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Research published in the American Journal of Psychiatry suggests that anti-inflammatory treatments may be an effective intervention for depression, but only for individuals with an overactive immune system. The study found that when patients are selected based on elevated inflammation markers, these drugs reduce both general depressive symptoms and the inability to feel pleasure. This distinction helps explain why previous clinical trials, which did not account for inflammatory status, often produced inconsistent results.
Depression is a leading cause of disability worldwide. Current treatments, such as selective serotonin reuptake inhibitors, do not work for every patient. Approximately one-third of individuals do not achieve full recovery even after trying multiple standard antidepressants. This gap in treatment efficacy has led scientists to investigate other biological systems that might contribute to mood disorders. Over the last two decades, research has increasingly pointed to the immune system.
Evidence suggests that a significant minority of people with depression have chronic, low-grade inflammation. This condition is often referred to as inflammatory depression. In these cases, the immune system behaves as if the body is fighting an infection or healing an injury, even in the absence of physical trauma. This immune activation releases proteins called cytokines. These proteins can interact with the brain to produce symptoms such as fatigue, lack of motivation, and low mood.
Previous clinical trials attempted to treat depression with anti-inflammatory drugs. The results of these past studies were inconsistent. Some trials showed a benefit, while others showed no effect compared to placebos. The authors of the current study hypothesized that these mixed results stemmed from a lack of precision.
“One of the major challenges that we face when treating depression is that clinicians tend to use a one-size-fits-all approach, even though we suspect that there are different biological, psychological, and environmental causes of depression,” said study author Naoise Mac Giollabhui, a staff psychologist at the Depression Clinical Research Program at Massachusetts General Hospital and Assistant Professor at Harvard Medical School.
“There is strong evidence that some depressed people exhibit chronic inflammation and that these people are less likely to respond to conventional antidepressant therapies. We wanted to test whether anti-inflammatory treatments work for depressed individuals with chronic inflammation.”
“Of course, anti-inflammatories don’t make much sense as a treatment for most depressed people who don’t have any alterations in immune function. The hope is that we will soon be able to deliver on the promise of a precision medicine approach and identify the right treatment for the right person. For inflammatory depression, this could mean developing treatments that target dysregulated immune function, which is something we are actively working on.”
To test this hypothesis, the research team conducted a systematic review and meta-analysis. This method allows scientists to combine data from multiple independent studies to increase statistical power. They searched major medical databases, including MEDLINE, Embase, and PsycINFO, for randomized controlled trials conducted up to February 2025. The search focused on studies that compared pharmacological anti-inflammatory treatments against placebos in adults with depression.
The researchers applied strict inclusion criteria to ensure the validity of their findings. They only included trials that assessed depressive symptom severity or anhedonia. Anhedonia is a core symptom of depression defined as a reduced ability to experience pleasure.
Most importantly, the analysis was limited to trials that recruited individuals with an inflammatory phenotype or provided data allowing for a subgroup analysis of such patients. The researchers defined an inflammatory phenotype as having levels of C-reactive protein at or above 2 milligrams per liter. C-reactive protein is a substance produced by the liver in response to inflammation.
The review process identified 11 randomized controlled trials that met the specific criteria for elevated inflammation. These studies included a combined total of 321 participants. The treatments utilized in these trials varied. They included non-steroidal anti-inflammatory drugs, such as celecoxib, and cytokine inhibitors, such as infliximab and minocycline. Some studies used these drugs as a standalone treatment, while others used them alongside standard antidepressants.
Two reviewers independently extracted data from the selected studies to minimize errors. They looked at changes in symptom scores from the beginning of the trial to the end. They also examined secondary outcomes, such as remission rates and safety data. The researchers used statistical models to calculate the average effect of the treatments across the different trials.
The analysis revealed that anti-inflammatory treatments resulted in a reduction of depressive symptom severity compared to placebo. The magnitude of this effect was moderate. This finding supports the idea that suppressing immune activation can alleviate mood symptoms in the specific subgroup of patients with high inflammation. The data suggests that failing to account for inflammatory status in previous research likely obscured the potential benefits of these medications.
In addition to general depressive symptoms, the researchers found a reduction in anhedonia. The effect of the treatment on anhedonia was slightly stronger and more consistent than the effect on overall depression scores. This is a notable finding because anhedonia is often difficult to treat with conventional antidepressants. The link between inflammation and anhedonia is supported by previous research showing that immune signaling can disrupt the brain’s reward circuitry.
