Study Reignites Debate on the Chemical Imbalance Theory of Depression

Researchers Review Evidence, Reject Longstanding Theory

Is depression caused by low serotonin levels? A recently published paper has raised questions and sparked debate about a longstanding assumption. Photo by Chris Hondros/Getty Images

Based on a systematic review of 17 medical studies, a recently published paper has raised questions and sparked debate about the chemical imbalance theory of depression. Although the study did not perform additional research, after synthesizing and evaluating evidence in the principal relevant areas, the authors conclude the longstanding theory is unproven.

Serotonin is a monoamine neurotransmitter, a chemical that regulates mood, sleep, appetite, and sexual desire. The chemical imbalance theory suggests that depression is caused by lowered serotonin levels in the brain.

The paper, published July 20 in the journal Molecular Psychiatry by a multi-national team of researchers, is entitled “The serotonin theory of depression: a systematic umbrella review of the evidence.” The paper questions the “chemical imbalance” theory that began in the 1960s, based on the premise that reduced serotonin activity causes depression. This hypothesis was derived from the fact that the first two specifically antidepressant drugs, discovered in the 1950s, were both shown to increase brain levels of serotonin. Therefore, early experiments assumed a causal relationship between serotonin and depression.

Subsequently, a variety of antidepressants often referred to as “happy pills” were developed, promoted around, and reinforced this theory.

Although many professionals and the public still accept the serotonin theory of depression, the authors of the paper said they found no conclusive evidence that depression is associated with, or caused by, reduced serotonin concentration or activity in the brain. The study also calls into question whether raising serotonin levels via antidepressants is a reliable treatment for depression.

Although clinical experts have determined that antidepressants help in the treatment of severe depression, their mechanism is not entirely understood.

Reaction to the Study

Expert reaction to the study was immediate and vigorous. The day the paper was published, Britain’s Science Media Centre published a round-up of various experts and their responses.

Among them was Michael Bloomfield, Ph.D., psychiatrist and researcher at University College, London. While Bloomfield said that “the hypothesis that depression was caused by a chemical imbalance in serotonin was a really important step forward in the middle of the 20^th century,“ he called the review ”unsurprising.“ He noted, ”I don’t think I’ve met any serious scientists or psychiatrists who think that all causes of depression are caused by a simple chemical imbalance in serotonin.”

Phil Cowen, a professor of psychopharmacology at Oxford University, has studied the effects of serotonin on depressed patients for 30 years.  He believes “no mental health professional” today would support the view that a complex disorder like depression stems from “a deficiency in a single neurotransmitter.”

Professor Gitte Moos Knudsen, head of the Department of Neurology and Neurobiology Research Unit at Denmark’s University Hospital of Copenhagen, said the study is based on a misconception, namely that “depression is a single disease with a single biochemical deficit.” Today, Knudsen notes, “it is largely accepted that depression is a heterogeneous disorder with potentially multiple underlying causes.”

Rethinking How Anti-Depressants Work

Although the July 20 paper did not focus on the pros and cons of using antidepressants, their mechanism of action in treating depression has become the focus of discussion. This is because most of the antidepressants used today have roots in the questionable chemical imbalance theory.

In response to the study, Frederick Sundram, deputy head of psychological medicine at the University of Auckland, New Zealand, wrote that the mechanism of action for antidepressants is not yet fully understood. He believes there may be other mechanisms at work, such as neuroplasticity. In addition, he wrote, 30 to 40 percent of the efficacy of antidepressants is due to a placebo effect.

Sundram claimed the brain chemical imbalance theory takes a simplified approach to a very complex human condition, an approach that is not shared by most psychiatrists. For example, he said, if someone has a history of personal trauma and lives under the constant stress of social isolation, unemployment, economic problems, leading to depression, antidepressants are unlikely to solve the problem.

