Mental Health and Inflammation
The collective knowledge of a scientific field is ever-expanding. The rate of expansion however can change suddenly due to a single observation that often leaves scientists saying, “hmmm… that’s odd.” I like to refer to it as the light bulb moment.
The field of psychiatry desperatly needs a light bulb moment. The United States and other countries around the world are experiencing a mental health epidemic that shows no sign of slowing as the rates of suicide, depression, and anxiety have never been higher.
But is it possible that a light bulb moment has already occurred? One that kickstarts a paradigm shift slowly changing the way health professionals understand the causes of mental illness.
In this article, we explain why the field of psychiatry has been stagnant over the last 50 years and why inflammation in the body, not a neurotransmittter imbalance, is better suited to explain the causes of mental illnness in a subset of people.
But first, let’s time travel to the late 1950s, the last time there was a revolutionary observation that led to a burst of new psychiatric knowledge.
What Does An Antibiotic Have To Do With Modern-day Psychiatry?
The psychiatric field experienced a “light bulb moment” over 60 years ago when physicians observed that an antibiotic called iproniazid caused tuberculosis patients to suddenly feel an unreasonable sense of euphoria. Scientists and pharmaceutical companies alike said to themselves, “hmmm… that’s odd.” The race was on to find a scientific explanation for this peculiar observation as doing so likely meant a cure for depression, or so they thought.
It didn’t take long for a 1958 British Journal of Pharmacology paper to report that treating (only three) rats with iproniazid boosted adrenaline and noradrenaline levels in the urine. The field of psychiatry interpreted these less-than-rigorous results as proof that iproniazid’s euphoric effects were attributed to boosting neurotransmitter levels in the brain. This observation, in part, kickstarted the development of monoamine oxidase inhibitors, drugs that boosted serotonin, norepinephrine, and dopamine levels by preventing their breakdown.
However, it took roughly 30 more years before the first SSRI (selective serotonin reuptake inhibitors) became licensed by the FDA to treat depression.
SSRI's Followed Decades of Psychiatric Stagnation
Prozac, the world’s first selective serotonin reuptake inhibitor (SSRI) was introduced in 1987 by Eli Lilly and Company. This drug was marketed as a drug that boosts the ‘feel good’ neurotransmitter, serotonin, in the brain of patients. Since Prozac’s market entry, many pharmaceutical companies developed their own neurotransmitter-boosting drugs.
But, there was a conundrum. If all mental health issues are caused by an imbalance of neurotransmitters one would expect the explosion of new neurotransmitter-modulating pharmaceuticals to cure all mental illness.
Obviously, that did not happen as we are currently experiencing a mental health epidemic in the U.S. In fact, “there have been no major new advances in drug treatment, or psychological treatment come to that, for depression or any other mental health disorder [since Prozac]”, explains Dr. Edward Bullmore in his book The Inflamed Mind.
Treatment-Resistant Depression
Up to one-third of patients with clinical depression do not respond to anti-depressants, a condition known as treatment-resistant depression. Yet, the standard of care for all patients with clinical depression is treatment with anti-depressants.
Dr. Golam Khandaker, psychiatrist at the University of Cambridge explains, “the current approach of a ‘one-size-fits-all’ medicine to treat depression is problematic. All currently available antidepressants target a particular type of neurotransmitter (serotonin), but a third of patients do not respond to these drugs”
He also states that the future of treating depression might involve identifying otherwise healthy patients for hidden signs of inflammation in the blood followed by “[using] anti-inflammatory drugs in psychiatry for certain patients with depression”.
Serotonin In The Brain Of Depressed Patients
Many depressed patients on SSRIs report that their anti-depressant does work. That means either:
- SSRIs are indeed boosting serotonin levels in the brain
- SSRIs regulate other biological processes that alleviate depression
Let’s examine the former. Peer-reviewed data suggests there is no scientific evidence that people with depression have decreased levels of serotonin in the brain. This could mean current technology lacks the resolution to measure minute differences in serotonin levels in the synaptic cleft (between neurons).
However, is it also possible that SSRIs are reducing depression in patients by fixing a different biological pathway that is broken?
SSRIs Have Anti-inflammatory Properties
Numerous scientific studies demonstrate that SSRIs and SNRIs can reduce neuroinflammation by reducing the amount of pro-inflammatory cytokines circulating in the blood.
