DOI: 10.1002/JLB.

MR0119-023R

REVIEW

The interplay between depression and tuberculosis

Kehong Zhang1,2 Xin Wang1 Jie Tu3 Han Rong4 Oliver Werz2
Xinchun Chen1

1 Guangdong Provincial Key Laboratory of

Regional Immunity and Diseases, Department of Abstract

Pathogen Biology, Shenzhen University School
of Medicine, Shenzhen, China
2 Department of Pharmaceutical/Medicinal
Chemistry, Institute of Pharmacy,
Friedrich-Schiller-University Jena,
Jena, Germany
3 The Brain Cognition and Brain Disease Institute
(BCBDI), Shenzhen Institutes of Advanced
Technology, Guangdong Provincial Key
Laboratory of Brain Connectome and Behavior,
Chinese Academy of Sciences, Shenzhen, China
4 Shenzhen Kangning Hospital, Shenzhen Mental
Health Center, Shenzhen, China
Correspondence
Dr. Xinchun Chen, Guangdong Provincial Key
Laboratory of Regional Immunity and Diseases,
Department of Pathogen Biology, Shenzhen Uni-
versity School of Medicine, Shenzhen 518054,
China.
Email: chenxinchun@szu.edu.cn
Depression is a major mental health condition and is expected be the most debilitating and
widespread health disorder by 2030. Tuberculosis (TB) is also a leading cause of morbidity
and mortality worldwide and interestingly, is a common comorbidity of depression. As such,
much attention has been paid to the association between these 2 pathologies. Based on clinical
reports, the association between TB and depression seems to be bidirectional, with a substan-
tial overlap in symptoms between the 2 conditions. TB infection or reactivation may precipitate
depression, likely as a consequence of the host’s inflammatory response and/or dysregulation
of the hypothalamic–pituitary–adrenal axis. Nevertheless, few studies have considered whether
patients with depression are at a higher risk for TB. In this review, we discuss the hypotheses on
the association between depression and TB, highlighting the immuno-inflammatory response and
lipid metabolism as potential mechanisms. Improving our understanding of the interplay between
these 2 disorders should help guide TB clinical care and prevention both in patients with comorbid
depression and in the general population.
KEYWORDS
depression, tuberculosis, Mycobacterium tuberculosis, inflammation, lipid metabolism,
antidepressant therapy

1 INTRODUCTION ence, resulting in higher rates of morbidity, mortality, drug-resistance,

Tuberculosis (TB) is a chronic inflammatory disease caused by
Mycobacterium tuberculosis (Mtb) infection; it poses a substantial threat
to human health, with >10,000,000 cases of active TB, and 1,700,000
deaths reported in 2018.1 Comorbid mental illness is a notable,
unrecognized challenge to TB care and prevention, particularly in
high-burden countries. Indeed, numerous reports have identified a
high rate of mental illness, including depression and anxiety, among
patients with TB.2–4 As such, there has been an increasing focus on
the interplay between mental illness, including depression and chronic
anxiety, and TB.5 Those living with comorbid TB and depression are at
a greater risk of poor health-seeking behaviors and medication adher-
Abbreviations: AA, arachidonic acid; BDNF, brain-derived neurotrophic factor; CRP,
C-reactive protein; HPA, hypothalamic-pituitary-adrenal axis; LXA4 , lipoxin A4 ; MIF, M𝜙
migration inhibitory factor; MMP, matrix metalloproteinase; Mtb, Mycobacterium tuberculosis;
NALP3, NACHT, LRR, and PYD domains-containing protein 3; PPAR-𝛾, peroxisome
proliferator-activated receptor-gamma; PRRs, pattern recognition receptors; PTB,
pulmonary tuberculosis; PUFA, polyunsaturated fatty acid; TB, tuberculosis; TREG cells,
regulatory T cells.
and ongoing disease transmission.6,7 Additionally, several anti-TB
drugs, including isoniazid and cycloserine, may precipitate depression,
anxiety, or psychosis.8,9 How depression increases the risk of TB,
and reciprocally, whether TB infection or reactivation may lead to
depression remains to be elucidated. This review considers our current
understanding of the inflammatory, immune, and lipid metabolism
changes involved in depression and TB. We hypothesize that depres-
sion might increase TB susceptibility and antidepressant drugs might
be useful for TB treatment as host-directed therapy candidates (Fig. 1).
2 ASSOCIATION BETWEEN DEPRESSION
AND TB
2.1 Prevalence of depression in patients with TB
In 2017, the World Health Organization (WHO) reported that
>300 million individuals, across all age groups, are living with
depression.10 At its worst, depression can lead to death due to suicide.

