Depression is Caused by Low Serotonin Levels, Right?

What’s New in Psychology?

 Depression is Caused by Low Serotonin Levels, Right?

 Jim Windell

             Is depression caused by an imbalance of neurotransmitters? Is it low serotonin levels that bring about depression?

           For many years the chemical imbalance theory of depression has been popular within the medical and mental health fields. It is perhaps no coincidence that while this theory, that’s been around since the 1990s, has been gaining traction, there has also been 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 almost 37 million adults in the U.S. now taking antidepressants.

           The authors of a new study, published recently in Molecular Psychiatry, indicate that many people take antidepressants because they have been led to believe their depression has a biochemical cause. However, new research that comes out of University College London suggests that this belief is not grounded in evidence. Furthermore, the study suggests that depression is not likely caused by a chemical imbalance while calling into question what antidepressants do.

            The research, led by Professor Joanna Moncrieff, a Professor of Psychiatry at University College London and a consulting psychiatrist at North East London NHS Foundation Trust, is an umbrella review of existing meta-analyses and systematic reviews. The umbrella review aimed to capture all relevant studies that have been published in the most important fields of research on serotonin and depression. Some of the studies included in the review involved tens of thousands of participants.

           The 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, 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.

           Some of the 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.

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

           According to lead author Moncrieff, “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.”

           Moncrieff went on to say that, “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 University College London and at North East London Foundation Trust, said: “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.”

           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.”

           The authors encourage further research and advice into treatments that might focus instead on managing stressful or traumatic events in people's lives. Strategies to help managing stress and trauma would include psychotherapy along with other practices such as exercise or mindfulness – or addressing underlying contributors such as poverty, stress and loneliness.

           To read the original study, find it with this reference:

Joanna Moncrieff, Ruth E. Cooper, Tom Stockmann, Simone Amendola, Michael P. Hengartner, Mark A. Horowitz. (2022). The serotonin theory of depression: a systematic umbrella review of the evidence. Molecular Psychiatry; DOI: 10.1038/s41380-022-01661-0

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