“There was a lot of variability in the link between anti-inflammatory treatments and change in depression symptom severity,” Mac Giollabhui told PsyPost. “This is probably not surprising giving how heterogenous the presentation of depression is and how much variability there was in the potency of treatments used. However, it also suggests that we treat these results cautiously and consider them as requiring replication and confirmation in large-scale, randomized controlled trials.”
“Interestingly, the signal was stronger and more uniform for anhedonia. There is a very compelling body of evidence suggesting that inflammation may be specifically linked with energy-related symptoms of depression, like anhedonia. However, the number of studies measuring anhedonia was quite modest, so again further confirmatory work is needed.”
The researchers also evaluated the safety of these interventions. The analysis showed no significant difference in the occurrence of serious adverse events between the participants receiving anti-inflammatory drugs and those receiving a placebo. This suggests that, within the context of these short-term trials, the treatments were generally safe. The duration of the treatments in the included studies ranged from 2 weeks to 12 weeks.
Despite the reduction in symptom severity, the researchers did not find a statistically significant increase in response or remission rates. Response is typically defined as a 50 percent reduction in symptoms, while remission refers to a near-complete absence of symptoms. The patients on anti-inflammatories showed improvement, but the data did not definitively show that they were more likely to reach these specific clinical thresholds than those on placebo.
These findings have implications for the development of precision medicine in psychiatry. The results suggest that C-reactive protein could serve as a useful biomarker. Clinicians could potentially measure this protein to identify patients who might benefit from anti-inflammatory therapies. This aligns with a growing movement to move away from a “one-size-fits-all” approach to treating mental health conditions.
However, the total sample size of 321 participants is relatively small for a meta-analysis. This limits the certainty of the conclusions and results in wide confidence intervals. The small sample size meant that the researchers had limited power to detect differences based on demographic characteristics like age or sex.
Another limitation is the heterogeneity of the included studies. The trials used different types of medications with different mechanisms of action. Some drugs targeted specific cytokines, while others had broader anti-inflammatory effects. The dosages and treatment durations also varied significantly. It remains unclear which specific anti-inflammatory agent is the most effective for treating depression.
The researchers also pointed out that C-reactive protein is a non-specific marker. While it indicates the presence of inflammation, it does not reveal the cause. Elevated levels can result from many factors, including infection, tissue injury, or obesity. It is possible that more specific biomarkers could better identify the patients most likely to respond to immune-targeted treatments.
“We have made a lot of progress in better understanding the causes and presentation of inflammatory depression, but we are still relatively early in the process,” Mac Giollabhui explained. “The immune system is very closely related to metabolic- and stress-related pathways, which makes disentangling causal pathways tricky.”
“We are also early on in the process of understanding what is the best way to treat inflammatory depression and we are lacking definitive clinical trials that specific anti-inflammatory treatments at a specific dose for a specific duration work in a specific population. All to say, we are making progress but there is still a lot more work to be done!”
Future research is needed to replicate these findings in larger, well-powered trials. The researchers emphasize the need for studies that recruit patients specifically based on their inflammatory status. Future work should also investigate the long-term safety of using anti-inflammatory medications for depression. Depression is often a chronic condition, and the long-term use of some anti-inflammatory drugs carries health risks.
The researchers also suggest that future trials should include better measures of anhedonia. Most current studies use questionnaires that focus on the enjoyment of experiences. They often neglect the motivational aspects of anhedonia, such as the drive to pursue rewarding activities. Understanding how inflammation affects different aspects of reward processing could help refine treatment strategies.
“Ultimately, we want these findings to translate into better treatments in the clinic,” Mac Giollabhui said. “We have shown that anti-inflammatory treatments can reduce depressive symptom severity and anhedonia in depressed individuals with high levels of inflammation; however, the review demonstrated that much of the work, to date, has been conducted in small clinical trials and, therefore, these findings require replication and confirmation in large-scale, randomized controlled trials – those studies still need to happen.”
“Beyond that, we need to develop effective anti-inflammatory treatment strategies, and this will require a more precise understanding of the specific mechanisms causing inflammatory depression so that they can be targeted through treatments. Many of the medications we examined in our study have broad-acting effects on immune function and are associated with significant risks following long-term use, making them poorly suited to treat depression, which typically first occurs early in life.”
“Once we understand the immune-based mechanism, we can identify a medication that targets the underlying problem,” Mac Giollabhui added. “Ultimately, the hope is that we will be able to develop a suite of anti-inflammatory treatments – medications, naturally-occurring compounds, lifestyle interventions – that could be then used to treat inflammatory depression.”
The study, “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,” was authored by Naoise Mac Giollabhui, Annelise A. Madison, Melis Lydston, Emma Lenoel Quang, Andrew H. Miller, and Richard T. Liu.
