Why Don't Antidepressants Work With Autoimmune Disease? The Depression-Inflammation Loop, with Dr. Aimie Apigian

A solo episode of The Biology of Trauma^® podcast with Dr. Aimie Apigian.

Antidepressants often underperform in people with autoimmune disease because the depression is being driven by inflammation rather than by brain chemistry alone, and medications that target serotonin are pushing against an inflammatory current that keeps running. Inflammatory signalling raises the activity of the serotonin transporter that an SSRI is designed to block, and it diverts tryptophan away from serotonin production, which means the medication is working against biology rather than with it.

That is a statement about mechanism. It is not a reason to stop a medication, and nothing in this episode should be read that way.

There is a person Dr. Aimie keeps meeting. She has a diagnosis, Hashimoto's or lupus or rheumatoid arthritis. She has been working on it for years with diet, supplements and specialists. Underneath all of it she is flat. Not sad, flat. She mentioned it to her doctor and was offered an antidepressant, which did little.

Dr. Aimie recognises her because she was her. What became a health crash in 2014, during her third year of surgery residency, started about a year earlier with depression. She was assessed, told it was burnout, and started on an antidepressant. That was long before the fatigue arrived and long before anyone found the autoimmunity.

Dr. Aimie Apigian, MD MS MPH, is a double board-certified physician in preventive and addiction medicine, author of the national bestseller The Biology of Trauma, and the founder of Trauma Healing Accelerated.

Depression and autoimmune disease are associated in both directions, each running close to double the risk of the other, and depression can appear in the two years before an autoimmune diagnosis is made. Early adversity, altered cortisol signalling and chronic low-grade inflammation sit upstream of both. That inflammatory route produces a depression that reads as flatness rather than sadness, and it responds poorly to medications aimed at brain chemistry. The starting point is shifting nervous system state, because a body still running survival physiology has limited capacity to respond to anything else.

Which comes first, depression or autoimmune disease?

Depression can often come first, and the evidence points to a loop between the two rather than a line. A 2024 systematic review and meta-analysis in BMJ Mental Health pooled 47 studies covering 40.77 million people. People with an autoimmune condition carried a relative risk of 1.85 for developing depression. People with depression carried a relative risk of 1.84 for developing an autoimmune condition. The association runs close to double in both directions.

Two calibrations belong with those numbers, and Dr. Aimie supplies both in the episode. Doubling a small chance still leaves a small chance, so the useful reading is that this is more likely for me rather than that this will happen to me. And correlation running in two directions does not establish that either causes the other. What it establishes is that these two travel together far more than chance would predict, which makes treating them as unrelated hard to defend.

One detail worth adding for anyone checking the source: the confidence interval on the depression-to-autoimmunity direction is wide, 1.10 to 3.09, so that half of the finding is less precisely estimated than the other.

 What does the research show about depression arriving first?

Depression and anxiety show up in the window before an autoimmune diagnosis is made. A Danish nationwide register study of 5,084 people with multiple sclerosis, matched against 24,771 controls, looked at the two years preceding diagnosis. In that window the odds ratio for a depression or anxiety diagnosis was 1.4. The odds ratio for being prescribed a tricyclic antidepressant was 1.90.

The prescriptions ran higher than the diagnoses. Something was being treated before it was being named.

An odds ratio of 1.4 is modest, and plenty of ordinary exposures raise odds by that much. What makes it worth attention is the direction and the consistency. Some proportion of people are sitting in a psychiatrist's office with a depression that will not respond, already inside the early biology of an autoimmune process that has not yet reached the threshold of the panels being run.

A separate Danish cohort of roughly 1.1 million people found that depression was associated with a raised risk of later autoimmune disease, with an incidence rate ratio of 1.25, and it scaled. More depression, more risk. Less depression, less risk.

Dose-response: when the size of an exposure tracks up and down alongside the size of the outcome. It is one of the ways researchers separate a biological relationship from two things that happen to sit near each other. The Adverse Childhood Experiences studies found the same pattern, which is a large part of why they were taken seriously.

What sits upstream of both depression and autoimmunity?

Early adversity sits upstream of both, and the effect is real and small rather than large. A 2025 systematic review and meta-analysis in Brain, Behavior, and Immunity pooled 45 effect sizes from 27 studies, covering 8,728 cases and 3,298,392 controls, and found a standardised effect of 0.30 for childhood adversity on later autoimmune disease.

