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Depression Is Not Caused by Chemical Imbalance in the Brain

We don’t know how antidepressants work.

Key points

  • There is no convincing evidence that depression is caused by serotonin abnormalities.
  • Many people take antidepressants believing their depression has a biochemical cause. Research does not support this belief.
  • The notion that antidepressants work by elevating serotonin levels is not supported by the evidence.

Major depression is one of the most common psychological disorders, affecting more than 23 million adults and adolescents each year in the U.S. It carries economic costs in the hundreds of billions and is a major risk factor for suicide.

The causes of depression have been long debated, yet a common explanation holds that the culprit is “chemical imbalance” in the brain. This notion emerged, not coincidentally, in the late '80s with the introduction of Prozac—a drug that appeared to be helpful in treating depression by increasing levels of the brain neurotransmitter serotonin.

Pushed heavily by the pharmaceutical industry, as well as reputable professional organizations such as the American Psychiatric Association, this storyline has since become the dominant narrative with regard to depression, accepted by the majority of people in the U.S., and leading more and more people to think of their psychological difficulties in terms of chemical brain processes. Depression treatment, in turn, has leaned ever more heavily on antidepressant medications, widely touted as the first, and best, intervention approach.

Source: vdnhieu/Pixabay

The idea that depression is caused by chemical imbalance in the brain—specifically lower serotonin levels—and can therefore be treated effectively with drugs that restore that balance appeared for a while to be an all-around winner. It provided clear answers for both physicians and their suffering patients—an elegant explanation of the symptoms and a readily available remedy in pill form; pharma companies made money.

Before long, however, two nontrivial problems have emerged regarding this promising storyline. First, antidepressant drugs turned out to be far less effective in treating depression than once hoped and advertised. About half of patients get no relief from these medications, and many of those who do benefit find the relief to be incomplete and accompanied by distressing side effects.

Moreover, research has shown that drug effects are often no better than those achieved via placebo, and may not lead to a better quality of life in the long term. A 2010 review of the literature summarized: “Meta-analyses of FDA trials suggest that antidepressants are only marginally efficacious compared to placebos and document profound publication bias that inflates their apparent efficacy… Conclusions: The reviewed findings argue for a reappraisal of the current recommended standard of care of depression.” Antidepressant medication is no miracle cure.

Second, the "chemical imbalance" hypothesis—the notion that low serotonin causes depression and that antidepressants work by elevating those levels—has failed to find empirical support. Over the past several decades, research into the serotonin-depression link has branched out into multiple lines of inquiry. Studies have looked to compare levels of serotonin and serotonin products—as well as variations in genes involved in serotonin transport—for depressed vs. non-depressed people. Other studies sought to artificially lower serotonin levels (by depriving their diets of the amino acid required to make serotonin), looking to establish a link between low serotonin and depression.

A recent (2022) exhaustive "umbrella review" (a review of meta-analyses and other reviews) of this diverse literature by Joanna Moncrieff of University College London and colleagues examined the accumulated evidence in all the above lines of inquiry. The conclusions are clear: “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.”

Lead author Joanna Moncrieff said, "I think we can safely say that after a vast amount of research conducted over several decades, there is no convincing evidence that depression is caused by serotonin abnormalities, particularly by lower levels or reduced activity of serotonin... Many people take antidepressants because they have been led to believe their depression has a biochemical cause, but this new research suggests this belief is not grounded in evidence."

The review did find a strong link between adverse and traumatic life events and the onset of depression, which points to the possibility that environmental stress factors in the emergence of the disorder more heavily than do internal brain processes. Moncrieff notes: “One interesting aspect in the studies we examined was how strong an effect adverse life events played in depression, suggesting low mood is a response to people's lives and cannot be boiled down to a simple chemical equation."

The upshot of all this for laypersons is twofold. First, you should realize that while antidepressants may work for you, they do not work for everybody, and we do not know how they work. Anyone who tells you differently is lying—to you or to themselves (or both).

Second, if you hear a medical professional using the term “chemical imbalance” to explain depression, you are hearing a fictional narrative (or a sales pitch), not scientific fact. Look for better-quality care.

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