One of my many part-time gigs in graduate school was working on a research study through the local children’s hospital. My job was to go visit with postpartum mothers in their homes and ask them questions about the depression they were experiencing. These new moms had been enrolled in a study to treat their postpartum depression, and my questions were to evaluate them after to see if their symptoms had improved.
The vast majority of the mothers lived in low-income housing with limited access to, well… most things. As research assistants, we were told to remove our clothes when we got back home so as not to bring bed bugs in from our visits. I’d sit with them on sunken couches or on the floor as they rocked their babies in their arms and cry when I asked about how often they felt sad or guilty.
To check in on their depressive symptoms, I was using an instrument called the SCID, the Structured Clinical Interview for DSM Disorders. As the title indicates, it was particular in how questions were asked and the data it was searching for. I wasn’t getting to explore the depths of these women’s despair. I didn’t get to ask them about who was helping them with nighttime feedings or how much stress they felt about not having transportation to the pediatrician’s office. I was there simply to go through the checklist, and perhaps give a reassuring smile where I could.
Using a standardized measurement tool and staying on script, it certainly appeared to me that the depression afflicting these women was pretty uniform. Loss of interest and pleasure? Check. Sleep problems? Check. Difficulty concentrating? Check. Feeling worthless much of the time? Check.
There wasn’t much variability to their experience, it seemed, but I wasn’t allowed to explore any variability. Such is the nature of research, of course, and not without good reason when it comes to clinical trials. But what was happening for me as a young graduate student was that depression as an condition was coming to be crystallized as a very specific set of symptoms, almost predictable in its presentation.
What else would one expect? All I was allowed to use was my structured instrument, one that circularly asked only if they were experiencing the very things that had already been decided were depression. As the saying goes, when all you have is a hammer, everything looks like a nail.
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Many of the women I sat with that year very likely did have depression, or at least met the criteria for how we were defining it. They also were in a postpartum haze, were facing constant financial precarity, were chronically sleep deprived, and in many cases had problematic and sometimes even violent relationships. You could call them depressed or you could say they were deep in the trenches of the hardest and most egregious systemic failures. Both would be true.
Meanwhile, the depression that so often shows up postpartum is actually a little more uniform than other flavors of depression. While we still don’t have a single causal model for postpartum mood disturbances, we can somewhat more easily point to some of the biological shifts that are happening in this period and feel like we have a grasp on some of what’s happening. Drastic declines in things like progesterone and thyroid hormones help us understand the sluggishness and sadness that some birthing people feel, for example.
But even still, the fact that we can’t do a quick blood draw and assess the presence or absence of depression, even in this very specific population – that actually tells us something significant. Scientists have, after all, been working to find a gene or any other consistent biomarker of depression for decades now. They have not been successful.
That doesn’t mean that researchers haven’t found biological correlates for what we call depression, however. We do in fact see physiological changes in people with depressive symptoms. For example, scientists have found greater inflammatory proteins in the bodies of people with depression. But findings like this don’t necessarily tell us what’s cause and what’s effect, and they don’t tell us why. They can help us find treatments and make existing treatments more effective (for example, researchers hope targeting inflammatory factors will make antidepressants more effective for more people).
One biological factor current researchers are studying is how depressive syndromes are linked to the limbic system, which is responsible for motivation, behavior, and memory. In the brains of people with depression, we see less firing of synapses and less overall activity. We again don’t know all of the reasons for this, but we can say with certainty that chronic unpredictable stress is related, which is as good a reason as any to do what we can to reduce that. [Notably, this is one of the ways we believe ketamine works so quickly for depression and why psychotherapy works well long-term – they increase synaptic activity and grow new connections.]
And yet we’re still left with important questions, ones that haven’t yet been satisfactorily answered by our existing science. Things like: Is depression actually a disease? Does depression have a set of specific causes? How do I make sense of these terrible feelings I’m having?
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One question that has been answered might actually surprise you because the lore around it has so integrated and persisted in our culture. The question is whether depression is a function of a chemical imbalance in the brain.
The answer to this long-standing quandary is no, and we have in fact known that for a while now. To understand why the chemical imbalance theory has taken such root in our psyches means looking not to science, but to marketing. Well, maybe a little to science first.
When an older class of antidepressants were created in the 1950s, ones that were called tricyclics, researchers knew that one of the things they did was to increase serotonin. That led to a model that included the idea that perhaps why these medicines worked for some was that they were addressing a deficiency in serotonin. By the time medication developers came out with the well-known SSRIs in the 1990s, marketing teams at the pharmaceutical companies latched on to this easy to digest explanation for how these actually complicated medicines work. Essentially, they told us that because the medicines increase serotonin, depression is a serotonin deficiency.
But depression isn’t caused by a serotonin deficiency, as a major paper published in 2023 established. The study was landmark and it combined hundreds of studies. To quote the authors, “The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”
Consider it like this, an explanation that comes from Nassir Ghaemi, a professor of psychiatry at Tufts. We know that aspirin inhibits prostaglandin and it reduces fever in people. Those things are true, and yet we couldn’t and wouldn’t say that “fever is a prostaglandin disorder.” It helps to take it when we have a fever, but it’s not because we have an inherent malfunction in it. To take this a step farther, it also doesn’t give us any information about what actually caused the fever.
As both a person who has experienced depression and a treatment provider, the dying of the serotonin hypothesis initially came as a hard blow. It was so neat, so tidy. It gave an elegant, biologically-based explanation that also didn’t require me to change much of anything about my life, or even really look at it. I felt somewhat reassured knowing I was born this way.
But as I discussed several months ago, research in the last decade has shown that while biological explanations for mental illness lead to us blaming ourselves less for the condition, they actually increase others’ negative perceptions of us. The idea that something is “faulty” in the chemical balance or the wiring is more fraught than it might seem.
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In one of the most fascinating developments in depression research I’ve personally seen, just this year researchers at Stanford Medicine were able to use a combination of magnetic brain imaging and machine learning to show six different subtypes of depression. The scientists called these “biotypes” and while they have yet to give them fun titles, they each represented a different set of brain effects and behavioral symptoms.
In one biotype for example, patients showed an overactivity in the cognitive regions of the brain. In another type, patients struggled more with feeling under threat and highly anxious, struggling with their focus and attention. In yet another, patients felt more of the traditional sadness we associate with depression, and had a hard time with planning and executing tasks.
What was additionally so promising about this study is that the researchers could identify which of the biotypes seemed to best respond to different treatments, which included a few medications and behavioral therapy. While the data not far enough along to predict treatment response perfectly, it is a wildly big step toward more precision in depression treatment.
But what excites me most about this study and hopefully others that will follow, is that it challenges the notion that depression itself is one thing. It helps to undermine the idea of it as a singular illness that affects us as humans in a singular way.
I’d describe my own brand of depression as overthinking to the point of functional freeze, a burnout kind that historically doesn’t last too long and is responsive to intervention when I care for myself enough to get it. Others I know are sadder. Still others are irritable and angry. And then, of course, there’s what we do with depression. Some of us drink. Some of us isolate. Some of us over-work. Some of us rage. And each of those actions or inactions shapes the duration and experience of it, too.
What if we thought of depression not as a concrete biological illness, but rather as a varied syndrome that invites a deeper dive. Some might worry that this feels like a delegitimizing of a potentially debilitating experience, but I actually think it gives it greater weight. It asks us to understand that symptoms that we see are only the tip of the iceberg.
While we still don’t have a cause for depression, we can imagine many pathways to the core experience of despair. Like a migraine, the underlying causes could be very different among us. We might start to recognize certain triggers and be able to adjust for or avoid them. We might get better at treating it when it comes. We might not know if it will come back next week or never again.
There may actually be so much more hope in a new paradigm of depression.
