You may have heard, “Depression is a chemical imbalance in the brain”.

This is what we are taught about depression (and other mental illnesses) from medical professionals, social media, TV, movies, and our peers. Some of us can even point to specific chemicals, such as serotonin. The major form of antidepressants used to treat major depressive disorders, SSRIs (selective serotonin reuptake inhibitors) are widely known- Lexapro, Celexa, Prozac, Zoloft, and more. But even though this explanation is commonly circulated and accepted as truth… is this the whole picture? And if it isn’t, then what is?

The Serotonin Theory

The notion that a lack of serotonin was involved in depression originated in the 1950s and 1960s with the rise of tricyclic antidepressant medications. These medications were known to increase serotonin in the brain. Because of this, researchers and doctors used a simplistic reductionism method to determine that if medications meant to treat depression cause a rise in serotonin, then depression must be caused by a lack of serotonin. Unfortunately, science and the etiology, or origin, of diseases is rarely that simple! This theory, however, did help to destigmatize mental illness. It placed the cause of depression on chemicals and biology instead of personal fault.

From this theory, albeit a somewhat faulty theory, SSRIs were developed. Serotonin is a neurotransmitter, akin to a chemical messenger in the brain. It is thought to have an impact on mood, emotions, and healthy sleep cycles. Once serotonin is used by the brain, it is absorbed by nerve cells in a process also called “reuptake”. SSRIs work to block this reuptake or reabsorption, allowing for more serotonin in the brain to be used. A 2020 article found that antidepressants worked to improve symptoms (not necessarily eliminate symptoms) in 40-60 out of 100 people, after taking them for 6-8 weeks. Side effects include insomnia, headaches, gastrointestinal distress, dry mouth, dizziness, decreased libido, and even suicidal thoughts in very severe (and rare) cases.

Evidence Against the Serotonin Theory

SSRIs are not completely ineffective. The question becomes, do they work due to the increased levels of serotonin or is it something else? Let’s review the evidence mounting against the serotonin theory.

There are 14 different receptors that serotonin binds to, but most of the research has been done on one receptor, known as 5- HT(1a). These receptors inhibit the release of serotonin pre-synoptically (synapses are the spaces between neurons that transmit information and neurotransmitters). If depression were caused by lower levels of serotonin, then theoretically, these receptors should be more active (because they would be inhibiting, therefore lowering, the release of serotonin). Research has found no evidence of differing levels of activity in 5-HT(1a) receptors in patients with depression versus controls (people without depression).

Serotonin transporter proteins (SERT) are molecules that take serotonin out of the synapse, thus lowering the availability of serotonin to the brain. If depression is caused by lower serotonin, and the problem is within the serotonin transporter proteins, then we would expect SERT activity to be higher in patients with depression versus patients without depression. The data, however, does not support this theory. More research does need to be conducted, though. Many of the patients in these studies have used SSRI medications in the past, which could impact their brain circuitry and skew results.

Tryptophan is an amino acid that is converted to serotonin in the body. A lack of tryptophan in the diet would result in a lower level of serotonin. Tryptophan depletion studies have been conducted in which patients were deprived of the amino acid tryptophan to decrease serotonin levels. There was no impact on mood in patients who were deprived of tryptophan versus patients who were not deprived of tryptophan.

More well-designed studies are needed, but we can conclude that a lack of serotonin is not the only cause, or even a cause, of depression.

Depression, the Limbic System, and the Brain

The limbic system of the brain is involved in behavior, memory, and emotional responses. Patients with depression have pathologies of the limbic system and physical changes in the brain. There is a loss of synaptic activity, which is associated with a decrease in brain derived neurotrophic factor (BDNF). BDNF helps the brain create new connections, repairs failing brain cells, and protects existing brain cells. It is important for learning, memory, and protection against neurodegenerative diseases. There is a decrease in overall metabolic activity and a reduction in the size of the prefrontal cortex, the area of the brain responsible for cognitive control such as reasoning, problem solving, impulse-control, creativity, and critical thinking.

Earlier we mentioned that SSRIs were somewhat effective in treating depression, even if serotonin may not be the cause, or full cause, of the disease. Why is that? It has been shown that the increase in serotonin may promote positive changes to the limbic system itself. When the system is flooded with serotonin, the changes within the limbic system help treat the symptoms of depression, but are not a cure, nor does it prevent a relapse from occurring.

