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NOTE: We typically try to let this sort of research speak for itself, this topic is complicated and fraught with risks. Depression, Anxiety, and mood disorders in general are very real and can have awful consequences. To be perfectly clear:

– This research DOES NOT show that mood is “just in your head” or that you can “just get over it.”
– It DOES confirm that tragic & traumatic life events have a direct effect on mood.
– It DOES call into question the assumed causal relationship between low serotonin and mood disruption (i.e. that depression is CAUSED by low serotonin).

In other words: We have determined that we don’t actually understand everything happening in the human brain. For that reason alone, DO NOT STOP TAKING PRESCRIBED MEDICATION WITHOUT CONSULTING YOUR DOCTOR FIRST!

A major review of prior research led by University College London (UCL) scientists states that after decades of study, there remains no clear evidence that serotonin levels or serotonin activity are responsible for depression.

The new umbrella review – an overview of existing meta-analyses and systematic reviews – published in Molecular Psychiatry suggests that depression isn’t caused by a chemical imbalance and poses the question of what antidepressants do. Most antidepressants are selective serotonin reuptake inhibitors (SSRIs), which were initially said to work by adjusting abnormally low serotonin levels. There are no other accepted pharmacological means by which antidepressants affect the symptoms of depression.

Lead author Professor Joanna Moncrieff, a Professor of Psychiatry at UCL and a consultant psychiatrist at North East London NHS Foundation Trust (NELFT), said: 

“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.

“The popularity of the ‘chemical imbalance’ theory of depression has coincided with a huge increase in the use of antidepressants. Prescriptions for antidepressants have risen dramatically since the 1990s, with one in six adults in England and 2% of teenagers now being prescribed an antidepressant in a given year.

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.”

The goal of the umbrella review was to capture all relevant studies published in the most significant fields of research on serotonin and depression. The studies included in the review involved tens of thousands of participants.

Research comparing serotonin levels 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 possibly 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. 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. Levels and mood may be linked in those with a family history of depression, but there was no evidence of it being causal.

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. They 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. An earlier, 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 extensive, more comprehensive studies suggested that was a false finding.

Together, these findings led the authors to conclude that there is “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”

The researchers say their findings are important as studies show that as many as 85-90% of the public believes depression is caused by low serotonin or a chemical imbalance. However, a growing number of scientists and professional bodies are starting to recognize the chemical imbalance framing as an over-simplification. There is also evidence that believing that a chemical imbalance causes low mood leads people to have a pessimistic outlook on the likelihood of recovery and the possibility of managing moods without medical help. This is important because most people will meet the criteria for anxiety or depression at some point in their lives.

They also found evidence from a large meta-analysis that people who used antidepressants had lower serotonin levels 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 instead focus on managing stressful or traumatic events in people’s lives. For example, psychotherapy, alongside other practices such as exercise or mindfulness, or addressing underlying contributors such as poverty, stress, and loneliness might be beneficial.

Professor Moncrieff said, “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.”

Co-author Dr. Mark Horowitz, a training psychiatrist and Clinical Research Fellow in Psychiatry at UCL and NELFT, noted,

“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. 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.”

Professor Moncrieff added, “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. We believe this situation has been driven partly by 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.”  

It’s important to note that the researchers caution anyone considering withdrawing from antidepressants to seek the advice of a health professional, given the risk of adverse effects following withdrawal. Professor Moncrieff and Dr. Horowitz are conducting ongoing research on how to stop taking antidepressants gradually.