Received: 19 February 2019 Revised: 19 May 2019 Accepted: 7 June 2019

J Leukoc Biol. 2019;1–9. www.jleukbio.org 2019
c Society for Leukocyte Biology 1
2 ZHANG ET AL .

Adverse effects of anti-TB medication

Non-adherence to treatment

Social: Biological: Behavioral:

✓ Stigma ✓ Malnutrition ✓ Smoking history
✓ Marital status ✓ Immune ✓ Drug abuse
✓ Low income modulation
Depression Tuberculosis
Risk factors F I G U R E 1 Interplay between depression
and TB. TB, tuberculosis
1. Increased inflammatory response
Biological? 2. Immunosuppression
3. Alteration of lipid metabolism

Antidepressant therapy?

✓ Improvement of TB outcome
✓ Reduction of depression co-morbidity

The prevalence of depression is high among individuals with chronic
diseases11–14 : in particular, psychiatric morbidities are common in
patients with TB.15–18 Depression is one of the most frequently
reported inter-current mental disorders in patients with TB,18,19
particularly for individuals diagnosed with posttraumatic stress
disorder.20 Furthermore, the prevalence of depression in patients with
TB is reportedly more than 3 times higher than in “healthy” patients
without TB.3,7,21 Several cross-sectional studies have shown that the
rate of depression among patients with TB > 35 years old is as high
as 40–70%,22,23 with an even higher rate in patients >65 years, and
patients with lower income and education.18,24,25 Studies from Peltzer
et al. and Aamir et al. reported that the prevalence rates of depression
among patients with TB in low-income countries ranged between 46%
and 80%.18,19
2.1.1 Risk factors
The risk factors for depressive symptoms in TB vary by age, patient
demographics and modifiable lifestyle factors. Such risk factors include
marital status, namely divorce18,26 ; dyspnea and other clinical symp-
toms of pulmonary tuberculosis (PTB) or other chronic respiratory
diseases27,28 ; social pressures or stigma following a diagnosis of TB
among young individuals24 ; low income25,29 ; and smoking history.17,30
Interestingly, it is unclear whether or not alcohol consumption is a risk
factor for depression in TB.31,32 However, no risk factors specific to
TB that are associated with comorbid depression have been identified
in patients with TB.19,33 A prospective controlled trial in India found
that psychological intervention significantly improved compliance of
anti-TB treatment.34 Such data suggest that further investigation into
the risk factors and/or mechanisms underlying comorbid depression in
patients with TB is warranted. A number of factors, including social
stigmatization, financial situation, malnutrition, human immunodefi-
ciency virus (HIV)-coinfection during treatment, and TB misconcep-
tions and treatment adherence are associated with a lower chance of
recovery from TB.35–38 Adherence itself is influenced by the type of
regimen-specific setting, financial status, social and behavioral factors,
and the presence of caregivers,39,40 but many now consider that it may
be strongly mediated by the effects of comorbid depression.19,41
Reciprocally, the high prevalence of depression among patients with
TB may be associated with non-adherence to TB treatment because
of adverse effects.42,43 Several medications used in TB treatment
have notable adverse psychiatric effects.5,44 while others, such as
rifampicin, can reduce the effective dose of anti-psychotics.5 Clearly,
the coexistence of depression and TB complicates the diagnosis and
management of these 2 diseases, as they may influence each other
and change the clinical process,45 and efficient drugs that do not elicit
adverse effects are urgently required.
2.2 Prevalence of TB in patients with depression
Many studies have elucidated an association between depression
and subsequent risk of TB.46,47 A nationwide database conducted
by researchers in Korea revealed that patients with depression
were at 2.63-fold higher risk of contracting TB. Most interestingly,
they found that the relationship between the 2 conditions showed
a dose-response, whereby patients with more severe depression
were at a higher risk of contracting TB than patients with less severe
depression.48 Similarly, a cohort study conducted in Taiwan reported
that the incidence of PTB was 1.16-fold higher in those with depression
than those without depression.49 Others have suggested that latent TB
infection may pose a significant risk for progression to active TB in indi-
