Introduction

Tuberculosis (TB), a communicable disease caused by Mycobacterium tuberculosis, is one of the leading infectious causes of mortality worldwide [1]. While it primarily affects the lungs (pulmonary TB), it can be found in other places throughout the body (extrapulmonary TB). The COVID-19 pandemic accelerated deaths due to TB as less attention, and subsequently funding, has been paid to TB [1,2]. This resulted in ~10.8 million people developing new cases of active TB in 2023 with ~1.25 million deaths due to TB disease [1]. Active TB refers to disease in which TB bacteria are replicating and causing clinical symptoms. Pulmonary TB is typically symptomatic and infectious while extrapulmonary TB is usually symptomatic but not transmissible. This contrasts with latent TB, a state in which an individual is infected but asymptomatic and non-infectious. It is estimated that billions of individuals worldwide have latent TB [1]. Furthermore, TB can be classified by drug resistance with ~400,000 persons with TB (PWTB) having multidrug-resistant TB (MDR-TB) in 2023 [1]. Despite this large burden, TB is vastly underfunded leading to under-supported research endeavors and national TB programs left without appropriate funding to successfully combat the large TB burdens that they may face [1–5]. This results in gaps in TB diagnosis, treatment, and care in high TB burden settings [6–8].

One such gap in care is in the screening, diagnosis, and treatment of comorbidities in PWTB [9]. While the diagnosis and treatment protocols of infectious comorbidities of TB such as Human Immunodeficiency Virus (HIV) have been extensively researched [10–13], the diagnosis and treatment of comorbid mental health disorders have received little attention, despite their impacts on TB treatment [9,14,15]. Depression is one such overlooked comorbidity with potentially large impacts on PWTB [16,17]. Depression, a common mental health condition characterized by persistent sadness, loss of interest or pleasure, and functional impairment, can affect quality of life if not properly managed [18]. While clinically defined in various tools, its expression and recognition vary across cultural contexts, increasing its diagnostic and treatment complexity [19].

Depression appears to impact PWTB more frequently than the general population. One systematic review estimates the depression prevalence amongst PWTB to be 45% [20]. Depression may not only be a consequence of TB, but also a risk factor due to its effects on immune function, health-seeking behavior, and treatment engagement [15,21,22]. TB-depression co-occurrence can be thought of as a syndemic, or an interacting set of conditions that cluster within social disadvantage (e.g., stigmatization of health conditions and economic vulnerability) that results in an increased burden of disease [23–25]. The burden of depression may also vary by TB subtype. For example, individuals with extrapulmonary TB may face diagnostic uncertainty that heightens psychological distress [26,27]. Those with MDR-TB often endure prolonged treatment, more severe side effects, greater economic uncertainty, and greater social isolation, all of which may increase the risk or severity of depression [28,29].

Given this complex interplay, most PWTB are never screened for depression, let alone receive treatment for depression. This is due to a lack of providers, funding, cultural norms, and stigma [20,22,30,31]. From a public health perspective, untreated depression contributes to delays in TB diagnosis and treatment initiation [30,32], non-adherence to TB medications [33,34], and ultimately increases negative TB outcomes such as loss to follow up and death [35,36].

Despite the significant impact of depression in PWTB, research has largely been limited to prevalence surveys. Few studies have used longitudinal designs and even fewer explore the methodologies used to screen, diagnose, or treat depression in PWTB. This may be in part due to diagnostic challenges posed by overlapping symptoms, such as TB-related fatigue, weight loss, and general malaise, all of which can masquerade as signs of depression, leading to misdiagnoses or missed diagnoses.

Given the substantial burden of depression among PWTB and the large focus on prevalence estimates within the literature, a scoping review is particularly needed to broadly map the existing evidence, identify the most pressing knowledge gaps, and clarify how research has been conducted when studying these comorbid conditions. Therefore, we aim to conduct a scoping review to examine the methodologies used to study depression in PWTB, including diagnostic and treatment methodologies, identifying research gaps and highlighting opportunities for improved methodological approaches.

