Think back to the last time you had the flu or COVID-19. You probably felt exhausted, unmotivated, withdrawn – and maybe even miserable and depressed?
These symptoms are not caused by the virus, but are triggered by your own body. When immune cells detect an infection, they trigger an inflammatory response, releasing cytokines (i.e., proteins that coordinate the immune response). Cytokines also signal the brain, causing various changes in brain functions and triggering a reorganisation of your behaviours to promote rest, including fatigue, social withdrawal, and loss of interest in daily activities (Lasselin J., 2021).
These symptoms help preserve the body’s energy so that your immune system can use it for immune defence. The sickness feelings are thus normal and probably helpful responses, when restricted to the short-lived, common acute infections (Dantzer R., 2023).
But what if this response occurs in someone already psychologically vulnerable, such as a person with major depressive disorder?
Inflammation is now recognised as a risk factor for depression (e.g., Tsang R., The Mental Elf, 2025; Kappelmann N. et al., 2021). In fact, inflammation-associated depression is considered a biological subtype of depression, found in about one-quarter of people with major depression. It is characterised by chronic, low-level inflammation, and often does not respond well to standard antidepressant treatment (Haroon E. et al., 2018). This calls for the development of new therapies that will target inflammation-related processes (Lawson K., The Mental Elf, 2024).
But a major challenge remains: how can we reliably identify individuals with this form of depression? A promising strategy may involve evaluating individuals’ vulnerability to inflammatory challenges (Lasselin J. et al., 2021) – an avenue recently explored by Savitz and colleagues (2025).
Inflammation induces behavioural changes and negative mood that can help fight infections, in short-lived common infections. But when chronic, it can also negatively affect mood and behaviour persistently. How can we reliably identify individuals with inflammation-associated depression?
Methods
Savitz et al. conducted a double-blind, randomised controlled trial (pre-registration: NCT03142919) with 64 adults diagnosed with major depressive disorder, split into groups based on their levels of an inflammatory protein called C-reactive protein (CRP): high (CRP≥3 mg/L, n=26) vs low (CRP≤1.5 mg/L, n=38) inflammation. Within each group, half of the participants received an intravenous injection of lipopolysaccharide (LPS; 0.8 ng/kg), and the other half received an intravenous injection of saline (placebo).
LPS is a component of gram-negative bacteria and has been repeatedly used to temporarily activate the immune system. It induces the release of cytokines in the body, which in turn induces a state of acute inflammation for a few hours and allows us to study the brain and behavioural effects of inflammation (Schedlowski M. et al., 2014).
Psychological and inflammatory outcomes were assessed at multiple time points post-injection. Anhedonia was assessed using SHAPS (Snaith Hamilton Pleasure Scale), and other mood symptoms were assessed with the POMS (Profile of Mood State). Depressive symptoms were also assessed using MADRS (Montgomery-Åsberg Depression Rating Scale).
Results
Effect of LPS on immune proteins
As expected, LPS administration triggered an acute increase in the blood concentrations of the inflammatory cytokine interleukin-6 (IL-6), which returned to baseline 6h post-injection. No such change was observed in the placebo condition.
This inflammatory response was significantly stronger in individuals with elevated CRP before LPS injection, compared to the low-CRP group. In the high-CRP group, the IL-6 increase was also accompanied by a rise in body temperature (from ~97.5°F (36.1°C) to ~99°F (37.2°C) on average), whereas no significant change in body temperature occurred in the low-CRP group.
Effect of LPS on psychological outcomes
At baseline, anhedonia scores (SHAPS) were elevated, in line with scores found in patients with major depressive disorder (Trøstheim M. et al., 2020). These scores increased further following LPS administration, while no change in scores was seen in the placebo condition. The LPS-induced increase in anhedonia scores was greater in the high-CRP group and also correlated with IL-6 levels. POMS scores did not significantly differ between groups, though a slight increase was observed for the fatigue score in this group.
Interestingly, depressive symptoms (MADRS) decreased 24 hours post-LPS administration in the high-CRP group only, suggesting a transient antidepressant effect. Such an effect was also observed in the only previous study using LPS administration in individuals with depression (Bauer J. et al., 1995). However, a similar short-term drop in MADRS scores was observed 6 hours after placebo in the high-CRP group only.
LPS triggered an inflammatory response and mood changes in those with higher baseline inflammation, including stronger anhedonia symptoms acutely post-LPS, and a brief drop in depressive symptoms the day after receiving LPS.
Conclusions
The findings of Savitz et al. found that individuals with depression and elevated CRP levels exhibited heightened IL-6 and anhedonic responses to acute immune activation, compared to individuals with depression and lower levels of CRP.
