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<!doctype html> <html data-n-head-ssr lang="en" data-n-head="%7B%22lang%22:%7B%22ssr%22:%22en%22%7D%7D"> <head > <link data-n-head="ssr" rel="icon" type="image/png" sizes="16x16" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_16-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="icon" type="image/png" sizes="32x32" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_32-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="apple-touch-icon" type="image/png" sizes="180x180" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_180-tenantFavicon-Frontiers.png"> <title>Frontiers | The Tuberculosis-Depression Syndemic and Evolution of Pharmaceutical Therapeutics: From Ancient Times to the Future</title><meta data-n-head="ssr" charset="utf-8"><meta data-n-head="ssr" name="viewport" content="width=device-width, initial-scale=1"><meta data-n-head="ssr" data-hid="charset" charset="utf-8"><meta data-n-head="ssr" data-hid="mobile-web-app-capable" name="mobile-web-app-capable" content="yes"><meta data-n-head="ssr" data-hid="apple-mobile-web-app-title" name="apple-mobile-web-app-title" content="Frontiers | Articles"><meta data-n-head="ssr" data-hid="theme-color" name="theme-color" content="#0C4DED"><meta data-n-head="ssr" data-hid="description" property="description" name="description" content="The interplay between tuberculosis and depression has been problematic since the humoralists. Over the centuries similarities in disease management have tran..."><meta data-n-head="ssr" data-hid="og:title" property="og:title" name="title" content="Frontiers | The Tuberculosis-Depression Syndemic and Evolution of Pharmaceutical Therapeutics: From Ancient Times to the Future"><meta data-n-head="ssr" data-hid="og:description" property="og:description" name="description" content="The interplay between tuberculosis and depression has been problematic since the humoralists. Over the centuries similarities in disease management have tran..."><meta data-n-head="ssr" data-hid="keywords" name="keywords" content="non-communicable disease,History,Isoniazid,Psychiatry,antidepressant,Treatment,multidrug resistance,policy,syndemic,Depression,Tuberculosis"><meta data-n-head="ssr" data-hid="og:site_name" property="og:site_name" name="site_name" content="Frontiers"><meta data-n-head="ssr" data-hid="og:image" property="og:image" name="image" content="https://images-provider.frontiersin.org/api/ipx/w=1200&f=png/https://www.frontiersin.org/files/Articles/617751/fpsyt-12-617751-HTML/image_m/fpsyt-12-617751-g001.jpg"><meta data-n-head="ssr" data-hid="og:type" property="og:type" name="type" content="article"><meta data-n-head="ssr" data-hid="og:url" property="og:url" name="url" content="https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2021.617751/full"><meta data-n-head="ssr" data-hid="twitter:card" name="twitter:card" content="summary_large_image"><meta data-n-head="ssr" data-hid="citation_volume" name="citation_volume" content="12"><meta data-n-head="ssr" data-hid="citation_journal_title" name="citation_journal_title" content="Frontiers in Psychiatry"><meta data-n-head="ssr" data-hid="citation_publisher" name="citation_publisher" content="Frontiers"><meta data-n-head="ssr" data-hid="citation_journal_abbrev" name="citation_journal_abbrev" content="Front. Psychiatry"><meta data-n-head="ssr" data-hid="citation_issn" name="citation_issn" content="1664-0640"><meta data-n-head="ssr" data-hid="citation_doi" name="citation_doi" content="10.3389/fpsyt.2021.617751"><meta data-n-head="ssr" data-hid="citation_firstpage" name="citation_firstpage" content="617751"><meta data-n-head="ssr" data-hid="citation_language" name="citation_language" content="English"><meta data-n-head="ssr" data-hid="citation_title" name="citation_title" content="The Tuberculosis-Depression Syndemic and Evolution of Pharmaceutical Therapeutics: From Ancient Times to the Future"><meta data-n-head="ssr" data-hid="citation_keywords" name="citation_keywords" content="non-communicable disease; History; Isoniazid; Psychiatry; antidepressant; Treatment; multidrug resistance; policy; syndemic; Depression; Tuberculosis"><meta data-n-head="ssr" data-hid="citation_abstract" name="citation_abstract" content="<p>The interplay between tuberculosis and depression has been problematic since the humoralists. Over the centuries similarities in disease management have transpired. With the advent of isoniazid chemotherapy, transformation of tuberculosis patients from morbidly depressive to euphoric was noted. Isoniazid was thereafter widely prescribed for depression: hepatotoxicity ending its use as an antidepressant in 1961. Isoniazid monotherapy led to the emergence of drug resistant tuberculosis, stimulating new drug development. Vastly increased investment into antidepressants ensued thereafter while investment in new drugs for tuberculosis lagged. In the 21st century, both diseases independently contribute significantly to global disease burdens: renewed convergence and the resultant syndemic is detrimental to both patient groups. Ending the global tuberculosis epidemic and decreasing the burden of depression and will require multidisciplinary, patient-centered approaches that consider this combined co-morbidity. The emerging era of big data for health, digital interventions and novel and repurposed compounds promise new ways to treat both diseases and manage the syndemic, but absence of clinical structures to support these innovations may derail the treatment programs for both. New policies are urgently required optimizing use of the current advances in healthcare available in the digital era, to ensure that patient-centered care takes cognizance of both diseases.</p>"><meta data-n-head="ssr" data-hid="citation_pdf_url" name="citation_pdf_url" content="https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2021.617751/pdf"><meta data-n-head="ssr" data-hid="citation_online_date" name="citation_online_date" content="2021/04/15"><meta data-n-head="ssr" data-hid="citation_publication_date" name="citation_publication_date" content="2021/06/01"><meta data-n-head="ssr" data-hid="citation_author_0" name="citation_author" content="Van Der Walt, Martie"><meta data-n-head="ssr" data-hid="citation_author_institution_0" name="citation_author_institution" content="Tuberculosis Platform, South African Medical Research Council, South Africa"><meta data-n-head="ssr" data-hid="citation_author_1" name="citation_author" content="Keddy, Karen H."><meta data-n-head="ssr" data-hid="citation_author_institution_1" name="citation_author_institution" content="Tuberculosis Platform, South African Medical Research Council, South Africa"><meta data-n-head="ssr" data-hid="dc.identifier" name="dc.identifier" content="doi:10.3389/fpsyt.2021.617751"><link data-n-head="ssr" rel="manifest" href="/article-pages/_nuxt/manifest.c499fc0a.json" data-hid="manifest"><link data-n-head="ssr" rel="canonical" href="https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2021.617751/full"><script data-n-head="ssr" data-hid="newrelic-browser-script" type="text/javascript">window.NREUM||(NREUM={});NREUM.info = {"agent":"","beacon":"bam.nr-data.net","errorBeacon":"bam.nr-data.net","licenseKey":"598a124f17","applicationID":"588603994","agentToken":null,"applicationTime":3.221632,"transactionName":"MQcDMkECCkNSW0YMWghNIgldDQFTRxd1IGFJTQ==","queueTime":0,"ttGuid":"12a20a3a140dd8cd"}; (window.NREUM||(NREUM={})).init={privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]},distributed_tracing:{enabled:true}};(window.NREUM||(NREUM={})).loader_config={agentID:"594400880",accountID:"230385",trustKey:"230385",xpid:"VgUHUl5WGwYIXFdSBAgOUg==",licenseKey:"598a124f17",applicationID:"588603994"};;/*! 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class="Ibar__userArea"></div></div></div></nav> <div class="ArticlePage"><div><div class="Layout Layout--withAside Layout--withIbarMix ArticleDetails"> <main class="Layout__main"> <div class="ArticleDetails__main"><div class="ArticleLayoutHeader"><div class="ArticleLayoutHeader__info"><p class="ArticleLayoutHeader__info__title"> MINI REVIEW article </p> <p class="ArticleLayoutHeader__info__journalDate"><span>Front. Psychiatry</span> <span>, 01 June 2021</span></p> <p class="ArticleLayoutHeader__info__journalDate"> Sec. Psychopharmacology </p> <p class="ArticleLayoutHeader__info__doiVolume"><span> Volume 12 - 2021 | </span> <a href="https://doi.org/10.3389/fpsyt.2021.617751" class="ArticleLayoutHeader__info__doi"> https://doi.org/10.3389/fpsyt.2021.617751 </a></p> </div>  <p class="ArticleLayoutHeader__isPartOfRT"><span class="ArticleLayoutHeader__isPartOfRT__label">This article is part of the Research Topic</span> <span class="ArticleLayoutHeader__isPartOfRT__title">Ancient Diseases and Medical Care: Paleopathological Insights</span> <span class="Link__wrapper"><a aria-label="View all 8 articles" href="https://www.frontiersin.org/research-topics/16256/ancient-diseases-and-medical-care-paleopathological-insights/magazine" target="_self" data-event="customLink-link-a_viewAll8Articles" class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right"><span>View all 8 articles</span></a></span></p></div> <div class="ArticleDetails__main__content"><div class="ArticleDetails__main__content__main ArticleDetails__main__content__main--fullArticle"><div class="JournalAbstract"><div class="JournalAbstract__titleWrapper"><h1>The Tuberculosis-Depression Syndemic and Evolution of Pharmaceutical Therapeutics: From Ancient Times to the Future</h1> </div> </div> <div class="JournalFullText"><div class="JournalAbstract"> <a id="h1" name="h1"></a> <div class="authors"><span class="author-wrapper notranslate"> <img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="\nMartie Van Der Walt
" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Martie Van Der Walt<sup>*</sup></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/1103481" class="user-id-1103481"><img class="pr5" src="https://loop.frontiersin.org/images/profile/1103481/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Karen H. Keddy">Karen H. Keddy</a></span></div> <ul class="notes"><li class="pl0">Tuberculosis Platform, South African Medical Research Council, Pretoria, South Africa</li> </ul> <p>The interplay between tuberculosis and depression has been problematic since the humoralists. Over the centuries similarities in disease management have transpired. With the advent of isoniazid chemotherapy, transformation of tuberculosis patients from morbidly depressive to euphoric was noted. Isoniazid was thereafter widely prescribed for depression: hepatotoxicity ending its use as an antidepressant in 1961. Isoniazid monotherapy led to the emergence of drug resistant tuberculosis, stimulating new drug development. Vastly increased investment into antidepressants ensued thereafter while investment in new drugs for tuberculosis lagged. In the 21st century, both diseases independently contribute significantly to global disease burdens: renewed convergence and the resultant syndemic is detrimental to both patient groups. Ending the global tuberculosis epidemic and decreasing the burden of depression and will require multidisciplinary, patient-centered approaches that consider this combined co-morbidity. The emerging era of big data for health, digital interventions and novel and repurposed compounds promise new ways to treat both diseases and manage the syndemic, but absence of clinical structures to support these innovations may derail the treatment programs for both. New policies are urgently required optimizing use of the current advances in healthcare available in the digital era, to ensure that patient-centered care takes cognizance of both diseases.</p> <div class="clear"></div> </div> <div class="JournalFullText"> <a id="h2" name="h2"></a><h2>Introduction</h2> <p class="mb15">Tuberculosis contributes considerably to human disease burdens. In 2018, the estimated incidence was 10.0 million cases globally, with 1.45 million deaths (<a href="#B1">1</a>); the estimated prevalence, including latent infection, was 1.93 billion in 2017 (<a href="#B2">2</a>). Globally, the highest disease burdens were reported from South-East Asia (44%) – 27% of cases occurring in India – and Africa (24%) (<a href="#B1">1</a>).