Methods

This section is presented in accordance with the scoping review framework by Arskey and O’Malley [37] and refined by Levac et al [38] which guided the methodology of our scoping review. This framework consists of six steps: 1) Identifying the research question 2) Identifying relevant studies 3) Study selection 4) Charting the data 5) Collating, summarizing, and reporting the results and 6) Consultation with stakeholders on study findings.

Identification of relevant studies

Table 1 includes the eligibility criteria for this scoping review. We searched the following electronic databases: MEDLINE, Embase, Global Health, the Cochrane Library, the WHO Regional Libraries, Africa-Wide Information, and PsycINFO. These databases were selected for their relevance to the scope of this review: MEDLINE, Embase, Global Health, and the Cochrane Library are widely used for biomedical and public health research; the WHO Regional Libraries and Africa-Wide Information are included to ensure geographic representation, particularly from high TB burden regions such as sub-Saharan Africa; and PsycINFO is included for its comprehensive coverage of psychological and mental health research. The preliminary search strategy, constructed by a trained medical librarian (LR) after several weeks of testing various combinations of terms to ensure maximum reach, focused on combinations of terms related to “tuberculosis” and terms related to “depression” (S1 File).

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Table 1. Study eligibility criteria.

https://doi.org/10.1371/journal.pone.0322753.t001

We did not include date restrictions. The electronic database search will be supplemented by manual searches, including the screening of reference lists from all included studies to identify any additional relevant articles that may have been initially missed.

Charting the data

After piloting the data extraction tool, we will extract data using Covidence. We will extract pertinent study details which can be found in Table 2. Additionally, if the authors identify any limitations relevant to the research question, such as methodological limitations, we will extract this data. One author (AJG) will extract the data with a second reviewer (PT) checking extracted data for accuracy. These two authors will routinely meet during the data extraction phase to ensure the extraction tool is capturing all relevant data needed to answer the overall research question.

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Table 2. Data extraction.

https://doi.org/10.1371/journal.pone.0322753.t002

Results

Discussion

This scoping review will explore the existing literature on the intersection between depression and TB allowing us to identify research gaps. Importantly, this will allow us to understand methodological gaps that exist and approaches that researchers have historically taken to tackle these two diseases concurrently.

Findings from this review could contribute to advancing research beyond cross-sectional prevalence surveys by encouraging the use of other quantitative, qualitative, and mixed-methods study designs that can better inform evidence-based practice. Furthermore, this review could underscore the urgent need for validated diagnostic tools and specialized treatment approaches to address overlapping symptoms between TB and depression, ultimately supporting the development of more effective strategies.

Strengths of our review will include methodological rigor as we are using the Levac et al framework to ensure a systematic and transparent approach to study identification and selection. This will be enhanced through the use of RE-AIM to synthesize results, providing a structured lens to assess how methodological approaches to researching TB and depression have created a knowledge base as well as gaps in studying the diseases concurrently. Finally, the planned stakeholder consultations will add depth and practical relevance to the final interpretation of findings, ensuring methodological rigor and relevance to global TB and mental health research practices.

Our review will have some limitations that are worth discussing a priori. First, we have limited the search to English language studies. Given the burden of tuberculosis in non-English speaking countries, this may exclude several studies that would otherwise be eligible. Second, we are beginning this search with the term depression, a Western term, and its associated synonyms. Many countries use alternate terms for depression, such as shenjing shuairuo (nervous weakness) in China or yuutsu in Japan, meaning that our initial search may not fully capture the available literature. Given the long list of terms that could be used by different countries, it is not likely we will capture all possible terms and subsequently may miss eligible publications. Third, scoping reviews cannot make definitive conclusions about intervention effectiveness or causality given their focus on describing existing literature. However, it may be appropriate to conduct a subsequent systematic review and meta-analysis to assess public health impact of depression-related interventions amongst PWTB. Finally, as with all scoping reviews, the breadth of study types and topics can make data synthesis more complex than in a systematic review. We believe our use of RE-AIM to structure the results, regardless of study type, will aid in creating meaningful outputs.

Conclusions

This scoping review will advance understanding of how depression screening, diagnosis, and treatment have been studied in the context of tuberculosis by systematically mapping existing methodologies and identifying critical research gaps to guide future public health research and intervention development.

Supporting information

Acknowledgments

We would like to thank both Yale University and Johns Hopkins University for providing institutional support for this work.