Please Stop Saying "Chemical Imbalance"

Hey Team,

Today, I’ll be diving into the controversy surrounding the chemical imbalance theory. After recently starting the book “This Is Your Brain on Food”1 by Uma Naidoo, MD, a 2020 book by a psychiatrist and hearing her state “Serotonin, a key chemical deficient in the brains of depressed and anxious people…” within the first 20 pages, I have been pushed to the point where I couldn’t take it anymore. Here is a deep dive on the lie we (mostly) all believe.

For decades, the public has been told that depression is caused by a “chemical imbalance” in the brain, often attributed to a serotonin deficiency or, more broadly, to imbalances in monoamine neurotransmitters.2 This theory gained traction in the 1960s when researchers observed that imipramine, an early antidepressant initially developed as an antipsychotic, alleviated depressive symptoms. Scientists later discovered that imipramine inhibited the reuptake of norepinephrine and, to a lesser extent, serotonin. This led to the hypothesis that depression might stem from a deficiency of these neurotransmitters. The theory gained further momentum in the 1970s and 1980s with the development of selective serotonin reuptake inhibitors (SSRIs) like Prozac, which were marketed as “correcting” serotonin imbalances. After all, it's easy to believe that if you have a chemical imbalance you ought to take a compound to “fix” that imbalance. The simplicity of this explanation made it highly marketable, and by the 1990s, pharmaceutical companies, psychiatrists, and even public health campaigns were reinforcing the idea that depression was a biological disease caused by low serotonin levels. This narrative persists today, despite mounting evidence to the contrary that I will now go over.

While I acknowledge that mental illness involves biological processes (e.g., brain function) rather than outdated notions like demonic possession, promoting the chemical imbalance theory as fact—primarily to benefit pharmaceutical companies rather than genuinely serving the public—is something I cannot support. The serotonin theory of depression was always speculative, yet it was presented to the public as an established fact. A comprehensive review published in Molecular Psychiatry synthesized decades of research on serotonin, including biological levels, receptor activity, transporter function, and genetic influences.3 The findings? No consistent evidence supports the idea that serotonin plays a causal role in depression. Studies measuring serotonin or its metabolites in blood, cerebrospinal fluid, or brain tissues (post modem) have found no meaningful differences between people with depression and those without it. Imaging studies on serotonin transporters and receptors have yielded weak and inconsistent results. Tryptophan depletion studies, which directly lower serotonin levels, do not induce depression in most people. Large-scale genetic analyses involving over 100,000 participants have debunked any meaningful link between serotonin-related genes and depression. In fact, some research suggests that long-term antidepressant use may actually lower serotonin levels rather than restore them. Despite this, the chemical imbalance myth remains deeply embedded in public consciousness—not because it’s scientifically valid, but because it’s a convenient, profitable narrative perpetuated through marketing and repetition. And even if we do hear of contrary claims, we believe the lie more than the correction.

Even with the wealth of research debunking the chemical imbalance theory, I still encounter books, articles, and lectures by modern psychiatrists who continue to present it as fact. This isn’t just a case of public misunderstanding—it’s still being taught to and by medical professionals. When I first started antidepressant therapy, multiple providers, including my doctor and therapist, framed my depression as a “chemical imbalance.” This framing reinforced the idea that my symptoms could be “fixed” like a vitamin deficiency, offering a simplistic solution to my suffering. While I don’t entirely blame them—they may simply have been unaware of the research—I firmly believe that psychological suffering should not be reduced to such a reductive explanation. What I was told had a profound effect on me. While relieving to learn that my condition wasn’t “my fault” it felt disempowering, as if my entire subjective experience, my suffering, and my struggles could be boiled down to a chemical equation. If depression were truly as simple as “low serotonin,” correcting it should be straightforward. Yet, the reality is far more complex.

One of the most compelling pieces of evidence against the chemical imbalance model comes from the STARD trial, the largest and most comprehensive study on antidepressant effectiveness ever conducted.4 The trial tested multiple classes of antidepressants with different mechanisms of action—some targeting serotonin, others targeting norepinephrine or dopamine—and found that they all had roughly the same effectiveness in treating depression. If depression were caused by a serotonin imbalance, SSRIs should have been significantly more effective than drugs acting on other neurotransmitters. But they weren’t. This study demonstrates that these drugs do not work by “correcting” a specific chemical imbalance—because no such imbalance has been proven to exist. More importantly, the STARD trial revealed that antidepressants barely work for most people. Even after multiple medication switches, only about 30-40% of patients achieved full remission during the first treatment step, and many of those who remitted relapsed within a year.

Some defenders of the chemical imbalance model argue that antidepressants don’t work better because the imbalance varies from person to person. However, if this were true, we would expect those with more severe depression—presumably those with the most significant “chemical imbalance”—to have the strongest response to these drugs. But the data show the opposite. A meta-analysis of all clinical trial data submitted to the FDA, including both published and unpublished studies, found that antidepressants barely outperformed placebos.5Their small statistical advantage wasn’t due to greater efficacy in severe depression but rather because placebo responses were lower in the most severely depressed patients. In other words, the worse someone’s depression, the less likely they were to respond to anything—including placebo—but the drugs themselves did not work significantly better for these patients.

The reality is that antidepressants simply aren’t very effective for most people. While they do help some people—and those experiences shouldn’t be dismissed—the majority of patients do not achieve lasting relief. When the best available research shows that antidepressants barely outperform placebos, don’t work better for the most severely depressed, and fail the majority of people who take them, it becomes clear that they are not correcting any kind of underlying biochemical deficiency. Yet, despite all this evidence, and dare I say common sense/ logical reasoning, the “chemical imbalance” narrative remains pervasive—not because it’s true, but because it has been an incredibly useful tool for marketing antidepressants. Science has moved on, and so should we.

Depression is a complex, multifaceted condition shaped by a dynamic and unique interplay of psychological and biological factors—none of which can be reduced to a simple serotonin deficiency. Emotional information processing, including an individual's perception of themselves and the future, plays a crucial role.6 These processes rely not only on serotonin but also on an intricate network of over 50 neuroactive compounds that regulate brain function.7 Clinging to outdated and reductive frameworks risks oversimplifying mental health and obstructing more meaningful, personalized approaches—ones that empower and serve individuals rather than reducing their experience to a 'broken' neurotransmitter system.

While I appreciate that we have come to view mental illness as biological in origin, promoting the chemical imbalance theory as fact—primarily to benefit pharmaceutical companies—is something I cannot support. It’s time to move beyond this outdated narrative and embrace a better understanding and discussion of mental health that prioritizes nuance, utility and reality.

The following is a quote that I find deeply insightful, though I acknowledge is a little dramatic in describing everyone who uses the term “chemical imbalance”

“It is difficult to get a man to understand something when his salary depends upon his not understanding it.” -Upton Sinclair