Treating Inflammation to Relieve Depression, Anhedonia

Anti-inflammatory treatment was found to reduce depressive symptoms and anhedonia in selected patients, in a meta-analysis of controlled trials with cohorts exhibiting an inflammatory phenotype.¹

Lead author Naoise Mac Giollabhui, PhD, Departments of Psychiatry, Massachusetts General Hospital and Harvard Medical School, and colleagues characterize the systematic review and meta-analysis as "the first to examine the effect of anti-inflammatory medications, compared to placebo, on anhedonia and depressive symptoms severity in depressed individuals exhibiting an inflammatory phenotype and without medical comorbidity."

The investigators point out that while previous meta-analyses have found anti-inflammatory treatments useful in reducing depressive symptoms in individuals with comorbid medical conditions such as rheumatoid arthritis, less is known about their efficacy for depressed individuals without comorbidity. In addition, they note that the analyses were not limited to trials with cohorts with inflammatory phenotype as indexed by C-reactive protein (CRP) levels, nor sufficiently distinguished those with anhedonia, which has been associated with increased immune activation.²

Mac Giollabhui discussed the utility of CRP levels in identifying inflammatory phenotype among individuals with symptoms of depression with Psychiatric Times.

"CRP is an inexpensive, reliable biomarker for systematic inflammation with interpretable clinical cut-offs, which makes it useful," he explained. "Elevated CRP is also a risk factor for cardiovascular disease and could be indicative of other underlying medical condition—alterative causes of elevated CRP should be assessed," he added.

Mac Giollabhui pointed out that elevated CRP is also associated with lower likelihood of responding to conventional antidepressants, and so should be considered when developing a depression treatment plan.

"Careful assessment of potentially modifiable sources of inflammation might be useful at shaping recommendations and treatment goals in depressed individuals with high levels of inflammation," Mac Giollabhui suggested. "Adiposity, substance use, and poor diet are all known to be associated with depression and to contribute to inflammation. Working with the patient to target these contributing factors would likely be of benefit to depressed individuals with high levels of inflammation."

Assessing Anti-Inflammatory Effect on Depression

The 19 randomized, placebo-controlled trials (RCTs) included in the meta-analysis were conducted with adults with clinical or subclinical depression and elevated C-reactive protein levels or other measured inflammatory biomarkers who had received a pharmacological anti-inflammatory as either adjunctive or monotherapy. The analysis focused on 11 studies which had used an established clinical cutoff for low-grade inflammation of CRP ≥2mg/L. Anti-inflammatory agents included interleukin-6 inhibitors, mitogen-activated protein kinase inhibitors, minocycline, nonsteroidal anti-inflammatory drugs (NSAIDs), recombinant interleukin, and tumor necrosis factor inhibitors.

In the 11 trials applying the CRP cutoff, the investigators found that anti-inflammatory treatment led to a reduction in anhedonia (Hedges' g=0.40 [95% CI=0.08-0.71]) and depressive symptom severity (g=0.35 [0.05-0.64]) when compared with placebo. They noted no significant difference in occurrence of serious adverse events between anti-inflammatory and placebo groups. There was also, however, no significant difference in likelihood of treatment response or remission.

The statistically significant difference between anti-inflammatory and placebo remained across 14 studies with a larger range of cutoffs for inflammatory phenotype, although with less magnitude of reduction in depressive symptom severity.The investigators indicated that the treatment effect compared with placebo was not moderated by such factors as treatment-resistant status, administration as adjunct or monotherapy, or the anti-inflammatory drug class.

In an accompanying editorial, Femke Lamers, PhD, Department of Psychiatry, Amsterdam University Medical Center and Amsterdam Public Health Mental Health Research Program, welcomed the meta-analysis as progress in developing more advanced precision medicine approaches in psychiatry.³

"Low-grade inflammation is a promising treatment target for certain subgroups of people with depression," Lamers observed. "A call was made recently to include inflammatory depression as a specifier for major depressive disorder in DSM-6, even if only for research purposes, as it would boost efforts to develop novel interventions for this phenotype.”

"For such personalized psychiatry to be fully realized, however, gaps in our knowledge need to be filled first," Lamers cautioned.

Mac Giollabhui and colleagues agree with the need for additional, and well-designed research. "In addition to a dearth of well-powered studies recruiting on the basis of elevated inflammation, this review highlights multiple sources of heterogeneity in medications used—as well as dosage and duration, enrollment inclusion and exclusion criteria, and target engagement," they remarked.

Mac Giollabhui elaborated on these concerns, and on the difficulty in applying the findings of this meta-analysis to current practice. "I agree that definitive RCTs are needed to help guide practitioners, and in their absence, practitioners should be caution when considering using existing medications. Based on this systematic review, there seemed to be a more consistent effect on anhedonia as compared to depressive symptoms, and so that might indicate that depressed individuals with high inflammation for whom anhedonia is present might be more likely to respond to anti-inflammatory strategies,” he said.

"Many of the anti-inflammatories analyzed in this review were quite potent in nature and are accompanied by significant side effects and long-term risks—eg, malignancies, and so may not be practical or advised in most clinics," he cautioned.

"There are compelling data that low-risk lifestyle-based interventions, such as omega-3 supplementation, adoption of a Mediterranean-style diet, exercise, and heated therapies are effective at reducing depression and inflammation. These could be good options for clinicians to consider, especially if indicated for a specific patient," Mac Giollabhui advised.

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

References

1. Mac Giollabhui N, Madison AA, Lydston M, et al. 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. Am J Psychiatry. 2026; 183(1):70-78.

2. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016; 16:22-34.

3. Lamers F. Targeting inflammation: how meta-analysis can advance precision psychiatry. Am J Psychiatry. 2026; 183(1):10-11.