Therapy can cause similar changes to the limbic system, and these changes may be more permanent than medications. The “catch” however, is that therapy can take much longer than medications. Patients may start to see some improvement in symptoms within 2-4 weeks of starting a medication. One study found that it took 6 months of weekly therapy (21 sessions) to see a clinically significant response in about 50% of the patients. It can take anywhere from 52-75 sessions to see clinical success with therapy. Many patients opt to use mediation and talk therapy- medications work much quicker, but the therapy may produce longer lasting changes, so they complement each other well.

 Depression and the Immune System

An emerging area of research is focused on examining the link between the immune system and depression. The immune system is a complex system within the body that protects and fights against diseases. We know that dysregulation within the immune system can cause and promote a variety of diseases and mental illness, such as depression, may be one of them.

Immune cells within the central nervous system (CNS) are called microglia, and they make up 5-10% of all brain cells. Their main function is to promote homeostasis, a state of equilibrium and balance, within the CNS. They play a role in synapse pruning (eliminating old, unused synapses) and neurogenesis (formation of new neurons).

Microglia can produce cytokines. Cytokines are a variety of proteins that stimulate or sometimes slow down the immune system. Some, but not all, are inflammatory. Low activity levels of inflammatory cytokines in the brain is actually a good thing, as it helps promote neuroplasticity. Neuroplasticity is important because it helps the brain modify, change, and adapt to needs. Excessive inflammatory immune activation in the brain disrupts neuronal function by impairing neurotransmitter communication, disrupting the synthesis/ reuptake/ release of neurotransmitters, and impacting neurocircuit functions, including mood and cognition. Both physical and psychological stress has been known to increase cytokine activity in the brain, past healthy levels.

Some patients with depression have increased immune activity, but not all depressed patients present with increased inflammation, as measured by various inflammatory markers in the blood. More research is needed to determine why some patients have increased immune activity, and if this activity is casual or not.

Chronic Stress and Depression

Stress plays a major role in the daily lives of most Americans. We live in a culture that is focused on productivity and efficiency, usually at the expense of relaxation and well-being. Stress isn’t solely a psychological phenomenon- it has real, measurable impacts on our brain. It can decrease neurogenesis and dendrite complexity. Stress causes hypertrophy, or an enlargement, in the nucleus accumbens (responsible for motivation) and amygdala (responsible for fear). It also decreases BDNF in the prefrontal cortex and hippocampus. Remember, BDNF is a protein that is important in brain health. Chronic stress plays a major role in epigenetic modifications to depression. Epigenetics is a term used to describe the way behaviors and environments impact gene expression. It can promote depression and even produce a resistance to antidepressants. Mature coping mechanisms and resiliency are protective against depression.

What Works for Depression?

As mental health issues become more prevalent, more research needs to be done on the underlying causes of and treatments for mental health disorders. While we are learning that serotonin may not be solely responsible for depression, there are still treatments. Even though SSRIs may not work exactly the way scientists initially thought they did, they can still help improve symptoms in many people. Talk therapy, especially when coupled with medications, are extremely effective and can even create permanent changes and results. Proper nutrition, especially the Mediterranean diet, has been shown to increase dendrite complexity, synaptic density, and BNDF, reversing some of the changes to the brain caused by depression. More recent studies have shown that exercise can be just as effective as antidepressants for treatment of major depressive disorder.

It is important to mention, never abruptly stop taking antidepressant medications, even if you think they are not working. Talk to your provider about your concerns. They may have you taper off to avoid withdrawal symptoms before trying any new treatment. Modyfi has professionals specializing in medication management, talk therapy, exercise, and nutrition to treat depression as well as other mental health concerns. You can Book Online to get started today or text us at 833-3-MODYFI for more information.

Sources:

Beurel, E., Toups, M., & Nemeroff, C. B. (2020). The Bidirectional Relationship of Depression and Inflammation: Double Trouble. Neuron, 107(2), 234–256. https://doi.org/10.1016/j.neuron.2020.06.002

InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. Depression: How effective are antidepressants? [Updated 2020 Jun 18]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK361016/

Misaghi A. , Page K., Puder D. (Hosts).(2022). Is depression a  chemical imbalance? (No. 155). [Audio podcast episode] In Psychiatry & Psychotherapy. https://www.psychiatrypodcast.com/psychiatry-psychotherapy-podcast/episode-155-is-depression-a-chemical-imbalance

Moncrieff, J., Cooper, R. E., Stockmann, T., Amendola, S., Hengartner, M. P., & Horowitz, M. A. (2022). The serotonin theory of depression: A Systematic Umbrella Review of the evidence. Molecular Psychiatry. https://doi.org/10.1038/s41380-022-01661-0