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

Martinez, Priscilla MPhil, PhD*,†; Tsai, Alexander C. MD, PhD‡,§; Muzoora, Conrad MBBCh, MMed; Kembabazi, Annet BA; Weiser, Sheri D. MD, MPH; Huang, Yong PhD; Haberer, Jessica E. MD, MS; Martin, Jeffrey N. MD¶,#; Bangsberg, David R. MD, MPH‡,‖,**,††,‡‡; Hunt, Peter W. MD¶,#

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 1st, 2014 - Volume 65 - Issue 4 - p 456–462
doi: 10.1097/QAI.0000000000000062
Clinical Science

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: Indoleamine 2,3-dioxygenase-1-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.

*Norwegian Center for Addiction Research, University of Oslo, Oslo, Norway;

Alcohol Research Group, School of Public Health, University of California, Berkeley, CA;

Center for Global Health, Massachusetts General Hospital, Boston, MA;

§Division of Global Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA;

Mbarara University of Science and Technology, Mbarara, Uganda;

University of California at San Francisco, San Francisco, CA;

#Division of HIV/AIDS, San Francisco General Hospital, University of California San Francisco, CA;

**Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA;

††Department of Global Health and Population, Harvard School of Public Health, Boston, MA; and

‡‡Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Boston, MA.

Correspondence to: Priscilla Martinez, MPhil, PhD, Alcohol Research Group, University of California, Berkeley, 6475 Christie Avenue, Suite 400, Emeryville, CA 94608-1010 (e-mail:

The Uganda AIDS Rural Treatment Outcomes Study was funded by US National Institutes of Health (NIH) R01MH054907 and P30AI27763, and the Sullivan Family Foundation.

Presented at the 19th Conference on Retroviruses and Opportunistic Infections, March 6, 2012, Seattle, WA.

The authors have no conflicts of interest to disclose.

P.M. and A.C.T. contributed equally to this work.

Received July 18, 2013

Accepted November 03, 2013

© 2014 by Lippincott Williams & Wilkins