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  • Keith R. Holden, M.D.

Depression's Root Cause is Not a Chemical Imbalance

The chemical or neurotransmitter imbalance theory of depression is only a theory. The fact is this chemical imbalance theory of depression has never been scientifically proven to exist. Some studies have shown neurotransmitter level variations in certain mental disorders but none have proven causation. More important, none of those studies have proven that neurotransmitter imbalances are the root cause of the disorder because it's impossible to determine what came first, the chicken or the egg. Many people believe the chemical imbalance theory is a fact so I wrote this article to shed more light on this common misconception and review some other theories for the root causes of depression.

One of the best scientific articles written about how the chemical imbalance myth has been perpetuated is “The Media and the Chemical Imbalance Theory of Depression” published in the social sciences journal Society in 2008. I encourage you to read it because it’s a fascinating discussion and is available for free at

This article describes how the chemical imbalance theory was vigorously promoted by the pharmaceutical industry and how the mainstream media was duped into perpetuating this myth. The final summary by the authors still stands today - “there is not a single peer-reviewed article that can accurately be cited to directly support claims of serotonin deficiency in any mental disorder.”

So now that you know the chemical imbalance theory of depression is unproven, let’s look at what might be possible root causes of depression. First, the brain is an incredibly complex organ that will never be completely understood. Second, the mind, or consciousness that arises from the brain is even more complex. The hard question of consciousness yet to be explained by the most intelligent scientist is how the brain produces various states of mental experiences such as the perception of color and the feeling of an emotion.

Root Causes of Depression

Because of this complexity, the likely causes of depression in different individuals is complex and varied like individual fingerprints. What we do know is that nature and nurture combine to give us the answer. Our unique genetics and unique environmental influences combine to determine whether or not we experience depression. By environmental influences I mean everything from the food we eat to the toxins we’re exposed to, and everyday experiences such as stressful life events. Those nature and nurture issues are the origin, which in turn may influence changes in our brain including neurotransmitter imbalances. But the neurotransmitter imbalance, if it occurs in any individual with depression, is not the root cause.

Traumatic life experiences and even the character trait of pessimism may predispose certain individuals to depression. Adverse childhood experiences definitely play a role in certain people because the experiences permanently change areas of the brain related to stress hormone management and epigenetically alter one’s genes through a process called methylation. Both of those changes can significantly contribute to lifelong depression in certain individuals.

But some of the most interesting scientific evidence discusses how uncontrolled inflammation contributes to mood disorders. A study published in JAMA Psychiatry in August 2013 showed that having an autoimmune disease and being hospitalized for a severe infection increases the risk of developing a mood disorder. This is because research shows that mood disorders are linked to uncontrolled inflammation.

The authors say, “Experimental activation of inflammation in humans and animals induces symptoms of mood disorders. Infections cause the release of proinflammatory cytokines responsible for the symptoms of mood disorders and autoimmune diseases are associated with the formation of brain-reactive antibodies, which induce changes in neurotransmitter and neuroendocrine function.”

In other words, inflammation and infection cause the production of chemicals, which change how neurotransmitters and hormones are released in the body and brain. In addition, inflammation triggered by bacteria and viruses can cause the immune system to create antibodies against parts of the brain. When these antibodies are formed, the immune system is tricked into attacking the brain.

So as you can see, the root causes of depression are many and vary from individual to individual. What is clear is that the root cause of depression is not simply a chemical imbalance, which may explain why many people don’t benefit from the use of antidepressants.

Keith R. Holden, M.D.

Author of's best-selling course and book "Power of the Mind in Health and Healing."

Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 1998;14(4):245-58.

Benros ME, Waltoft BL, Nordentoft M, et al. Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiatry. 2013;70(8):812-20.

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