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Metaflammation and Mental Health

An integrative psychiatrist's approach to mental wellness

Key points

  • Gut microbiome imbalance—dysbiosis, leaky gut—leads to a chronic, systemic inflammatory response (metaflammation).
  • Neuroinflammation (leaky brain) is associated with cognitive decline and mental health disorders, including major depression.
  • Major depression can present in 227 different combinations of symptoms, or endophenotypes.
  • Simple laboratory tests for inflammation help inform more personalized and effective mental health care.

By David Scheiderer, MD, MBA

A Unifying Theory of Mental Illness

Over the years as a practicing integrative psychiatrist, my mantra has always been: a personalized treatment for the most personal of all illnesses. No one suffers like those who have mental illnesses like depression, anxiety, bipolar, mood, and neurodegenerative disorders. I feel it is my job to treat the whole person in the most appropriate way possible.

Mental Illness
Source: Solarseven/Dreamstime

But while I want to personalize treatment, at the same time I need data to guide my treatment decision-making process. And I've got to have a virtual peg board onto which to place this data. One of the most useful peg boards I have found (my unifying theory of mental illness) stems from the converging lines of evidence that chronic degenerative conditions, including most mental disorders, have been rising rapidly in recent years. In fact, they have overtaken infections as the leading cause of death and illness. And systemic inflammation (metaflammation) plays an important role in the process.

The Problem with Inflammation

Metaflammation, regardless of how it presents, follows a common pathway rooted in a disrupted, dysbiotic gut microbiome and intestinal hyperpermeability (leaky gut). This condition allows bacteria, toxins, and other small molecules to leak into the bloodstream. Once in circulation, these undesirables trigger the body’s immune system, which can lead to a widespread inflammatory response and degradation of the blood-brain barrier.

Where there is chronic, smoldering inflammation in the body, there is also inflammation in the brain. That neuroinflammation can then lead to any number of cognitive and mood disorders, ranging from brain fog to major depression.

Depression: Not Just a Diagnosis but a Spectrum

The diagnosis of major depression requires that a patient check five out of the nine criteria established in the DSM. How many different combinations of symptoms (endophenotypes) are possible? The answer is: 227. Two hundred and twenty seven different endophenotypes of depression. For example, a person can meet the criteria for diagnosis of depression and not be able to sleep—or sleep all the time. Not be able to eat—or eat all the time. Not be able to sit still—or not be able to move. Which of those endophenotypes, those 227 unique symptomatic presentations, is associated with inflammation?

Two Minds
Source: Elenabsl/Dreamstime

The answer is atypical, or immunometabolic, depression—sleeping all the time, eating all the time, fatigue, fatigue, fatigue, co-existing PTSD, fibromyalgia, and chronic fatigue syndome. In this type of depression, treating inflammation and the gut overall seems to work.

To do this requires a lot of nutritional support: gut-brain–targeted probiotics (psychobiotics), fish oil, vitamin D3, L-methylfolate, and N-acetyl cysteine. These supplements are given right alongside an antidepressant, when necessary, for those people who are suffering with intestinal hyper-permeability and neuroinflammation due to leaky gut. Additionally, that inflammatory state further informs the type of antidepressant I prescribe

Inflammation Is Information

A clinical study1 conducted a few years ago evaluated the influence of inflammation on clinical response to escitalopram (an SSRI, or selective serotonin reuptake inhibitor) and nortriptyline (a SNRI, or selective norepinephrine reuptake inhibitor). Of great interest to me was that the authors concluded that a very simple laboratory test, measuring C-reactive protein (CRP, a marker of systemic inflammation), can accurately predict therapeutic outcomes. They showed that people with low CRP levels (low inflammation) responded significantly better to the SSRI escitalopram, while those with high CRP levels (high inflammation) saw significantly greater improvement with the SNRI nortriptlyline.

I order measures of CRP and other markers of inflammation for all of my patients. When there is evidence of metaflammation, and medication is needed, they're going to get a norepinephrine-dominant treatment strategy, not a serotonin-dominant strategy. This approach has proven to be a successful strategy.

Nicky Linzey/Dreamstime
Joy of Life
Source: Nicky Linzey/Dreamstime

A Holistic Approach for Life

Ultimately, regardless of the reason why a patient comes to see me, I use my unifying theory—this mind-body thought process—to help guide my treatment decisions. Whether that be medication, psychotherapy, or the all-important life hacks including a whole-food diet, daily exercise, sunshine, sleep, and healthy interpersonal relationships, integrating a holistic approach to personalized care helps me better understand my patient's needs. And it helps my patients regain and sustain their joy of life.


1. Uher R, Tansey KE, Dew T, Maier W, Mors O, Hauser J, Dernovsek MZ, Henigsberg N, Souery D, Farmer A, McGuffin P. An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am J Psychiatry. 2014 Dec 1;171(12):1278-86. doi: 10.1176/appi.ajp.2014.14010094.

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