Addressing the tuberculosis-depression syndemic to end the tuberculosis epidemic

Abstract

Tuberculosis (TB) and depression act synergistically via social, behavioral, and biological mechanisms to magnify the burden of disease. Clinical depression is a common, under-recognized, yet treatable condition that, if comorbid with TB, is associated with increased morbidity, mortality, community TB transmission, and drug resistance. Depression may increase risk of TB reactivation, contribute to disease progression, and/or inhibit the physiological response to anti-tuberculosis treatment because of poverty, undernutrition, immunosuppression, and/or negative coping behaviors, including substance abuse. Tuberculous infection and/or disease reactivation may precipitate depression as a result of the inflammatory response and/or dysregulation of the hypothalamic-pituitary-adrenal axis. Clinical depression may also be triggered by TB-related stigma, exacerbating other underlying social vulnerabilities, and/or may be attributed to the side effects of anti-tuberculosis treatment. Depression may negatively impact health behaviors such as diet, health care seeking, medication adherence, and/or treatment completion, posing a significant challenge for global TB elimination. As several of the core symptoms of TB and depression overlap, depression often goes unrecognized in individuals with active TB, or is dismissed as a normative reaction to situational stress. We used evidence to reframe TB and depression comorbidity as the 'TB-depression syndemic', and identified critical research gaps to further elucidate the underlying mechanisms. The World Health Organization's Global End TB Strategy calls for integrated patient-centered care and prevention linked to social protection and innovative research. It will require multidisciplinary approaches that consider conditions such as TB and depression together, rather than as separate problems and diseases, to end the global TB epidemic.

Figure 1

The tuberculosis-depression syndemic model. This image can be viewed online in color at http://www.ingentaconnect.com/content/iuatld/ijtld/2017/00000021/00000008/art000.…

Figure 2

Hypothesized mechanisms through which depression-related immunosuppression increases the risk of TB reactivation and/or weakens the physiological response to treatment. IDO = indoleamine 2,3-dioxygenase; Th = T helper; TB = tuberculosis.

Figure 3

Effects of M. tuberculosis hypothesized to promote excitotoxicity and reduced monoaminergic neurotransmission, leading to depression. Infection with M. tuberculosis activates expression of pro-inflammatory cytokines, which stimulate the production of kynurenine and its metabolites, quinolinic acid and kynurenic acid, with opposing effects on NMDA-Rs (right side of diagram), and may lower production of serotonin (5-hydroxytryptamine), dopamine, and norepinephrine (left side). Tryptophan and kynurenine cross the blood-brain barrier, and can undergo the metabolic steps pictured here in the periphery or central nervous system. Kynurenine can be converted to kynurenic acid in astroglia or to quinolinic acid in infiltrating macrophages and microglia. Quinolinic acid increases glutamate release and leads to lipid peroxidation, thus contributing to excitotoxicity, oxidative stress and, ultimately, neurodegeneration. TDO = tryptophan 2,3-dioxygenase; IDO = indoleamine 2,3-dioxygenase; PAH = phenylalanine 4-hydroxylase; KMO = kynurenine-3-monooxygenase (also known as kynurenine-3-hydroxylase); KAT = kynurenine aminotransferases; TPH = tryptophan hydroxylase; NMDA-R = N-methyl-D-aspartate receptor.