• On July 20, a paper titled “The serotonin theory of depression: a systematic umbrella review of the evidence” was published in Molecular Psychiatry, and the authors found no evidence linking depression to low levels of serotonin

  • The paper calls into question the serotonin “chemical imbalance” hypothesis that depression is primarily caused by biological factors 

  • This research presents an opportunity to reconsider how we talk about depression so that people fully understand their treatment options

“Our comprehensive review of the major strands of research on serotonin shows there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity.” 

With that one sentence, the widely held belief that serotonin imbalance causes depression received a major blow.

Reactions to the Molecular Psychiatry paper have ranged from triumphant vindication from those who have been trying to debunk the serotonin-related “chemical imbalance” theory and decrying the over-prescription of SSRIs, to confusion from people taking them, and concern from clinicians like me who worry that the wrong conclusions are being drawn. And as is often the case in heated debates, some nuance is getting lost in the conversation. 

As someone with a clinical background who has treated many patients with depressive symptoms, I think it’s important to contextualize the study’s findings and consider the implications in terms of how we treat, and talk about, depression.


First, some background: The idea that depression is caused by what is sometimes referred to as a “chemical imbalance” due to dysregulation of serotonin first emerged in the 1960s. It became more popular and widespread in the 1990s when Selective Serotonin Reuptake Inhibitors (SSRIs) like Prozac came on the market, with research validating their efficacy in treating depression. 

It’s not hard to understand why this theory was so compelling—it presented a narrative that depression was not the result of some kind of personal failing or inability to “cheer up,” but rather due to something biological. This helped reduce stigma in the eyes of the public because, after all, no one has control over their own brain chemistry. Some saw SSRIs and other drugs as a silver bullet that could save lives and end so much suffering. 

Although this enticingly simple explanation caught on in the media and spread, mental health practitioners have always been aware that the serotonin hypothesis was just one of many, and the evidence linking the serotonin system to depression was weak. We know that for many patients, particularly those with mild or moderate symptoms, SSRIs and other antidepressants are not always the best approach (or at least not always the best approach to try first).

Making sense of the researchers’ findings

It’s important to understand that the Molecular Psychiatry article does not claim

  • that SSRIs don’t work—no one should, in light of this research, stop taking medication that has been prescribed to them without consulting their doctor

  • that there are no biological factors that cause depression to develop; in other words, disproving the serotonin theory does not invalidate other chemical hypotheses

It’s also useful to point out there are a number of medications we know to be effective without knowing exactly how they work. For example, it took scientists more than 50 years to understand why stimulants can alleviate the symptoms of ADHD. 

Along similar lines, the umbrella review demonstrates that we don’t fully understand the mechanism through which antidepressants including SSRIs can improve depressive symptoms for some people. As David Rettew, M.D. explains in Psychology Today, “Although we don’t know very well how antidepressants work, it doesn’t change the fact that for millions of people, they do.”  

But let’s not forget that they don’t work for everyone; up to 30% of people with Major Depressive Disorder (MDD) do not respond to SSRIs. And 38% report experiencing weight gain, sleepiness, and sexual dysfunction, but endure these unpleasant side effects, possibly because they believe medication is the only way to manage their depression.       

So where does that leave us?

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We have many tools at our disposal for treating depression

Depression is a complex and highly personal disorder. Fortunately, there are many evidence-based approaches, including cognitive behavioral therapy, mindfulness, and positive psychology, that can be efficacious on their own or when used in conjunction with medication. And technology has made it easier for people to access care digitally and virtually if they prefer or it’s more convenient than in-person treatment. 

Prior to joining the team at Twill, I used to tell my patients something like this: “There are many theories as to what causes depression, but no one theory has gained a critical mass of research support to date. Many, including me, believe that depression is caused by a complex interaction of biological, psychological, and social factors. The good news is that even though we are not 100% clear on the causes, there are many treatments that have been shown to be effective for many people. Let’s talk about options and what you might want to try.”

While helpful in reducing stigma, using “chemical imbalance” to explain depression is imprecise at best. The science has spoken and our understanding of the determinants of depression is still evolving. While SSRIs and other antidepressants have changed many people’s lives for the better, there are other treatments out there worth exploring if they don’t work for you or you cannot tolerate the side effects. 

My hope is that knowing that there isn’t one catch-all explanation and cure for depression is a step in the right direction. More transparency about the myriad contributing factors and different options for treatment can empower people living with depression to make educated decisions about their mental healthcare. 

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