</p> <p class="mb15">Depression is forecast to be the greatest contributor to global disease burdens by 2030 (<a href="#B3">3</a>). Official World Health Organization estimates for the lifetime prevalence of depressive disorders are 10–15%, affecting over 120 million people world-wide (<a href="#B4">4</a>). From 1990 to 2007, the prevalence of major depression increased by 33.4%, increasing a further 14.3% over the following 10 years (<a href="#B2">2</a>), particularly affecting South Asia (predicted point prevalence [PPP] of 8.6), Africa and the Middle East (PPP of 6.6), the lowest incidence reported from North America (PPP of 3.7) (<a href="#B5">5</a>). Global deaths associated with major depression were estimated in excess of 2.2 million in 2010 (<a href="#B6">6</a>), with a 20-fold greater suicide risk than the general population (<a href="#B4">4</a>). Unlike tuberculosis (<a href="#B1">1</a>), comprehensive management policies for depression are not universally available (<a href="#B7">7</a>).</p> <p class="mb0">Meta-analysis of data from low-and middle-income countries (LMICs) suggests adult tuberculosis patients have 1.98, 1.75, and 3.68 higher odds for subsyndromal depression, brief depressive episodes, and depressive episodes, respectively, compared to adults without tuberculosis (<a href="#B8">8</a>). Nonetheless, past wisdom on disease associations was lost in the latter half of the 20th century, as chemotherapeutics developed in parallel, allowing patient-centered management to diverge. This review highlights the syndemic, presenting potential policy solutions offered by the digital era, arguing that clinical structures should be developed permitting patient-centered co-management of tuberculosis and depression.</p> <a id="h3" name="h3"></a><h2>The Interaction Between Tuberculosis and Depression</h2> <p class="mb15">Singer et al. have defined the criteria for a syndemic:</p> <p style="margin-top:0em;margin-bottom:0em;margin-left:1.4em;text-indent:-1.5em;text-align:left">(1) “Two (or more) diseases or health conditions cluster within a specific population;</p> <p style="margin-top:0em;margin-bottom:0em;margin-left:1.4em;text-indent:-1.5em;text-align:left">(2) Contextual and social factors create the conditions in which two (or more) diseases or health conditions cluster; and</p> <p style="margin-top:0em;margin-bottom:1em;margin-left:1.4em;text-indent:-1.5em;text-align:left">(3) The clustering of diseases results in adverse disease interaction, either biological or social or behavioral, increasing the health burden of affected populations” (<a href="#B9">9</a>).</p> <p class="mb0">The syndemics of HIV and tuberculosis and HIV and depression are well-recognized (<a href="#B10">10</a>), but that of tuberculosis and depression lags behind both. Up to 70% of tuberculosis patients may present with depression (<a href="#B11">11</a>, <a href="#B12">12</a>), associated with poor healthcare seeking behavior and disengagement from treatment, leading to poorer outcomes, including loss to follow-up and death (<a href="#B13">13</a>). Tuberculosis and depression share common risk factors, including homelessness, HIV co-infection, and alcohol and substance dependency (<a href="#B13">13</a>): depression thus increases the risk for acquiring tuberculosis. Successful treatment of antimicrobial susceptible tuberculosis requires patients take daily treatment consistently for 6 months to prevent acquisition of drug resistance: co-administration of antituberculotics with antidepressants may contribute to patients' discontinuing treatment due to side effects of co-therapy (<a href="#B11">11</a>). Some antituberculotics can have serious psychiatric side effects, exacerbating the depressive state (<a href="#B11">11</a>). Certain antidepressants can decrease the bioavailability of antituberculotics, or vice-versa, due to common metabolic pathways; rifampicin for instance is a powerful inducer of cytochrome P450 in the liver (<a href="#B11">11</a>). Conversely, isoniazid (INH) and linezolid, having monoamine oxidase inhibitor (MAOI) activity, may increase serotonin bioavailability, if given with selective serotonin reuptake inhibitors (SSRIs), causing serotonin syndrome (<a href="#B11">11</a>). INH may potentiate hepatic failure in patients with preceding liver damage (<a href="#B11">11</a>).</p> <a id="h4" name="h4"></a><h2>Past Wisdom, Tuberculosis, and Melancholia</h2> <p class="mb15">The Ancient Greeks and Roman humoralists described the interplay between tuberculosis and depression: Hippocrates (460-370 BCE) attributed diseases to imbalances between the four bodily fluid components (<a href="#B14">14</a>), theorizing a predominance of black bile resulted in melancholia and “fatal pulmonary” disease (<a href="#B15">15</a>). Early Sanskrit writings similarly included mental diseases among the causes of “consumption” (<a href="#B15">15</a>).</p> <p class="mb15">Prior to the 19th century, tuberculosis patients were predominantly managed at home or hospitalized (<a href="#B16">16</a>). Care of the mentally ill was the responsibility of relatives and friends; those considered dangerous or disruptive were dealt with by the community, being whipped out of town or more rarely admitted to general hospitals (<a href="#B17">17</a>). The 17th century Cartesian view of melancholia (depression) is noteworthy as Descartes believed it was rooted in the soul as the seat of human passions, although Descartes expounded the close linkages between the soul and the body, while promoting sleep, exercise and specific diets to “restore the balance of the humors” (<a href="#B18">18</a>).</p> <p class="mb15">By the 19th century, both diseases were treated through institutionalization: sanatoria for tuberculosis patients and asylums for patients with severe mental illness (<a href="#B16">16</a>, <a href="#B17">17</a>). Treatment of mental diseases was relatively crude and options limited. In the early 19th century, a London Hospital superintendent wrote: “confinement or restraint may be <i>imposed as a punishment</i> with some advantage, and on the whole, [he considered] <i>fear the most effectual principle by which to reduce the insane to orderly</i>” (our italics) (<a href="#B17">17</a>). By the mid-19th century, recognition of the infectious nature of tuberculosis meant management evolved to specialized sanatoria offering bedrest, nutrition, and sunshine (<a href="#B19">19</a>). “Classes” for tuberculosis patients unable to access sanatoria were introduced in 1905 by Joseph Pratt, a Boston physician, supported by “friendly visitors” – trained nurses functioning as social workers (initiating the hospital social work program) (<a href="#B20">20</a>). In Pratt's assessment, he “never fully realized at the time the great influence of [their] class meetings in giving new patients courage and hope. Many of them never could have been induced to follow the strict rest treatment if they had not seen with their own eyes others who had regained their health by doing it” (<a href="#B20">20</a>).</p> <p class="mb0">Pratt extended the concept to enhance psychotherapy programs for patients with anxiety neuroses in the early 1930s, founding, with others introducing psychiatric group therapy (<a href="#B20">20</a>). Whether due to the emerging era of 20th century super-specialization or to narrowing of management foci, references to the association between tuberculosis and mental illness waned after the mid-1950s; only in recent years has the syndemic regained recognition (<a href="#B21">21</a>).</p> <a id="h5" name="h5"></a><h2>The Development of Antituberculotics</h2> <p class="mb0">Para-amino-salicylic acid (PAS) for tuberculosis treatment was developed in 1940 (<a href="#F1">Figure 1</a>), followed by streptomycin in 1943 (<a href="#B22">22</a>, <a href="#B23">23</a>). PAS was moderately effective, but streptomycin showed tuberculosis is amenable to chemotherapy. Drug resistance to streptomycin emerged soon after the first patients were treated and monotherapy was stopped; PAS and streptomycin were used in combination, limiting the emergence of resistance to either drug (<a href="#B23">23</a>). The search for new antituberculotics continued, and iproniazid/INH was introduced in 1951 (<a href="#Box1">Box 1</a>) (<a href="#B22">22</a>). As with streptomycin, INH monotherapy resulted in resistance, guiding the introduction of combined drug regimens necessary for effective treatment (<a href="#B23">23</a>). INH remains central to tuberculosis treatment today due to its highly bactericidal mechanism of action. Rifampicin, a rifamycin, was then developed in 1966 (<a href="#F1">Figure 1</a>), proving highly effective combined with INH for treating drug-susceptible tuberculosis (<a href="#B23">23</a>). Thereafter, investing in tuberculosis control in high-income countries stopped, as incidence declined and living conditions and nutrition improved (<a href="#B25">25</a>). Tuberculosis became viewed as a disease of poverty, predominantly affecting underdeveloped countries: limited market returns detracted from new drug development.</p> <div class="DottedLine"></div> <div class="Imageheaders">FIGURE 1</div> <div class="FigureDesc"> <a href="https://www.frontiersin.org/files/Articles/617751/fpsyt-12-617751-HTML/image_m/fpsyt-12-617751-g001.jpg" name="figure1" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/617751/fpsyt-12-617751-HTML/image_m/fpsyt-12-617751-g001.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/617751/fpsyt-12-617751-HTML/image_m/fpsyt-12-617751-g001.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/617751/fpsyt-12-617751-HTML/image_m/fpsyt-12-617751-g001.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/617751/fpsyt-12-617751-HTML/image_m/fpsyt-12-617751-g001.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/617751/fpsyt-12-617751-HTML/image_m/fpsyt-12-617751-g001.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/617751/fpsyt-12-617751-HTML/image_m/fpsyt-12-617751-g001.jpg" alt="www.frontiersin.org" id="F1" loading="lazy"> </picture> </a> <p><strong>Figure 1</strong>. Evolution of pharmaceutical treatment for tuberculosis and depression from the pre-chemical era to recent drug trials. This information is not exhaustive. Many more classes of anti-tuberculotics have been developed compared with categories of antidepressants, with recent renewed interest in the development of antidepressants, based on the recent calculations of the growing importance of depression as a significant contribution to disease burdens. A gradual increase in lithium usage, which may be off-label in some countries, is shown by the graded coloring. <i>Classes of anti-tuberculotics:</i> <sup>a</sup>Aminoglycosides; <sup>b</sup>Para-aminosalicylic acid; <sup>c</sup>Thiosemicarbazones; <sup>d</sup>Hydrazines; <sup>e</sup>Pyrazine; <sup>f</sup>Serines; <sup>g</sup>Thioamide; <sup>h</sup>Ethylenediamines; <sup>i</sup>Rifamycins; <sup>j</sup>Fluoroquinolones; <sup>k</sup>Diarylquinoline; <sup>l</sup>Nitroimidazole; <sup>m</sup>Oxazolidinone. <i>Categories of antidepressants:</i> <sup>n</sup>Monoamine oxidase inhibitor (MAOI); <sup>O</sup>Tricyclic antidepressants; <sup>p</sup>Tetracyclic antidepressants; <sup>q</sup>Selective serotonin reuptake inhibitor (SSRI); <sup>r</sup>Serotonin-norepinephrine reuptake inhibitors (SNRI); <sup>s</sup>Serotonin receptor antagonist with serotonin reuptake inhibition (SARI); <sup>t</sup>NMDA glutamergic ionoceptor blockers; <sup>u</sup>Noradrenergic α<sub>2</sub>-receptor antagonist with specific serotonergic receptors-2 and−3 antagonism (NASSA); <sup>v</sup>Aminoketone; <sup>w</sup>Atypical antipsychotic.</p> </div> <div class="clear"></div> <div class="DottedLine"></div> <div class="DottedLine"></div> <p class="mb15" id="Box1"><strong>BOX 1</strong>. The discovery and development of isoniazid (INH) (<a href="#B22">22</a>, <a href="#B24">24</a>).</p> <p class="mb0">Isoniazid and serendipity</p> <p class="mb0">Hydrazine has its origins in industrial chemistry and was produced by three chemistry pioneers, working independently. The compound was most probably originally synthesized in 1875 at the University of Berlin by Emil Fischer, who named it “hydrazine.” Pure anhydrous hydrazine was first prepared by Lobry de Bruyn in 1895, working for the German government in an effort to develop explosives from alcohol solutions. Simultaneously, between 1890 and 1894, Theodor Curtius at the University of Munich discovered hydrazine sulfate. However, further work on the new compound stopped during World War I. The antituberculotic properties were discovered by Gerhard Domagk in Germany in 1927, while testing a range compounds in animal studies to identify new antimicrobials, including, amongst others, the sulphonamides.