On the scale researchers use, 0.2 counts as small and 0.8 counts as large, so this sits near the small end. The authors describe it that way themselves. Heterogeneity between the studies was high, meaning they disagreed with one another, and the authors' own statistical checks suggested publication bias may be present, which means studies finding nothing may never have been published and the true effect could be smaller rather than larger.

So the sentence "childhood trauma causes autoimmune disease" goes further than the evidence supports, and Dr. Aimie declines to say it.

What she does say is anchored in a 2025 study in Psychological Medicine that examined two large cohorts of women, the Icelandic Stress-And-Gene-Analysis cohort of 22,423 women and the UK Biobank cohort of 86,492 women. Adverse childhood experiences were associated with autoimmune disease in a dose-response pattern. Then the researchers asked a question most studies skip: how much of that association travels through mental health. Their causal mediation analysis found that roughly a quarter of it was mediated through depressive, anxiety and PTSD symptoms.

Mediation: the portion of a relationship between two things that runs through a third thing on the way. Here it means depression is part of the road from healthy to diagnosed, carrying some of the load rather than watching from the side of it.

How does early adversity turn into inflammation?

Through cortisol signalling that stops landing. Early adversity changes how the nervous system organises itself for survival, which alters adrenaline, the endocrine system and the immune system together. Over time immune cells become less responsive to cortisol.

That last piece is the one worth holding. Cortisol is one of the ways the body turns inflammation off. When the receptors stop responding to it, the off switch stops working. Cortisol levels can be adequate or even high and it changes nothing, because the message is not landing, which is often why the levels climb in the first place. The result is chronic low-grade inflammation as a default state.

A 2026 review in the Journal of Neuroinflammation traces that whole chain: early adversity, then neuroimmune changes, then chronic low-grade inflammation reaching the brain, then changes in the regions that handle emotion, ending in both depression and autoimmune pathology. That is a peer-reviewed immunology journal describing the sequence Dr. Aimie experienced and has been teaching.

Why does this depression feel flat rather than sad?

Because the brain is responding to inflammatory signalling in the same way it responds to an infection. In 2008 Robert Dantzer and colleagues published a paper in Nature Reviews Neuroscience titled "From inflammation to sickness and depression: when the immune system subjugates the brain," describing what is called sickness behaviour.

Anyone who has had genuine influenza already knows the state. No appetite, no movement, no wish to see anyone or hold a conversation, and no interest in the things that usually bring pleasure. Not sadness about any of it. Flatness.

That is a coordinated biological programme running underneath mood. Conservation. Hibernation. And it is why the same inflammatory signalling in an autoimmune process can produce the same shape.

Sickness behaviour: the coordinated set of changes, including withdrawal, low motivation and loss of interest, that the brain produces in response to inflammatory signalling from the immune system. It is the state you already know from having the flu.

Classic depression tends to present as sadness, a sense of worthlessness and anhedonia, with emotional content to it. The inflammatory pattern presents as the absence of emotion rather than the presence of a negative one. Slowed movement and thinking. Knowing exactly what you want to do and finding no drive available to do it. Dr. Aimie describes thinking about riding her bike, something that had always brought her joy, and finding not reluctance but nothing at all.

This is also why working on thoughts may not move it. That work addresses a level above where the state is being set, which is in the cells, with the immune system.

Functional freeze: the therapy-side name for this state of conservation and shutdown, arriving after a system has been mobilising for long enough to reach exhaustion. Early on a person still works and still functions. That capacity narrows over time, and the usual strategies of more caffeine or more effort stop returning anything.

Why don't antidepressants work the way they should here?

Because inflammation is actively working against the mechanism the medication depends on. Inflammatory cytokines increase the activity of the serotonin transporter, which is the very target an SSRI is designed to block, so the medication is pushing against a current running harder because of the inflammation. Cytokines also divert tryptophan down the kynurenine pathway and away from serotonin production in the first place. Serotonin is the precursor to melatonin, which is part of why sleep starts to come apart alongside mood.

Dr. Aimie was started on sertraline, then bupropion was added when the first was not doing enough. Together they helped some without resolving it, and the withdrawal effects were significant enough that she felt held on medications that were not relieving the depression. The message she was given was that her chemistry was off and this would likely be lifelong.

