Chronic Inflammation and Mental Health

Inflammation has become a major focus in functional medicine and psychiatry. While claims that chronic inflammation is the “root cause” of nearly all chronic illness—and even aging—may overreach the evidence, its relevance to mental and physical illness is increasingly difficult to ignore.

Growing transdiagnostic evidence implicates inflammation in depression, bipolar disorder, schizophrenia and psychosis, autism, and PTSD. Yet inflammation does not map neatly onto DSM diagnoses; inflammatory abnormalities cross diagnostic categories and may identify biologically meaningful subgroups.^1–5 Low-grade systemic inflammation, for example, is present in approximately 1 in 4 patients with depression and has been associated with poorer outcomes, including treatment resistance. ¹⁹

For mental health clinicians, the important questions are why inflammation becomes chronic, how it affects the brain, how to recognize and measure it, and what we can do about it.

When Does Inflammation Become Chronic?

The inflammatory response is designed to deal with threat, mount a defense, resolve, and return to homeostasis. Chronic inflammation can persist for several different reasons: the inflammatory signal remains, previous exposures have changed how the immune system responds, normal resolution has failed—or several of these processes are occurring simultaneously.

The first possibility is often the most clinically actionable. Many common conditions and lifestyle factors can keep the inflammatory signal active: metabolic dysfunction, visceral adiposity, an inflammatory diet, chronic or occult infection, autoimmune disease, smoking, environmental toxins, periodontal disease, sleep deprivation or obstructive sleep apnea, and ongoing psychological stress.

But chronic inflammation can also reflect the biological imprint of past exposures. We have long recognized that the adaptive immune system has memory. More recently, we have learned that innate immune cells can also undergo persistent metabolic and epigenetic reprogramming following inflammatory exposures—a phenomenon known as trained immunity.^6,7 A later challenge may therefore provoke a different, and sometimes exaggerated, response. Within the brain, a related phenomenon known as microglial priming may alter how strongly microglia respond to a subsequent immune or stress signal. In this sense, trained immunity provides an intriguing biological parallel to the idea of “PTSD of the immune system.” The original threat may be gone, but the prior experience has changed how the system responds to future challenges rather than simply leaving inflammation continuously switched on.

Finally, inflammation may persist when normal resolution is impaired. Resolution is an active biological program involving specialized pro-resolving lipid mediators, macrophage function, clearance of damaged cells, and restoration of homeostasis.^8,9 It can be disrupted by aging, metabolic dysfunction and obesity, oxidative stress, nutritional and fatty-acid status, ongoing infection or tissue injury, and altered immune regulation. Genetic variation may also play a role, although the clinical significance of individual SNPs is less established.

These mechanisms frequently coexist. In a patient with metabolic dysfunction, childhood trauma, poor sleep, and prior inflammatory insults, inflammation may be simultaneously metabolic, psychological, immunologic, and environmental.

When Psychological Trauma Becomes Biological

Trauma may leave more than psychological memories. Adverse childhood experiences have been associated with a wide range of later physical and mental health outcomes, and a meta-analysis found childhood trauma associated with elevated inflammatory markers CRP, IL-6, and TNF-α in adulthood.¹⁰

Early adversity can become biologically embedded through dysregulation of the HPA axis and sympathetic nervous system, altered immune-cell function, microglial activation, and epigenetic changes.¹¹ In other words, adversity may not simply produce inflammation at the time of the stressor; it may change how the organism responds to future challenges.

Adults with histories of childhood adversity have shown altered regulation of stress-responsive genes in monocytes following a new psychosocial stressor.¹² Childhood trauma has also been associated with epigenetic changes involving FKBP5, an important regulator of glucocorticoid signaling.¹³

Biological signatures of severe trauma may extend across generations. Descendants of Holocaust survivors have shown differences in FKBP5 methylation¹⁴, and families exposed to war-related violence have shown trauma-associated epigenetic signatures across multiple generations.¹⁵ However, evidence for intergenerational epigenetic transmission in humans remains limited and difficult to separate from genetic inheritance, pregnancy, parenting, shared environment, and later life experiences. Whether these changes contribute to chronic inflammation remains unknown.

How Inflammation Affects the Brain

Peripheral inflammation can influence the brain through circulating cytokines, signaling at the blood-brain barrier, and neural pathways such as the vagus nerve. Peripheral inflammation and neuroinflammation are not synonymous, but systemic immune activation can alter the neuroimmune environment and brain function.^1,16

The Kynurenine Pathway

One of the best-described links between inflammation and brain function involves tryptophan metabolism. Pro-inflammatory cytokines activate indoleamine 2,3-dioxygenase (IDO), shifting tryptophan toward the kynurenine pathway and potentially reducing its availability for serotonin synthesis. Kynurenine crosses the blood-brain barrier and can be metabolized by microglia toward quinolinic acid, an NMDA receptor agonist that, when excessive, can promote glutamatergic signaling, oxidative stress, and excitotoxicity. Astrocytes are an important source of kynurenic acid, which has opposing effects at the NMDA receptor but, when excessive, can also disrupt glutamatergic and cholinergic signaling and cognition. Thus, inflammation may affect brain function by altering both kynurenine metabolism and the balance of its downstream metabolites.^17,18

Microglia, Neurotransmission, and Neuroplasticity

Microglia, the resident immune cells of the CNS, respond to infection, injury, cellular stress, and peripheral immune signals. Persistent or dysregulated activation can alter cytokine, glutamate, and dopamine signaling; reward circuitry; oxidative balance; mitochondrial and neurotrophic function; and synaptic plasticity, potentially contributing to fatigue, anhedonia, reduced motivation, psychomotor slowing, and cognitive difficulties.^1,16 These interconnected effects on neuroimmune activity and brain function may help explain why inflammatory abnormalities occur across psychiatric diagnoses rather than mapping neatly onto a single disorder.