</p> <p class="mb0">Yet again a war stopped further work in hydrazine. It was used by the Germans in WWII as a component of rocket fuel, and large stocks remained when the war ended, which was freely donated to civilian chemical companies interested in developing pharmaceuticals. After the war, Domagk returned to his earlier work on the sulphonamides in an attempt to find an alternative to streptomycin. Although he was unsuccessful, his work was instrumental in the eventual investigation of hydrazine in animals.</p> <p class="mb0">In 1950/1 two research teams working independently of each other, discovered the compound's strong antituberculotic potency. Herman Hyman Fox, working at Hoffman-La Roche in New Jersey, studied the semi-carbazones, knowing that they have antituberculotic potential. When he investigated these compounds in mice, he coincidently included some of the intermediaries, among which was INH/propiozid. Harry Yale at Squibb Institute of Medical Research in New Jersey simultaneously investigated various compounds as antituberculotic drugs in mice. Both researchers made a comparable unexpected discovery of the strong <i>in vivo</i> activity of the intermediary. After this, clinical trials were almost immediately conducted in hospitals in the New York State.</p> <p class="mb0">The success of INH against tuberculosis led to renewed interest for the development of other antituberculotics, eventually leading to the discovery of pyrazinamide, ethionamide and rifampicin. The history of INH highlights the speed of research: after the discovery after its antituberculotic properties, a mere 2 years of the animal tests, it was used in humans.</p> <div class="DottedLine"></div> <a id="h6" name="h6"></a><h2>Isoniazid, Serendipity, and the First Antidepressant</h2> <p class="mb15">Monoamine oxidase was first described by Mary Hare at Oxford University in 1928, although its role in depression was not recognized until the 1950s (<a href="#B26">26</a>). Serendipity decreed that development of antituberculous drugs would lay the foundation of psychopharmacology (<a href="#B22">22</a>, <a href="#B27">27</a>). In 1950, when INH was investigated in a clinical trial of 44 patients believed to have terminal tuberculosis at Sea View Hospital, New York, unexpected positive side effects occurred (<a href="#B16">16</a>). Patients became less depressed, engaged socially and displayed improved appetites (<a href="#B24">24</a>). The remarkable effects of INH, coined the “miracle drug,” were documented in the news and media frenzy ensued. The Associated Press reported that the patients were “dancing in the halls tho' they had holes in their lungs,” having undergone an astonishing transformation from morbid depression to euphoria; reports completely disregarding how effective INH was for tuberculosis (<a href="#B16">16</a>).</p> <p class="mb15">The mood enhancing characteristics of INH, which deaminates the biogenic amines (<a href="#B26">26</a>), were investigated clinically among psychiatric patients by Nathan Kline in 1957, who described INH as a “psychic energizer” (<a href="#B27">27</a>). Seventy percent of patients institutionalized for depression showed marked improvement and similar improvements were observed in ambulatory patients (<a href="#B27">27</a>). The term “antidepressant” was coined for the mood elevating properties; by the end of the 1950s, INH was used by an estimated 400,000 psychiatric patients (<a href="#B27">27</a>, <a href="#B28">28</a>).</p> <p class="mb0">Use of INH and iproniazid as antidepressants ended in 1961: hepatotoxicity in doses used in depressed patients halted treatment programs and INH was launched solely for treatment of tuberculosis (<a href="#B29">29</a>). Nevertheless, this landmark event contributed to the modern view of a biological basis for psychoses, shifting the approach from management of depression as a psychodynamic process.</p> <a id="h7" name="h7"></a><h2>Development of New Antituberculotics</h2> <p class="mb15">The earlier successes with combination therapy for tuberculosis underwent reversal in the 1980s, when an outbreak due to <i>Mycobacterium tuberculosis</i> strains resistant to INH and rifampicin occurred in New York (<a href="#B30">30</a>). Soon afterwards, strains with comparable resistance patterns emerged from other parts of the world (<a href="#B30">30</a>). These patients had high mortality and limited treatment options due to the paucity of effective drugs. The simultaneous emergence of HIV in the 1980s accelerated the crisis and drug-resistant tuberculosis was recognized as a global emergency (<a href="#B31">31</a>).</p> <p class="mb15">A rise in tuberculosis incidence globally continued through the 1990s and mortality rates increased, in both high-income and LMICs (<a href="#B2">2</a>), potentially reversing all earlier gains made in tuberculosis control. A period of massive investment in research and development of new antituberculotics compounds followed (<a href="#F1">Figure 1</a>). Academia, governments, philanthropy, industry collaborated in revising approaches to clinical testing in order to optimize time periods in which to bring these to market (<a href="#B32">32</a>). Between 2010 and the present, investment into research and development of new antituberculotics has exceeded that of the preceding 40 years. Currently, there are a number of new compounds in development and various phases of clinical trials (<a href="#B33">33</a>).</p> <p class="mb15">In contrast to the antidepressants, for the first time since 1960, two new drugs from completely new categories, bedaquiline and delaminid, became available for tuberculosis treatment in the mid-2000s (<a href="#B34">34</a>). Both hold promise of shortening the treatment period and the potential impact on treatment may be similar to the hype that INH offered almost 70 years ago (<a href="#B34">34</a>). A recent meta-analysis of 50 studies suggests that regimes that include bedaquiline with linezolid, later generation fluoroquinolones, clofazimine, and carbapenems were positively associated with treatment success of multidrug-resistant tuberculosis, compared with the modest results of older second-line drugs (<a href="#B35">35</a>).</p> <p class="mb15">Challenges to treatment of tuberculosis have been compounded by the side effects of the many drugs' required for combination regimens to affect a cure in multidrug resistant (MDR) or extremely drug resistant (XDR) infection. These include fluoroquinolones and cycloserine/terizidone, which may cause psychiatric side effects and suicidal symptoms (<a href="#B36">36</a>). Withdrawal of these drugs from the regimen can result in an inadequate treatment, requiring a longer duration of treatment or delaying the patients' response to treatment. Side effects of other drugs though milder, include gastro-intestinal disturbances, and peripheral neuropathy; the long duration may result in a morbid and depressed patient. Optimization of new treatment regimes, including of length of treatment, remains a priority (<a href="#B35">35</a>).</p> <p class="mb0">Similar to the discovery of the anti-depressive properties of INH, it has been suggested that drugs developed for other indications may be repurposed for the management of drug resistant tuberculosis. As side effect and toxicity profiles of such compounds have been elucidated, this could hopefully hasten the introduction to the market. This includes folate inhibitors, sulfamethoxazole-trimethoprim, the antileprotic dapsone, β-lactam agents other than carbapenems and mefloquine, an antimalarial (<a href="#B37">37</a>). Compounds developed for other purposes may also have anti-mycobacterial properties, including the anti-hypercholesterolaemia statins (<i>M. tuberculosis</i> uses cholesterol uptake in the macrophage to depress the host's immune response), antihistamines and neuroleptics including phenothiazines, anticonvulsants, anticancer drugs, such as tyrosine kinase inhibitors, and non-steroidal anti-inflammatories (<a href="#B37">37</a>).</p> <a id="h8" name="h8"></a><h2>Evolution of Antidepressants</h2> <p class="mb15">INH and the related compound iproniazid (<a href="#B28">28</a>) made two fundamental contributions to the development of psychiatry,</p> <p style="margin-top:0em;margin-bottom:0em;margin-left:1.5em;text-indent:-1.5em;text-align:left">(1) recognition of the social health aspect to depression, changing the nature of psychiatric care of depressive patients, and</p> <p style="margin-top:0em;margin-bottom:1em;margin-left:1.5em;text-indent:-1.5em;text-align:left">(2) the neurobiological origin of certain psychiatric conditions (<a href="#B38">38</a>).</p> <p class="mb15">The MAOI activity of INH gave researchers an indispensable research tool for neurobiology and psychopharmacology (<a href="#B38">38</a>), permitting the first aetiopathological hypothesis of any common mental disorder. The identification of the mechanisms of action of MAOIs provided the model for the next four decades for most of the present antidepressants, including a cyclopropylamine, tranylcypromine (an amphetamine analog), and phenelzine, a hydrazine derivative, which dominated the market for MAOIs by the mid-1980s (<a href="#B26">26</a>) (<a href="#F1">Figure 1</a>).</p> <p class="mb15">The second category of antidepressants developed included the tricyclic antidepressants (TCA), imipramine and related compounds (<a href="#F1">Figure 1</a>), antihistamine derivatives preceding phenothiazines, revolutionizing the history of biological psychiatry. In a recurring theme, the first phenothiazine was synthesized in 1883 as a potential chemical dye, followed by iminodibenzyle in 1898. Proving ineffective as a dye, iminodibenzyle was shelved for 50 years, until interest in sedatives began increasing (<a href="#B39">39</a>). Roland Kuhn, contracted by Geigy to examine the non-existent sedative effects of the iminodibenzyle derivative G 22150 in 1948, proposed its potential as an antipsychotic in 1954, but it proved too toxic for use. Geigy offered the alternative G 22355, with the homologous side chain to that on chlorpromazine in 1957. Kuhn expounded imipramine's antidepressant potential in 1958 (<a href="#B38">38</a>, <a href="#B39">39</a>), generating a new era of rational drug design, in which newer antidepressants are designed to act on a particular site, receptor or enzyme (<a href="#B38">38</a>) (<a href="#F1">Figure 1</a>). Similar to antituberculous therapy, drugs combinations from different antidepressant categories were frequently combined, particularly for refractory cases of major depression (<a href="#B40">40</a>). During this period the element lithium was recognized as highly efficacious in preventing depressive relapse. Initially used to control manic episodes in bipolar disorders, lithium was gradually introduced as maintenance management against repeated depressive episodes (<a href="#B41">41</a>). The original study investigators observed that: “Instead of having a suicide rate of seven per thousand, which is the norm, we had a suicide rate of less than one per thousand”; further meta-analysis in 1999 calculated that relapse rates for major depression averaged 74% on placebo, compared with 29% on lithium (<a href="#B41">41</a>). Focusing on manic-depression, further trials with antiepileptics, valproate and carbamazepine, between the 1960s and 1990s, which proved more successful in controlling mania in manic-depression, and lamotrigine for both manic and depressive episodes, ensued, of which only lamotrigine is FDA approved for maintenance therapy of manic depression (<a href="#B42">42</a>).</p> <p class="mb15">In the late 1970s and early 1980s, the antidepressant zimelidine, was developed, an antihistamine and the first of the SSRIs. Although zimelidine was later withdrawn due to toxicity, the increase in knowledge of the mechanisms of depression led to the development of serotonin and norepinephrine (noradrenaline) reuptake inhibitors (SNRI) (<a href="#F1">Figure 1</a>) (<a href="#B38">38</a>). Interest in novel antidepressants thereafter waned with the recognition of “treatment intolerant” forms of depression to categories of antidepressants then available, delayed treatment responses, and unsustained remission (<a href="#B43">43</a>).</p> <p class="mb15">Attention focused on chemical alteration of available drugs, reducing side-effects, promoting faster onset of action and providing more universal therapeutic action (<a href="#F1">Figure 1</a>).