Immunopsychiatry, what a wonderful phrase.Immunopsychiatry, ain’t no passin’ craze.
Unlike Hakuna Matata, however, immunopsychiatry is far from a carefree philosophy. It is the study of how our immune system can influence our mental health (Jones H., 2026; Zwiep J., 2026), relevant to up to one-third of patients with depression (Osimo et al., 2019). While the field has advanced rapidly in recent years, important questions remain about how inflammation shapes behaviour, particularly those relevant to mental health.
A lack of motivation is a key feature of depression. Every day, our brains weigh up effort against reward, constantly deciding whether something is worth pursuing. But what if inflammation influences that calculation? The fatigue, social withdrawal, and reduced activity that often accompany a cold, flu, or a depressive episode are not random inconveniences; they are part of a coordinated response known as sickness behaviour, designed to support recovery (Hansson L., 2025; Lasselin J., 2025). In these moments, the body faces a difficult decision:
Should we continue pursuing rewards or conserve energy for recovery?
Understanding how inflammation influences this decision may help explain why motivation changes during both physical illness and mental health conditions like depression. While both acute and chronic inflammation have been linked to changes in behaviour, it remains unclear whether they affect motivation in similar ways.
Chat and colleagues (2026) brought these two processes together, exploring how different inflammatory states shape effort-based decision making and reward motivation, providing new insights into how inflammation may contribute to motivational symptoms in depression.
Methods
Chat et al. (2026) used a randomised, double-blind, placebo-controlled crossover design to study 35 young adults. All participants were free from current or previous medical or psychiatric disorders, with 14 classified as obese (BMI >30 kg/m²) and 21 as normal weight (BMI 18.5-25 kg/m²).
Everyone attended two visits, approximately 1-2 weeks apart, and received the following interventions in a random counterbalanced order:
Blood samples were collected to measure C-reactive protein (CRP; used alongside obesity as a marker of chronic low-grade inflammation) and interleukin-6 (IL-6; used as a marker of acute inflammatory response) levels. Approximately 2-3 hours after each injection, participants completed the Effort Expenditure for Rewards Task (EEfRT), which assesses willingness to expend effort for monetary reward through repeated choices between low-effort/low-reward and high-effort/high-reward tasks.
Statistical models were adjusted for age, study session, EEfRT trial characteristics (reward magnitude and probability), and, where appropriate, sex.
Results
Chronic low-grade inflammation and obesity
Participants with obesity had higher CRP levels than normal-weight participants, consistent with obesity being associated with chronic low-grade inflammation. Examining the placebo condition allowed the authors to assess obesity and chronic inflammation in the absence of an experimentally induced inflammatory response. They found that, in the placebo condition, people with obesity were less likely to choose the high-effort option than normal-weight participants (β = -3.11, 95% CI [-5.37 to -0.84], p = .007). This effect weakened in sensitivity analyses that excluded three influential participants, but the association remained.
Higher baseline CRP concentrations were also associated with fewer high-effort choices (β = -0.33, 95% CI [-0.65 to -0.02], p = .04), a finding that remained in sensitivity analyses. This means that those with evidence of inflammation in their blood appeared less willing to work harder for a reward.
These findings suggest that chronic low-grade inflammation may be associated with a reduced willingness to expend effort for reward. However, evidence that this effect was specific to smaller rewards was less convincing. While the main analyses suggested that people with obesity or higher CRP were particularly less likely to choose high-effort options for lower-value rewards, these interactions disappeared in sensitivity analyses. This suggests that the overall association between chronic inflammation and reduced effort was more robust than the idea that inflammation specifically alters responses to reward size.
Acute inflammation
Receiving LPS was not associated with changes in effort expenditure (β = 0.51, 95% CI [-0.65 to 1.67], p = .39). Similarly, higher IL-6 levels were not associated with fewer high-effort choices overall (β= 0.001, 95% CI [-0.001 to 0.002], p = .24).
However, those who experienced a greater inflammatory response appeared to behave differently when larger rewards were available. Specifically, higher IL-6 concentrations were found to reduce the influence of reward magnitude on decision making (β = -0.0004, 95% CI [-0.0006 to -0.0001], p = .01). This means that larger rewards were less effective at encouraging effortful behaviour among those with stronger inflammatory responses. This finding remained robust in sensitivity analyses.
The “double hit” hypothesis
But does low-grade inflammation amplify the behavioural effects of an acute immune challenge? In other words, is there a double hit?
The short answer is no.
Neither obesity status nor baseline CRP modified the relationship between IL-6 responses and reward motivation, meaning participants with evidence of chronic inflammation were no more susceptible to the motivational effects of acute inflammation than those without it.
Conclusions
The authors concluded that acute and chronic inflammation may affect reward-related behaviour in different ways, noting:
Lipopolysaccharide-induced and low-grade inflammation may alter how effort is allocated towards reward: low-grade inflammation reduced the willingness to expend effort, while acute inflammation dampened reward sensitivity.
Contrary to expectations, there was no evidence that low-grade inflammation amplified the behavioural effects of an acute immune challenge.
Overall, these findings suggest that different inflammatory states may shape motivated behaviour through distinct pathways, offering a more nuanced understanding of the relationship between inflammation and reward motivation. This may help inform future interventions targeting anhedonia and other reward-related symptoms.
Strengths and limitations
Strengths
This study has several notable strengths. The randomised, double-blind, placebo-controlled cross-over design is well suited to experimental immunopsychiatry because each participant acts as their own control, reducing confounding from individual differences and allowing stronger causal conclusions about experimentally induced inflammation.