viduals with mental illness, together with poor nutrition or crowded
living conditions.47 It also seems that negative coping behaviors in
those suffering from depression such as substance abuse and miscon-
duct associate with a higher incidence of TB not only through latent
TB reactivation, but also by delaying seeking clinical treatment.50
2.2.1 Comprehensive nursing
Mental health is a core component of a patient’s overall well-being.
Consequently, mental-health support is considered in the WHO End
TB strategy and Zero TB.51,52 Many countries, including the UK,
ZHANG ET AL .
Germany, and Australia, rely on patient-reported outcomes and have
focused several medical interventions and health policy decision-
making in TB patients.53 Such health interventions include the
development of social protection and patient-centered care comprise
comprehensive nursing, which can help to reduce negative mood and
can potentially promote rapid recovery in patients with TB and comor-
bid depression. Therefore, in addition to developing efficient depres-
sion treatments to decrease adverse effects, more data are required
on specific comorbid mental disorders with TB to develop better inter-
ventions. Of note, combined TB drug treatment with nursing care may
be efficient in improving TB outcomes by intervening on depression.
2.2.2 Antidepressants
Some experts consider that patients with comorbid depression and
chronic disease can benefit from antidepressant treatment.54–56 How-
ever, efficient pharmacological treatments for these affected patients
are lacking, and is thus an important issue for patients and society.57
The beneficial effects of adjunctive antidepressant therapy in anti-TB
treatment was noted in the early 1960s, when a low dose of chlorme-
thiazole was described to have an anti-mycobacterial inhibitory
effect.58 Chlopromazine was then later reported to also have anti-
TB activity in vitro.59 Phenothiazines and thioridazine have also been
investigated for their favorable combined antidepressant and anti-TB
effects in mice and preclinical studies.60–62 Another antidepressant
drug, trifluperazine, has also been shown to have a potential role in
anti-TB treatment.63 Aditionally, one study conducted in Peru showed
that psychotherapy with adjunctive psychotropic medications in the
anti-TB treatment of patients with MDR-TB resulted in improved treat-
ment adherence, completion, and social rehabilitation compared to
patients treated with anti-TB treatment alone.64 Today, linezolid is
an effective first-line anti-TB treatment that has been reported as a
monoamine oxidase inhibitor with antidepressant properties.65,66
2.2.3 Immune modulation
Antidepressant therapy has been associated with altered immune
functions.67 For example, previous meta-analyses have indicated that
antidepressant drugs treatment may decrease circulating levels of
IL-1𝛽 and IL-6, TNF-𝛼, and the C-C motif ligand 2 chemokine.68–71
However, considering the high degree of heterogeneity in those pro-
inflammatory mediators, it is difficult to conclude whether antide-
pressant drugs contribute or not to the therapeutic benefits through
immuno-inflammatory pathways.71,72 Other studies have reported
that IL-2 and IL-6 function in regulating monoamine neurotransmitters
or the hypothalamic–pituitary–adrenal axis, which leads to an imbal-
ance to the nerve–endocrine–immune network and aggravation of
depressive symptoms.73,74 Taken together, novel and effective antide-
pressant drugs that target the immune system may also be beneficial in
comorbid depression and TB.
Clearly the integration of mental healthcare (including nursing and
antidepressant drugs) into primary-care settings and specifically, into
TB treatment regimens, has the potential to improve outcomes in
patients with TB and comorbid depression.
3
3 POTENTIAL MECHANISMS UNDERLYING
INCREASED TB SUSCEPTIBILITY
IN DEPRESSION
Increased susceptibility to TB may originate from effects of depression
on the immune response. These effects represent a source of systemic
stress (including acute and chronic stress) that impacts on the brain
and modifies various neuroendocrine and behavioral functions. Here,
we focus primarily on chronic stress, which is typically associated
with depression.75 Activation of the inflammatory response in TB may
elevate cytokine levels and induce depressive symptoms,76 which we