</p> <p class="mb0">Management protocols are now being reviewed to improve understanding and address the intense social and economic burdens that accompany depression (<a href="#B44">44</a>), although comprehensive guidelines are lacking in many countries and only 25% of guidelines identify enablers and barriers to implementation (<a href="#B7">7</a>). Treatment of the depressed patient requires insight into depression as a medical condition, psycho-social aspects leading to poor treatment uptake, problems with treatment availability, and treatment disruption, similar to the broader view required for antituberculous treatment (<a href="#B43">43</a>). Controlling depression will require novel chemotherapeutic approaches (<a href="#B45">45</a>). Learning from the INH experience, re-examination and repurposing of drugs, including anesthetics, anti-epileptics, anti-hyperlipidemic statins and antibiotics may enable antidepressant research to focus on novel targets, particularly for refractory and resistant cases (<a href="#B46">46</a>). Compounds acting on the glutamate and γ-aminobutyric acid (GABA) neurotransmitter systems, recognizing the role of these systems in major depression have been reviewed (<a href="#B47">47</a>), based on ketamine activity (an anesthetic developed in the 1900s), which is antidepressant in low doses (<a href="#B48">48</a>, <a href="#B49">49</a>). Compounds such as rapastinel and apimostinel have shown early phase II efficacy, with low toxicity (<a href="#B49">49</a>). Other novel targets include excitatory amino acid transporter-2 (EAAT-2) reuptake enhancers and metabotropic glutamergic receptors as positive or negative modulators (<a href="#B47">47</a>).</p> <a id="h9" name="h9"></a><h2>The Impact of the Digital ERA</h2> <p class="mb15">The current rate of decline of tuberculosis incidence remains too slow and it could potentially remain a major contributor to infectious disease burdens beyond 2050 (<a href="#B50">50</a>), until the 22nd century (<a href="#B51">51</a>). The World Health organization has set the “End Tuberculosis Strategy” goal to eliminate tuberculosis by 2035, requiring vast investments in the discovery and development of new tools for tuberculosis control, including an effective vaccine (<a href="#B52">52</a>), but wider understanding of the patient as an individual, obstacles to successful management and why treatment failures occur, and addressing the economic and social determinants of disease, are of equal importance (<a href="#B51">51</a>, <a href="#B53">53</a>). The Global Plan to Stop Tuberculosis estimated that the funding gap to realize the 2035 elimination target at USD1.3 billion (<a href="#B51">51</a>).Development of new drugs for tuberculosis and new drug design has benefited from computational tools for rational drug design and identification of new drug targets, and digital health solutions hold promise for new antituberculotics (<a href="#B32">32</a>, <a href="#B37">37</a>, <a href="#B54">54</a>). Mobile phone communications between treatment provider and tuberculosis patients can be used to customize patient support, without the patient having to come to the clinic (<a href="#B55">55</a>). Electronic pill box dispensers already monitor if patients access treatment as prescribed, and if not, prompt care providers to intervene timeously before treatment is abandoned (<a href="#B55">55</a>). Deep learning has permitted the identification of novel compounds. A pioneering deep learning algorithm has identified a new broad-spectrum antimicrobial, halicin, that showed killing of <i>M. tuberculosis</i> at 16 μg/mL (<a href="#B56">56</a>), named for the computer HAL in “2001: A Space Odyssey” (<a href="#B57">57</a>). The novel mechanism of action suggests currently recognized resistance mechanisms would not affect halicin's antimicrobial potential (<a href="#B56">56</a>).</p> <p class="mb0">The current outlook for depression remains concerning, as global disease burdens increase, compounded by the paucity of management guidelines (<a href="#B7">7</a>): treatment demands will likely grow, necessitating innovative solutions. Potentiation of currently available bioactive compounds through methylation, altering the solubility, could enhance binding affinity and drug metabolism up to a factor of 2,000, permitting use of lower drug dosages: reduced side effects and improved safety profiles should decrease default rates (<a href="#B58">58</a>). Inexpensive novel techniques have been successfully used for citalopram, an antidepressant, and tedizolid (<a href="#B58">58</a>), an oxazolidinone with significant antituberculotic activity (<a href="#B59">59</a>). Improved computational power and artificial intelligence to mine health information data sets for depression may reveal genetic predisposition, psychiatric sub-types and identify new biochemical pathways for treatment previously unrecognized with classical approaches (<a href="#B60">60</a>). Mobile-health interventions enable confidential customized treatment and patient support (<a href="#B61">61</a>–<a href="#B63">63</a>). Self-help applications may prevent depression, prior to its development into full disease, decreasing demands on health resources (<a href="#B60">60</a>, <a href="#B62">62</a>, <a href="#B63">63</a>). Deep learning algorithms targeting single nucleotide polymorphisms as genetic biomarkers may predict clinical treatment outcomes and adverse drug reactions in patients with major depressive disorder treated with antidepressants (<a href="#B64">64</a>).</p> <a id="h10" name="h10"></a><h2>Discussion</h2> <p class="mb0">The right of everyone to greater standards of mental and physical health has been emphasized at a high-level United Nations meeting on tuberculosis in 2018 (<a href="#B51">51</a>). Patient-centered care of tuberculosis and depression requires multidisciplinary approaches for integrated management of risk factors and co-morbidities (<a href="#B7">7</a>, <a href="#B53">53</a>, <a href="#B64">64</a>). A recent study showed only five of 26 countries, 21 of which are high tuberculosis-incidence, had standard protocols for the co-management of other disorders: supposed barriers to program integration included limited capacity, not perceiving mental health as problematic, resource insufficiencies and social stigmata of tuberculosis and mental disease (<a href="#B65">65</a>), despite mounting evidence of the association internationally (<a href="#B8">8</a>, <a href="#B66">66</a>–<a href="#B71">71</a>), possibly accounting for the lack of comprehensive guidelines for addressing comorbidities with depression identified in LMICs (<a href="#B7">7</a>). Nonetheless, integration of HIV and tuberculosis programs has greatly reduced patient morbidity and mortality (<a href="#B53">53</a>); integration of diabetes with tuberculosis programs improved treatment outcomes of both (<a href="#B72">72</a>).</p> <a id="h11" name="h11"></a><h2>Conclusion</h2> <p class="mb0">As treatments evolve, big data and mobile health technologies should facilitate easier monitoring of potential drug interactions–beneficial or detrimental–to optimize therapies. Integrating tuberculosis management and mental health within health systems can and should be designed according to patient needs (<a href="#B8">8</a>, <a href="#B65">65</a>). In the absence the urgent introduction of policies permitting patient-centered management of the syndemic, the public health implications are grave and the global outlook for both diseases remains bleak.</p> <a id="h12" name="h12"></a><h2>Author Contributions</h2> <p class="mb0">MV conceptualized paper. Both authors contributed to the writing of the paper and approved the final submission.</p> <a id="h13" name="h13"></a><h2>Funding</h2> <p class="mb0">Funding was provided by the South African Medical Research Council.</p> <a id="h14" name="h14"></a><h2>Conflict of Interest</h2> <p class="mb0">MV and KK are employed by the South African Medical Research Council.</p> <a id="h15" name="h15"></a><h2>Acknowledgments</h2> <p class="mb0">Emily Gomes and Linda Olivier for editorial support.</p> <a id="h16" name="h16"></a><h2>References</h2> <div class="References" style="margin-bottom:0.5em; margin-left:2em;"> <p class="ReferencesCopy1" style="margin-left:0.7em; text-indent:-1.1em;"><a name="B1" id="B1"></a> 1. World Health Organization. <i>Global Tuberculosis Report 2019</i>. Geneva, Switzerland: World Health Organization (2019). 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(2017) 389:951–63. doi: 10.1016/S0140-6736(17)30402-6</p> <p style="margin-left:1em;" class="ReferencesCopy2"><a href="https://pubmed.ncbi.nlm.nih.gov/28271846" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1016/S0140-6736(17)30402-6" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=E+Mendenhall&author=BA+Kohrt&author=SA+Norris&author=D+Ndetei&author=D+Prabhakaran+&publication_year=2017&title=Non-communicable+disease+syndemics%3A+poverty,+depression,+and+diabetes+among+low-income+populations&journal=Lancet&volume=389&pages=951-63" target="_blank">Google Scholar</a></p> </div> </div> <div class="thinLineM20"></div> <div class="AbstractSummary"> <p><span>Keywords:</span> history, isoniazid, psychiatry, antidepressant, policy, syndemic, depression, tuberculosis</p> <p><span>Citation:</span> Van Der Walt M and Keddy KH (2021) The Tuberculosis-Depression Syndemic and Evolution of Pharmaceutical Therapeutics: From Ancient Times to the Future. <i>Front. Psychiatry</i> 12:617751. doi: 10.3389/fpsyt.2021.617751</p> <p id="timestamps"><span>Received:</span> 16 October 2020; <span>Accepted:</span> 15 April 2021;<br> <span>Published:</span> 01 June 2021.</p> <div><p>Edited by:</p> <a href="http://loop.frontiersin.org/people/368476/overview">Lawrence Toll</a>, Florida Atlantic University, United States</div> <div><p>Reviewed by:</p> <a href="http://loop.frontiersin.org/people/388360/overview">James E. Barrett</a>, Drexel University, United States<br> <a href="http://loop.frontiersin.org/people/8132/overview">Francisco Lopez-Munoz</a>, Camilo José Cela University, Spain</div> <p><span>Copyright</span> © 2021 Van Der Walt and Keddy. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p> <p><span>*Correspondence:</span> Martie Van Der Walt, <a id="encmail">bWFydGllLnZhbmRlcndhbHRAbXJjLmFjLnph</a></p> <div class="clear"></div> </div></div></div> <p class="AbstractSummary__disclaimer"><span>Disclaimer: </span> All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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src="https://loop.frontiersin.org/images/profile/368476/32" alt="Lawrence Toll" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Lawrence Toll </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Florida Atlantic University, United States </div></div></a></div></div> <div class="ArticleDetailsEditors"><div class="ArticleDetailsEditors__editors"><div class="ArticleDetailsEditors__title">Reviewed by</div> <a href="https://loop.frontiersin.org/people/8132/overview" data-event="editorInfo-a-franciscoLopezMunoz" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/8132/32" alt="Francisco Lopez-Munoz" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Francisco Lopez-Munoz </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Camilo José Cela University, Spain </div></div></a><a href="https://loop.frontiersin.org/people/388360/overview" data-event="editorInfo-a-jamesEBarrett" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/388360/32" alt="James E Barrett" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> James E Barrett </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> College of Medicine, Drexel University, United States </div></div></a></div></div> <div class="ArticleDetailsGlossary ArticleDetailsGlossary--open"><button class="ArticleDetailsGlossary__header"><div class="ArticleDetailsGlossary__header__title">Table of contents</div> <div class="ArticleDetailsGlossary__header__arrow"></div></button> <div class="ArticleDetailsGlossary__content"><ul class="flyoutJournal"> <li><a href="#h1">Abstract</a></li> <li><a href="#h2">Introduction</a></li> <li><a href="#h3">The Interaction Between Tuberculosis and Depression</a></li> <li><a href="#h4">Past Wisdom, Tuberculosis, and Melancholia</a></li> <li><a href="#h5">The Development of Antituberculotics</a></li> <li><a href="#h6">Isoniazid, Serendipity, and the First Antidepressant</a></li> <li><a href="#h7">Development of New Antituberculotics</a></li> <li><a href="#h8">Evolution of Antidepressants</a></li> <li><a href="#h9">The Impact of the Digital ERA</a></li> <li><a href="#h10">Discussion</a></li> <li><a href="#h11">Conclusion</a></li> <li><a href="#h12">Author Contributions</a></li> <li><a href="#h13">Funding</a></li> <li><a href="#h14">Conflict of Interest</a></li> <li><a href="#h15">Acknowledgments</a></li> <li><a href="#h16">References</a></li> </ul> </div></div>  <div 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The journal actively welcomes submissions which support and advance the UN’s Sustainable Development Goals (SDGs), notably SDG 3: good health and well-being\u003C\u002Fp\u003E\n\n\u003Cp\u003EManuscripts that focus primarily on the physiological aspects of diseases, such as cancer or stroke, without a foundation in psychiatric or mental health issues are not suitable for publication in this journal. Similarly, studies that primarily investigate the physical effects of treatments, such as side effects or motor function, without a foundation in mental health are also not within the scope of this journal. Furthermore, research that is purely statistical or demographic in nature, without a foundation in psychiatric practice or theory, is not appropriate for this journal. General Commentary articles as well as Book Reviews are only accepted in Frontiers in Psychiatry upon invitation.