Reversal of the Kynurenine pathway of tryptophan catabolism may improve depression in ART-treated HIV-infected Ugandans.
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.


METHODS
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.
Priscilla
P
Martinez
Alexander C
AC
Tsai
Conrad
C
Muzoora
Annet
A
Kembabazi
Sheri D
SD
Weiser
Yong
Y
Huang
Jessica E
JE
Haberer
Jeffrey N
JN
Martin
David R
DR
Bangsberg
Peter W
PW
Hunt
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D003863:Depression / Q000188:drug therapy*; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007737:Kynurenine / Q000097:blood / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D010949:Plasma / Q000737:chemistry; D016896:Treatment Outcome; D014364:Tryptophan / Q000097:blood / Q000378:metabolism*; D014454:Uganda
C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan