‘No convincing evidence’: Study upends theory depression caused by chemical imbalance, low serotonin

It’s long been viewed that depression is caused by a chemical imbalance. In fact, up to 90% of people believe that depression is caused by low serotonin or a chemical imbalance. However, a new study turns this theory on its head.

Researchers from University College London reveal in a major study that there is no clear evidence that serotonin levels or serotonin activity are responsible for depression. The umbrella review — an overview of existing meta-analyses and systematic reviews — also calls into question what antidepressants do for patients. Most antidepressants are selective serotonin reuptake inhibitors and are said to work by correcting abnormally low serotonin levels.

Researchers say there is no other accepted pharmacological mechanism by which antidepressants affect depression symptoms.

“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 study lead author Joanna Moncrieff, a professor of psychiatry at University College London and a consultant psychiatrist at North East London NHS Foundation Trust, in a statement.

Moncrieff states that the popularity of the chemical imbalance theory has coincided with a rapid rise in the use of antidepressants. “Many people take antidepressants because they have been led to believe their depression has a biochemical cause, but this new research suggests this belief is not grounded in evidence,” she says.

The review analyzed studies that involved tens of thousands of participants. In analysis that compared levels of serotonin and its breakdown products in the blood or brain fluids, researchers did not find a difference between people diagnosed with depression and healthy control participants.

There was weak and inconsistent evidence regarding serotonin receptors and the serotonin transporter — the protein targeted by many antidepressants — suggesting there was higher levels of serotonin activity in people with depression. Researchers, though, say their findings are most likely explained by the use of antidepressants among people diagnosed with depression.

Researchers also analyzed studies where serotonin levels were artificially lowered in hundreds of people by depriving their diets of the amino acid required to make serotonin. These previous studies were cited as demonstrating that a serotonin deficiency is linked to depression. However, researchers say, a meta-analysis conducted in 2007 and a sample of recent studies found that lowering serotonin in this way did not produce depressive symptoms in hundreds of healthy volunteers.

In studies looking at gene variation, including the serotonin transporter gene, in tens of thousands of patients, researchers found no difference in these genes between people with depression and health controls. The studies also delved into how stressful life events affected a person’s risk of becoming depressed. A well-known study found a relationship between stressful events, the type of serotonin transporter gene a person had and the chance of depression, but more comprehensive studies suggest this was a false finding.

There is “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations,” researchers concluded.

Researchers also report that people who took antidepressants had lower levels of serotonin in their blood. They believe it’s possible that long-term antidepressant use reduces serotonin concentrations. This could “imply that the increase in serotonin that some antidepressants produce in the short term could lead to compensatory changes in the brain the produce the opposite effect in the long term.”

“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,” explains Moncrieff. “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.”

Even though the study did not review the efficacy of antidepressants, researchers encourage further analysis and advice into treatments that might focus on managing stressful or traumatic events in people’s lives.

“I had been taught that depression was caused by low serotonin in my psychiatry training and had even taught this to students in my own lectures. Being involved in this research was eye-opening and feels like everything I thought I knew has been flipped upside down,” says study co-author Dr. Mark Horowitz, a training psychiatrist and clinical research fellow in psychiatry at University College London and the North East London NHS Foundation Trust. “One interesting aspect in the studies we examined was how strong an effect adverse life events played in depression, suggesting low mood is a response to people’s lives and cannot be boiled down to a simple chemical equation.”

Researchers warn that anyone considering withdrawing from antidepressants should seek a health professional’s advice.

“Thousands of people suffer from side effects of antidepressants, including the severe withdrawal effects that can occur when people try to stop them, yet prescription rates continue to rise,” says Moncrieff. “We believe this situation has been driven partly be the false belief that depression is due to a chemical imbalance. It is high time to inform the public that this belief is not grounded in science.”

The study is published in Molecular Psychiatry.

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