The kynurenine pathway in relation to depression and anhedonia symptom severity among women with HIV

The kynurenine pathway (KP) has been implicated in cytokine-induced depression and anhedonia, a core depression symptom. We examined KP metabolites in relation to depression and anhedonia symptom severity in women with and without HIV (WWH and WWoH).

Participants included 239 women (55% WWH, mean age 52 years). Depressive symptoms were measured using the Center for Epidemiologic Studies Depression (CES-D) scale and high depressive symptoms were defined as a score ≥16; anhedonia severity was quantified on two CES-D items. KP metabolites, including quinolinic acid (QA, NMDA receptor agonist) and kynurenic acid (KA, NMDA receptor antagonist), were measured using liquid chromatography-tandem mass spectrometry. Adjusted multivariable linear regression was used to compare metabolites among groups and to assess relationships of KP metabolites with anhedonia and depressive symptoms.

A greater proportion of WWH had high depression severity (CES-D ≥16) than WWoH (23% vs. 12%; p = .03). WWH with CES-D≥16 had greater QA compared to WWH with CES-D<16 (diff = 0.52 SD; p = .02). Using a dimensional quantitative approach, QA levels were positively associated with depressive ( $\beta$  = 0.25; p = .01) and anhedonia symptom severity ( $\beta$  = 0.24; p = .01) among WWH, but not in WWoH. Conversely, KA was inversely associated with anhedonia symptom severity in WWH ( $\beta$  = -0.20; p =.03) and WWoH ( $\beta$  = -0.23; p =.02).

This study extends understanding of the role of the KP in depression and anhedonia to WWH and suggests neuroactive metabolites as a possible underlying mechanism. The KP may affect reward neuro-circuitry through increased QA neurotoxicity and decreased KA neuroprotection.