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Research concludes low serotonin does not cause depression. What does that mean for SSRIs?

Woman taking pill.
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Close up of young woman taking prescription pill.

A psychiatrist and researcher in the United Kingdom led a team that analyzed 17 different reviews, meta-analyses, large single studies, and genetic studies into the low serotonin theory of depression. The research included hundreds of participants — both those diagnosed with depression and those who had not been.

The review, published in the journal Molecular Psychiatry, is called "The serotonin theory of depression: a systematic umbrella review of the evidence," and concludes that nowhere in the years of research reviewed has anyone found any evidence that low serotonin levels in the brain cause depression.

Dr. Joanna Moncrieff was the lead author of the review. She explained that her team also exmined the literature to determine whether any researcher had been able to induce depression in a subject by artificially lowering their serotonin levels. They had not.

What does that mean?

"First of all, it means that we have no evidence that people who are depressed have a chemical abnormality in their brain," Moncrieff explained. "It means that there is no evidence to support the serotonin theory, and that although there are many other theories or speculations about brain abnormalities that may be linked with depression, they have not been demonstrated either."

She added: "So we really cannot say that people who are depressed have any abnormality of their brain."

Tens of millions of Americans take selective serotonin reuptake inhibitors — SSRIs — to treat depression by addressing what was believed to be a chemical imbalance in the brain. While new research debunks this theory, there are a number of factors people should consider before getting off these medications.

Millions of Americans have treated their depression by increasing the level of serotonin in their brains with selective serotonin reuptake inhibitors since Prozac came on the market in 1988. Current popular SSRIs include Zoloft, Lexapro, Celexa, and Paxil. If low serotonin in the brain isn't the cause of depression, what does that say about the use of medications that increase the amount of serotonin in the brain to treat depression?

"We know that antidepressants, for example, produce emotional numbing effects. They numb both negative and positive emotions. And that effect may temporarily override or reduce people's underlying feelings of sadness," Moncrieff said.

Moncrieff also pointed out that the evidence SSRI anitdepressants work comes from randomized controlled trials that compare antidepressant depressants and placebo. The difference they found in these trials is between antidepressants and placebo is small, she said.

Dr. Jonathan Alpert, the chairman of the Council on Research at the American Psychiatric Association, sent TPR a statement responding to the conclusions of Moncrieff's review.

“It is important to separate the issue of mechanisms — which the review in Molecular Psychiatry focused on — from the issue of effectiveness," Alpert wrote.

"With respect to mechanisms, the hypothesis that antidepressants work by boosting serotonin and/or the other two monoamine neurotransmitters (dopamine or norepinephrine) was generated in the 1960s based on the best evidence at the time. It was an elegant hypothesis but overly simplistic," Alpert continued. "Numerous studies over the ensuring decades have failed to show consistently low serotonin levels in people with depression."

Alpert added that with regard to the effectiveness of SSRI medications, studies have consisently shown that they work better than plecebos.

"In some cases they are have only modest benefit but in some cases are truly life saving," he wrote. "They remain a very important, evidenced based treatment for clinical depression."

Scientists don’t know how SSRIs work — when they do work — to treat depression. Alpert concluded, "That we’ve learned steadily that antidepressants don’t work simply by boosting serotonin ... doesn’t in any way alter the fact that these medications worked and continue to work for millions of individuals whose quality of life and safety are profoundly affected by depression."

Moncrieff disgreed. "I would say two things to that. First of all, whether antidepressants work, I would say is debatable because the evidence from randomized controlled trials is so weak. But secondly, I would say that how antidepressants work or how they have their effects is crucially important," she said.

Moncrieff hoped her research will change the way people who take SSRIs think about their medication.

"I would encourage people to think carefully about what they think the drugs are really achieving … to realize that these drugs are drugs. They are drugs that change the normal state of the body and brain. And I would encourage people to think carefully. Are those changes really helpful for me or not?"

But Moncrieff stressed that no one should stop taking SSRI medications suddenly and without talking to their prescribing doctor. The safest way to stop taking an SSRI is to do it slowly, tapering down the dose over time under the care of a physician.

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Bonnie Petrie can be reached at Bonnie@TPR.org and on Twitter at @kbonniepetrie