03. Anti-Inflammatory Agents: Can They Target Anhedonia in Depression?

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A few months ago on Quick Takes, we discussed the concept of an inflammatory subtype of depression and whether this might be something we see in a future edition of the DSM. We talked about the fact that up to 25% of adults with depression have elevated inflammatory markers including C-reactive protein (CRP) and that they may experience specific features of depression including prominent anhedonia, fatigue and psychomotor slowing. We mentioned that this subtype seems to respond less robustly to traditional antidepressants like SSRIs and SNRIs but may preferentially respond to mediators of dopamine activity.

In that episode, we touched briefly on the idea that anti-inflammatory medications can sometimes be helpful for patients with depression especially those displaying features of or other findings consistent with the inflammatory subtype. But I noted that the findings were inconsistent and it didn’t seem like there was yet enough evidence to suggest that anti-inflammatory medications were ready for primetime. Just a few months later, we start to make a little bit of progress there thanks to a recent meta-analysis published in the American Journal of Psychiatry. That’s the focus of today’s episode of Quick Takes.

Meta-Analysis Targeted Inflammatory Phenotype and Anhedonia

The meta-analysis we’re looking at today is fairly specific. It looked at anti-inflammatory treatments compared with placebo in patients with the inflammatory phenotype of depression and focused on reduced anhedonia specifically as an outcome as well as depressive symptom severity.

Those nuances are important because as the authors point out and as we highlighted last time, the results of a lot of the individual trials are mixed. The authors today argue that this is partly because many of those trials did not restrict enrollment to subjects with elevated inflammatory markers and did not specifically examine the response of symptoms like anhedonia most associated with inflammatory depression. In other words, anti-inflammatory treatments may not be effective for patients who don’t have the correct phenotype that they target.

In today’s meta-analysis, the authors included 14 studies total but focused on 11 that used a cut-off marker of a CRP greater than 2 mg/L for analysis. Four of these 11 studies also included anhedonia as an outcome measure. The authors additionally chose to focus on patients without medical comorbidities because prior meta-analyses have already suggested that anti-inflammatories are effective for depressive symptoms in certain medical populations like patients with rheumatoid arthritis.

Modest Improvement in Symptoms and Anhedonia

The main finding today is that anti-inflammatory drugs significantly reduce depressive symptoms and anhedonia with modest effect sizes though they did not affect treatment response defined as greater than 50% reduction in symptoms or depression remission rates.

Both the authors and an accompanying editorial make it clear that the findings are considered preliminary given the small number and heterogeneous nature of the studies, small sample sizes and modest effect sizes with wide confidence intervals. They emphasized that the outcomes in terms of depressive symptoms may be primarily driven by large effect sizes across a modest number of small-sample randomized controlled trials, and noted that the largest studies included in the meta-analysis actually reported very small effect sizes.

Improvement in anhedonia specifically, however, does seem more consistent across those four studies and demonstrated a larger effect size in the meta-analysis.

Multiple Anti-Inflammatory Agents Studied

One notable thing about the studies included in this meta-analysis is that they involved a lot of different anti-inflammatory agents:

• Five studies involved NSAIDs like celecoxib
• Five involved minocycline
• Four involved TNF inhibitors
• Others involved IL-6 inhibitors, mitogen-activated protein kinase inhibitors and recombinant IL-2

I was interested to see minocycline pop up in five of the studies because it has also been shown to be effective for catatonia in a small number of case reports. That was historically thought to possibly be due to some NMDA receptor antagonism but given the inflammatory hypothesis for catatonia and the success of minocycline here, I could imagine it could just as easily be due to anti-inflammatory properties.

Treatment duration in the studies included in this meta-analysis ranged from 2 to 12 weeks which is a pretty broad range. It’s also worth mentioning that the anti-inflammatory medications were used adjunctively rather than monotherapy in the vast majority of included studies.

Is Routine CRP Screening Warranted?

One question raised by this meta-analysis is whether we should be checking CRPs on all of our depressed patients and using them to guide potential treatment. The answer at least for now would seem to be no.

While CRP is associated with neuro-inflammation, it’s very nonspecific. It may not be stable and it tends to vary in a sex-specific manner making it non-ideal as a biomarker. The hope is to find a better inflammatory biomarker that is more reliable and specific to depression but we aren’t there yet.

For now, CRP does seem to be the best option but it has a lot of drawbacks and I don’t routinely check it in my depressed patients.

Anti-Inflammatory Agents for Clinical Use

The other big question would seem to be whether these anti-inflammatory agents are ready for primetime as treatment for depressed patients. Again, the answer seems to be no or at least in most cases not quite yet. Although the meta-analysis and prior studies have shown that they are well tolerated, we haven’t yet reached a stage of precision psychiatry where strategies such as these are ready to be deployed on a larger scale.

Now, I suppose you could make the argument that if you are managing a patient with treatment-resistant depression who seems to have the inflammatory subtype, has an elevated CRP above 2, has prominent anhedonia and has failed first- and second-line agents, it could be reasonable to consider a time-limited off-label trial of, say, celecoxib or minocycline as an adjunctive strategy. But I think you would really need to be thoughtful about patient selection and about explaining the risks, benefits and limitations of the evidence base.

You’d also want to have clear expectations that the target would be the anhedonia specifically and remember that anti-inflammatories have not been shown to improve response or remission rates in depression.

Understanding Anhedonia Conceptually

One final thing I took away from this meta-analysis and the accompanying editorial is a more nuanced understanding of anhedonia. The scales used in several of the studies to measure anhedonia examined specific nuanced features of the phenomenon.

• Anticipatory anhedonia is the inability to look forward to future hypothetical pleasure and it is thought to be related to dopamine-mediated reward prediction and motivation. Patients with anticipatory anhedonia can’t imagine themselves enjoying anything.
• Consummatory anhedonia is the inability to experience pleasure in the moment thought more related to hedonic circuits involving the opioid and endocannabinoid systems.

Anhedonia has other facets as well including elements of effort and motivation. It turns out that the most commonly used scale for anhedonia primarily examines consummatory anhedonia and excludes the other facets.

Distinguishing Anhedonia in its Multiple Dimensions

Understanding the full spectrum of anhedonia can provide us with a helpful framework to guide our questioning of patients around their ability to find pleasure. Demoralized patients, for example, typically do not endorse anticipatory anhedonia perhaps suggesting that their reward prediction systems remain intact though they may struggle with being hopeful enough to actually project themselves into a hypothetical pleasurable experience.

This could explain why they don’t tend to benefit from traditional antidepressants. It’s a great example of how understanding nuanced distinctions like these in terms of specific psychiatric symptoms helps elucidate neurobiology and may even help to guide our treatment selection one day.

For now, I’m excited to see how things play out with regard to anti-inflammatories and depression over the next few years and I would not be surprised to be back here down the line announcing that we are finally ready to start incorporating such treatments in a targeted fashion.

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

Naoise Mac Giollabhui, Ph.D., Annelise A. Madison, Ph.D., Melis Lydston, M.L.S., Emma Lenoel Quang, Andrew H. Miller, M.D., and Richard T.

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.

Reference

Mac Giollabhui, N.; Madison, A.; Lydston, M.; Lenoel Quang, E.; Miller, A. & Liu, R. (2026). 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. American Journal of Psychiatry; 183(1):70-79.