Over 50 years ago, British Psychiatrist Alec Coppen proposed the hypothesis that Depression is linked to a low levels of Serotonin in the brain.

This lead to the commonly known statement that "depression is a chemical imbalance."

Understanding brain chemistry was difficult in the past, because direct investigation of neurochemistry in the living human brain was not possible. The belief in the 'chemical imbalance theory' led to a significant rise in antidepressant prescriptions, despite lacking scientific evidence.

Modern research focuses on complex brain circuits involved in mood disorders, rather than single neurotransmitters like serotonin. 

Public perception often links depression to low serotonin levels, but experts consider it an oversimplification. Lead author Joanna Moncrieff, a psychiatrist at UCL and NELFT, emphasises that decades of research haven't provided convincing evidence for serotonin abnormalities causing depression.

This study included tens of thousands of participants, and found no significant differences in serotonin levels between depressed individuals and healthy controls.

Serotonin 

Serotonin plays a role in cognition, influencing how the brain processes information related to reward, punishment, and decision-making.

An umbrella review aimed to gather evidence on the serotonin theory's validity by examining six areas of research: serotonin and its metabolite levels, serotonin receptors, the serotonin transporter (SERT), tryptophan depletion studies, the SERT gene, and gene-stress interactions.

The review found no convincing evidence supporting the serotonin theory. Studies on serotonin and its metabolites, serotonin receptors, and the SERT gene showed no association with depression. Brain imaging on serotonin receptors and the serotonin transporter showed slight alterations in depressed people, but the findings provided weak and inconsistent evidence which were most likely influenced by antidepressant use among the depressed individuals.

Genetic influence

Artificially lowering serotonin levels in healthy volunteers' diets didn't induce depression, even in those with a family history of depression, further undermining the serotonin deficiency hypothesis.

Large genetic studies found no difference in serotonin-related gene variations between depressed individuals and controls, suggesting genetics alone do not cause depression.

Antidepressants

The serotonin theory of depression has been influential for decades and has been a basis for using antidepressants.

The assumption that antidepressants work by correcting a serotonin imbalance supports the serotonin theory, however alternative explanations exist, such as the placebo effect or emotional blunting.

The study questions the effectiveness of antidepressants, most of which are selective serotonin reuptake inhibitors (SSRIs) that were originally thought to correct abnormally low serotonin levels.

Belief in the chemical imbalance theory may affect individuals' outlook on recovery and treatment options, leading to a reliance on medication. Long-term antidepressant use may reduce serotonin concentrations, potentially altering brain function over time.

The researchers caution against abruptly discontinuing antidepressants due to potential withdrawal effects and advocate for informed decision-making regarding antidepressant use. Professor Moncrieff and Dr. Horowitz are conducting ongoing research into safe methods for gradually stopping antidepressants.

Despite recent questioning of the chemical imbalance theory, it remains influential in textbooks, research, and public perception.

Alternative treatments

Co-author Dr. Mark Horowitz emphasises the significant impact of adverse life events on depression, challenging the idea of depression as a simple chemical imbalance.

The authors suggest that managing stressful life events through addressing underlying contributors like poverty and loneliness may be more effective than antidepressants.

The authors state that further research is needed to explore alternative treatments for depression, such as exercise, and addressing underlying contributors like stress and loneliness.

Due to the combination of stress, trauma, lifestyle factors, mindset and physiology, the way that we help people make change is why our approach seems to be very effective in helping people overcome depression.

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References:

Fifty years on: Serotonin and depression. Jauhar S, Cowen PJ, Browning M. J Psychopharmacol. 2023 March

No evidence that depression is caused by low serotonin levels, finds comprehensive review. News release. University College London; July 20, 2022

The serotonin theory of depression: a systematic umbrella review of the evidence. Moncrieff, J., Cooper, R.E., Stockmann, T. et al. Mol Psychiatry. (2023)