Inflammatory Depression: Why Some Patients Don't Improve With Antidepressants

Not all depression is the same. In some patients, the illness is linked to a state of chronic inflammation in the body, which directly affects brain function and reduces the ability to feel pleasure. This study showed that anti-inflammatory medications can help reduce depressive symptoms and anhedonia in people with elevated inflammation in their blood. Considering inflammation as part of the diagnosis may be essential for improving depression treatments in the future.

Depression is one of the most common and disabling mental disorders in the world, affecting hundreds of millions of people of different ages and social contexts. It is characterized by persistent symptoms such as profound sadness, loss of interest or pleasure in daily activities, fatigue, changes in sleep and appetite, difficulty concentrating, and, in more severe cases, suicidal thoughts.

From a biological point of view, depression is not a single disease, but a set of conditions that can have different origins in the brain and body. The brain areas most frequently involved include the prefrontal cortex, responsible for emotional control and decision-making; the hippocampus, essential for memory and stress regulation; and the reward system, which involves structures such as the nucleus accumbens and is directly linked to feelings of pleasure and motivation.

Despite the wide availability of antidepressants, a large proportion of patients do not show sufficient improvement with traditional treatments, indicating an urgent need for new therapeutic approaches.

In recent decades, scientific evidence has pointed to a significant portion of depression cases being associated with alterations in the immune system, giving rise to the concept of "inflammatory depression." In this subtype, the body presents a state of chronic low-grade inflammation, even in the absence of apparent infections.

Inflammation is a natural bodily response to injury or threats, but when it becomes persistent it can affect brain function. Genetic studies, extensive analyses of proteins and molecules in the blood, laboratory experiments, and clinical observations show that about a quarter of people with depression have elevated levels of inflammatory markers in their circulation.

One of the most studied is C-reactive protein, produced by the liver in response to inflammation. Elevated levels of this protein have been associated not only with the presence of depression but also with the risk of developing the disorder in the future.

These inflammatory signals in the blood are not confined to the body, as they can directly influence the brain. Inflammatory molecules can alter communication between neurons, reduce the formation of new brain connections, and interfere with neurotransmitter systems such as serotonin and dopamine.

This helps explain why inflammation is especially associated with symptoms such as anhedonia, which is the difficulty or inability to feel pleasure, and neurovegetative changes, which include alterations in sleep, appetite, and energy. Experimental studies in humans show that artificial activation of the immune system, even in healthy individuals, can induce temporary depressive symptoms, reinforcing the causal relationship between inflammation and mood.

Given these findings, researchers began investigating whether anti-inflammatory drugs could help treat depression, especially in people with clear signs of inflammation. Previous studies have shown that these medications can reduce depressive symptoms in patients who already have inflammatory diseases, such as rheumatoid arthritis.

However, the results were inconsistent when these treatments were tested in people with depression without other associated physical illnesses. One of the main hypotheses for these contradictory results is that many studies did not specifically select patients with elevated inflammation, the group that theoretically would have the greatest chance of benefiting from this type of intervention. Another important limitation was the lack of focus on specific symptoms, such as anhedonia, which appears to be more directly linked to inflammation than to depression as a whole.

To clarify these issues, the researchers conducted a systematic review and a meta-analysis, which are scientific methods used to gather, critically evaluate, and combine the results of several independent studies.

In this type of analysis, only studies with rigorous methodology are included, allowing for more reliable conclusions than those based on a single experiment. The authors exclusively selected randomized clinical trials, considered the gold standard of clinical research, in which participants are randomly assigned to receive the active medication or a placebo, a substance with no therapeutic effect.

The included studies analyzed the effect of anti-inflammatory medications in people diagnosed with depression who presented objective signs of inflammation in the blood, mainly elevated levels of C-reactive protein.

Furthermore, the researchers ensured that the participants did not have other inflammatory medical conditions, to isolate the effect of inflammation associated with depression itself. International scientific databases were extensively searched, and the data were independently evaluated by different reviewers, reducing the risk of errors or biases.

By analyzing the combined results of eleven studies, the researchers observed that anti-inflammatory treatments reduced both anhedonia and the overall severity of depressive symptoms in people with elevated inflammation. This means that these patients showed an improvement in their ability to experience pleasure and a decrease in depressive symptoms overall.

However, no clear differences were observed in complete disease remission rates or overall clinical response, suggesting that the effects, while relevant, are not sufficient to lead all patients to full recovery. Importantly, the results were consistent regardless of age, sex, or specific type of anti-inflammatory medication used.

These findings reinforce the idea that inflammatory depression represents a specific subtype of depressive disorder, which may require personalized treatment strategies. Ignoring the inflammatory state of patients may explain why many previous studies have reached contradictory conclusions about the effectiveness of anti-inflammatory medications in depression.

By identifying which people actually have elevated inflammation, it becomes possible to better target treatments and move towards more personalized medicine, in which individual biology guides therapeutic decisions.

READ MORE:

Effect of Anti-Inflammatory Treatment on Depressive Symptom Severity and Anhedonia in Depressed Individuals With Elevated Inflammation: Systematic Review and Meta-Analysis of Randomized Controlled Trials

Naoise Mac Giollabhui, Annelise A. Madison, Emma Lenoel Quang, Andrew H. Miller, and Richard T. Liu

American Journal of Psychiatry. In Advance. 9 December 2025

https://doi.org/10.1176/appi.ajp.20241115

Abstract:

Studies evaluating the effect of anti-inflammatory treatment on depressive symptom severity and anhedonia in depressed individuals report mixed results. In this preregistered systematic review and meta-analysis, the authors evaluated whether anti-inflammatory treatments, compared to placebo, reduce anhedonia and depressive symptom severity in depressed individuals with an inflammatory phenotype. The authors included randomized controlled trials of pharmacological anti-inflammatory treatments that assessed anhedonia or depressive symptom severity and recruited depressed individuals with an inflammatory phenotype or measured baseline inflammatory biomarkers that permitted post hoc analysis. A search was conducted in February 2025 of MEDLINE, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and PsycINFO. Multiple reviewers independently applied criteria, and discrepancies were resolved via consensus. Two reviewers independently extracted data and cross-checked for errors. In randomized controlled trials (k=11) using an established cutoff for elevated inflammation (C-reactive protein ≥2 mg/L), both anhedonia (Hedges’ g=0.40, 95% CI=0.08, 0.71) and depressive symptoms (Hedges’ g=0.35, 95% CI=0.05, 0.64) were reduced, but no differences in treatment response (relative risk=1.28, 95% CI=0.997, 1.64) or remission rates (relative risk=1.18, 95% CI=0.71, 1.95) were observed. Results did not vary by clinical, interventional, or demographic characteristics. Anti-inflammatory treatments may be safe and effective at reducing depressive symptoms and anhedonia in depressed individuals with heightened inflammation. Not accounting for inflammatory status may help explain prior mixed findings.