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Does Psychiatry Endorse the Chemical Imbalance Theory of Depression?

Last Updated on July 29, 2022 by Carol Gillette


Chemical Imbalance Theory of Depression

Alternative to Meds Editorial Team
Medically Reviewed by Dr Samuel Lee MD

“Chemical imbalance” comes off as a simple, almost self-explanatory term, even for those of us with limited knowledge of medicine or chemistry. After all, the human body is full of different chemicals that help our various systems work. Therefore, we tend to accept “chemical imbalance” as a valid explanation for any number of emotional, behavioral, or psychological conditions. You might have heard the phrase in casual discussions about mental health, had it offered as a quick explanation for a child’s problematic behavior, or even picked it up in popular media.

What is a chemical imbalance in terms of psychology and depression? While various chemicals do, of course, play critical roles in all our bodily systems, including the brain, there is no such diagnosis as a “chemical imbalance” in mainstream, reputable psychiatry. The popularity of the term originated from drug labs and advertising, not from clinical trials.1

Is Depression Caused by a Chemical Imbalance?

In short, no. Depression is caused by a complex combination of interrelated factors. The actual roots of depression will look different for almost every one of the millions of people who experience it.

While chemical imbalance isn’t a term often found in proper, modern psychiatry, it’s still important to explore and understand the ways various chemicals affect brain function and your overall sense of well-being. Most of the chemicals implicated in depression and depression treatment are, unsurprisingly, those that send signals throughout your brain and the rest of your central nervous system. Such chemicals are known as neurotransmitters.

There are many naturally occurring neurotransmitters that have been linked to depression, mental health, and overall brain function through research.

Five most researched neurotransmitters include: 5
  • Serotonin
  • Norepinephrine
  • Dopamine
  • Glutamate
  • GABA




Many antidepressant pharmaceuticals on the market today work by attempting to manipulate serotonin levels. Selective serotonin reuptake inhibitors (SSRIs) are among the most prominent and long-standing depression meds. Lexapro, Zoloft, Paxil, and Prozac (or escitalopram, sertraline, paroxetine, and fluoxetine, respectively) are all SSRI drugs.

Serotonin is an important neurotransmitter that plays a critical role in mood regulation. It also helps the brain efficiently send signals related to hunger, sleepiness, pain, sickness, and all sorts of aspects of our emotional state.

While much of our body’s serotonin is found elsewhere, such as in the digestive tract, it is often most closely associated with the brain due to the critical messaging roles it plays in your nervous system. SSRIs are long-term maintenance drugs designed to build up in your body over time, and, consequently, withdrawals can be serious.



An important hormone, norepinephrine is perhaps most closely associated with the “flight or fight” response that occurs when you’re faced with a particularly stressful situation. It is also central to the way your brain and body process the more well-known flight or fight hormone, adrenaline.

Norepinephrine is also implicated in the regulation of blood pressure and the dilation of blood vessels. Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a class of drugs similar to SSRIs, but they manipulate your body’s norepinephrine as well as its serotonin. Effexor XR (venlafaxine) is one popular example.



Dopamine is found in the brain’s reward center and can be explained in a fairly simple way — the more dopamine you have, the better you feel. This pleasurable sensation can help to reinforce positive behavior, build meaningful relationships, or motivate us to perform at a high level.

However, it also plays a central role in the development of addiction. The euphoric dopamine release triggered by drug use, for example, can feel addictive in and of itself. Individuals are also subject to building up a dopamine tolerance. This means it will require more and more of the drug to continue achieving those pleasurable effects over time. In extreme cases, the dopamine “high” eventually becomes completely unattainable due to the high dose of drugs that would be required to achieve it, essentially “burning out” the user’s natural dopamine response.


Glutamate is an amino acid involved in conjuring up those excited, pleasurable sensations that come with mastering a new skill or recalling a favorite memory. In addition to playing a role in human brain health, it is also a naturally occurring substance in many foods.


Gamma-aminobutyric acid, usually shortened to GABA, has also been the focus of much pharmaceutical antidepressant research. GABA helps you to process negative emotions like fear and anxiety by blocking or attenuating certain types of nervous system signals. Healthy GABA levels can help someone feel more at ease and maintain their cool in a stressful situation.

