Is a serotonin deficiency to blame for depression? Probably not.

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A comprehensive review published in Molecular Psychiatry found scant evidence for the so-called serotonin hypothesis, suggesting that diminished serotonin pathways’ activity is associated with depression.

The authors conclude that the research provides “no consistent evidence of an association between serotonin and depression.” They also note they could not find support for “the hypothesis that depression is caused by lowered serotonin activity or concentrations.”

The Molecular Psychiatry article does, however, acknowledge that long-term use of antidepressants may lower serotonin concentration.

The broader idea that a chemical imbalance is to blame for depression has become a mainstream concept. The pioneering psychiatrist Joseph Schildkraut helped popularize the theory in the 1960s with a paper titled “The catecholamine hypothesis of affective disorders,” which would eventually become one of the most cited articles published by the American Journal of Psychiatry.

The related serotonin hypothesis of depression is now more than 50 years old.

Marketing for selective serotonin reuptake inhibitors (SSRIs) has helped cement its popularity. And research papers and textbooks backing the idea in recent decades have offered further support.

A Zoloft commercial noted that, “While the cause [of depression] is unknown, depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Prescription Zoloft works to correct this imbalance.”

While several psychiatrists have called the serotonin hypothesis of depression an “urban legend,” the idea has remained influential.

A paper published earlier this year in SSM Mental Health found significant evidence for the theory in research papers and support in many textbooks. However, some of the latter acknowledged that the idea was provisional.

While professional opinions on antidepressants vary significantly, some papers have cast double on their efficacy in the past two decades.

One paper in BMJ concluded that the benefits of antidepressants for patients with major depressive disorder are likely “minimal.” It concludes that the drugs “should not be used for adults with major depressive disorder before valid evidence has shown that the potential beneficial effects outweigh the harmful effects.”