consider may lead to the possible aggravation of TB infection or reac-
tivation. The interplay between lipid metabolism, lipid homeostasis,
depression, and Mtb in the host also creates a complex and dynamic
stress/pathogen–host interaction. Increasing our understanding of
the interplay between depression and TB in the inflammatory and
immune response and in lipid metabolism may provide insight into
how depression increases TB and a subsequent intervention strategy
for TB treatment. We discuss these relationships below.
3.1 Increased inflammatory responses mediating
the depression-TB axis
3.1.1 Pro-inflammatory cytokines
In patients with major depressive disorder, pro-inflammatory
cytokines and their receptors, acute phase proteins, chemokines,
and soluble adhesion molecules are increasingly expressed at the
early stage and released in peripheral blood and cerebrospinal fluid.77
A study from Miller AH et al. suggested that increased levels of
peripheral blood IL-1𝛽, IL-6, TNF-𝛼, and C-reactive protein (CRP)
are reliable biomarkers of inflammation in patients with depressive
symptoms.78 In addition, polymorphisms in those inflammatory
cytokine genes are associated with depression and the need for
antidepressant treatment.79 Studies in rodents have demonstrated
that low expression of brain-derived neurotrophic factor (BDNF) is
induced by depressive-like behaviors, which are in turn associated with
high expression of IL-1.80 IL-1 is a major counter-regulatory class of
inflammatory cytokines that controls the outcome of Mtb infection.81
3.1.2 NALP3 inflammasomes
Mtb activates the NACHT, LRR, and PYD domains-containing pro-
tein 3 (NALP3) inflammasome complex, which leads to caspase-
1 activation.82 Caspase-1 cleaves cytosolic pro-IL-1𝛽 and releases
mature IL-1𝛽 (a pro-inflammatory mediator).83,84 The NALP3 inflam-
masome is involved in the early control of Mtb replication.85,86 IL-1𝛽 is
also associated with neutrophil recruitment and fibroblast activation—
changes that are associated with severe lung damage.87,88 Although
the production of NLRP3- and caspase-1-independent IL-1𝛽 that is
promoted by Mtb can control PTB in NLAP3-deficient mice,85 the
overproduction of IL-1𝛽 due to depression has a negative impact on
inflammatory response,78 which may increase TB progression. TNF-𝛼
and IL-1𝛽 levels also positively correlate with the extent of pulmonary
involvement and the presence or size of tuberculous cavities.89,90 Both
4 ZHANG ET AL .
TNF-𝛼 and IL-1𝛽 also affect matrix metalloproteinase (MMP) secre-
tion; in turn, MMP release can activate or inactivate TNF-𝛼 and IL-1𝛽
production.91 Taken together, the overproduction of pro-inflammatory
cytokines may predispose to excessive inflammatory response.92
Excessive inflammation is detrimental to the host and consequently
results in TB progression, which promotes the recruitment of addi-
tional Mtb-permissive cells, cell death, and extracellular replication of
the bacilli.93
3.1.3 M𝝓 migration inhibitory factor
There has been increasing interest in the role of the pro-inflammatory
protein M𝝓 migration inhibitory factor (MIF) in depression and TB.94,95
MIF is an important regulator of innate immunity that is secreted pri-
marily by M𝝓s and T cells.96 This factor inhibits M𝝓 migration and pro-
motes the gathering, infiltration, and proliferation of M𝝓s at inflam-
matory sites. Furthermore, MIF helps induce inflammatory cytokine
production and is released in response to glucocorticoids.97 MIF also
seems to be critically involved in neurogenesis, and genetic deletion
of MIF in mice increases depression-like behaviors98 ; this phenotype
can be rescued upon recombinant MIF protein delivery.99 Finally, com-
monly occurring low-expression MIF alleles confer an increased risk of
TB in certain populations.100 Together, MIF seems to be a crucial medi-
ator in the innate immune response to Mtb: decreased MIF expression
in patients with depression increases susceptibility to TB by dysregu-
lating the inflammatory response. Further studies that clarify the exact
mechanism of how MIF elicits its function to affect TB progression are
now needed.
Overall, the increased production of pro-inflammatory cytokines
as a result of depression may predispose an excessive inflammatory
response, through which Mtb is more permissive to replicate. This
process, overall, leads to the development of TB.
3.2 Depression suppresses protective immunity