\u003C\u002Fp\u003E\n\n\u003Cp\u003EFrontiers in Psychiatry is committed to advancing the discovery and developments in the field by allowing unrestricted access to articles, and communicating scientific knowledge to researchers and the public alike.\u003C\u002Fp\u003E",palette:"purple",impactFactor:"4.7",citeScore:"5.4",citations:"170000",showTagline:e,twitter:"@FrontPsychiatry",__typename:"Journal"},currentFrontiersJournal:{id:r,name:o,slug:s,printISSN:g,shortName:E,electronicISSN:F,abbreviation:X,specialtyId:e,publicationDate:e,isOnline:h,isOpenForSubmissions:h,spaceId:c,field:{id:Y,domainId:n,__typename:Z},__typename:a},articleHubSlug:g,articleHubPage:G,currentArticle:{id:617751,doi:_,title:H,acceptanceDate:new Date(1618502274000),receptionDate:new Date(1602852552000),publicationDate:new Date(1622505600000),isPublished:h,abstract:$,researchTopic:{id:16256,title:"Ancient Diseases and Medical Care: Paleopathological Insights",articlesCount:aa,isMagazinePage:h,slug:"ancient-diseases-and-medical-care-paleopathological-insights",isOpenForSubmission:m},articleType:{id:99,name:"Mini Review"},stage:{id:I,name:g},keywords:["non-communicable disease",ab,"Isoniazid","Psychiatry","antidepressant","Treatment","multidrug resistance","policy","syndemic","Depression","Tuberculosis"],authors:[{id:l,firstName:ac,lastName:"Van Der Walt",givenNames:ac,isCorresponding:m,isProfilePublic:m,userId:l,affiliations:[{organizationName:ad,countryName:ae,cityName:g,stateName:g,zipCode:g}]},{id:af,firstName:ag,lastName:"Keddy",givenNames:ag,isCorresponding:m,isProfilePublic:h,userId:af,affiliations:[{organizationName:ad,countryName:ae,cityName:g,stateName:g,zipCode:g}]}],editors:[{id:ah,firstName:ai,lastName:"Toll",givenNames:ai,isCorresponding:m,isProfilePublic:h,userId:ah,affiliations:[{organizationName:"Florida Atlantic University",countryName:aj,cityName:g,stateName:g,zipCode:g}]}],reviewers:[{id:ak,firstName:al,lastName:"Lopez-Munoz",givenNames:al,isCorresponding:m,isProfilePublic:h,userId:ak,affiliations:[{organizationName:"Camilo José Cela University",countryName:"Spain",cityName:g,stateName:g,zipCode:g}]},{id:am,firstName:"James",lastName:"Barrett",givenNames:"James E",isCorresponding:m,isProfilePublic:h,userId:am,affiliations:[{organizationName:"College of Medicine, Drexel University",countryName:aj,cityName:g,stateName:g,zipCode:g}]}],journal:{id:r,slug:s,name:o,shortName:E,electronicISSN:F,field:{id:Y,domainId:n,__typename:Z},specialtyId:e,journalSectionPaths:[{section:an,__typename:"journal_journalSectionPath"}],__typename:a},section:an,impactMetrics:{views:10599,downloads:1829,citations:J},volume:K,articleVolume:"Volume 12 - 2021",relatedArticles:[],isPublishedV2:m,contents:{titleHtml:H,fullTextHtml:"\u003Cdiv class=\"JournalAbstract\"\u003E\n\u003Ca id=\"h1\" name=\"h1\"\u003E\u003C\u002Fa\u003E\n\n\u003Cdiv class=\"authors\"\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\n\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"\\nMartie Van Der Walt
\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EMartie Van Der Walt\u003Csup\u003E*\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F1103481\" class=\"user-id-1103481\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F1103481\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Karen H. Keddy\"\u003EKaren H. Keddy\u003C\u002Fa\u003E\u003C\u002Fspan\u003E\u003C\u002Fdiv\u003E\n\u003Cul class=\"notes\"\u003E\u003Cli class=\"pl0\"\u003ETuberculosis Platform, South African Medical Research Council, Pretoria, South Africa\u003C\u002Fli\u003E\n\u003C\u002Ful\u003E\n\u003Cp\u003EThe interplay between tuberculosis and depression has been problematic since the humoralists. Over the centuries similarities in disease management have transpired. With the advent of isoniazid chemotherapy, transformation of tuberculosis patients from morbidly depressive to euphoric was noted. Isoniazid was thereafter widely prescribed for depression: hepatotoxicity ending its use as an antidepressant in 1961. Isoniazid monotherapy led to the emergence of drug resistant tuberculosis, stimulating new drug development. Vastly increased investment into antidepressants ensued thereafter while investment in new drugs for tuberculosis lagged. In the 21st century, both diseases independently contribute significantly to global disease burdens: renewed convergence and the resultant syndemic is detrimental to both patient groups. Ending the global tuberculosis epidemic and decreasing the burden of depression and will require multidisciplinary, patient-centered approaches that consider this combined co-morbidity. The emerging era of big data for health, digital interventions and novel and repurposed compounds promise new ways to treat both diseases and manage the syndemic, but absence of clinical structures to support these innovations may derail the treatment programs for both. New policies are urgently required optimizing use of the current advances in healthcare available in the digital era, to ensure that patient-centered care takes cognizance of both diseases.\u003C\u002Fp\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"JournalFullText\"\u003E\n\u003Ca id=\"h2\" name=\"h2\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EIntroduction\u003C\u002Fh2\u003E\n\u003Cp class=\"mb15\"\u003ETuberculosis contributes considerably to human disease burdens. In 2018, the estimated incidence was 10.0 million cases globally, with 1.45 million deaths (\u003Ca href=\"#B1\"\u003E1\u003C\u002Fa\u003E); the estimated prevalence, including latent infection, was 1.93 billion in 2017 (\u003Ca href=\"#B2\"\u003E2\u003C\u002Fa\u003E). Globally, the highest disease burdens were reported from South-East Asia (44%) – 27% of cases occurring in India – and Africa (24%) (\u003Ca href=\"#B1\"\u003E1\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EDepression is forecast to be the greatest contributor to global disease burdens by 2030 (\u003Ca href=\"#B3\"\u003E3\u003C\u002Fa\u003E). Official World Health Organization estimates for the lifetime prevalence of depressive disorders are 10–15%, affecting over 120 million people world-wide (\u003Ca href=\"#B4\"\u003E4\u003C\u002Fa\u003E). From 1990 to 2007, the prevalence of major depression increased by 33.4%, increasing a further 14.3% over the following 10 years (\u003Ca href=\"#B2\"\u003E2\u003C\u002Fa\u003E), particularly affecting South Asia (predicted point prevalence [PPP] of 8.6), Africa and the Middle East (PPP of 6.6), the lowest incidence reported from North America (PPP of 3.7) (\u003Ca href=\"#B5\"\u003E5\u003C\u002Fa\u003E). Global deaths associated with major depression were estimated in excess of 2.2 million in 2010 (\u003Ca href=\"#B6\"\u003E6\u003C\u002Fa\u003E), with a 20-fold greater suicide risk than the general population (\u003Ca href=\"#B4\"\u003E4\u003C\u002Fa\u003E). Unlike tuberculosis (\u003Ca href=\"#B1\"\u003E1\u003C\u002Fa\u003E), comprehensive management policies for depression are not universally available (\u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EMeta-analysis of data from low-and middle-income countries (LMICs) suggests adult tuberculosis patients have 1.98, 1.75, and 3.68 higher odds for subsyndromal depression, brief depressive episodes, and depressive episodes, respectively, compared to adults without tuberculosis (\u003Ca href=\"#B8\"\u003E8\u003C\u002Fa\u003E). Nonetheless, past wisdom on disease associations was lost in the latter half of the 20th century, as chemotherapeutics developed in parallel, allowing patient-centered management to diverge. This review highlights the syndemic, presenting potential policy solutions offered by the digital era, arguing that clinical structures should be developed permitting patient-centered co-management of tuberculosis and depression.\u003C\u002Fp\u003E\n\u003Ca id=\"h3\" name=\"h3\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EThe Interaction Between Tuberculosis and Depression\u003C\u002Fh2\u003E\n\u003Cp class=\"mb15\"\u003ESinger et al. have defined the criteria for a syndemic:\u003C\u002Fp\u003E\n\u003Cp style=\"margin-top:0em;margin-bottom:0em;margin-left:1.4em;text-indent:-1.5em;text-align:left\"\u003E(1) “Two (or more) diseases or health conditions cluster within a specific population;\u003C\u002Fp\u003E\n\u003Cp style=\"margin-top:0em;margin-bottom:0em;margin-left:1.4em;text-indent:-1.5em;text-align:left\"\u003E(2) Contextual and social factors create the conditions in which two (or more) diseases or health conditions cluster; and\u003C\u002Fp\u003E\n\u003Cp style=\"margin-top:0em;margin-bottom:1em;margin-left:1.4em;text-indent:-1.5em;text-align:left\"\u003E(3) The clustering of diseases results in adverse disease interaction, either biological or social or behavioral, increasing the health burden of affected populations” (\u003Ca href=\"#B9\"\u003E9\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EThe syndemics of HIV and tuberculosis and HIV and depression are well-recognized (\u003Ca href=\"#B10\"\u003E10\u003C\u002Fa\u003E), but that of tuberculosis and depression lags behind both. Up to 70% of tuberculosis patients may present with depression (\u003Ca href=\"#B11\"\u003E11\u003C\u002Fa\u003E, \u003Ca href=\"#B12\"\u003E12\u003C\u002Fa\u003E), associated with poor healthcare seeking behavior and disengagement from treatment, leading to poorer outcomes, including loss to follow-up and death (\u003Ca href=\"#B13\"\u003E13\u003C\u002Fa\u003E). Tuberculosis and depression share common risk factors, including homelessness, HIV co-infection, and alcohol and substance dependency (\u003Ca href=\"#B13\"\u003E13\u003C\u002Fa\u003E): depression thus increases the risk for acquiring tuberculosis. Successful treatment of antimicrobial susceptible tuberculosis requires patients take daily treatment consistently for 6 months to prevent acquisition of drug resistance: co-administration of antituberculotics with antidepressants may contribute to patients' discontinuing treatment due to side effects of co-therapy (\u003Ca href=\"#B11\"\u003E11\u003C\u002Fa\u003E). Some antituberculotics can have serious psychiatric side effects, exacerbating the depressive state (\u003Ca href=\"#B11\"\u003E11\u003C\u002Fa\u003E). Certain antidepressants can decrease the bioavailability of antituberculotics, or vice-versa, due to common metabolic pathways; rifampicin for instance is a powerful inducer of cytochrome P450 in the liver (\u003Ca href=\"#B11\"\u003E11\u003C\u002Fa\u003E). Conversely, isoniazid (INH) and linezolid, having monoamine oxidase inhibitor (MAOI) activity, may increase serotonin bioavailability, if given with selective serotonin reuptake inhibitors (SSRIs), causing serotonin syndrome (\u003Ca href=\"#B11\"\u003E11\u003C\u002Fa\u003E). INH may potentiate hepatic failure in patients with preceding liver damage (\u003Ca href=\"#B11\"\u003E11\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ca id=\"h4\" name=\"h4\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EPast Wisdom, Tuberculosis, and Melancholia\u003C\u002Fh2\u003E\n\u003Cp class=\"mb15\"\u003EThe Ancient Greeks and Roman humoralists described the interplay between tuberculosis and depression: Hippocrates (460-370 BCE) attributed diseases to imbalances between the four bodily fluid components (\u003Ca href=\"#B14\"\u003E14\u003C\u002Fa\u003E), theorizing a predominance of black bile resulted in melancholia