Could this contribute to the reported efficacy of SSRI’s and SNRI’s?
Answering this question starts by understanding a peculiar observation made by oncologists over 30 years ago.
Pro-inflammatory Cytokines Cause Depression
In the late 1980s, oncologists began treating cancer patients with pro-inflammatory cytokines called interferon alpha (IFN-a) and tumor necrosis factor-alpha (TNFa). The oncologists noticed something unexpected. A subset of their patients developed severe depression soon after the cytokines were delivered into their patient’s bloodstream.
Was this a predictable response? After all, they were diagnosed with cancer and are being given what could have been toxic amounts of pro-inflammatory cytokines. Wouldn’t that also make you depressed?
Dr. Andrew Miller, Emory University was one of the first psychiatrist’s to interview a IFN-a-treated patient, said in an interview, “I really expected to see somebody under a blanket who’s shivering and shaking and miserable and toxic, and something that we typically see, and something like sepsis, where somebody’s very sick.”
What he actually saw was a “woman was very nicely dressed, makeup was on that looked very nice”, not a deathly ill patient.
Although these patients were not depressed before receiving immunotherapy, they met the clinical definition of depression. This depression can be prevented by giving the cancer patients an anti-depressant two weeks before starting the immunotherapy.
If inflammation can cause mental health conditions what causes the inflammation?
Chronic Inflammatory Conditions and Mental Health
Inflammation is a blanket term used to describe white blood cells and the molecules they release, which protect our bodies from a threat. That threat can be an infectious disease (virus, bacteria, parasite, or a prion), a rogue cancer cell, or toxins in our environment. When your body encounters one of these threats a rapid spike in inflammation occurs. Chronic inflammation, or persistent inflammation, occurs when the spike in inflammation remains high and does not return to baseline levels.
There are countless peer-reviewed manuscripts linking chronic inflammatory conditions to mental illnesses, referenced in the table below. Most studies we highlight pool the data of numerous scientific reports, known as a meta-analysis. These meta-analyses provide more robust data sets, strengthening scientific conclusions.
Disease/Syndrome Category | Disease Name | Cause | Mental Health Conditions |
Autoimmune Disease | Sjögren’s Syndrome | Autoimmune attack on moisture-producing glands | |
| Rheumatoid Arthritis | Autoimmune attack on joints | Depression, Anxiety, Mood Disorders, Cognitive Impairment |
| Ankylosing Spondylitis | Autoimmune inflammation of the spine and sacroiliac joints | Depression, Anxiety, Stress, Cognitive Dysfunction |
| Juvenile Arthritis | Autoimmune inflammation of the joints in children | Depression, Anxiety, Behavioral Problems |
| Psoriatic Arthritis | Autoimmune inflammation of the joints and skin | Depression, Anxiety, Psoriasis, Mood Disorders |
| Lupus | Autoimmune attack on healthy tissues throughout the body | Depression, Anxiety, Mood Disorders, Cognitive Dysfunction |
| Psoriasis | Unknown, believed to involve genetic predisposition and dysregulated immune response | Depression, Anxiety, Stress, Cognitive Dysfunction |
| Celiac Disease | Immune reaction to gluten proteins in genetically predisposed individuals | Depression, Anxiety, Irritability, Cognitive Impairment |
| PANDAS/PANS | Cause by infections such as Streptococcus pyogenes, Borellia burgdorferi, Influenza, EBV, HSV, and others | Obsessive-Compulsive Disorder (OCD), Anxiety Disorders, Tourette Syndrome-like Symptoms |
Chronic Disease/Syndrome | Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | Unknown, possibly immune system dysfunction or viral infection | Depression, Anxiety, Cognitive Impairment, Sleep Disorders |
| Postural Orthostatic Tachycardia Syndrome (POTS) | Dysfunction of autonomic nervous system or autoimmune mechanisms | Anxiety, Depression, Cognitive Impairment, Fatigue |
| Inflammatory Bowel Diseases & Syndromes | Unknown, combination of genetic predisposition, environmental factors, and dysregulated immune response | Anxiety, Depression, Stress, Cognitive Impairment |
| Mast Cell Activation Syndrome (MCAS) | Inappropriate activation of mast cells | Anxiety, Panic Attacks, Depression, Cognitive Impairment |
| Ehlers Danlos Syndrome (EDS) | Genetic disorder affecting connective tissue | Anxiety, Depression, Stress, Cognitive Dysfunction |
