“No convincing evidence” that depression is caused by low serotonin levels, say study authors

BMJ 2022; 378 doi: https://doi.org/10.1136/bmj.o1808 (Published 20 July 2022)

Cite this as: BMJ 2022;378:o1808

The authors of a large review say there is no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations, and have questioned the reasons behind high prescribing rates of antidepressants.

They say the chemical imbalance theory of depression is still wrongly being put forward by some professionals and the public widely believes it.

Other clinicians say, however, that the notion of depression being because of a simple chemical imbalance is outmoded anyway, and that antidepressants remain a useful option for patients alongside other approaches including talking therapies.

The systematic umbrella review, published in Molecular Psychiatry, looked at the existing overviews of research on serotonin and depression including systematic reviews and meta-analyses.1

Joanna Moncrieff, professor of psychiatry at University College London, consultant psychiatrist at North East London NHS Foundation Trust, and the study’s lead author, 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 review found that 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 controls.

Research on serotonin receptors and the serotonin transporter found weak and inconsistent evidence suggestive of higher levels of serotonin activity in people with depression. The authors say these findings are likely to be explained by the use of antidepressants among people diagnosed with depression.

The authors also looked at studies where serotonin levels were artificially lowered in 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. 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.

The authors argue that the public overwhelmingly believes that depression is caused by low serotonin or other chemical abnormalities and this belief leads to a pessimistic outlook on the likelihood of recovery and the possibility of managing moods without medical help.

“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 hypothetical and unproven abnormalities,” said Moncrief.

“In particular, the idea that antidepressants work in the same way as insulin for diabetes is completely misleading. 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.”

Emphasis in psychiatry training

The authors say that psychiatric textbooks still give the lowered serotonin theory extensive coverage. Mark Horowitz, a training psychiatrist and clinical research fellow in psychiatry at University College London and an author on the study, 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.”

A position statement from the Royal College of Psychiatrists published in 2019 stated, “The original idea that antidepressants ‘correct a chemical imbalance in the brain’ is an oversimplification, but they do have early physiological effects and effects on some aspects of psychological function.”2
The college says antidepressants can induce changes in the function of brain areas that are associated with the improvement in depressive symptoms and in animal studies they have been shown to increase the number and function of brain cells and the connections between them. They also exert effects on the processing of emotional information within a few hours of drug administration.

NICE recommended treatment

A spokesperson for the Royal College of Psychiatrists said, “Antidepressants are an effective, NICE recommended treatment for depression that can also be prescribed for a range of physical and mental health conditions. Treatment options such as medication and talking therapy play an important role in helping many people with depression and can significantly improve people’s lives. Antidepressants will vary in effectiveness for different people, and the reasons for this are complex, which is why it’s important that patient care is based on each individual’s needs and reviewed regularly.

“We would not recommend for anyone to stop taking their antidepressants based on this review, and encourage anyone with concerns about their medication to contact their GP.”

In June, NICE published its first guideline in 12 years on managing depression in adults and this recommends offering a range of evidence based treatment options to patients—from psychological therapies to antidepressants.3

Commenting on the study, Allan Young, director of the centre for affective disorders at the Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, said that most psychiatrists adhere to the biopsychosocial model with very few people subscribing to a simple chemical imbalance theory. “The use of these drugs is based on clinical trial evidence which informs their use for patients. This review does not change that.”

Phil Cowen, professor of psychopharmacology at the University of Oxford, said, “No mental health professional would currently endorse the view that a complex heterogenous condition like depression stems from a deficiency in a single neurotransmitter.” However, he added that from his own research there is quite good evidence that tryptophan depletion results in depressive symptoms in some remitted depressed patients.

Cowen added that systematic umbrella reviews leave significant room for interpretation and that what is left out can be as important as what is included. For example, a meta-analysis published in Molecular Psychiatry in 2021, that was not included, concluded that metabolic changes in the peripheral blood were associated with major depressive disorder, particularly decreased L-tryptophan.

“The possible role of serotonin in depression is a separate question from the antidepressant effects of selective serotonin reuptake inhibitors.” He said he was puzzled by the implication that antidepressant drugs could work only by correction of a prior corresponding chemical imbalance. “No current theory of antidepressant action derived from either human or animal studies makes this assertion.”

References
 

01.  Moncrieff J, Cooper R, Stockmann T, et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry2022;(July). doi:10.1038/s41380-022-01661-0.

02.  Royal College of Psychiatrists. Position statement on antidepressants and depression. May 2019. www.rcpsych.ac.uk/docs/default-source/improving-care/better-mh-policy/position-statements/ps04_19-antidepressants-and-depression.pdf.

03.  NICE. Depression in adults: treatment and management. June 2022. www.nice.org.uk/guidance/ng222.

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