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. By reviewing randomized controlled trials that specifically enrolled individuals 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 shaped 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 on developing safer, targeted anti-inflammatory approaches.
Key Facts
- Inflammation-Linked Depression: Anti-inflammatory drugs reduced depressive severity in people with measurable chronic inflammation.
- Improved Anhedonia: Treatments also lessened anhedonia, suggesting benefits extend beyond mood.
- Subtype Identified: Results support an immune-related subtype of depression that may respond to tailored interventions.
Source: Mass General
Naoise Mac Giollabhui, PhD, of the Department of Psychiatry at Mass General Brigham, is the lead author of a paper published in American Journal of Psychiatry, “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.” Richard Liu, PhD, of the Department of Psychiatry at Mass General Brigham, is the senior author.
Q: How would you summarize your study for a lay audience?
At any given moment in time, more than 400 million individuals worldwide are battling depression. The antidepressant treatments that we currently have don’t work for many and there is a real need for new, effective treatments.
Over the last 20 years, there has been increasing evidence that some depressed individuals have chronic, low-grade inflammation that might be driving their symptoms.
This observation of a dysregulated immune system led to clinical trials in which depressed individuals were given a variety of anti-inflammatory treatments. The results of these clinical trials, however, were mixed.
We hypothesized that results may have been mixed because these trials did not target the subset of depressed individuals exhibiting immune dysfunction – if there is no inflammation to begin with, anti-inflammatory medication won’t be very helpful!
So, our study was designed to determine whether anti-inflammatory medications are effective when given to depressed individuals who are actively exhibiting chronic, low-grade inflammation.
Q: What question were you investigating?
We investigated whether anti-inflammatory medications are effective in reducing depressive symptom severity and anhedonia (decreased ability to feel pleasure) in a subset of depressed individuals 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 could determine the effect of anti-inflammatory medication on depressive symptom severity and anhedonia in depressed individuals with elevated levels of inflammation.
Q: What did you find?
We identified up to 11 randomized controlled trials in which anti-inflammatory medications were administered in up to 321 depressed individuals with elevated levels of inflammation.
We found that anti-inflammatory medications significantly reduced both depressive symptom severity and anhedonia at the study endpoint.
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 using anti-inflammatory medications and lifestyle-based interventions.
Q: What are the next steps?
There’s a lot of work that needs to be done to develop immune 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 more potent anti-inflammatory medications have serious side-effects that make them sub-optimal 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 L.I.F.E. Foundation Research Grant (NMG), Harvard University’s Mind Brain Behavior Interfaculty Initiative (NMG), and Massachusetts’s General Hospital Translational Clinical Research Center’s Early Career Investigator (NMG).
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 for Boehringer Ingelheim. No other authors have disclosures to report.
Key Questions Answered:
A: Individuals 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. The analysis suggests these treatments are effective only when inflammation is present. For individuals without immune dysregulation, anti-inflammatory drugs do not appear to reduce symptoms, highlighting the need for personalized treatment approaches.
A: The trials included a range of anti-inflammatory approaches, from pharmaceutical agents that directly lower inflammation to medications that modulate immune signaling. Across these varied treatments, the overall trend showed meaningful symptom reduction in patients with elevated inflammation.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this psychopharmacology and depression research news
Author: Cassandra Falone
Source: Mass General
Contact: Cassandra Falone – Mass General
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“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” by Naoise Mac Giollabhui et al. American Journal of Psychiatry
Abstract
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
Objective:
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.
Methods:
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.
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 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.
Conclusions:
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.
