Reversal of the Kynurenine Pathway of Tryptophan Catabolism May Improve Depression in ART-Treated HIV-Infected Ugandans

Abstract

Background Major depressive disorder is highly prevalent among HIV-infected persons, and depression symptom severity improves during the course of HIV antiretroviral therapy (ART). The potential biologic pathways explaining these phenomena remain unclear. We investigated the extent to which ART-mediated suppression of the kynurenine pathway of tryptophan catabolism (via indoleamine 2,3-dioxygenase-1 and potentially other sources) may correlate with improvements in depression symptom severity in this setting. Method We used the first year of data from the Uganda AIDS Rural Treatment Outcomes Study, a prospective cohort of 504 HIV-infected individuals initiating their first ART regimen in rural Uganda. We fitted random-effects regression models to estimate the associations between plasma tryptophan, plasma kynurenine, dietary diversity, and self-reported depression symptom severity. Results Greater depressive symptoms were associated with both lower plasma tryptophan and higher plasma kynurenine/tryptophan (KT) ratio over 12-month follow-up. In multivariable-adjusted models, declines in KT ratio and increases in plasma tryptophan levels partially explained ART-mediated improvements in depressive symptom severity. The association between KT ratio and depression symptom severity was stronger among persons with protein-deficient diets than among those with protein-rich diets. Conclusions IDO-mediated tryptophan catabolism may contribute to depression symptom severity among HIV-infected individuals, particularly among those with poor dietary protein intake. ART-mediated improvements in depressive symptom severity may also be at least partially mediated by immunologic mechanisms. Interventions to reduce immune activation, and dietary protein supplementation, may be promising strategies to further reduce depression in this setting.

Socioeconomic Gradients in Internalized Stigma Among 4,314 Persons with HIV in Sub-Saharan Africa

“…Consistent with insights derived from social stress theory [17] and modified labeling theory [5,18,19], internalized stigma among persons with HIV has been associated with isolation and depression [20–23], as well as failure to link to care [24]. These findings are consistent with the elevated prevalence of depression in this vulnerable population [25] and are extremely problematic given the well-known relationships between depression, treatment adherence, and poor health outcomes [26–28]. Among persons with HIV engaged in care, stigma has also been described as a major barrier to treatment adherence and retention in care [29,30].…”

Addressing the tuberculosis–depression syndemic to end the tuberculosis epidemic

“…37 An alternative hypothesis is that inflammation-associated depression may stem from neurotoxic metabolites of Trp via the Kyn pathway, particularly quinolinic acid (QUIN), an agonist of the N-methyl D-aspartate (NMDA) receptor. 34,38,39 This hypothesis is supported by findings showing depressive symptoms in patients administered therapeutic cytokines to correlate with higher levels of Kyn and QUIN in blood and cerebrospinal fluid (CSF), 40 and lower blood proportions of a neuroprotective Kyn metabolite, the NMDA antagonist kynurenic acid (KA). 38 …”

“…As an alternative to the 5-HT-depletion hypothesis, inflammation-associated depression may stem from immunosuppressive and neurotoxic metabolites of Trp via the Kyn pathway, KA and QUIN, which are respectively antagonist and agonist to the NMDA receptor. 34,38,39 The relevance of IDO and the Kyn pathway for depression in the context of tuberculous infection is instantiated by a mouse model in which TB vaccination with bacille Calmette-Guérin (BCG), an attenuated form of TB, induces IDO activation and triggers chronic depressive-like behaviors via the Kyn pathway, whereas knockout mice lacking IDO do not develop depressive-like behaviors. 41 Similarly, if inflammation is induced in mice by lipopolysaccharide administration, depressive-like behaviors can be prevented by pretreatment with IDO blockers.…”

Quinolinic acid/tryptophan ratios predict neurological disease in SIV-infected macaques and remain elevated in the brain under cART

“…Such deficits may contribute to the incidence of mood disorders such as depression that are commonly seen in HIV-infected patients (Heaton et al 2010; Ances and Ellis 2007; Chibanda et al 2014). Others have reported modest associations between KP activation and depression, both in hepatitis C-infected individuals treated with IFNα/ribavirin therapy (Raison et al 2010) as well as in HIV-infected individuals before and during cART (Martinez et al 2014). However, we did not find a significant correlation between QUIN/TRP ratios and striatal serotonin levels in our chronically infected animals.…”