In March, the World Health Organization (WHO) published a report that mirrors Sundram’s view. The report noted that the global prevalence of anxiety and depression rose 25 percent in 2020, during the COVID-19 pandemic. The WHO said that people’s anxiety and depression were exacerbated by feelings of isolation under lockdowns, financial worries, and fear of illness or death for themselves and their loved ones. All of these are issues for which an antidepressant alone may be insufficient.

The Royal College of Psychiatrists, a British mental health authority, responded to the study by citing its position paper on antidepressants (pdf), which states that although the idea of using antidepressants “to correct a chemical imbalance in the brain” is too simplistic, they do have early physiological and psychological effects.

The Royal College suggests that “antidepressants treat the symptoms of depression but do not directly address any underlying psychosocial causes, so medication is often combined with psychotherapy that can improve the patient’s ability to cope with difficult life situations.”

An Integrative Medicine Perspective

Dr. Jing-Duan Yang is a psychiatrist and founder of the Yang Institute of Integrative Medicine. In a video presentation on Aug. 20, Yang explained why the chemical imbalance theory has become so prevalent. Yang said that once a theory developed by science becomes tied to a product, its promotion and subsequent researchers tend to exaggerate or embellish the original scientific evidence.

Drawing from his 20 years of clinical experience, Dr. Jing-Duan Yang believes antidepressants do work for some patients. However, “it remains to be seen if [they work] in the way that was originally hypothesized,” he said.

Dr. Yang believes antidepressant drugs have helped to reduce inflammation in the brain, and some studies suggest depression is related to the inflammatory response in the brain. Therefore these drugs may improve serotonin function but by some other mechanism.

Antidepressant Side Effects Should Prompt Caution

Yang said although antidepressants are clinically proven and effective for many people, most have a variety of side effects, so patients should be cautious when using them.

Yang gave the example of a patient he treated for nearly twenty years. The patient used the common drug Cymbalta for about ten years to improve her serotonin and norepinephrine function against anxiety and depression. The patient reported side effects such as weight gain and increased blood pressure.

After switching the patient to Lexapro, a drug that simply improves serotonin function, her anxiety and depression improved once again. But it wasn’t long before she started gaining weight again. She began having other disturbing side effects such as decreased libido, blurred vision, and a feeling that ants and bugs were crawling over her body.

Yang said the most serious concern about this and other common antidepressants is their black box warning, which warns that teens and young adults are prone to more suicidal thoughts and tendencies in the first few weeks of taking the drug. In addition, for some people, anti-depressants increase symptoms of depression.

Traditional Chinese Medicine Treats Depression

Dr. Dong Shidao, a traditional Chinese medicine (TCM) doctor living in New Zealand, told The Epoch Times that TCM believes depression is strongly linked to the liver and its response to human emotions.

Chinese medicine believes the liver plays a key role in controlling the flow of qi—usually translated as “vital energy”— through the body. When the liver is free of emotional turmoil, qi flows smoothly, and depression is avoided. Depression occurs when negative emotions disrupt the liver’s functioning, and the flow of qi becomes stagnant or blocked.

Dong believes people become prone to liver qi stagnation when they allow worries and anxiety to remain unchecked. Instead of learning to care for themselves by developing support systems and good relationships, people today spend too much time on their cell phones and computers, says Dong. They don’t know how to calm their worries in a healthy way, in order to avoid liver-related depression.

Dong believes “the stress of modern society only makes depression worse.“ To make his point, he uses a famous Chinese saying: ”If the righteousness exists within, the evil will not enter.” He predicts that the more society devolves, the more vulnerable people will be to depression.

“Chinese medicine also has medication to treat liver qi stagnation,” said Dong. “But medication and acupuncture focus on unblocking and adjusting the whole body.” TCM frequently uses a botanical formulation called Xiao Chi Hu Tang. The seven-herb formula was developed 1,800 years ago in China by Dr. Zhang Zhongjing and is still relied upon today to treat liver and gastrointestinal disorders.