Inflammation and Depression: Rethinking What Drives Mood Disorders

By Dr. Styliani Spyridi , Consultant Psychiatrist

Could some forms of depression be driven not just by psychological or social factors, but by the immune system itself?

This is the provocative question explored in a recent randomized controlled trial by Savitz et al. (2025), published in the American Journal of Psychiatry. Their findings provide important insights into a biologically distinct subtype of depression—one linked to chronic low-grade inflammation—and open the door to targeted immunological treatments in psychiatry.

 The Study at a Glance

Savitz and colleagues conducted a double-blind, randomized trial involving 64 adults diagnosed with major depressive disorder (MDD). Participants were grouped based on baseline levels of C-reactive protein (CRP)—a biomarker of inflammation—into:

High-inflammation group (CRP ≥ 3 mg/L)

Low-inflammation group (CRP ≤ 1.5 mg/L)

Each group was then randomly assigned to receive either lipopolysaccharide (LPS)—a compound that induces acute immune activation—or a placebo (saline injection). LPS is known to provoke a transient inflammatory response, making it a useful experimental tool in psychoneuroimmunology research.

Participants were monitored over time for changes in:

Inflammatory markers (IL-6)

Anhedonia (measured by SHAPS)

Mood (via POMS and MADRS scales)

 What They Found

LPS administration led to a robust immune response in all participants, but the reaction was significantly stronger in the high-CRP group, with greater increases in IL-6 and body temperature.

Anhedonia symptoms increased significantly in the high-CRP group post-LPS, and this increase correlated with IL-6 levels, suggesting a direct link between inflammation and reduced capacity for pleasure.

Interestingly, depressive symptoms (MADRS scores) temporarily improved 24 hours after LPS in the high-CRP group. A similar effect was observed in a 1995 study by Bauer et al., possibly linked to alterations in REM sleep or neuroimmune feedback mechanisms.

The low-CRP group did not show notable changes in mood or inflammatory markers, suggesting that baseline inflammation may shape how the brain and body respond to immune stress.

 Clinical Reflections: Why This Matters

As a psychiatrist, these findings feel particularly relevant. Depression is not a monolith; we often observe patients who don’t respond to first-line treatments and exhibit symptoms such as anhedonia, fatigue, or cognitive slowing—often accompanied by metabolic or inflammatory markers in bloodwork.

This study supports the growing body of evidence that a subset of patients may have “inflammation-associated depression”—a biologically distinct condition marked by persistent low-grade inflammation. This subgroup may not respond well to SSRIs or SNRIs but could benefit from anti-inflammatory strategies, such as:

Cytokine inhibitors (e.g., IL-6 blockers)

Anti-inflammatory lifestyle interventions (diet, exercise, sleep hygiene)

Novel immunomodulatory agents currently in trials

It also raises important diagnostic questions: Should we routinely test CRP or other markers in treatment-resistant depression? Could inflammatory challenges like LPS be used clinically to identify responsive subtypes?

 Moving Toward Precision Psychiatry

Savitz et al.’s work highlights the urgent need for biologically informed subtyping of depression. While the study had limitations—such as a modest sample size and lack of a healthy control group—it lays crucial groundwork.

The use of LPS as a probe for immune-brain interaction is especially promising. It may help identify which patients have an exaggerated inflammatory-mood response, and who might benefit from personalized, immunologically targeted therapies.

This is not about replacing our current understanding of depression—but about refining it. For some patients, the missing piece of the puzzle may not lie in neurotransmitters alone, but in cytokines, immune dysregulation, and the body’s response to stress at a cellular level.

 Citation:

Savitz J, Figueroa-Hall LK, Teague TK, et al. (2025). Systemic Inflammation and Anhedonic Responses to an Inflammatory Challenge in Adults With Major Depressive Disorder: A Randomized Controlled Trial. American Journal of Psychiatry, 182(6), 560–568. https://doi.org/10.1176/appi.ajp.20240142