against TB
The potential role of the innate immune system in the pathophysiology
of major depression and TB infection in humans has received substan-
tial attention. Now, T cells, which are pivotal in disease prevention
and inactivation, are currently being considered in the activation of
adaptive immune responses in both patients with depression and TB.
When chronic depression is sustained, the number of T cells and B
cells may temporarily increase to attack invading pathogens. Their
overproduction becomes maladaptive or detrimental due to reduced
T-cell availability and leukocyte stimulatory activity, resulting in an
overall down-regulation of the body’s defense system.
In terms of protective immunity, most studies have focused on
CD4+ T cells, but the data thus far are controversial. Severe depres-
sion is associated with lower CD4+ T cell counts, which indicates that
depression might influence immune function.101,102 By contrast, sev-
eral studies have shown an increase in the percentage of CD4+ T cells
or the CD4/CD8 ratio in depressive disorder.103–105 Nevertheless, it is
in accordance that T cells immunity has been altered in patients with
depression, which might be involved in increased susceptibility to TB.
First, the differentiation and polarization of CD4+ T cells are altered
among patients with major depression disorder, as different ratios of
Th1, Th17, and Treg.106,107 Second, the receptors for neurotransmitter
on T cells is altered and T cells cannot appropriately function in depres-
sive patients.108 Third, the proinflammatory cytokines microenviron-
ment somehow inhibit the function of T cells.92 Therefore, in spite of
the number of CD4+ T cells in depression may or may not decreased,
the functions of CD4+ T cells might be suppressed due to reduction
proliferative response of T cell and induction of T cell apoptosis.109
In addition, the stimulation or suppression of T cells and NK
cells in the peripheral and CNS among patients with depression
indicates the interactions between the innate and adaptive immune
systems.110,111 Furthermore, a higher level of Th2 cells and lower
levels of IL-2 and IFN-𝛾 cytokines in patients with major depression
have been described.106,111 During active TB, Mtb antigen-specific
Th1 response is enhanced by secreting large quantities of IFN-𝛾.112
Therefore, the dynamic changes in Th1/Th2 cells due to depression in
patients with TB might suppress the promotion and regulation of Th1
responses, and thus inhibit protective immunity. In addition, stress-
induced depressive-like behaviors reduce T-cell trafficking and avail-
ability, which is partly associated with glucocorticoids or increased T-
cell apoptosis.92 Further elucidation of T-cell pathology might provide
insights into the immune system contribution to depression and TB
infection. Thus far, we propose that depression may increase the risk
of TB infection by inhibiting the host immune response against TB. Fur-
ther investigations to test this hypothesis will be beneficial for clinical
care and TB prevention in patients with depression.
3.3 Depression influences TB susceptibility via
alterations to lipid metabolism
During TB infection, Mtb enters the lungs via the aerosol route,
usually via phagocytosis by alveolar M𝝓s. These infected M𝝓s exhibit
a “foamy” phenotype due to the formation and accumulation of lipid
bodies.113–115 The host lipid bodies are hydrolyzed to fatty acids by
extracellular lipolytic enzymes of Mtb,116 which provide energy to
the bacilli during intracellular persistence and reactivation, and as
a precursor for the synthesis of bacterial cell envelope lipids.117,118
A recent review concluded that lipid degradation is important for
maintaining intracellular survival and Mtb replication, and lipolytic
enzymes may potentiate M𝝓 antimicrobial activity and thus can be
beneficial to improve the immune status of the host.119 Lipid accu-
mulation and metabolism thus seem to be crucial steps in maintaining
Mtb pathophysiology.
Considerable evidence also suggests that lipid metabolism serves
a key role in depression.120,121 For example, a recent study reported
that the disturbance of phospholipid metabolism may promote inflam-
mation in the CNS of patients with major depressive disorders.122
Peng et al. found that low serum levels of free thyroxine affects the
lipid profile in patients with major depressive disorder and who have
