How the Depression-Inflammation Connection is Reshaping Treatment Paradigms

Inflammation is emerging as a key driver of depression for up to one-third of patients—and it may hold the key to more personalized care. In this interview, Charles Raison, MD, Psych Congress Steering Committee Member, shares some of the key insights from his session presented at the 2025 Psych Congress: “The Role of Inflammation in Depression: Bridging Science and Clinical Innovations."

Dr Raison unpacks the latest science linking inflammation to brain circuitry, explains when and how to use hs-CRP in practice, and explores treatment strategies—pharmacologic and behavioral—that can sharpen therapeutic choices and improve outcomes for patients with major depressive disorder (MDD). 

For more news and insights from the 2025 Psych Congress in San Diego, CA, visit the meeting newsroom here on Psych Congress Network. 

Psych Congress Network (PCN): How is our understanding of the link between inflammation and depression evolving, and what makes this such a pivotal moment in MDD research?   

Charles Raison, MD: Over the past decade, 2 advances have reshaped how we think about inflammation in major depressive disorder (MDD). First, we’ve moved beyond asking whether inflammation can cause depression to asking for whom it matters most. The answer appears to be a meaningful minority: roughly a quarter to a third of people with MDD show persistent, low-grade elevations in peripheral inflammatory markers, and this biology maps onto symptom profiles characterized by anhedonia, motivational deficits, and, often, anxiety. 

Second, neurobiological data now link that inflammatory state to specific brain changes. Inflammation shows a particular affinity for dopaminergic circuits, especially within the ventral striatum—a hub for reward and hedonic tone. Convergent evidence indicates that inflammatory signaling dampens dopamine function in this region, and fMRI studies consistently report reduced medial prefrontal–ventral striatal connectivity in depressed patients with elevated inflammation relative to equally ill patients without it. 

Together, these findings support the view that inflammation may define one of the most coherent and clinically actionable subtypes of depression. It’s no surprise that there is growing interest in formalizing an “inflammatory depression” specifier within future diagnostic frameworks and, more immediately, in using inflammatory markers to guide more personalized care. 

PCN: Increased inflammation is relevant for 20%-30% of depressed patients. What biomarkers or clinical features should providers look for to identify these patients in practice? 

Dr Raison: Inflammation is a complex set of interrelated processes that evolved to help organisms survive infection. The immune system has 2 primary arms: the innate immune system, which doesn’t rely on antigen recognition, and the adaptive immune system, which produces targeted defenses such as antibodies against specific pathogens. 

With that said, there’s a widely available, standardized blood test that serves as a good overall summary of inflammatory activity: high-sensitivity C-reactive protein (hs-CRP). Many studies now show that hs-CRP helps identify people with chronic, low-grade elevations in inflammation that are relevant to the pathogenesis of depression and have treatment implications. 

So, for clinicians who want to know whether a patient may have a more inflammation-based depression, a standard hs-CRP is your best first step. Other markers—such as cytokines—exist, but they’re less standardized and therefore less helpful in routine practice. 

There are also behavioral and body-based indicators of higher inflammation. Obesity is a common one: people with obesity tend to have elevated inflammation, and when they’re depressed, that inflammatory signal is often higher. Inflammation also targets pathways that reduce pleasure and motivation—anhedonia. Data from my colleagues at Emory suggest that combining hs-CRP with a measure of anhedonia may predict who’s most likely to benefit from anti-inflammatory strategies better than hs-CRP alone. 

PCN: How might patients with increased inflammation respond differently to the standard of care for depression, and what other treatment modalities could be beneficial for this subgroup? 

Dr Raison: It seems obvious that depressed patients with elevated inflammation might be especially likely to respond to a drug that lowers inflammation, because the inflammation is contributing to their depression. This turns out to be what the data show: studies indicate that only depressed patients with higher levels of inflammation benefit from pharmacologic anti-inflammatory strategies. In fact, several studies suggest that depressed patients without elevated inflammation can do worse on anti-inflammatories than on placebo. 

So the first point is that an inflammatory subtype of depression is more likely to benefit from anti-inflammatory treatments than other depressed patients. 

There’s also an interesting signal—needing confirmation—that people with depression and increased inflammation may be less likely to respond to standard antidepressants, particularly serotonergic agents (SSRIs), even at modest elevations of hs-CRP. That finding has been reported in several studies and is currently the most robust in this area. 

