Did Science Get It Wrong About Serotonin?

Molecular Psychiatry

A major review, recently published in Molecular Psychiatry, is sending shock waves throughout the medical community. The big reveal is that serotonin may not be the cause of depression.

Researchers from he University College of London (UCL) conducted an exhaustive overview of serotonin and depression. Their conclusion is that depression is not likely caused by a chemical imbalance. They also call into question what antidepressants do. Most antidepressants are selective serotonin reuptake inhibitors (SSRIs), which were originally said to work by correcting abnormally low serotonin levels. There is no other accepted pharmacological mechanism by which antidepressants affect the symptoms of depression, say the scientists.

“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,” says lead author Joanna Moncrieff, a professor of psychiatry at UCL.

The use of SSRIs has skyrocketed since the 1990s, largely driven by the ‘chemical imbalance’ theory of depression. People believe they need these antidepressants to correct an underlying biochemical imbalance. However, this is likely not be the case, say London researchers.

Study Details

The umbrella review 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 (comparison) participants.

Research 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 researchers say the findings are likely explained by the use of antidepressants among people diagnosed with depression, since such effects were not reliably ruled out.

The authors 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. 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.

Is It in the Genes?

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.”

Studies show that as many as 85-90% of the public believe that depression is caused by low serotonin or a chemical imbalance. A growing number of scientists and professional bodies are recognizing the chemical imbalance framing as an over-simplification. There is also evidence that believing that low mood is caused by a chemical imbalance leads people to have a pessimistic outlook on the likelihood of recovery, and the possibility of managing moods without medical help.

People on Antidepressants Have Lower Serotonin Levels

The authors also found evidence from a large meta-analysis that people who used antidepressants had lower levels of serotonin in their blood. They concluded that some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentrations. The researchers say this may imply that the increase in serotonin that some antidepressants produce in the short term could lead to compensatory changes in the brain that produce the opposite effect in the long term.

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. 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,” said Professor Moncrieff.

Conclusion

“This review suggests that the huge research effort based on the serotonin hypothesis has not produced convincing evidence of a biochemical basis to depression. This is consistent with research on many other biological markers. We suggest it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.”

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