attempted suicide.123 Pan et al. showed that the antidepressant drug
fluoxetine induces lipid metabolism abnormalities by acting on the
liver in both mouse models of depression and affected patients.124
ZHANG ET AL .
While additional studies to clarify the alterations to lipid metabolism
in patients with depression are required, it is possible that manip-
ulating lipid metabolism may be a potential therapeutic target for
anti-TB treatment.
Mtb infection increases the expression of peroxisome proliferator-
activated receptor-gamma (PPAR-𝛾)—a member of the lipid-activated
nuclear receptor superfamily in a TLR2-dependent manner. Further-
more, Mtb activates PPAR-𝛾 to accumulate in lipid bodies.125,126
PPAR-𝛾 may function as a fatty acid sensor and lead to the regulation
of downstream genes involved in lipid biogenesis and testicular recep-
tor 4 and its target genes.127 Depression leads to microglial activa-
tion in the CNS and M𝝓 activation in the periphery via TLR-mediated
signaling128,129 and may be involved in similar pathways as Mtb infec-
tion to influence lipid droplet formation. Interestingly, diet is a known
factor considered to be important in the development and treatment
of depression.130 Specifically, the dietary fatty acids involved in lipid
metabolism may act with certain brain regions to regulate the neu-
ral processes underlying depressive-like behaviors.131 As mentioned
above, Mtb preferentially causes the metabolism of host-derived lipids
(fatty acids), and the bacteria then utilize the substrates to estab-
lish or maintain the disease.132 Polyunsaturated fatty acid (PUFA) is
an essential fatty acid that can be metabolized to arachidonic acid
(AA).133,134 Epidemiological data suggest that omega-3 PUFA con-
sumption may be inversely correlated with the prevalence and sever-
ity of depression.135,136 In terms of the role of AA in Mtb infection,
cyclooxygenases and lipoxygenases convert AA into the eicosanoids
prostaglandin E2 (PGE2 ) and lipoxin A4 (LXA4 ), respectively.137 A pre-
vious study showed that virulent strains of Mtb promoted the pro-
duction of LXA4 , thereby stimulating M𝝓 necrosis and mycobacterial
spread.138 This finding is in agreement with other studies reporting
that eicosanoids influence infected M𝝓 death, including M𝝓 apoptosis
stimulated by PGE2 , leading to an early immune response, whereas M𝝓
necrosis leads to a delayed immune responses.138–140 Taken together,
the decline in AA may be due to lower PUFA levels in patients with
depression, which indirectly influences eicosanoid levels that nega-
tively regulate Mtb-infected M𝝓 death. The overall result is increased
lung damage due to uncontrolled Mtb infection.
4 CONCLUDING REMARKS
The prevalence of comorbid depression with TB is high. Interestingly,
depression alone is a risk factor for TB. During anti-TB treatment, non-
adherence to treatment and adverse treatment effects are common,
which can lead to delayed recovery or increasingly severe comorbid
depression-like symptoms. Antidepressant drugs together with effec-
tive nursing measures that help maintain good mental health, might
help decrease depressive symptoms in patients with TB. Although
reports have indicated the possibility of a bidirectional association
between depression and TB infection, whether and how depression
increases the risk of TB remains unclear. Clarifying this mechanism
presents a challenge; however, the overview provided here of the
aspects of immuno-inflammatory and lipid metabolism might help to
5
direct research efforts that aim to improve the efficacy of TB therapy
and reduce comorbidity with depression.
AUTHORSHIP
K.Z. wrote the review and drew the figure; X.W., J.T., H.R., O.W., and X.C.
edited the review.
ACKNOWLEDGMENTS
This study was supported by the Guangdong Provincial Key Labora-
tory of Regional Immunity and Diseases (grant no. 2019B030301009),
Twelve-Fifth Mega-Scientific Project on “prevention and treatment
of AIDS, viral hepatitis and other infectious diseases” (grant no.
2017ZX10201301-001-001/002), the Natural Science Foundation of
China Grant (grant nos. 81525016 and 81671984).
DISCLOSURE
The authors declare no conflicts of interest.
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How to cite this article: Zhang K, Wang X, Tu J, Rong
H, Werz O, Chen X. The interplay between depression and
tuberculosis. J Leukoc Biol. 2019;1–9. https://doi.org/10.1002/
JLB.MR0119-023R