These results lend support to the existence of an inflammation-associated subtype of depression, which may be biologically primed to react more strongly to acute inflammatory stimuli. The study also highlights the potential of experimental immune challenges, such as LPS administration, as a tool for identifying individuals with inflammation-associated depression. Notably, the transient antidepressant effect observed one day after LPS exposure warrants further investigation.
The study suggests that people with depression and high inflammation may react more strongly to immune stress, pointing to a distinct subtype that could benefit from targeted treatment.
Strengths and limitations
This study is the first to investigate the acute immunological and psychological effects of experimental inflammation in individuals with major depressive disorder. Despite its inherent challenges, the trial was rigorously conducted, pre-registered, and employed stringent exclusion criteria. By using an immune challenge to probe physiological and psychological vulnerability, the study advances both the field of immunopsychiatry and the application of experimental inflammation for investigating mechanisms underlying inflammation-associated depression.
Nevertheless, several limitations should be considered. As acknowledged by the authors, the sample size was relatively small – though typical for LPS studies given the strong effect sizes and logistical complexity involved. Still, larger cohorts would improve statistical power to detect group differences in LPS-induced responses and improve the generalisability of findings.
A major limitation is the absence of a healthy control group receiving LPS. Without this comparison, it remains unclear whether the high-CRP group exhibited a heightened response or if the low-CRP group showed a blunted one – as suggested by their lack of body temperature response. This distinction could significantly affect the interpretation of the findings.
Another challenge concerns the classification of inflammation based on CRP levels. CRP concentration is influenced by numerous other factors (e.g., Horn S.R. et al., 2018), and the extent to which these were accounted for is unclear. Repeated sampling could help confirm persistent low-grade inflammation. Moreover, whether CRP is an adequate proxy for inflammation remains debated (e.g., Del Giudice & Gangestad, 2018).
Finally, the specificity of the psychological response to LPS in individuals with inflammation-associated depression warrants further exploration. Is the effect limited to anhedonia, or might it extend to other affective domains such as anxiety, or to other aspects of sickness behaviour like fatigue? To better characterise inflammation-associated depression, future studies should include a broader psychological symptom profile using additional self-report tools and behavioural assessments.
This well-controlled, pioneering study explores immune effects in depression, but it is limited by a relatively small sample size and lack of a healthy control group for comparison.
Implications for practice
If you think back to how you felt when you had the flu or COVID-19, and compare that to how others respond – you might notice how these responses vary? In my experience conducting LPS studies, participants show markedly different responses to the same immune challenge. One of the clearest differences is emotional reactivity: while some exhibit minimal emotional impact, despite sometimes strong somatic symptoms, others report distress, anxiety, and negative mood (Lasselin J., 2021). The study by Savitz et al. highlights the value of the model of LPS administration in exploring the factors that underlie these inter-individual differences, to provide insights into what might underlie susceptibility to inflammation-associated depression (Lasselin J., 2021; Lasselin J. et al., 2021).
Importantly, the findings by Savitz et al. reinforce the idea that major depressive disorder comprises distinct subtypes, with inflammation-associated depression likely driven by different biological mechanisms than other forms. As the authors note, developing targeted immunomodulatory treatments will require careful stratification of patients (e.g. Khandaker G.M. et al., 2018). Colleagues and I argue that LPS administration may even serve as a useful tool for identifying those most likely to benefit from such therapies (Lasselin J., et al. 2021).
Finally, the transient antidepressant effect of LPS observed in patients with depression and low-grade inflammation is particularly intriguing. A similar effect was reported in an earlier study (Bauer J. et al., 1995), where the authors suggested that a pronounced reduction in REM sleep following LPS administration might be a contributing mechanism. This warrants further investigation as a potential pathway in the development, or treatment of inflammation-associated depression.
People respond very differently to immune challenges, especially in emotional impact, and studies like Savitz et al.’s help reveal how these differences may explain distinct types of depression linked to inflammation and guide targeted treatments.
Statement of interests
I served as a reviewer of this manuscript prior to its publication in the American Journal of Psychiatry.
I am an expert in the use of the lipopolysaccharide (LPS) administration model in humans and have conducted multiple studies employing this approach. A central focus of my research is understanding inter-individual differences in sickness behaviour.
To refine the writing of this piece, I used ChatGPT to help improve clarity and style after drafting the initial text.
Links
Primary paper
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. Am J Psychiatry 2025 182(6) 560-568. doi: 10.1176/appi.ajp.20240142
Other references
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Kappelmann N, Arloth J, Georgakis MK, et al (2021). Dissecting the Association Between Inflammation, Metabolic Dysregulation, and Specific Depressive Symptoms: A Genetic Correlation and 2-Sample Mendelian Randomization Study. JAMA Psychiatry 2021 78(2) 161-170. doi: 10.1001/jamapsychiatry.2020.3436
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