is a postdoc in Denny’s lab, and Denny describes Chen as her “right hand.”
“Most students leave my lab with no patents, or perhaps one. Honestly, with Bri I lose track,” she adds, with a laugh. (Chen says she’s filed six nonprovisional patents—formal patents that will be reviewed by the patent office—but even she has lost track of the informal provisional ones.)
Among the many patents she’s filed, one stands out. It’s for a mental-health application of a peptide drug called Bay 55-9837 that she’s currently investigating in animal models. Originally developed by Bayer in 2002 as a potential treatment for diabetes, the drug binds to and activates a receptor in the brain called VPAC2, which is known to regulate stress responses in female mice. Chen’s idea is that it could also serve as a “vaccine” for mental illness, which women could take in the wake of a trauma.
Chen and her colleagues discovered the compound’s potential for warding off negative mental effects of trauma in a roundabout way. They knew ketamine, an anesthetic sometimes used to treat depression, reduces the likelihood that people at risk for psychiatric disorders will develop them, but they wanted to investigate exactly how it does that. Chen decided to test whether ketamine was acting through the VPAC2 receptor or some other mechanism, so she used Bay 55-9837 while administering it, as a means to dial activity of the receptor up and down during testing. In the process, she discovered that the drug was effective in female mice—but not males—as a prophylactic on its own, without any ketamine involved.
Early results suggest that one dose of the drug is enough to prevent a whole range of fearful, depressive, and anxiety-like behaviors in female mice. Not only that, but it appears to have very long-lasting effects after a single dose is administered. It’s a finding that’s hugely promising, although Chen warns there’s still a lot to investigate—including safety, possible side effects, and dosing levels—before it can be tested in humans.
Chen is optimistic about the drug’s potential but acknowledges it could fail at a future clinical hurdle. It’s crucial to “proceed with caution and make sure we have all the data so that we can ensure the safety of any potential future patients,” she adds. “Women’s mental health is definitely an urgent matter, but that just means it is even more important for us to make sure that we are as informed and careful as possible when developing treatments.”
Her main goal as a researcher, she explains, is to contribute to how we understand the specific neurobiological mechanisms behind the ways women respond to stress. In the longer term, she hopes a more sex-specific approach will be adopted by other fields within medicine. It’s a way of treating people that could lead to far better outcomes, she argues.
“If we can make female-specific antidepressants, why stop there?” she says. “Couldn’t we start developing female-specific drugs to treat cardiac disease or autoimmune disorders? Could we start developing male-specific drugs to treat diseases as well? Overall, I think we could use this approach to move toward a more widespread model of personalized medicine where we use sex to inform treatment plans to improve the health of all patients.”