and “fatal pulmonary” disease (\u003Ca href=\"#B15\"\u003E15\u003C\u002Fa\u003E). Early Sanskrit writings similarly included mental diseases among the causes of “consumption” (\u003Ca href=\"#B15\"\u003E15\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EPrior to the 19th century, tuberculosis patients were predominantly managed at home or hospitalized (\u003Ca href=\"#B16\"\u003E16\u003C\u002Fa\u003E). Care of the mentally ill was the responsibility of relatives and friends; those considered dangerous or disruptive were dealt with by the community, being whipped out of town or more rarely admitted to general hospitals (\u003Ca href=\"#B17\"\u003E17\u003C\u002Fa\u003E). The 17th century Cartesian view of melancholia (depression) is noteworthy as Descartes believed it was rooted in the soul as the seat of human passions, although Descartes expounded the close linkages between the soul and the body, while promoting sleep, exercise and specific diets to “restore the balance of the humors” (\u003Ca href=\"#B18\"\u003E18\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EBy the 19th century, both diseases were treated through institutionalization: sanatoria for tuberculosis patients and asylums for patients with severe mental illness (\u003Ca href=\"#B16\"\u003E16\u003C\u002Fa\u003E, \u003Ca href=\"#B17\"\u003E17\u003C\u002Fa\u003E). Treatment of mental diseases was relatively crude and options limited. In the early 19th century, a London Hospital superintendent wrote: “confinement or restraint may be \u003Ci\u003Eimposed as a punishment\u003C\u002Fi\u003E with some advantage, and on the whole, [he considered] \u003Ci\u003Efear the most effectual principle by which to reduce the insane to orderly\u003C\u002Fi\u003E” (our italics) (\u003Ca href=\"#B17\"\u003E17\u003C\u002Fa\u003E). By the mid-19th century, recognition of the infectious nature of tuberculosis meant management evolved to specialized sanatoria offering bedrest, nutrition, and sunshine (\u003Ca href=\"#B19\"\u003E19\u003C\u002Fa\u003E). “Classes” for tuberculosis patients unable to access sanatoria were introduced in 1905 by Joseph Pratt, a Boston physician, supported by “friendly visitors” – trained nurses functioning as social workers (initiating the hospital social work program) (\u003Ca href=\"#B20\"\u003E20\u003C\u002Fa\u003E). In Pratt's assessment, he “never fully realized at the time the great influence of [their] class meetings in giving new patients courage and hope. Many of them never could have been induced to follow the strict rest treatment if they had not seen with their own eyes others who had regained their health by doing it” (\u003Ca href=\"#B20\"\u003E20\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EPratt extended the concept to enhance psychotherapy programs for patients with anxiety neuroses in the early 1930s, founding, with others introducing psychiatric group therapy (\u003Ca href=\"#B20\"\u003E20\u003C\u002Fa\u003E). Whether due to the emerging era of 20th century super-specialization or to narrowing of management foci, references to the association between tuberculosis and mental illness waned after the mid-1950s; only in recent years has the syndemic regained recognition (\u003Ca href=\"#B21\"\u003E21\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ca id=\"h5\" name=\"h5\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EThe Development of Antituberculotics\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EPara-amino-salicylic acid (PAS) for tuberculosis treatment was developed in 1940 (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E), followed by streptomycin in 1943 (\u003Ca href=\"#B22\"\u003E22\u003C\u002Fa\u003E, \u003Ca href=\"#B23\"\u003E23\u003C\u002Fa\u003E). PAS was moderately effective, but streptomycin showed tuberculosis is amenable to chemotherapy. Drug resistance to streptomycin emerged soon after the first patients were treated and monotherapy was stopped; PAS and streptomycin were used in combination, limiting the emergence of resistance to either drug (\u003Ca href=\"#B23\"\u003E23\u003C\u002Fa\u003E). The search for new antituberculotics continued, and iproniazid\u002FINH was introduced in 1951 (\u003Ca href=\"#Box1\"\u003EBox 1\u003C\u002Fa\u003E) (\u003Ca href=\"#B22\"\u003E22\u003C\u002Fa\u003E). As with streptomycin, INH monotherapy resulted in resistance, guiding the introduction of combined drug regimens necessary for effective treatment (\u003Ca href=\"#B23\"\u003E23\u003C\u002Fa\u003E). INH remains central to tuberculosis treatment today due to its highly bactericidal mechanism of action. Rifampicin, a rifamycin, was then developed in 1966 (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E), proving highly effective combined with INH for treating drug-susceptible tuberculosis (\u003Ca href=\"#B23\"\u003E23\u003C\u002Fa\u003E). Thereafter, investing in tuberculosis control in high-income countries stopped, as incidence declined and living conditions and nutrition improved (\u003Ca href=\"#B25\"\u003E25\u003C\u002Fa\u003E). Tuberculosis became viewed as a disease of poverty, predominantly affecting underdeveloped countries: limited market returns detracted from new drug development.\u003C\u002Fp\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 1\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"FigureDesc\"\u003E\n\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F617751\u002Ffpsyt-12-617751-HTML\u002Fimage_m\u002Ffpsyt-12-617751-g001.jpg\" name=\"figure1\" target=\"_blank\"\u003E\n\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F617751\u002Ffpsyt-12-617751-HTML\u002Fimage_m\u002Ffpsyt-12-617751-g001.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F617751\u002Ffpsyt-12-617751-HTML\u002Fimage_m\u002Ffpsyt-12-617751-g001.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F617751\u002Ffpsyt-12-617751-HTML\u002Fimage_m\u002Ffpsyt-12-617751-g001.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F617751\u002Ffpsyt-12-617751-HTML\u002Fimage_m\u002Ffpsyt-12-617751-g001.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F617751\u002Ffpsyt-12-617751-HTML\u002Fimage_m\u002Ffpsyt-12-617751-g001.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F617751\u002Ffpsyt-12-617751-HTML\u002Fimage_m\u002Ffpsyt-12-617751-g001.jpg\" alt=\"www.frontiersin.org\" id=\"F1\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\n\u003Cp\u003E\u003Cstrong\u003EFigure 1\u003C\u002Fstrong\u003E. Evolution of pharmaceutical treatment for tuberculosis and depression from the pre-chemical era to recent drug trials. This information is not exhaustive. Many more classes of anti-tuberculotics have been developed compared with categories of antidepressants, with recent renewed interest in the development of antidepressants, based on the recent calculations of the growing importance of depression as a significant contribution to disease burdens. A gradual increase in lithium usage, which may be off-label in some countries, is shown by the graded coloring. \u003Ci\u003EClasses of anti-tuberculotics:\u003C\u002Fi\u003E \u003Csup\u003Ea\u003C\u002Fsup\u003EAminoglycosides; \u003Csup\u003Eb\u003C\u002Fsup\u003EPara-aminosalicylic acid; \u003Csup\u003Ec\u003C\u002Fsup\u003EThiosemicarbazones; \u003Csup\u003Ed\u003C\u002Fsup\u003EHydrazines; \u003Csup\u003Ee\u003C\u002Fsup\u003EPyrazine; \u003Csup\u003Ef\u003C\u002Fsup\u003ESerines; \u003Csup\u003Eg\u003C\u002Fsup\u003EThioamide; \u003Csup\u003Eh\u003C\u002Fsup\u003EEthylenediamines; \u003Csup\u003Ei\u003C\u002Fsup\u003ERifamycins; \u003Csup\u003Ej\u003C\u002Fsup\u003EFluoroquinolones; \u003Csup\u003Ek\u003C\u002Fsup\u003EDiarylquinoline; \u003Csup\u003El\u003C\u002Fsup\u003ENitroimidazole; \u003Csup\u003Em\u003C\u002Fsup\u003EOxazolidinone. \u003Ci\u003ECategories of antidepressants:\u003C\u002Fi\u003E \u003Csup\u003En\u003C\u002Fsup\u003EMonoamine oxidase inhibitor (MAOI); \u003Csup\u003EO\u003C\u002Fsup\u003ETricyclic antidepressants; \u003Csup\u003Ep\u003C\u002Fsup\u003ETetracyclic antidepressants; \u003Csup\u003Eq\u003C\u002Fsup\u003ESelective serotonin reuptake inhibitor (SSRI); \u003Csup\u003Er\u003C\u002Fsup\u003ESerotonin-norepinephrine reuptake inhibitors (SNRI); \u003Csup\u003Es\u003C\u002Fsup\u003ESerotonin receptor antagonist with serotonin reuptake inhibition (SARI); \u003Csup\u003Et\u003C\u002Fsup\u003ENMDA glutamergic ionoceptor blockers; \u003Csup\u003Eu\u003C\u002Fsup\u003ENoradrenergic α\u003Csub\u003E2\u003C\u002Fsub\u003E-receptor antagonist with specific serotonergic receptors-2 and−3 antagonism (NASSA); \u003Csup\u003Ev\u003C\u002Fsup\u003EAminoketone; \u003Csup\u003Ew\u003C\u002Fsup\u003EAtypical antipsychotic.\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Cp class=\"mb15\" id=\"Box1\"\u003E\u003Cstrong\u003EBOX 1\u003C\u002Fstrong\u003E. The discovery and development of isoniazid (INH) (\u003Ca href=\"#B22\"\u003E22\u003C\u002Fa\u003E, \u003Ca href=\"#B24\"\u003E24\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EIsoniazid and serendipity\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EHydrazine has its origins in industrial chemistry and was produced by three chemistry pioneers, working independently. The compound was most probably originally synthesized in 1875 at the University of Berlin by Emil Fischer, who named it “hydrazine.” Pure anhydrous hydrazine was first prepared by Lobry de Bruyn in 1895, working for the German government in an effort to develop explosives from alcohol solutions. Simultaneously, between 1890 and 1894, Theodor Curtius at the University of Munich discovered hydrazine sulfate. However, further work on the new compound stopped during World War I. The antituberculotic properties were discovered by Gerhard Domagk in Germany in 1927, while testing a range compounds in animal studies to identify new antimicrobials, including, amongst others, the sulphonamides.\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EYet again a war stopped further work in hydrazine. It was used by the Germans in WWII as a component of rocket fuel, and large stocks remained when the war ended, which was freely donated to civilian chemical companies interested in developing pharmaceuticals. After the war, Domagk returned to his earlier work on the sulphonamides in an attempt to find an alternative to streptomycin. Although he was unsuccessful, his work was instrumental in the eventual investigation of hydrazine in animals.\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EIn 1950\u002F1 two research teams working independently of each other, discovered the compound's strong antituberculotic potency. Herman Hyman Fox, working at Hoffman-La Roche in New Jersey, studied the semi-carbazones, knowing that they have antituberculotic potential. When he investigated these compounds in mice, he coincidently included some of the intermediaries, among which was INH\u002Fpropiozid. Harry Yale at Squibb Institute of Medical Research in New Jersey simultaneously investigated various compounds as antituberculotic drugs in mice. Both researchers made a comparable unexpected discovery of the strong \u003Ci\u003Ein vivo\u003C\u002Fi\u003E activity of the intermediary. After this, clinical trials were almost immediately conducted in hospitals in the New York State.\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EThe success of INH against tuberculosis led to renewed interest for the development of other antituberculotics, eventually leading to the discovery of pyrazinamide, ethionamide and rifampicin. The history of INH highlights the speed of research: after the discovery after its antituberculotic properties, a mere 2 years of the animal tests, it was used in humans.