Measuring Inflammation in Psychiatric Practice

No single laboratory test can determine whether inflammation is contributing to a patient’s psychiatric illness, and peripheral inflammatory markers are not direct measures of neuroinflammation. Nevertheless, several inexpensive and widely available tests can provide useful evidence of systemic inflammatory activity.

High-sensitivity C-reactive protein (hs-CRP) is probably the most familiar. Produced by the liver in response to inflammatory signaling, particularly IL-6, hs-CRP provides a nonspecific measure of systemic inflammation. In psychiatric research, an hs-CRP ≥3 mg/L is commonly used to identify patients with elevated systemic inflammation. In a meta-analysis of patients with depression, approximately 27% had CRP levels >3 mg/L, supporting the concept of an inflammatory subgroup rather than inflammation as a universal feature of depression.¹⁹

Another source of information is already sitting in almost every psychiatric patient’s chart: the CBC with differential.

Several inflammatory indices can be calculated from routine CBC values:

• NLR: neutrophils ÷ lymphocytes
• MLR: monocytes ÷ lymphocytes
• PLR: platelets ÷ lymphocytes
• SII: platelets × neutrophils ÷ lymphocytes
• SIRI: neutrophils × monocytes ÷ lymphocytes

Evidence connecting these measures to psychiatric illness is rapidly growing. A 2025 meta-analysis of more than 205,000 participants found higher NLR and SII in people with depression.²⁰ A 2026 meta-analysis found elevated CBC-derived inflammatory ratios in bipolar disorder, particularly during mania.²¹

Similar findings have been reported in schizophrenia. In a study examining the same patients during psychotic exacerbation and remission, NLR, MLR, PLR, SII, and SIRI were all higher during acute psychosis than in healthy controls.²²

These markers may also have clinical relevance. In a 2024 study of young adults with major depression, NLR, PLR, SII, and SIRI were elevated compared with healthy controls. Among patients with recent suicide attempts, MLR and SIRI were higher, while NLR best distinguished patients with and without suicide attempts. SIRI also decreased following SSRI treatment, although baseline SII and SIRI did not predict treatment response.²³

Taken together, these findings suggest that readily available inflammatory markers may eventually help identify inflammatory subgroups and provide information about illness state or clinical risk. For now, they remain nonspecific markers of systemic inflammation, not diagnostic tests for psychiatric disease, and standardized psychiatric cutoffs have not yet been established.

Finding inflammation is only the beginning. An abnormal marker should trigger a search for the source, ideally not simply a supplement or anti-inflammatory prescription. The answer may lie among the metabolic, infectious, inflammatory, sleep-related, environmental, nutritional, or psychological drivers discussed earlier.

From Measuring Inflammation to Treating the Patient

Identifying inflammation is useful only if it changes what we do.

The first step is to ask what is driving it. Metabolic dysfunction, visceral adiposity, sleep disruption or apnea, infection, inflammatory or autoimmune disease, smoking, diet, physical inactivity, and chronic stress should be addressed when possible, potentially benefiting both inflammation and psychiatric symptoms.

Conventional treatments may also influence inflammatory pathways; antidepressants, lithium, exercise, and omega-3 fatty acids have all been associated with changes in inflammatory signaling.^29,30

In a landmark 2013 trial, the TNF-α antagonist infliximab did not improve treatment-resistant depression overall, but patients with higher baseline inflammation appeared more likely to benefit.²⁴ Similarly, the CO-MED trial suggested that baseline CRP might differentiate response to antidepressant strategies.²⁵ Anti-inflammatory approaches, including minocycline, have shown promise but inconsistent results, while pooled analyses suggest that inflammatory and metabolic abnormalities predict somewhat poorer antidepressant outcomes.^26,27

The field is now moving toward prospective biomarker-guided treatment. Trials such as INSTA-MD are testing whether patients with major depression can be stratified by inflammatory status and treated accordingly.²⁸

We cannot yet use hs-CRP or CBC-derived inflammatory indices to select a specific treatment. But these biomarkers may eventually identify patients for whom immune and metabolic dysregulation are meaningful treatment targets.

We have come full circle to a central principle of functional psychiatry: look for the biological drivers contributing to each patient’s symptoms. Research is increasingly identifying biologically meaningful subgroups and treatments targeted to those differences, yet clinical implementation inevitably lags behind discovery. At Psychiatry Redefined, our goal is to help close that gap by bringing emerging evidence into clinical practice.

My hope is that this article encourages one practical step in that direction: adding a simple assessment of inflammation to routine psychiatric care. Finding inflammation may not tell us what to treat, but it may tell us where to start looking.