Infectious Disease | Long COVID | Persistent symptoms following COVID-19 infection | Depression, Anxiety, Cognitive Impairment, Fatigue |
| Toxoplasmosis | Toxoplasma gondii infection | Schizophrenia |
| Lyme Disease | Borellia burgdorferi infection | Obsessive-Compulsive Disorder (OCD), Anxiety Disorders, Tourette |
| Tuberculosis | Mycobacterium tuberculosis infection | Depression, Anxiety |
| Infectious ME/CFS | Epstein Barr Virus Infection | Depression, Anxiety, Cognitive Impairment, Sleep Disorders |
Chronic Allergic Disease | Chronic Sinusitis | Immune response to allergens | Anxiety, Mood Swings, Irritability, Fatigue, Sleep Disturbances |
| Mast Cell Activation Syndrome (MCAS) | Inappropriate activation of mast cells | Anxiety, Panic Attacks, Depression, Cognitive Impairment |
Healthy Individuals Are Also at Risk
One common misconception about the immune system’s ability to harm the brain is that only patients suffering from chronic inflammatory diseases are susceptible to disruptions in mental health. However, numerous studies suggest that is not true. For instance, otherwise healthy individuals with depression, anxiety, sleep disorders, bipolar disorder, or mood disorders have all been found to have elevated pro-inflammatory cytokine levels in their blood.
So, what is the trigger that is causing healthy people to development mental health issues?
Stress Alone Can Cause Inflammation
To understand the role of stress on the brains, let’s learn what happens when humans are subjected to extreme stress.
Post-Traumatic Stress Disorder (PTSD) is a mental health condition that can develop after experiencing extremely stressful or traumatic events. The mental health effects of PTSD are profound. Roughly 80% of people with PTSD have one or more additional mental health diagnoses and 56% of those with PTSD have thought about committing suicide.
A meta-analysis of 54 pooled studies consisting of 8,394 patients shows that patients with PTSD have elevated pro-inflamamtory cytokines in their blood. So, is stress triggering the inflammation?
Can Stress Triggering Inflammation-Driven Mental Health Issues?
Studies show that chronic stress continuously activates the fight or flight branch of our nervous system, the sympathetic nervous system, causing inflammation in the body. This can occur by experiencing armed conflict in a war or stressful situations that the majority of people face such as public speaking, separation from a spouse, or the death of a loved one. Not to minimize the source of the stress, but stress is stress no matter the stimulus. Everyone is susceptible to stressful life circumstances that can cause inflammation in our bodies at any time.
It goes without saying that chronic stress can cause mental health issues such as depression, anxiety, and sleep difficulties. But could the stress-induced psychiatric issues actually be caused by inflammation as opposed to chemical imbalances in the brain (or both)?
To answer this question we need to understand how inflammation in the body can invade and harm the brain.
How Can Inflammation In the Body Harm The Brain?
The Blood-Brain Barrier
Blood vessels located in organs such as the liver, kidney, small intestine have holes in the wall of the vessel. These holes allow molecules to exit blood vessels and enter the tissue. However, the vessels in the brain are different.
Brain blood vessels have a barrier called the blood-brain barrier (BBB), which excludes entry of harmful molecules, like pro-inflammatory cytokines, into the brain. However, there is an exception to that rule… stress.
Stress Can Make the Blood-Brain Barrier Leaky
Numerous studies demonstrate that inflammation in the body can enter the brain by temporarily making the BBB leaky. Understanding how this occurs in humans is difficult to address experimentally, so researchers turn to mice.
Studies show that when mice are socially stressed, by being prematurely separated from their mothers or are bullied by large aggressive mice, they produce inflammatory cytokines in the blood, which causes a leaky blood-brain barrier. In other words, the stress allows the inflammatory cytokines in the body to enter brain regions such as the amygdala and the prefrontal cortex. These responses are associated with anxiety-like and depression-like symptoms in mice, which can be restored by blocking the inflammation.
Anti-inflammatory Drugs and Mental Illness
Major Depression
If inflammation is causing mental health conditions in a subset of people then anti-inflammatories should be effective therapies for treating mental illness.