\u003C\u002Fp\u003E\n\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\n\u003Ca id=\"h6\" name=\"h6\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EIsoniazid, Serendipity, and the First Antidepressant\u003C\u002Fh2\u003E\n\u003Cp class=\"mb15\"\u003EMonoamine oxidase was first described by Mary Hare at Oxford University in 1928, although its role in depression was not recognized until the 1950s (\u003Ca href=\"#B26\"\u003E26\u003C\u002Fa\u003E). Serendipity decreed that development of antituberculous drugs would lay the foundation of psychopharmacology (\u003Ca href=\"#B22\"\u003E22\u003C\u002Fa\u003E, \u003Ca href=\"#B27\"\u003E27\u003C\u002Fa\u003E). In 1950, when INH was investigated in a clinical trial of 44 patients believed to have terminal tuberculosis at Sea View Hospital, New York, unexpected positive side effects occurred (\u003Ca href=\"#B16\"\u003E16\u003C\u002Fa\u003E). Patients became less depressed, engaged socially and displayed improved appetites (\u003Ca href=\"#B24\"\u003E24\u003C\u002Fa\u003E). The remarkable effects of INH, coined the “miracle drug,” were documented in the news and media frenzy ensued. The Associated Press reported that the patients were “dancing in the halls tho' they had holes in their lungs,” having undergone an astonishing transformation from morbid depression to euphoria; reports completely disregarding how effective INH was for tuberculosis (\u003Ca href=\"#B16\"\u003E16\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EThe mood enhancing characteristics of INH, which deaminates the biogenic amines (\u003Ca href=\"#B26\"\u003E26\u003C\u002Fa\u003E), were investigated clinically among psychiatric patients by Nathan Kline in 1957, who described INH as a “psychic energizer” (\u003Ca href=\"#B27\"\u003E27\u003C\u002Fa\u003E). Seventy percent of patients institutionalized for depression showed marked improvement and similar improvements were observed in ambulatory patients (\u003Ca href=\"#B27\"\u003E27\u003C\u002Fa\u003E). The term “antidepressant” was coined for the mood elevating properties; by the end of the 1950s, INH was used by an estimated 400,000 psychiatric patients (\u003Ca href=\"#B27\"\u003E27\u003C\u002Fa\u003E, \u003Ca href=\"#B28\"\u003E28\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EUse of INH and iproniazid as antidepressants ended in 1961: hepatotoxicity in doses used in depressed patients halted treatment programs and INH was launched solely for treatment of tuberculosis (\u003Ca href=\"#B29\"\u003E29\u003C\u002Fa\u003E). Nevertheless, this landmark event contributed to the modern view of a biological basis for psychoses, shifting the approach from management of depression as a psychodynamic process.\u003C\u002Fp\u003E\n\u003Ca id=\"h7\" name=\"h7\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EDevelopment of New Antituberculotics\u003C\u002Fh2\u003E\n\u003Cp class=\"mb15\"\u003EThe earlier successes with combination therapy for tuberculosis underwent reversal in the 1980s, when an outbreak due to \u003Ci\u003EMycobacterium tuberculosis\u003C\u002Fi\u003E strains resistant to INH and rifampicin occurred in New York (\u003Ca href=\"#B30\"\u003E30\u003C\u002Fa\u003E). Soon afterwards, strains with comparable resistance patterns emerged from other parts of the world (\u003Ca href=\"#B30\"\u003E30\u003C\u002Fa\u003E). These patients had high mortality and limited treatment options due to the paucity of effective drugs. The simultaneous emergence of HIV in the 1980s accelerated the crisis and drug-resistant tuberculosis was recognized as a global emergency (\u003Ca href=\"#B31\"\u003E31\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EA rise in tuberculosis incidence globally continued through the 1990s and mortality rates increased, in both high-income and LMICs (\u003Ca href=\"#B2\"\u003E2\u003C\u002Fa\u003E), potentially reversing all earlier gains made in tuberculosis control. A period of massive investment in research and development of new antituberculotics compounds followed (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E). Academia, governments, philanthropy, industry collaborated in revising approaches to clinical testing in order to optimize time periods in which to bring these to market (\u003Ca href=\"#B32\"\u003E32\u003C\u002Fa\u003E). Between 2010 and the present, investment into research and development of new antituberculotics has exceeded that of the preceding 40 years. Currently, there are a number of new compounds in development and various phases of clinical trials (\u003Ca href=\"#B33\"\u003E33\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EIn contrast to the antidepressants, for the first time since 1960, two new drugs from completely new categories, bedaquiline and delaminid, became available for tuberculosis treatment in the mid-2000s (\u003Ca href=\"#B34\"\u003E34\u003C\u002Fa\u003E). Both hold promise of shortening the treatment period and the potential impact on treatment may be similar to the hype that INH offered almost 70 years ago (\u003Ca href=\"#B34\"\u003E34\u003C\u002Fa\u003E). A recent meta-analysis of 50 studies suggests that regimes that include bedaquiline with linezolid, later generation fluoroquinolones, clofazimine, and carbapenems were positively associated with treatment success of multidrug-resistant tuberculosis, compared with the modest results of older second-line drugs (\u003Ca href=\"#B35\"\u003E35\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EChallenges to treatment of tuberculosis have been compounded by the side effects of the many drugs' required for combination regimens to affect a cure in multidrug resistant (MDR) or extremely drug resistant (XDR) infection. These include fluoroquinolones and cycloserine\u002Fterizidone, which may cause psychiatric side effects and suicidal symptoms (\u003Ca href=\"#B36\"\u003E36\u003C\u002Fa\u003E). Withdrawal of these drugs from the regimen can result in an inadequate treatment, requiring a longer duration of treatment or delaying the patients' response to treatment. Side effects of other drugs though milder, include gastro-intestinal disturbances, and peripheral neuropathy; the long duration may result in a morbid and depressed patient. Optimization of new treatment regimes, including of length of treatment, remains a priority (\u003Ca href=\"#B35\"\u003E35\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003ESimilar to the discovery of the anti-depressive properties of INH, it has been suggested that drugs developed for other indications may be repurposed for the management of drug resistant tuberculosis. As side effect and toxicity profiles of such compounds have been elucidated, this could hopefully hasten the introduction to the market. This includes folate inhibitors, sulfamethoxazole-trimethoprim, the antileprotic dapsone, β-lactam agents other than carbapenems and mefloquine, an antimalarial (\u003Ca href=\"#B37\"\u003E37\u003C\u002Fa\u003E). Compounds developed for other purposes may also have anti-mycobacterial properties, including the anti-hypercholesterolaemia statins (\u003Ci\u003EM. tuberculosis\u003C\u002Fi\u003E uses cholesterol uptake in the macrophage to depress the host's immune response), antihistamines and neuroleptics including phenothiazines, anticonvulsants, anticancer drugs, such as tyrosine kinase inhibitors, and non-steroidal anti-inflammatories (\u003Ca href=\"#B37\"\u003E37\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ca id=\"h8\" name=\"h8\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EEvolution of Antidepressants\u003C\u002Fh2\u003E\n\u003Cp class=\"mb15\"\u003EINH and the related compound iproniazid (\u003Ca href=\"#B28\"\u003E28\u003C\u002Fa\u003E) made two fundamental contributions to the development of psychiatry,\u003C\u002Fp\u003E\n\u003Cp style=\"margin-top:0em;margin-bottom:0em;margin-left:1.5em;text-indent:-1.5em;text-align:left\"\u003E(1) recognition of the social health aspect to depression, changing the nature of psychiatric care of depressive patients, and\u003C\u002Fp\u003E\n\u003Cp style=\"margin-top:0em;margin-bottom:1em;margin-left:1.5em;text-indent:-1.5em;text-align:left\"\u003E(2) the neurobiological origin of certain psychiatric conditions (\u003Ca href=\"#B38\"\u003E38\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EThe MAOI activity of INH gave researchers an indispensable research tool for neurobiology and psychopharmacology (\u003Ca href=\"#B38\"\u003E38\u003C\u002Fa\u003E), permitting the first aetiopathological hypothesis of any common mental disorder. The identification of the mechanisms of action of MAOIs provided the model for the next four decades for most of the present antidepressants, including a cyclopropylamine, tranylcypromine (an amphetamine analog), and phenelzine, a hydrazine derivative, which dominated the market for MAOIs by the mid-1980s (\u003Ca href=\"#B26\"\u003E26\u003C\u002Fa\u003E) (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EThe second category of antidepressants developed included the tricyclic antidepressants (TCA), imipramine and related compounds (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E), antihistamine derivatives preceding phenothiazines, revolutionizing the history of biological psychiatry. In a recurring theme, the first phenothiazine was synthesized in 1883 as a potential chemical dye, followed by iminodibenzyle in 1898. Proving ineffective as a dye, iminodibenzyle was shelved for 50 years, until interest in sedatives began increasing (\u003Ca href=\"#B39\"\u003E39\u003C\u002Fa\u003E). Roland Kuhn, contracted by Geigy to examine the non-existent sedative effects of the iminodibenzyle derivative G 22150 in 1948, proposed its potential as an antipsychotic in 1954, but it proved too toxic for use. Geigy offered the alternative G 22355, with the homologous side chain to that on chlorpromazine in 1957. Kuhn expounded imipramine's antidepressant potential in 1958 (\u003Ca href=\"#B38\"\u003E38\u003C\u002Fa\u003E, \u003Ca href=\"#B39\"\u003E39\u003C\u002Fa\u003E), generating a new era of rational drug design, in which newer antidepressants are designed to act on a particular site, receptor or enzyme (\u003Ca href=\"#B38\"\u003E38\u003C\u002Fa\u003E) (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E). Similar to antituberculous therapy, drugs combinations from different antidepressant categories were frequently combined, particularly for refractory cases of major depression (\u003Ca href=\"#B40\"\u003E40\u003C\u002Fa\u003E). During this period the element lithium was recognized as highly efficacious in preventing depressive relapse. Initially used to control manic episodes in bipolar disorders, lithium was gradually introduced as maintenance management against repeated depressive episodes (\u003Ca href=\"#B41\"\u003E41\u003C\u002Fa\u003E). The original study investigators observed that: “Instead of having a suicide rate of seven per thousand, which is the norm, we had a suicide rate of less than one per thousand”; further meta-analysis in 1999 calculated that relapse rates for major depression averaged 74% on placebo, compared with 29% on lithium (\u003Ca href=\"#B41\"\u003E41\u003C\u002Fa\u003E). Focusing on manic-depression, further trials with antiepileptics, valproate and carbamazepine, between the 1960s and 1990s, which proved more successful in controlling mania in manic-depression, and lamotrigine for both manic and depressive episodes, ensued, of which only lamotrigine is FDA approved for maintenance therapy of manic depression (\u003Ca href=\"#B42\"\u003E42\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EIn the late 1970s and early 1980s, the antidepressant zimelidine, was developed, an antihistamine and the first of the SSRIs. Although zimelidine was later withdrawn due to toxicity, the increase in knowledge of the mechanisms of depression led to the development of serotonin and norepinephrine (noradrenaline) reuptake inhibitors (SNRI) (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E) (\u003Ca href=\"#B38\"\u003E38\u003C\u002Fa\u003E). Interest in novel antidepressants thereafter waned with the recognition of “treatment intolerant” forms of depression to categories of antidepressants then available, delayed treatment responses, and unsustained remission (\u003Ca href=\"#B43\"\u003E43\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb15\"\u003EAttention focused on chemical alteration of available drugs, reducing side-effects, promoting faster onset of action and providing more universal therapeutic action (\u003Ca href=\"#F1\"\u003EFigure 1\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EManagement protocols are now being reviewed to improve understanding and address the intense social and economic burdens that accompany depression (\u003Ca href=\"#B44\"\u003E44\u003C\u002Fa\u003E), although comprehensive guidelines are lacking in many countries and only 25% of guidelines identify enablers and barriers to implementation (\u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E). Treatment of the depressed patient requires insight into depression as a medical condition, psycho-social aspects leading to poor treatment uptake, problems with treatment availability, and treatment disruption, similar to the broader view required for antituberculous treatment (\u003Ca href=\"#B43\"\u003E43\u003C\u002Fa\u003E). Controlling depression will require novel chemotherapeutic approaches (\u003Ca