Conversely, there are findings suggesting that patients with increased inflammation may respond better to agents with noradrenergic or dopaminergic properties—for example, bupropion or the dopamine agonist pramipexole. These results are still preliminary and need replication in larger trials, which are underway. Over the next few years, we should learn whether a simple blood test like CRP can help determine whether a given patient is more likely to respond to a serotonergic versus noradrenergic/dopaminergic approach. Stay tuned. 

PCN: Beyond pharmacology, how do lifestyle factors—like diet, sleep, or exercise—modulate inflammation in MDD, and how should clinicians integrate this into treatment planning? 

Dr Raison: As I said in response to the prior question, people who are depressed without elevated inflammation shouldn’t be treated with pharmacologic anti-inflammatory strategies. The paradox, however, is that almost everyone benefits from behavioral practices that improve health and lower inflammation—especially diet, sleep, and exercise. When done well, each has anti-inflammatory and antidepressant effects: better sleep reduces depression risk, regular exercise is comparable to medications for many patients, and highly processed diets are linked to greater depression risk. If you want more background, see our paper, “The Role of Inflammation in Depression: From Evolutionary Imperative to Modern Treatment Target” (Nature Reviews Immunology, 2016). 

Why behavioral anti-inflammatory strategies seem broadly helpful while pharmacologic ones should be reserved for those with clear inflammatory elevation remains unclear. However, clinically, the takeaway is simple: any behavioral strategy that works as an antidepressant also tends to reduce inflammatory tone. Implementing these can be challenging because they run against features of modern life—when you’re depressed, it’s easier to skip exercise, overeat processed food, and sleep poorly. Still, we should work to implement these as fully as possible for each patient because they benefit both mental and physical well-being. 

PCN: What are the key research gaps that need to be addressed before inflammation-targeted strategies become standard in MDD care? 

Dr Raison: I think the most pressing research gap doesn’t concern inflammation-targeted strategies per se, but whether an inflammatory biomarker like CRP can actually predict differential antidepressant response. If people with lower CRP are more likely to respond to SSRIs, while those with higher CRP are less likely to respond to SSRIs and more likely to benefit from bupropion or a dopaminergic agent, that would be immediately clinically relevant. 

The challenge is that current findings largely come from post hoc analyses rather than trials designed for this purpose. Studies now underway are asking these questions prospectively; if they replicate, it would be huge. Imagine a simple, same-day blood test in clinic that meaningfully improves your first-choice antidepressant selection using drugs already on the shelf—that would be a major clinical win. 

There are also open questions specific to inflammation-targeted approaches. First, what’s the best biomarker strategy—a simple test like CRP, or a more complex multimarker panel that might predict outcomes better? Second, which anti-inflammatory mechanisms are optimal? Cytokine-blocking biologics used in autoimmune disease may help but carry greater risk. It might be safer and more effective to modulate downstream pathways activated by inflammation—e.g., the kynurenine pathway—rather than suppress inflammation directly. In addition, because inflammation shows a tropism for dopamine, enhancing dopaminergic function may be especially helpful for anhedonia, a notoriously difficult symptom to treat. 

In summary, we need prospective, biomarker-guided trials; clearer biomarker algorithms; and head-to-head tests of anti-inflammatory versus downstream or dopaminergic strategies. As answers arrive, I expect we’ll get much better at targeting treatments to the subset of depressed patients with increased inflammation, advancing precision psychiatry. 

Charles Raison, MD, is a professor of human ecology and psychiatry in the Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison. Dr Raison also serves as Director of Clinical and Translational Research for Usona Institute, as Director of the Vail Health Behavioral Health Innovation Center, Director of Research on Spiritual Health for Emory Healthcare and as Visiting Professor in the Center for the Study of Human Health at Emory University in Atlanta, GA. Dr Raison’s research focuses on the examination novel mechanisms involved in the development and treatment of major depression and other stress-related emotional and physical conditions, as well as for his work examining the physical and behavioral effects of compassion training. More recently, Dr Raison has taken a leadership role in the development of psychedelic medicines as potential treatments for major depression. He was named one of the world’s most influential researchers by Web of Science for the decade of 2010-2019. Dr Raison received the Raymond Pearl Memorial Award from the Human Biology Association “in recognition of his contributions to our understanding of evolutionary biocultural origins of mental health and illness.” Dr Raison has also won the 2024 Emory University Science on Spiritual Health Torch and Trumpet Award “for a career devoted to the mental and spiritual health of humanity by responding and attending to suffering with a compassionate heart and a keen scientific mind.” With Vladimir Maletic he is author of The New Mind-Body Science of Depression published by W.W. Norton in 2017.