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Major research review: Depression not caused by serotonin imbalance

A comprehensive review of antidepressant research suggests depression is not caused by a chemical imbalance.

The Molecular Psychiatry paper raises questions about what the drugs really do.

"So there's no real evidence that depression is a result of low serotonin levels in the brain. But the thing that becomes is like, what do these drugs do? They're obviously boosting serotonin, which has some sort of an effect. So what is it that takes three to four weeks?" said ASU behavioral neuroscientist Foster Olive, who did not work on the study.

Modern antidepressants began in the 1950s, when anti-tuberculosis drugs caused unforeseen and still unexplained mood changes.

Over time, the drugs changed, but the lack of clear causes remained the same.

"There's a lot of assumptions that go on that are perfectly logical at the outset, but everything is more complicated than we originally think," said Olive. "Unfortunately, the brain is a big mystery, and so a lot of the medications and the research that goes on is a lot of trial and error."

Experts have long questioned modern selective serotonin reuptake inhibitors (SSRIs) like Prozac, Paxil and Zoloft, since they raise serotonin levels quickly but take weeks to produce antidepressant effects.

“That’s kind of puzzled people for a long time and, unfortunately, we still don't have a real clear-cut answer,” said Olive.

That doesn’t mean antidepressants don’t do something; just that the underlying mechanism at work remains unclear.

People should not stop taking SSRIs without consulting a physician. Sudden cessation can cause antidepressant discontinuation syndrome.

Nicholas Gerbis was a senior field correspondent for KJZZ from 2016 to 2024.