INTRODUCTION: Affective symptoms are prevalent features in people with multiple sclerosis (PwMS). Structural brain changes, as well as cytokine-driven synaptic and network alterations, might contribute to the development of these clinical features. In the present study, we evaluated the association between the cerebrospinal fluid (CSF) levels of the pro-inflammatory cytokine interferon-gamma (IFN-γ) at multiple sclerosis (MS) diagnosis and the subsequent development of depression and anxiety. METHODS: PwMS and a negative history for psychiatric disorders were recruited at MS onset. CSF IFN-γ concentrations were measured by Single Molecule Array. Socio-demographic and clinical information was collected, and all subjects underwent brain magnetic resonance imaging (MRI). After a mean follow-up time of 3 years, psychometric assessment was performed. Depressive symptoms were evaluated with the Beck Depression Inventory II, while the State and Trait Anxiety Inventory Y was used to assess anxiety symptoms. RESULTS: In our sample (n = 28), 21.4 % subjects suffered from clinically significant depression at follow-up, while the prevalence raised at 51.7 % for both state and trait anxiety. Subjects with clinically relevant depression presented greater disability levels at baseline (p = 0.020), as well as more severe state (p = 0.010) and trait (p <
0.001) anxiety at follow-up. Baseline IFN-γ concentrations were significantly higher in subjects who displayed clinically significant depression at follow-up (p = 0.037), an association that was not replicated for state and trait anxiety. No significant associations were found between brain MRI measures and psychiatric symptoms at follow-up. CONCLUSIONS: Proinflammatory cytokines might play a relevant role in the development of affective symptoms, particularly depressive, in PwMS. Their possible predictive value deserves further attention, possibly helping the early detection of at-risk subjects and the implementation of tailored treatments.