The study also addresses an important gap in the literature by attempting to examine acute and chronic low-grade inflammation within the same sample. This allowed the authors to directly compare their associations with reward-related behaviour and test the proposed “double hit” hypothesis.
The use of the EEfRT is another strength. Rather than relying on broad symptom questionnaires, the authors examined a specific aspect of reward processing, providing a more precise measure of motivation that may be more closely linked to inflammatory mechanisms.
Limitations
However, as always, several limitations must be considered:
Sample size and statistical power
The study included just 35 participants, 14 of whom had obesity. While I can certainly relate to the recruitment difficulties in this field, the small sample limits statistical precision and makes interaction effects particularly difficult to detect. Consequently, the absence of evidence supporting the proposed “double hit” hypothesis may represent a true null finding, or it may reflect limited statistical power.
Acute vs chronic inflammation
As the authors note, baseline CRP is widely used as an index of chronic low-grade inflammation, but a single measurement cannot establish how long elevated inflammation has been present in any individual. Recruiting participants with and without obesity strengthens this rationale, as obesity is commonly associated with persistent low-grade inflammation, although not everyone with obesity experiences the same degree or duration of inflammatory activation.
Furthermore, while the effects of acute inflammation could be examined experimentally using the randomised LPS challenge, the obesity and baseline CRP analyses were necessarily observational because these characteristics cannot be randomised. Consequently, the observed associations cannot establish that inflammation itself caused the behavioural differences.
Generalisability
Participants were young, physically healthy, and free from psychiatric disorders. While this strengthens the experimental design, it also limits the extent to which the findings can be generalised to people with depression. Experimental endotoxaemia is a valuable model of acute immune activation, but it remains uncertain how closely a transient LPS challenge reflects the persistent low-grade inflammation often implicated in psychiatric disorders.
Implications for practice
This study is unlikely to change clinical practice. It does not suggest that inflammatory markers should be routinely used to assess reward motivation, nor does it provide evidence that anti-inflammatory treatments are ready for widespread use in depression.
However, the findings do have important implications for immunopsychiatry research and the development of future treatments. One of the most valuable aspects of this study is its focus on a specific component of reward processing rather than broad measures of depression or anhedonia. Symptoms such as fatigue, reduced motivation, anhedonia, and apathy are often discussed together despite likely reflecting distinct underlying processes. By examining willingness to expend effort for reward, the authors focused on a more specific behavioural process that may be particularly relevant to inflammation.
The findings also raise important questions about how we interpret changes in motivation. Reduced effort expenditure is often viewed as a deficit, but from an evolutionary perspective it may represent an adaptive response. If the immune system requires energy to fight infection or recover from injury, conserving resources and avoiding unnecessary effort may be beneficial. The challenge for future research is understanding when these responses remain adaptive and when they become persistent and maladaptive, potentially contributing to depression.
This study also highlights several priorities for future work. Larger studies are needed to evaluate the proposed “double hit” hypothesis and determine whether chronic inflammatory states increase vulnerability to the behavioural effects of acute immune activation. Repeated inflammatory measurements would help distinguish chronic low-grade inflammation from temporary fluctuations, while studies in clinical populations could clarify whether these findings generalise to depression. Future research should also continue moving beyond broad symptom measures and examine specific aspects of reward processing, motivation, and anhedonia that may be more closely linked to immune function.
Sickness forces the body to make decisions about where limited resources should be spent. This study suggests that inflammation may not eliminate motivation altogether but instead shifts how effort and reward are weighed against one another.
Unlike Hakuna Matata, immunopsychiatry cannot promise “no worries for the rest of your days”. However, studies like this are helping us better understand how the immune system shapes motivation, bringing hope that more targeted treatments may eventually become available for people who continue to struggle with depression.
Statement of interests
Éimear Foley is an editor at the Mental Elf. She also works in the field of immunopsychiatry as a Senior Research Associate at the University of Bristol. Éimear acknowledges connecting with two of the authors of this paper (I. Chat & L. Hansson) at previous scientific conferences and is currently working on an unrelated research project with another of the paper’s co-authors (M. Treadway). The senior author of the paper (J. Lasselin) was an examiner for Éimear’s PhD viva in 2024. These professional connections have not influenced her appraisal of this paper. ChatGPT assisted with language refinement and formatting.
Editor
Edited by André Tomlin.
Links
Primary paper
Iris Ka-Yi Chat, Lina S. Hansson, Mats Lekander, Charlotta Jacobsen, Sven Benson, Johannes Hebebrand, Vera Bender, Analena Handke, Till Hasenberg, Michael T. Treadway, Harald Engler, Robert Dantzer, Manfred Schedlowski & Julie Lasselin (2026). Obesity, low-grade inflammation, and inflammatory response to immune challenge modulate willingness to expend effort for reward. Brain, Behavior, and Immunity, 136, 106548. https://doi.org/10.1016/j.bbi.2026.106548
Other references
Hansson, L. (2025). Does the flu shot make you feel sick? What this randomised trial tells us about vaccine-induced inflammation. The Mental Elf.
Jones, H. (2026). Is atypical depression a clinically and genetically distinct subtype? The Mental Elf.
Lasselin, J. (2025). Putting oil on the fire: Do people with high inflammation react differently to immune stress? The Mental Elf.
Osimo, E.F., Baxter, L.J., Lewis, G., Jones, P.B. & Khandaker, G.M. (2019). Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels. Psychological Medicine, 49(12), 1958-1970. https://doi.org/10.1017/S0033291719001454
Zwiep, J. (2026). Targeting inflammation in depression: a proof-of-concept worth following. The Mental Elf.
