Summary: A new analysis shows that anti-inflammatory medications may help reduce symptoms for a subset of people with depression who also have chronic low-grade inflammation. Reviewing randomized controlled trials that specifically enrolled people with elevated inflammatory markers, researchers found that anti-inflammatory treatments significantly reduced both overall depressive symptoms and anhedonia.
The findings highlight a distinct biological subtype of depression determined by immune dysregulation, offering a potential path toward more personalized treatment. Future work will focus on identifying biomarkers that reliably predict who will benefit and developing safer targeted anti-inflammatory approaches.
Key facts
Inflammation-related depression: Anti-inflammatory medications reduced the severity of depression in people with measurable chronic inflammation. Improved anhedonia: The treatments also reduced anhedonia, suggesting the benefits extend beyond mood. Identified subtype: Results support an immune-related subtype of depression that may respond to tailored interventions.
Source: General de Masas
Naoise Mac Giollabhui, PhD, of the Department of Psychiatry at Mass General Brigham, is the lead author of an article published in the American Journal of Psychiatry, “Effect of anti-inflammatory treatment on the severity of depressive symptoms and anhedonia in depressed individuals with high inflammation: systematic review and meta-analysis of randomized controlled trials.” Richard Liu, PhD, of the Department of Psychiatry at Mass General Brigham, is the lead author.
Q: How would you summarize your study for a lay audience?
At any given time, more than 400 million people around the world are struggling with depression. The antidepressant treatments we currently have do not work for many and there is a real need for new, effective treatments.
Over the past 20 years, there has been increasing evidence that some depressed people have chronic low-grade inflammation that could be causing their symptoms.
This observation of a dysregulated immune system led to clinical trials in which depressed people received a variety of anti-inflammatory treatments. However, the results of these clinical trials were mixed.
We hypothesize that the results may have been mixed because these trials did not target the subset of depressed people who exhibit immune dysfunction; If there is no inflammation to begin with, anti-inflammatory medications won’t be very helpful!
Therefore, our study was designed to determine whether anti-inflammatory medications are effective when administered to depressed individuals who actively exhibit chronic low-grade inflammation.
Q: What question were you investigating?
We investigated whether anti-inflammatory medications are effective in reducing the severity of depressive symptoms and anhedonia (decreased ability to feel pleasure) in a subset of depressed people with chronic low-grade inflammation.
Q: What methods or approach did you use?
We conducted a systematic review and meta-analysis of all randomized controlled trials in which we were able to determine the effect of anti-inflammatory medications on the severity of depressive symptoms and anhedonia in depressed people with high levels of inflammation.
Q: What did you find?
We identified up to 11 randomized controlled trials in which anti-inflammatory medications were given to up to 321 depressed people with high levels of inflammation.
We found that anti-inflammatory medications significantly reduced both the severity of depressive symptoms and anhedonia at the end of the study.
Q: What are the implications?
This suggests that there is a subtype of depression characterized by a dysregulated immune system that could be effectively treated with anti-inflammatory medications and lifestyle interventions.
Q: What are the next steps?
There is much work to be done to develop immunological biomarkers that more accurately identify who will benefit from anti-inflammatory treatment for depression and to develop treatment approaches that selectively target dysfunctional inflammatory physiology. At the moment, some of the most potent anti-inflammatory medications have serious side effects that make them suboptimal for use in a clinical setting.
Authorship: In addition to Mac Giollabhui and Liu, Mass General Brigham authors include Melis Lydston.
Funding: This work was supported by grants from the National Institute of Mental Health (K23MH132893, NMG; R01 MH115905, RTL; R01 MH124899, RTL; R21 MH130767, RTL; R01MH137793, RTL; K24 MH136418, RTL), a LIFE Foundation Research Grant (NMG), Harvard The University’s Cross-Faculty Mind, Brain, and Behavior Initiative (NMG) and Massachusetts General Hospital Early Career Investigator (NMG) Center for Clinical Translational Research.
Disclosures: Richard T. Liu is a consultant for Relmada Therapeutics. Andrew H. Miller is a consultant for Cerevel Therapeutics, Sirtsei Pharmaceuticals Inc., Freedom Biosciences. Naoise Mac Giollabhui is a consultant at Boehringer Ingelheim. No other authors have disclosures to report.
Key questions answered:
A: People with depression who also show biological signs of chronic low-grade inflammation, such as elevated inflammatory markers, are the most likely candidates. The study found that targeting this subgroup produces the clearest therapeutic benefit.
A: No. Analysis suggests that these treatments are effective only when inflammation is present. For people without immune dysregulation, anti-inflammatory medications do not appear to reduce symptoms, highlighting the need for personalized treatment approaches.
A: The trials included a variety of anti-inflammatory approaches, from pharmaceutical agents that directly reduce inflammation to drugs that modulate immune signaling. Across these varied treatments, the general trend showed a significant reduction in symptoms in patients with elevated inflammation.
Editorial notes:
This article was edited by a Neuroscience News editor. Magazine article reviewed in its entirety. Additional context added by our staff.
About this news about research in psychopharmacology and depression.
Author: Cassandra Falone
Source: General de Masas
Contact: Cassandra Falone – Mass General
Image: Image is credited to Neuroscience News.
Original Research: Closed access.
“Effect of anti-inflammatory treatment on the severity of depressive symptoms and anhedonia in depressed people with high inflammation: a systematic review and meta-analysis of randomized controlled trials” by Naoise Mac Giollabhui et al. American Journal of Psychiatry
Abstract
Effect of anti-inflammatory treatment on severity of depressive symptoms and anhedonia in depressed people with high inflammation: systematic review and meta-analysis of randomized controlled trials
Aim:
Studies evaluating the effect of anti-inflammatory treatment on the severity of depressive symptoms and anhedonia in depressed people provide mixed results. In this preregistered systematic review and meta-analysis, the authors assessed whether anti-inflammatory treatments, compared with placebo, reduce anhedonia and the severity of depressive symptoms in depressed people with an inflammatory phenotype.
Methods:
The authors included randomized controlled trials of pharmacological anti-inflammatory treatments that assessed anhedonia or the severity of depressive symptoms and recruited depressed individuals with an inflammatory phenotype or measured baseline inflammatory biomarkers that allowed post hoc analysis. In February 2025, a search was conducted in MEDLINE, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and PsycINFO. Criteria were applied independently by multiple reviewers and discrepancies were resolved by consensus. Two reviewers independently extracted data and checked them for errors.
Results:
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 not There were differences in response to treatment (relative). risk = 1.28, 95% CI = 0.997, 1.64) or remission rates (relative risk = 1.18, 95% CI = 0.71, 1.95). Results did not vary by clinical, interventional, or demographic characteristics.
Conclusions:
Anti-inflammatory treatments may be safe and effective in reducing depressive symptoms and anhedonia in depressed people with elevated inflammation. Failure to take inflammatory status into account may help explain previous contradictory findings.