Neurotransmitters and Depression

Neurotransmitters and Depression

The conventional wisdom among psychology and neuroscience experts has long held that low levels of neurotransmitters, like serotonin, norepinephrine, and dopamine, can be correlated to depression symptoms. While this holds true in a broad sense, it presents something of a “chicken or the egg” paradox. It’s not well understood or agreed upon whether a lack of these neurotransmitters is what causes depression, or the disease of depression is itself suppressing the production of these natural transmitters.

Many chemicals play crucial roles in sending signals throughout the central nervous system, and they are thus crucial components of overall mental health. However, environmental stimuli, learned behavior, and genetic factors are often just as important when it comes to someone’s overall mental health picture.

In any case, there is no evidence to suggest that “balancing” neurotransmitters or other chemicals represents some sort of cure for depression. Mental health is a deeply personal lifelong journey and not a chemical equation that can be neatly balanced with the right combination of ingredients.

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The History of Chemical Imbalance

The history of the phrase “chemical imbalance” is really the history of the scientific community debating back and forth over the course of decades. Over this time period, researchers were attempting to work out exactly how significant a role the levels of certain chemicals play in our mental health. Disagreements between psychiatrists and drug researchers have often been at the core of this story.1

So, when were the first chemical imbalance theories of depression and schizophrenia proposed? Chemical imbalance entered the discourse of legitimate medical and scientific communities in the mid-twentieth century. The term can be traced back to research into affective disorders conducted by J.J. Schildkraut in 1965. Schildkraut’s focus was primarily the neurochemical noradrenaline. Could add that Schildkraut transitioned from keenly advocating electric shock to advocating drugs to treat mental disorders. Experimenting on the urine of rat brains, he devised ways to classify mental disorders as biological rather than psychological disorders. For all of the hundreds of millions of antidepressant prescriptions sold every year, only a sparse percentage of patients report a satisfactory result.6

Chemical imbalance became a buzzword in popular lexicon due to the “serotonin theory” that came into prominence around the 1990s and built on Schildkraut’s work. Serotonin theory can be summarized fairly succinctly: the more serotonin someone has, the less depressed they will be. The emergence of this theory led to a wave of research and prescriptions for serotonin-manipulating antidepressant drugs. The serotonin theory continued to be favorably referenced in influential science textbooks, and even new research, well into the 2010s.

It is likely that not all the public debate about serotonin and chemical imbalance was held in good faith. By the time researchers and doctors had begun a robust academic dialogue about the merits and limitations of serotonin-based depression treatment, there were also large pharmaceutical companies involved.

These companies were making massive profits off antidepressant drugs. Their well-funded marketing and public relations departments were willing to go to great lengths to ensure their “serotonin boosting” depression treatments continued their market domination. 2 They were largely successful. Today, antidepressant drugs represent a $15 billion dollar market, roughly the entire national GDPs of Iceland and Jamaica combined.

It now seems possible that the hyperbolic debunking of serotonin theory, combined with the well-funded backlash to that debunking, harmed and marginalized legitimate criticism of chemical imbalance theory. Claims that chemical imbalances were not actually central to treating depression were frequently dismissed as “anti-science” or “fringe.” However, they were correct in that there is a great deal more to psychiatry and the treatment of depression than simply “balancing” the body’s level of a certain chemical.

SSRI-induced Serotonin Deficiency

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for depression and anxiety disorders. 7 Patients require several weeks or more of treatment before showing an improvement in mood, and many patients show only partial remission or fail to respond entirely. SSRIs treat depression by increasing levels of serotonin in the brain.

SSRIs block the reabsorption (reuptake) of serotonin into neurons. This makes more serotonin available to improve transmission of messages between neurons. SSRIs are called selective because they mainly affect serotonin (not other neurotransmitters).

Is Depression Scientifically Proven?

When we begin to question, or even outright doubt, longstanding theories of psychiatry and medicine, it can result in confusion and stress. Feeling misled and being left unsure of the correct path forward for treating depression can, itself, exacerbate the symptoms of depression and anxiety. You might even feel betrayed or gaslighted when you’ve been attempting to treat your depression with SSRIs or SNRIs for years, only to learn that these chemical imbalances may represent only a small part of the overall puzzle of effective, long-term depression treatment.

Faced with these doubts and concerns, you might begin to doubt science, medicine, and psychiatry on a greater scale. Make no mistake, however, that depression is a real and proven disease. Although we don’t have all the answers for how to eradicate it, effective treatments do exist — and not all of them are drug-based.