Do anti-inflammatory medications treat depression instead?

No, and the trial usually cited as proof does not show that. In 2013 Charles Raison and colleagues published a randomised controlled trial in JAMA Psychiatry of infliximab, which blocks TNF, in 60 people with treatment-resistant depression. The primary result was negative, with no main effect of treatment and no advantage over placebo overall.

What the trial found was an interaction. Participants who came in with high baseline inflammatory markers improved on infliximab. Participants who came in with low markers did worse than placebo. That is one trial in about 60 people, and it has not been replicated at scale. It is frequently quoted as evidence that anti-inflammatories treat depression, and it does not support that claim.

One more calibration. A meta-analysis of 37 studies covering 13,541 people with depression found low-grade inflammation, defined as CRP above 3 mg/L, in about 27 percent of them. So roughly a quarter. Depression across the population is not an inflammatory illness. If you carry an autoimmune condition, you are considerably more likely to sit inside that quarter, which is what makes the medication question worth asking in this population specifically.

What actually helps when depression and autoimmunity are looping?

Stop sequencing them, and start with nervous system state. The older model says treat the disease and mood will follow, or treat the mood and you will cope with the disease better. Both assume one sits downstream of the other, and the evidence points elsewhere. They share an upstream trigger, which means work aimed upstream reaches both.

The first step is the state itself. Dr. Aimie began with daily somatic exercises, simple and body-based, aimed at getting out of thinking and analysing and into moments of feeling safe enough. No medication does that piece. And the sequence matters, because a body still running full survival physiology has limited capacity to respond to anything else.

From there comes a biology of safety: nutrient status, the imbalances that can be identified and addressed, the one thing available today rather than everything at once. Safety first, then support, then expansion. The immune system adapted to survival, and an immune system that adapted can adapt again.

That is also where the protocols, the therapies and the long list of known-useful things become reachable, because the energy and the hope to attempt them are back online.

Key Takeaways

• Depression and autoimmune disease are associated in both directions, each carrying close to double the risk of the other across 47 studies and 40.77 million people.

• Depression and anxiety appear more often in the two years before a multiple sclerosis diagnosis, and antidepressant prescriptions in that window run higher than the diagnoses do.

• Depression is associated with later autoimmune disease in a dose-response pattern, which is one of the ways researchers separate a biological relationship from coincidence.

• Childhood adversity is associated with later autoimmune disease at a small effect size of 0.30, with high heterogeneity and probable publication bias, so the stronger causal claim is not supported.

• About a quarter of the association between childhood adversity and autoimmune disease appears to be mediated through depressive, anxiety and PTSD symptoms.

• Immune cells can become less responsive to cortisol over time, which leaves inflammation without a working off switch regardless of how high cortisol runs.

• Inflammatory depression presents as flatness and absent motivation rather than as sadness, which is the same sickness behaviour the brain produces during influenza.

• Inflammatory cytokines raise serotonin transporter activity and divert tryptophan down the kynurenine pathway, which is a mechanism for why serotonin-targeting medications underperform here.

• The infliximab trial for treatment-resistant depression was negative overall, and only the subgroup with high baseline inflammation improved, so anti-inflammatories are not an established treatment for depression.

• Roughly 27 percent of people with depression show low-grade inflammation, and people with autoimmune conditions are more likely to sit in that group.

Notable Quotes

1. "Your labs confirmed the autoimmune diagnosis. And the thing that no one prepared you for is that the hardest symptom is not the pain. It is that you stopped caring about your own life."

2. "Because there is a growing body of research and experience saying that depression and the autoimmunity are not in a straight line. They are in a loop. In fact, depression may precede an autoimmune diagnosis."

3. "Correlation running in both directions does not prove either one causes the other. It's showing that they coexist."

4. "Depression is part of the road from ‘I was healthy to I now have an autoimmune diagnosis.’"

5. "Cortisol is one of the ways your body turns inflammation off. And so when the receptors stop listening to it, the off switch stops working."

6. "This is biology. The depression and the autoimmunity then are not a weakness of character, and they're not even always genetics, and certainly not something that you should have efforted more will power to have handled better."

7. "Which means if antidepressants have underperformed for you, that outcome is information about what is happening in your biology. It is not information about your effort, it is information about your biology."

8. "The immune system has adapted to survival. And now the immune system can adapt to safety."

