What is the role of inflammation in major depressive disorder (MDD)? In a session called “What’s Hot: An Inflammatory Take on the Immune System in Psychiatry,” Charles L. Raison, MD, from the University of Wisconsin, Madison, presented recent findings in this area, including how subgroups of depressed individuals show increased levels of inflammatory biomarkers.
What is the role of inflammation in major depressive disorder (MDD)? In a session called “What’s Hot: An Inflammatory Take on the Immune System in Psychiatry,” Charles L. Raison, MD, from the University of Wisconsin, Madison, presented recent findings in this area, including how subgroups of depressed individuals show increased levels of inflammatory biomarkers.
These findings are sometimes misinterpreted to mean that MDD is an inflammatory condition, but that would be incorrect, he said. The topic is more complex than that, he added.
“Inflammation is becoming surprisingly relevant in clinical treatment,” said Raison, the director of clinical and translational research at the Usona Institute. Calling inflammation a relic left over from the time of earliest human development, he said it is now fueled by lifestyle, with a propensity to go haywire. But for evolutionary purposes, “inflammation was all that stood between a person from near certain death from infection,” he said.
Major depression is not an inflammatory disorder, he said—if it were, you would want to give an anti-inflammatory to every depressed person.
With that, however, there are caveats, which Raison delved into by presenting what he called a series of “thought experiments” and reviewing previous studies.
There is no doubt, he said, that inflammatory pathways in the brain interact with every system in the body. As a result, people might vary in their sensitivity to that or may have different vulnerabilities when it comes to effects on depression.
What if inflammation is only relevant for a subgroup of people with depression? Early on, Raison and his colleagues theorized that since people given interferon-alpha became depressed, reductions in depressive symptoms would correlate with reductions in inflammatory biomarkers. In other words, people with depression and high inflammation would respond to an intervention, but people who are depressed but are not inflamed would not.
In 1 study, 60 patients with treatment-resistant depression were randomized to receive either 3 infusions of the tumor necrosis factor (TNF) infliximab or a salt water placebo for 12 weeks. To Raison’s shock, salt water beat infliximab.
That was the study that proved that depression was not an inflammatory disorder, but they still had another theory that if inflammation was high, those patients would be the ones to respond to treatment. That was true in the salt water study—it was the high inflammation group that did respond to infliximab. He called this a “great mystery.”
“If major depression is a brain disorder, so the brain is broken, how can it be that turning off the signal from the body can undepress people?” he said.
This may mean that the brain is reacting to signals from the environment that a problem exists, he said. It may also suggest that inflammation may not also be bad for everyone, yet “inflammation can be a road into depression.”
“Don’t come up to the mike and ask me, ‘where does that cut-off begin?’” he told his audience. “There’s no answer to that.”
Inflammation's role in treatment
Raison reviewed several studies pointing to the role that increased inflammation has in inhibiting treatment response.
In 1 study, 102 patients with treatment-resistant MDD had higher levels of C-reactive protein (CRP), and patients who failed 3 or more trials had higher TNF, soluble TNF receptor 2, and interleukin-6 compared with individuals with 0 or 1 trial.
In another study, chronic inflammation from infection increased the rate of MDD and reduced the responsiveness of antidepressants, and another study showed inflammation reduced response to psychotherapy.
All of this information is useful only if it can help guide treatment decisions, and to that end, Raison showed results from a study that found that patients with high CRP levels responded better to the selective serotonin reuptake inhibitor (SSRI) escitalopram then they did to the tricyclic antidepressant nortriptyline.
In another study, bupropion added to an SSRI improved treatment response for those whose CRP levels were equal or greater than 1 mg/L. In fact, that was one of Raison’s takeaways—inflammatory biomarkers can help guide treatment, such as by adding a drug like bupropion to an SSRI.
There are also inflammatory differences by gender, he said, which can probably be explained by the role of inflammation in evolution during female childbearing years, during which “women paid a higher reproductive cost.” Inflammation reduces fertility, impairs lactation, and directs energy away from reproduction. Women may be more likely to develop depression because social withdrawal reduced exposure to pathogens, so women were able to survive with less inflammation and still avoid death from infection, he said.
The Push for Fair Pricing and Reform in Pharmacy Benefit Management
April 3rd 2025Amid growing legislative pressures and industry debates, pharmacy benefit managers (PBMs) are exploring new strategies to enhance transparency, reduce patient costs, and navigate the evolving healthcare landscape.
Read More
The Importance of Examining and Preventing Atrial Fibrillation
August 29th 2023At this year’s American Society for Preventive Cardiology Congress on CVD Prevention, Emelia J. Benjamin, MD, ScM, delivered the Honorary Fellow Award Lecture, “The Imperative to Focus on the Prevention of Atrial Fibrillation,” as the recipient of this year’s Honorary Fellow of the American Society for Preventive Cardiology award.
Listen
Using AI-Driven Strategies to Optimize Specialty Drug Costs, Manage Polypharmacy
April 2nd 2025As health care costs continue to rise, artificial intelligence (AI)-driven solutions are emerging as a powerful tool for managing specialty drug spending and polypharmacy risks, as showcased in recent research presented at the Academy of Managed Care Pharmacy 2025 conference.
Read More
Promoting Equity in Public Health: Policy, Investment, and Community Engagement Solutions
June 28th 2022On this episode of Managed Care Cast, we speak with Georges C. Benjamin, MD, executive director of the American Public Health Association, on the core takeaways of his keynote session at AHIP 2022 on public health policy and other solutions to promote equitable health and well-being.
Listen
How Recent Federal Policy Changes Are Shaping Managed Care Pharmacy
April 2nd 2025Federal legislative and regulatory changes are reshaping pharmacy practice, with key challenges in government funding, pharmacy benefit manager reform, and health care policy shifts—topics explored by experts at the Academy of Managed Care Pharmacy's annual meeting.
Read More
The IRA’s Unintended Consequences for Drug Pricing and Coverage
April 2nd 2025The Inflation Reduction Act (IRA) may be restricting Medicare Part D formularies, increasing patient costs, and stifling pharmaceutical innovation, experts warned at the Academy of Managed Care Pharmacy 2025 annual meeting.
Read More