Serotonin Theory of Depression Debunked
Jul 21, 2022 by News Staff
In a systematic umbrella review of previous relevant studies, a team of scientists from the United Kingdom, Switzerland and Italy synthesized and evaluated evidence on whether depression is associated with lowered serotonin concentration or activity.
The idea that depression is the result of abnormalities in brain chemicals, particularly serotonin, has been influential for decades, and provides an important justification for the use of antidepressants.
A link between lowered serotonin and depression was first suggested in the 1960s, and widely publicized from the 1990s with the advent of the Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants.
Although it has been questioned more recently, the serotonin theory of depression remains influential, with principal English language textbooks still giving it qualified support, leading researchers endorsing it and much empirical research based on it.
Surveys suggest that 80% or more of the general public now believe it is established that depression is caused by a ‘chemical imbalance.’
Many general practitioners also subscribe to this view and popular websites commonly cite the theory.
“It is always difficult to prove a negative, but 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,” said University College London’s Professor Joanna Moncrieff.
“The popularity of the ‘chemical imbalance’ theory of depression has coincided with a huge increase in the use of antidepressants.”
Their umbrella review, Professor Moncrieff and colleagues aimed to capture all relevant studies that have been published in the most important fields of research on serotonin and depression. The studies included in the review involved tens of thousands of participants.
Research that compared levels of serotonin and its breakdown products in the blood or brain fluids did not find a difference between people diagnosed with depression and healthy control participants.
The studies on serotonin receptors and the serotonin transporter, the protein targeted by most antidepressants, found weak and inconsistent evidence suggestive of higher levels of serotonin activity in people with depression.
“However, the findings are likely explained by the use of antidepressants among people diagnosed with depression, since such effects were not reliably ruled out,” the researchers said.
They also looked at studies where serotonin levels were artificially lowered in hundreds of people by depriving their diets of the amino acid required to make serotonin.
These studies have been cited as demonstrating that a serotonin deficiency is linked to depression.
A meta-analysis conducted in 2007 and a sample of recent studies found that lowering serotonin in this way did not produce depression in hundreds of healthy volunteers, however.
There was very weak evidence in a small subgroup of people with a family history of depression, but this only involved 75 participants, and more recent evidence was inconclusive.
Very large studies involving tens of thousands of patients looked at gene variation, including the gene for the serotonin transporter.
They found no difference in these genes between people with depression and healthy controls.
These studies also looked at the effects of stressful life events and found that these exerted a strong effect on people’s risk of becoming depressed — the more stressful life events a person had experienced, the more likely they were to be depressed.
A famous early study found a relationship between stressful events, the type of serotonin transporter gene a person had and the chance of depression. But larger, more comprehensive studies suggest this was a false finding.
These findings together led the authors to conclude that there is no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.
“The findings are important as studies show that as many as 85-90% of the public believes that depression is caused by low serotonin or a chemical imbalance,” they said.
“A growing number of scientists and professional bodies are recognizing the chemical imbalance framing as an over-simplification.”
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"While the study did not review the efficacy of antidepressants, the authors encourage further research and advice into treatments that might focus instead on managing stressful or traumatic events in people’s lives, such as with psychotherapy, alongside other practices such as exercise or mindfulness, or addressing underlying contributors such as poverty, stress and loneliness.
“Our view is that patients should not be told that depression is caused by low serotonin or by a chemical imbalance, and they should not be led to believe that antidepressants work by targeting these unproven abnormalities,” Professor Moncrieff said.
“We do not understand what antidepressants are doing to the brain exactly, and giving people this sort of misinformation prevents them from making an informed decision about whether to take antidepressants or not.” ....
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