Exploring the Relationship Between Inflammatory Biomarkers and Negative Symptoms Subtypes in Individuals at Ultra‐High Risk for Psychosis

Aims: Negative symptoms are a core component of schizophrenia, affecting up to 60% of individuals with the disorder. They are categorised into primary negative symptoms (PNS), which are intrinsic to the illness, and secondary negative symptoms, which arise from external factors such as depression or medication side effects. They can also be divided into diminished expression and amotivation/anhedonia subtypes. While inflammation has been implicated in schizophrenia and linked to negative symptoms, little is known about whether inflammatory profiles differ between negative symptom subtypes in individuals at Ultra‐High Risk (UHR) for psychosis.

Methods: We conducted a secondary analysis of 147 UHR participants from the Staged Treatment in Early Psychosis (STEP) study to examine whether inflammatory markers (Alpha‐2‐Macroglobulin, IL‐6, CRP, sICAM‐1, sVCAM‐1, and suPAR) differed across negative symptom subgroups, using multinomial and binomial logistic regression models adjusted for age, sex, smoking, and BMI.

Results: Overall, most inflammatory markers were not significantly associated with negative symptom subgroups. However, higher sICAM‐1 levels were associated with lower odds of primary negative symptoms compared with no negative symptoms. Additionally, younger age was associated with increased odds of PNS and amotivation, while smoking was associated with higher odds of secondary negative symptoms compared with no negative symptoms.

Discussion: These findings suggest that inflammation may not broadly distinguish negative symptom subtypes at the UHR stage, although sICAM‐1 may play a role in early illness processes. Limitations include sample ascertainment, potential misclassification of negative symptoms, and the relatively small number of participants with PNS. Future studies with larger samples and longitudinal designs are needed to clarify whether inflammatory changes contribute to the emergence of specific negative symptom subtypes.