Episode Takeaway

I keep meeting the same person, and for a long time I did not recognise that I had been her.

She has the diagnosis. She has done the work, for years. Diet, supplements, the specialists, the protocols that were supposed to be the answer. And underneath all of it she is flat. She is not crying. She is not describing sadness. She is describing an absence, a place where motivation used to live and does not any more. When she mentioned it, she was offered a medication, and the medication did not do much, and she quietly concluded that something must be wrong with her.

That conclusion is what I wanted to interrupt in this episode.

My own version started in 2014, in my third year of surgery residency, except it did not start there. It started about a year earlier with a depression that got called burnout. I was started on sertraline, then bupropion was added because the first was not enough, and the two of them together took the edge off without ever lifting it. What I remember most clearly is not the depression. It is being unable to come off the medications, feeling held by something that was not even relieving the thing it was prescribed for, and being told this was chemistry and probably lifelong. The fatigue came later. The autoimmunity was found later still.

What I understand now is that those things were never in a queue. They were in a loop, and something upstream was feeding both ends of it.

That is what the research says too, and I want to be careful about how far I take it. Depression and autoimmunity travel together in both directions. Depression shows up in the window before a diagnosis is made. Adversity early in life is associated with autoimmune disease later, at a small effect, with about a quarter of that association appearing to travel through mental health on the way. None of that proves causation, and I am not going to tell you that childhood trauma causes autoimmune disease, because the evidence does not support that sentence.

Here is what I will tell you. When your immune cells stop responding to cortisol, inflammation loses its off switch. When inflammation reaches the brain, it produces a state you already know from having the flu, where nothing is interesting and nothing is worth the effort, and there is no sadness in it at all. When that is what is driving your low mood, a medication aimed at serotonin is working against a current, which is exactly what the mechanism predicts and what many people live.

So if the antidepressant underperformed, that is information about your biology. It is not a verdict on your effort.

Disease is one of the five patterns we use to recognise that stored trauma is still shaping a life. And what adapted to toxic levels of stress can be repaired. The place to begin is not another protocol. It is your nervous system state, because a body still running survival physiology does not have the capacity to use the protocols yet. Safety first. Then support. Then expansion.

If you want to know whether one of those patterns is present for you, the assessment below takes two minutes and it is free.

Frequently Asked Questions

Why don't antidepressants work as well when you have an autoimmune disease? 

Inflammatory cytokines raise the activity of the serotonin transporter that SSRIs are designed to block, and they divert tryptophan away from serotonin production. The medication is working against an inflammatory current rather than in neutral conditions. Roughly a quarter of people with depression show low-grade inflammation, and people with autoimmune conditions are more likely to be among them.

Does this mean I should stop taking my antidepressant? 

No. Nothing in this episode is a recommendation to change or stop a medication, and stopping antidepressants without medical supervision carries real withdrawal risks that Dr. Aimie experienced herself. This is information to bring to the prescriber who knows your history.

Can depression start before an autoimmune diagnosis? 

Yes, and it is documented. In a Danish register study of 5,084 people with multiple sclerosis, the two years before diagnosis carried an odds ratio of 1.4 for a depression or anxiety diagnosis and 1.90 for a tricyclic antidepressant prescription, compared with matched controls.

What does inflammatory depression feel like compared with classic depression? 

Classic depression usually carries emotional content: sadness, worthlessness, anhedonia. The inflammatory pattern reads as the absence of emotion rather than the presence of a painful one. Flatness, slowed thinking and movement, and no available drive toward things you still know you want.

What is sickness behaviour? 

It is the coordinated set of changes the brain produces in response to inflammatory signalling from the immune system, described by Robert Dantzer and colleagues in 2008. Withdrawal, loss of appetite, no motivation, no interest. Anyone who has had influenza has experienced it.

Does childhood trauma cause autoimmune disease? 

The evidence does not support that claim. The pooled effect of childhood adversity on later autoimmune disease is small, at 0.30, with high disagreement between studies and signs of publication bias. There is an association, and dose-response patterns appear in large cohorts, and an association at that strength is not causation.

Do anti-inflammatory drugs treat depression? 

The randomised trial most often cited, infliximab for treatment-resistant depression, was negative on its primary outcome. Only participants with high baseline inflammatory markers improved, and those with low markers did worse than placebo. It was about 60 people and has not been replicated at scale.

