Chemical imbalance theory debunked as there is “no convincing evidence” that depression is caused by low serotonin levels

Despite the chemical imbalance theory widely being put forward by some professionals, a revolutionary review study has found that there is no link between depression and low serotonin levels.

The public widely believes that depression is the result of a chemical imbalance owing to low serotonin activity or concentrations. This is no surprise as many professionals still support this theory.

However, authors of a large systemic umbrella review, published in Molecular Psychiatry, argue that there is no support for this hypothesis. They have also questioned the high prescribing rates of antidepressants.

Some other clinicians agree 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.

Grainy photo of stooped over man with depression holding his head in his hands.
© Jakub Krechowicz

‘There is no convincing evidence that depression is caused by serotonin abnormalities’

“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” said Joanna Moncrieff, professor of psychiatry at University College London, consultant psychiatrist at North East London NHS Foundation Trust, and the study’s lead author.

The review looked at the existing overviews of research on serotonin and depression including systematic reviews and meta-analyses.

Researchers compared levels of serotonin and its breakdown products in the blood or brain fluids and did not find a difference between people diagnosed with depression and healthy controls.

In fact, studies on serotonin receptors and the serotonin transporter provide weak and inconsistent evidence suggestive of higher levels of serotonin activity in people with depression. These findings are likely explained by the use of antidepressants among people diagnosed with depression.

Artificially lowering serotonin does not produce depression

By analysing studies where serotonin levels were artificially lowered in people by depriving their diets of the amino acid required to make serotonin, the research team concluded that lowering serotonin did not produce depression in hundreds of healthy volunteers.

A small group of people with a family history of depression provided some evidence of this but overall the evidence was weak, and only involved 75 participants. More recent tests have been inconclusive.

Misinformation spreading pessimism

The public overwhelming believes that depression is caused by low serotonin or other chemical imbalances which is fostering pessimism.

Many depressed individuals believe that their depression is the result of a chemical imbalance and there is nothing they can do. They feel that depression management and recovery is unlikely 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,” stated 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.”

‘Everything I thought I knew has been flipped upside down’

“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 Mark Horowitz, a training psychiatrist and clinical research fellow in psychiatry at University College London and an author of the study.

This study really could be life-changing for individuals living with depression. Psychiatric textbooks still give the lowered serotonin theory extensive coverage – but this will likely now change.

The original idea that antidepressants ‘correct a chemical imbalance in the brain’ is an oversimplification

A statement from 2019 from the Royal College of Psychiatrists published in 2019 reads “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.”

Do antidepressants work?

The Royal College of Psychiatrists argues that antidepressants can improve depressive symptoms because the drugs induce changes in the function of certain brain areas. Animal studies prove that antidepressants increase the number and function of brain cells and the connections between them which exert effects on the processing of emotional information within a few hours of drug administration.

A spokesperson for the Royal College of Psychiatrists commented: “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, recommending a range of evidence based treatment options to patients which included psychological therapies and antidepressants.

New evidence suggests that high-doses of vitamin B6 supplements can help with anxiety and depression.

Psychiatrists do not endorse the chemical imbalance theory

Allan Young, director of the centre for affective disorders at the Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, believes that few psychiatrists subscribe to the simple chemical imbalance theory. Instead, they adhere to the biopsychosocial model.

“The use of these drugs is based on clinical trial evidence which informs their use for patients. This review does not change that,” he adds.

“No mental health professional would currently endorse the view that a complex heterogenous condition like depression stems from a deficiency in a single neurotransmitter,” explains Phil Cowen, professor of psychopharmacology at the University of Oxford.

Cowen adds, that from his own research, there is significant evidence that tryptophan depletion results in depressive symptoms in some remitted depressed patients.

What is left out can be as important as what is included

He believes 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.” Cowen is 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.”


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