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If It Isn’t Serotonin, What Causes Depression?

The serotonin etiology of depression is not supported by evidence.

Key points

  • There is little evidence supporting the hypothesis that depression is caused by a deficit in serotonergic function.
  • Effective antidepressant medications may influence one or more of at least five different neurotransmitters.
  • Neural networks underlying depressive symptoms can be perturbed by a variety of genetic and environmental factors.

For decades, some investigators and clinicians have promoted the theory that depression is caused by abnormalities involving the serotonin system. This hypothesis has been encouraged by pharmaceutical companies that have developed selective serotonin-reuptake inhibitor (SSRI) antidepressant medications. A recent systematic review by Joanna Moncrieff and colleagues published in the journal Molecular Psychiatry concludes that “the huge research effort based on the serotonin hypothesis has not produced convincing evidence of a biochemical basis to depression…We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.”

Analysis of Serotonin Research

These authors performed comprehensive (“umbrella”) analyses of earlier reviews, meta-analyses, other large single studies, and genetic studies. They categorized prior work into six groups: studies examining levels of serotonin and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA); studies of serotonin 5-HT1A receptor binding; studies of the serotonin transporter involved in the uptake of serotonin into cells; studies involving tryptophan depletion (tryptophan is the amino acid precursor of serotonin); studies of the gene that generates the serotonin transporter; and studies examining interactions between the gene responsible for the serotonin transporter and stress.

The results of their analyses led the authors to conclude that the serotonin hypothesis of depression is not substantiated by available evidence. Their argument is convincing and not surprising in light of modern neuroscience. If dysfunction in the serotonin system is not a primary cause of depressive symptoms, what are the implications in terms of antidepressant treatment?

Implications for Antidepressant Treatment

Depressive disorders are a complex group of illnesses. Genetic and environmental factors increase the risk of an individual developing depression. It is unlikely that the actual “causes” of psychotic depression or bipolar depression are the same as those underlying depression associated with personality disorders or substance use disorders. Nevertheless, all types of depressive disorders have overlapping symptoms involving changes in mood, interest, energy, sleep, appetite, motivation, concentration, self-image, and desire to live.

It is likely that this group of interrelated behaviors involves abnormalities in specific brain networks—i.e., groups of cells in different brain regions that function as a unit to generate various aspects of the mind including cognition (thinking), emotion, and motivation among other functions and behaviors. Neurons and glial cells involved in such neural networks are activated and regulated by a variety of neurotransmitters as well as by other chemicals such as growth factors that alter connections between cells. Therefore, it should not be surprising that drugs that affect one or more neurotransmitters have the potential to influence the neurocircuitry underlying depression and its symptoms. Various antidepressant medications powerfully influence the serotonergic, noradrenergic, dopaminergic, GABAergic, and glutamatergic neurotransmitter systems. These medications also have a variety of other effects that can modulate neuronal function including effects on inflammation, cellular stress, and neuronal plasticity (changeability).

The fact that certain classes of antidepressants influence one or more transmitter systems does not mean that deficits in those neurotransmitters are the actual causes of depression. Rather, it suggests that medications that influence certain neurotransmitters may have the ability to adjust the neurocircuitry responsible for symptoms common to depressive disorders regardless of the actual causes of these disorders. Hence, the question of whether antidepressants are effective in treating depression is separate from questions about brain mechanisms underlying depression. A nonpsychiatric example of this is the use of aspirin or acetaminophen to treat fever. These agents are effective in lowering fever, but typically have nothing to do with the cause of the fever.

The conclusion of the Moncrieff et al. paper that depression is not a serotonin-mediated disorder should not affect how a person views the efficacy of antidepressant medications. Rather, this paper debunks the oversimplified, but convenient, hypothesis that depression is primarily a serotonin-deficit disorder, reflecting a specific “chemical imbalance.”

This post was written by Eugene Rubin, M.D., Ph.D., and Charles Zorumski, M.D.


Moncrieff, J., Cooper, R.E., Stockman, T., Amendola, S., Hengartner, M.P., & Horowitz, M.A. (2022 Jul 20). The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry. doi: 10.1038/s41380-022-01661-0. Online ahead of print.