A research analysis aggregated the results from 30 randomized controlled trials (RCTs) involving 1610 participants investigating the effectiveness and safety of using anti-inflammatory agents as a treatment patients with major depression. Anti-inflammatory interventions considered in the analysis included,
- omega-3 fatty acids (omega-3 FA)
- N-acetylcysteine (NAC)
- cytokine inhibitors
- corticosteroids
- minocycline
- pioglitazone
- modafinil
- NSAIDs
- statins
While the authors noted limitations among a subset of studies, their analysis indicated that anti-inflammatory agents have the potential to safely and efficiently alleviate symptoms associated with major depression.
Bipolar Disorder, Schizophrenia, and Somatic Symptom Disorders
While blocking inflammation to treat mental illness is not a one-size-fits-all approach anti-inflammatories have shown promise in treating other mental health issues beyond depression.
A separate review of 53 randomized controlled trials found that anti-inflammatory agents were effective at treating bipolar disorder, and schizophrenia although the type of anti-inflammatory medication deemed effective differed based on the mental illness. This underscores the desperate need to develop selective anti-inflammatories tailor-made to treat specific mental health conditions.
Why The Inflammation Mental Health Connection Is Slowly Adopted
Diseases of the body and the mind are treated separately. The (two categories of) medical providers are trained separately, they bill insurance companies separately, and they conduct research separately.
This lack of overlap is largely perpetuated by physicians who assume that the immune system can only cause mental health conditions in extreme cases and by regulatory health agencies. For instance, while the U.S. National Institute of Mental Health (NIMH) recognizes that chronic diseases such as autoimmune diseases have a higher rate of mental illness they explain it is because patients are more likely to “feel sad or discouraged” after receiving a chronic disease diagnosis.
Longitudinal Studies
While some medical professionals do acknowledge the link between chronic inflammation and mental health conditions they don’t know if inflammation is causing mental illness or if the mental illness is causing the inflammation. We would argue that medical professionals either are not informed or are waiting for the link between chronic inflammation and mental health to become mainstream.
The way to circumvent this is through more gold-standard clinical studies called longitudinal studies. Longitudinal studies track patients over time. This allows more complex research questions to be answered for instance, “Do inflammatory markers increase in the blood before a patient develops depression?” or “Do the symptoms of depression disappear once the inflammatory markers in the blood disappear?”
The Brain Inflammation Collaborative's Contribution
We are the world’s first nonprofit committed to,
- Educating patients and health professionals about the connection between inflammation and mental health
- Advocating for patients suffering from both chronic inflammatory diseases and neuroinflammatory conditions
- Funding academic and clinical scientific research to advance our understanding of inflammation and mental health
We are Committed to Expanding Longitudinal Studies on Inflammation and Mental Health
To demonstrate our commitment to the cause, we have developed a clinical research platform, Unhide, designed to bridge the gap between academic researchers and clinical research. Unhide will benefit research by helping academic scientists access voluntarily submitted patient data and tissue samples to study complex human disease phenomena.
Unhide enables patients to monitor medical data, track symptoms longitudinally, identify patterns in both medical data and treatments, and record treatment outcomes. Patients can then share this information with physicians to inform treatment decisions. Additionally, Unhide empowers patients to contribute to pioneering research conveniently from their homes.
Together We Can Change Mental Health Treatment
Join us in revolutionizing mental health treatment by supporting the Brain Inflammation Collaborative. As a nonprofit dedicated to pioneering advancements in mental health care, we are committed to unraveling the complexities of inflammation and its impact on mental well-being.
With your generous donations, we can accelerate research efforts, develop innovative treatment approaches, and ultimately transform the landscape of mental health care. Your support will directly contribute to improving the lives of countless individuals affected by mental health disorders. Together, let’s pave the way for a brighter and healthier future for all.
Donate to the Brain Inflammation Collaborative today and be a part of this groundbreaking journey towards better mental health for everyone!
Written By
Matthew Menendez, Ph.D.
Director of Science Communication, Brain Inflammation Collaborative
Dr. Menendez has a passion for empowering patients navigating complex chronic diseases. Through innovative educational strategies, he bridges the gap between cutting-edge research and real-world understanding, helping individuals advocate for better care, access timely treatments, and reclaim their quality of life.