It is important to remember that science is a long-term process, and scientists are human beings susceptible to mistakes, misinterpretations, and biases like anyone else. While the scientific process is designed to reduce the influence of these human factors, it cannot eliminate them entirely. The process of coming up with a scientific theory, testing it, verifying those test results throughout the greater scientific community, and correctly interpreting what those results mean can take literal decades.

When science evolves and learns new things, it is not a condemnation or debunking of all the science that came before. In fact, this is an essential part of the scientific process. When you see science in this way, it becomes possible to appreciate and respect the work of scientists, doctors, and researchers while still being cautious about emerging science and retaining control of your own health decisions to find the best course forward in your own life.

Depression Is Subjective

Depression Is Subjective

It’s equally important to remember that depression is subjective, and most symptoms are felt without being outwardly visible. 3 It is not the sort of disease that can be measured by a lab test of a patient’s blood or other fluids. The great effort to change this by identifying a chemical that can be “balanced” to cure depression (and then manufactured and sold as a profitable drug) has arguably done great harm to public health at this point.

Despite all this, depression itself is very real and affects as many one in 20 adults. There are a variety of well-established, non-medicinal treatments available. CBT and other forms of psychological therapy as well as meditation, herbal remedies, exercise, lifestyle changes, diet modification, yoga, neurotoxin removal from the body, and many others are all potentially valuable parts of a pharmaceutical-free depression treatment regimen. 48


1. Ang, B., Horowitz, M., & Moncrieff, J. (2022). Is the chemical imbalance an ‘urban legend’? An exploration of the status of the serotonin theory of depression in the scientific literature. SSM-Mental Health, 2, 100098.

2. Lacasse, J. R., & Leo, J. (2005). Serotonin and depression: a disconnect between the advertisements and the scientific literature. PLoS medicine, 2(12), e392.

3. >Henkel, V., Mergl, R., Kohnen, R., Maier, W., Möller, H. J., & Hegerl, U. (2003). Identifying depression in primary care: a comparison of different methods in a prospective cohort study. Bmj, 326(7382), 200-201.

4. Edenfield, T. M., & Saeed, S. A. (2012). An update on mindfulness meditation as a self-help treatment for anxiety and depression. Psychology research and behavior management, 5, 131.

5. Almeida, O. P., Marsh, K., Alfonso, H., Flicker, L., Davis, T. M., & Hankey, G. J. (2010). B‐vitamins reduce the long‐term risk of depression after stroke: the VITATOPS‐DEP trial. Annals of neurology, 68(4), 503-510.

6. Dodd S, Bauer M, Carvalho AF, Eyre H, Fava M, Kasper S, Kennedy SH, Khoo JP, Lopez Jaramillo C, Malhi GS, McIntyre RS, Mitchell PB, Castro AMP, Ratheesh A, Severus E, Suppes T, Trivedi MH, Thase ME, Yatham LN, Young AH, Berk M.A clinical approach to treatment resistance in depressed patients: What to do when the usual treatments don’t work well enough? World J Biol Psychiatry. 2021 Sep;22(7):483-494. doi: 10.1080/15622975.2020.1851052. Epub 2020 Dec 8. PMID: 33289425.

7. Siesser WB, Sachs BD, Ramsey AJ, et al. Chronic SSRI treatment exacerbates serotonin deficiency in humanized Tph2 mutant mice. ACS Chem Neurosci. 2013;4(1):84-88. doi:10.1021/cn300127h

8. Genuis SJ. Toxic causes of mental illness are overlooked. Neurotoxicology. 2008 Nov;29(6):1147-9. doi: 10.1016/j.neuro.2008.06.005. Epub 2008 Jun 24. PMID: 18621076.

This content has been reviewed and approved by a licensed physician.

Dr. Samuel Lee

Dr. Samuel Lee is a board-certified psychiatrist, specializing in a spiritually-based mental health discipline and integrative approaches. He graduated with an MD at Loma Linda University School of Medicine and did a residency in psychiatry at Cedars-Sinai Medical Center and University of Washington School of Medicine in Seattle. He has also been an inpatient adult psychiatrist at Kaweah Delta Mental Health Hospital and the primary attending geriatric psychiatrist at the Auerbach Inpatient Psychiatric Jewish Home Hospital. In addition, he served as the general adult outpatient psychiatrist at Kaiser Permanente.  He is board-certified in psychiatry and neurology and has a B.A. Magna Cum Laude in Religion from Pacific Union College. His specialty is in natural healing techniques that promote the body’s innate ability to heal itself.

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Does Psychiatry Endorse the Chemical Imbalance Theory of Depression?
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