Where do I start if I have both depression and an autoimmune condition? 

With nervous system state rather than with another protocol. A body still running full survival physiology has limited capacity to respond to interventions. The sequence in the Biology of Trauma^® work is safety first, then support, then expansion.

In This Episode

• 00:00 Why the hardest symptom of an autoimmune diagnosis is often not the pain

• 02:41 The assumption this episode interrupts: that depression is simply a reasonable response to being ill

• 04:49 What "double the risk" does and does not mean

• 07:58 The Danish cohort of 1.1 million, and what a dose-response pattern tells us

• 09:45 Childhood adversity and autoimmune disease, and where the evidence stops

• 12:19 The quarter that travels through mental health on the way

• 13:54 Cortisol receptors that stop responding, and inflammation without an off switch

• 15:55 Sickness behaviour, the flu, and the bike ride that stopped sounding appealing

• 18:23 Conservation mode, hibernation mode, and why the diagnosis comes later

• 20:48 Why working on your thoughts may not be moving it

• 22:55 The mechanism behind antidepressants underperforming, and Dr. Aimie's own two medications

• 24:54 The infliximab trial, and what it does not prove

• 28:48 Safety, then support, then expansion

• 29:52 The free two-minute pattern assessment

  
  

Resources and Guides

• Discover Your Pattern For Stored Stress and Trauma, the free two-minute assessment referenced in this episode: biologyoftrauma.com/quiz

• The Biology of Trauma, the national bestselling book: biologyoftrauma.com/book

• The Foundational Journey: biologyoftrauma.com/self-help-foundational-journey

• Find a Biology of Trauma^® Professional: biologyoftrauma.com/find-a-practitioner

Related Podcast Episodes

• Episode 71: Understanding the Trauma Connection Between Attachment, Autoimmunity, and Fatigue If the flatness in this episode sounded familiar, this one takes the exhaustion side of the same state and explains why rest does not resolve it.

• Episode 66: Gabor Maté: The Biology Piece We Have Missed In Trauma and Depression (Part 1) For the listener who wants the wider case for why chronic illness and mood belong in one conversation rather than two.

• Episode 49: How Unresolved Anger Affects Autoimmune Conditions with Dr. Keesha Ewers For anyone whose flatness has something underneath it that never had anywhere to go.

Your Host

Dr. Aimie Apigian, MD MS MPH, is a double board-certified physician in preventive medicine and addiction medicine with master's degrees in biochemistry and public health. She is the author of the national bestseller The Biology of Trauma and the founder of Trauma Healing Accelerated, where she teaches the Biology of Trauma^® framework to individuals and to practitioners.

Research

1. Li Y, Zhao C, Sun S, et al. Elucidating the bidirectional association between autoimmune diseases and depression: a systematic review and meta-analysis. BMJ Mental Health. 2024.

2. Jørgensen KT, et al. Psychiatric co-morbidity in multiple sclerosis: the risk of depression and anxiety before and after MS diagnosis. Danish nationwide register study, 5,084 cases and 24,771 controls. 2015. PubMed 26041803

3. Andersson NW, et al. Depression and the risk of autoimmune disease: a nationally representative, prospective longitudinal study. Psychological Medicine. 2015. PubMed 26271451

4. Jesuthasan J, Watson R, Hafeez D, Lynch-Kelly D, Danese A, Pollak TA. Childhood adversity as a risk factor for autoimmune disease: a systematic review and meta-analysis with implications for psychiatry. Brain, Behavior, and Immunity. 2025. PubMed 40320015

5. Köhler-Forsberg O, Ge F, Aspelund T, et al. Adverse childhood experiences, mental distress, and autoimmune disease in adult women: findings from two large cohort studies. Psychological Medicine. 2025. PMC12017369

6. Neuroimmune programming of childhood trauma: comorbid mechanisms and developmental origins of depression and autoimmune diseases. Journal of Neuroinflammation. 2026. doi 10.1186/s12974-026-03810-6

7. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews Neuroscience. 2008;9(1):46-56. PubMed 18073775

8. Raison CL, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013. PubMed 22945416

9. Osimo EF, Baxter LJ, Lewis G, Jones PB, Khandaker GM. Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels. Psychological Medicine. 2019. PubMed 31258105

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