href=\"#B45\"\u003E45\u003C\u002Fa\u003E). Learning from the INH experience, re-examination and repurposing of drugs, including anesthetics, anti-epileptics, anti-hyperlipidemic statins and antibiotics may enable antidepressant research to focus on novel targets, particularly for refractory and resistant cases (\u003Ca href=\"#B46\"\u003E46\u003C\u002Fa\u003E). Compounds acting on the glutamate and γ-aminobutyric acid (GABA) neurotransmitter systems, recognizing the role of these systems in major depression have been reviewed (\u003Ca href=\"#B47\"\u003E47\u003C\u002Fa\u003E), based on ketamine activity (an anesthetic developed in the 1900s), which is antidepressant in low doses (\u003Ca href=\"#B48\"\u003E48\u003C\u002Fa\u003E, \u003Ca href=\"#B49\"\u003E49\u003C\u002Fa\u003E). Compounds such as rapastinel and apimostinel have shown early phase II efficacy, with low toxicity (\u003Ca href=\"#B49\"\u003E49\u003C\u002Fa\u003E). Other novel targets include excitatory amino acid transporter-2 (EAAT-2) reuptake enhancers and metabotropic glutamergic receptors as positive or negative modulators (\u003Ca href=\"#B47\"\u003E47\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ca id=\"h9\" name=\"h9\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EThe Impact of the Digital ERA\u003C\u002Fh2\u003E\n\u003Cp class=\"mb15\"\u003EThe current rate of decline of tuberculosis incidence remains too slow and it could potentially remain a major contributor to infectious disease burdens beyond 2050 (\u003Ca href=\"#B50\"\u003E50\u003C\u002Fa\u003E), until the 22nd century (\u003Ca href=\"#B51\"\u003E51\u003C\u002Fa\u003E). The World Health organization has set the “End Tuberculosis Strategy” goal to eliminate tuberculosis by 2035, requiring vast investments in the discovery and development of new tools for tuberculosis control, including an effective vaccine (\u003Ca href=\"#B52\"\u003E52\u003C\u002Fa\u003E), but wider understanding of the patient as an individual, obstacles to successful management and why treatment failures occur, and addressing the economic and social determinants of disease, are of equal importance (\u003Ca href=\"#B51\"\u003E51\u003C\u002Fa\u003E, \u003Ca href=\"#B53\"\u003E53\u003C\u002Fa\u003E). The Global Plan to Stop Tuberculosis estimated that the funding gap to realize the 2035 elimination target at USD1.3 billion (\u003Ca href=\"#B51\"\u003E51\u003C\u002Fa\u003E).Development of new drugs for tuberculosis and new drug design has benefited from computational tools for rational drug design and identification of new drug targets, and digital health solutions hold promise for new antituberculotics (\u003Ca href=\"#B32\"\u003E32\u003C\u002Fa\u003E, \u003Ca href=\"#B37\"\u003E37\u003C\u002Fa\u003E, \u003Ca href=\"#B54\"\u003E54\u003C\u002Fa\u003E). Mobile phone communications between treatment provider and tuberculosis patients can be used to customize patient support, without the patient having to come to the clinic (\u003Ca href=\"#B55\"\u003E55\u003C\u002Fa\u003E). Electronic pill box dispensers already monitor if patients access treatment as prescribed, and if not, prompt care providers to intervene timeously before treatment is abandoned (\u003Ca href=\"#B55\"\u003E55\u003C\u002Fa\u003E). Deep learning has permitted the identification of novel compounds. A pioneering deep learning algorithm has identified a new broad-spectrum antimicrobial, halicin, that showed killing of \u003Ci\u003EM. tuberculosis\u003C\u002Fi\u003E at 16 μg\u002FmL (\u003Ca href=\"#B56\"\u003E56\u003C\u002Fa\u003E), named for the computer HAL in “2001: A Space Odyssey” (\u003Ca href=\"#B57\"\u003E57\u003C\u002Fa\u003E). The novel mechanism of action suggests currently recognized resistance mechanisms would not affect halicin's antimicrobial potential (\u003Ca href=\"#B56\"\u003E56\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Cp class=\"mb0\"\u003EThe current outlook for depression remains concerning, as global disease burdens increase, compounded by the paucity of management guidelines (\u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E): treatment demands will likely grow, necessitating innovative solutions. Potentiation of currently available bioactive compounds through methylation, altering the solubility, could enhance binding affinity and drug metabolism up to a factor of 2,000, permitting use of lower drug dosages: reduced side effects and improved safety profiles should decrease default rates (\u003Ca href=\"#B58\"\u003E58\u003C\u002Fa\u003E). Inexpensive novel techniques have been successfully used for citalopram, an antidepressant, and tedizolid (\u003Ca href=\"#B58\"\u003E58\u003C\u002Fa\u003E), an oxazolidinone with significant antituberculotic activity (\u003Ca href=\"#B59\"\u003E59\u003C\u002Fa\u003E). Improved computational power and artificial intelligence to mine health information data sets for depression may reveal genetic predisposition, psychiatric sub-types and identify new biochemical pathways for treatment previously unrecognized with classical approaches (\u003Ca href=\"#B60\"\u003E60\u003C\u002Fa\u003E). Mobile-health interventions enable confidential customized treatment and patient support (\u003Ca href=\"#B61\"\u003E61\u003C\u002Fa\u003E–\u003Ca href=\"#B63\"\u003E63\u003C\u002Fa\u003E). Self-help applications may prevent depression, prior to its development into full disease, decreasing demands on health resources (\u003Ca href=\"#B60\"\u003E60\u003C\u002Fa\u003E, \u003Ca href=\"#B62\"\u003E62\u003C\u002Fa\u003E, \u003Ca href=\"#B63\"\u003E63\u003C\u002Fa\u003E). Deep learning algorithms targeting single nucleotide polymorphisms as genetic biomarkers may predict clinical treatment outcomes and adverse drug reactions in patients with major depressive disorder treated with antidepressants (\u003Ca href=\"#B64\"\u003E64\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ca id=\"h10\" name=\"h10\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EDiscussion\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EThe right of everyone to greater standards of mental and physical health has been emphasized at a high-level United Nations meeting on tuberculosis in 2018 (\u003Ca href=\"#B51\"\u003E51\u003C\u002Fa\u003E). Patient-centered care of tuberculosis and depression requires multidisciplinary approaches for integrated management of risk factors and co-morbidities (\u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E, \u003Ca href=\"#B53\"\u003E53\u003C\u002Fa\u003E, \u003Ca href=\"#B64\"\u003E64\u003C\u002Fa\u003E). A recent study showed only five of 26 countries, 21 of which are high tuberculosis-incidence, had standard protocols for the co-management of other disorders: supposed barriers to program integration included limited capacity, not perceiving mental health as problematic, resource insufficiencies and social stigmata of tuberculosis and mental disease (\u003Ca href=\"#B65\"\u003E65\u003C\u002Fa\u003E), despite mounting evidence of the association internationally (\u003Ca href=\"#B8\"\u003E8\u003C\u002Fa\u003E, \u003Ca href=\"#B66\"\u003E66\u003C\u002Fa\u003E–\u003Ca href=\"#B71\"\u003E71\u003C\u002Fa\u003E), possibly accounting for the lack of comprehensive guidelines for addressing comorbidities with depression identified in LMICs (\u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E). Nonetheless, integration of HIV and tuberculosis programs has greatly reduced patient morbidity and mortality (\u003Ca href=\"#B53\"\u003E53\u003C\u002Fa\u003E); integration of diabetes with tuberculosis programs improved treatment outcomes of both (\u003Ca href=\"#B72\"\u003E72\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\n\u003Ca id=\"h11\" name=\"h11\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EConclusion\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EAs treatments evolve, big data and mobile health technologies should facilitate easier monitoring of potential drug interactions–beneficial or detrimental–to optimize therapies. Integrating tuberculosis management and mental health within health systems can and should be designed according to patient needs (\u003Ca href=\"#B8\"\u003E8\u003C\u002Fa\u003E, \u003Ca href=\"#B65\"\u003E65\u003C\u002Fa\u003E). In the absence the urgent introduction of policies permitting patient-centered management of the syndemic, the public health implications are grave and the global outlook for both diseases remains bleak.\u003C\u002Fp\u003E\n\u003Ca id=\"h12\" name=\"h12\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAuthor Contributions\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EMV conceptualized paper. Both authors contributed to the writing of the paper and approved the final submission.\u003C\u002Fp\u003E\n\u003Ca id=\"h13\" name=\"h13\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EFunding\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EFunding was provided by the South African Medical Research Council.\u003C\u002Fp\u003E\n\u003Ca id=\"h14\" name=\"h14\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EConflict of Interest\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EMV and KK are employed by the South African Medical Research Council.\u003C\u002Fp\u003E\n\u003Ca id=\"h15\" name=\"h15\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAcknowledgments\u003C\u002Fh2\u003E\n\u003Cp class=\"mb0\"\u003EEmily Gomes and Linda Olivier for editorial support.\u003C\u002Fp\u003E\n\u003Ca id=\"h16\" name=\"h16\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EReferences\u003C\u002Fh2\u003E\n\u003Cdiv class=\"References\" style=\"margin-bottom:0.5em; margin-left:2em;\"\u003E\n\u003Cp class=\"ReferencesCopy1\" style=\"margin-left:0.7em; text-indent:-1.1em;\"\u003E\u003Ca name=\"B1\" id=\"B1\"\u003E\u003C\u002Fa\u003E 1. 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Mendenhall E, Kohrt BA, Norris SA, Ndetei D, Prabhakaran D. Non-communicable disease syndemics: poverty, depression, and diabetes among low-income populations. \u003Ci\u003ELancet\u003C\u002Fi\u003E. (2017) 389:951–63. doi: 10.1016\u002FS0140-6736(17)30402-6\u003C\u002Fp\u003E\n\u003Cp style=\"margin-left:1em;\" class=\"ReferencesCopy2\"\u003E\u003Ca href=\"https:\u002F\u002Fpubmed.ncbi.nlm.nih.gov\u002F28271846\" target=\"_blank\"\u003EPubMed Abstract\u003C\u002Fa\u003E | \u003Ca href=\"https:\u002F\u002Fdoi.org\u002F10.1016\u002FS0140-6736(17)30402-6\" target=\"_blank\"\u003ECrossRef Full Text\u003C\u002Fa\u003E | \u003Ca href=\"http:\u002F\u002Fscholar.google.com\u002Fscholar_lookup?author=E+Mendenhall&author=BA+Kohrt&author=SA+Norris&author=D+Ndetei&author=D+Prabhakaran+&publication_year=2017&title=Non-communicable+disease+syndemics%3A+poverty,+depression,+and+diabetes+among+low-income+populations&journal=Lancet&volume=389&pages=951-63\" target=\"_blank\"\u003EGoogle Scholar\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003C\u002Fdiv\u003E\n\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"thinLineM20\"\u003E\u003C\u002Fdiv\u003E\n\u003Cdiv class=\"AbstractSummary\"\u003E\n\u003Cp\u003E\u003Cspan\u003EKeywords:\u003C\u002Fspan\u003E history, isoniazid, psychiatry, antidepressant, policy, syndemic, depression, tuberculosis\u003C\u002Fp\u003E\n\u003Cp\u003E\u003Cspan\u003ECitation:\u003C\u002Fspan\u003E Van Der Walt M and Keddy KH (2021) The Tuberculosis-Depression Syndemic and Evolution of Pharmaceutical Therapeutics: From Ancient Times to the Future. \u003Ci\u003EFront. Psychiatry\u003C\u002Fi\u003E 12:617751. doi: 10.3389\u002Ffpsyt.2021.617751\u003C\u002Fp\u003E\n\u003Cp id=\"timestamps\"\u003E\u003Cspan\u003EReceived:\u003C\u002Fspan\u003E 16 October 2020; \u003Cspan\u003EAccepted:\u003C\u002Fspan\u003E 15 April 2021;\u003Cbr\u003E \u003Cspan\u003EPublished:\u003C\u002Fspan\u003E 01 June 2021.\u003C\u002Fp\u003E\n\u003Cdiv\u003E\u003Cp\u003EEdited by:\u003C\u002Fp\u003E \u003Ca href=\"http:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F368476\u002Foverview\"\u003ELawrence Toll\u003C\u002Fa\u003E, Florida Atlantic University, United States\u003C\u002Fdiv\u003E\n\u003Cdiv\u003E\u003Cp\u003EReviewed by:\u003C\u002Fp\u003E \u003Ca href=\"http:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F388360\u002Foverview\"\u003EJames E. Barrett\u003C\u002Fa\u003E, Drexel University, United States\u003Cbr\u003E \u003Ca href=\"http:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F8132\u002Foverview\"\u003EFrancisco Lopez-Munoz\u003C\u002Fa\u003E, Camilo José Cela University, Spain\u003C\u002Fdiv\u003E\n\u003Cp\u003E\u003Cspan\u003ECopyright\u003C\u002Fspan\u003E © 2021 Van Der Walt and Keddy. This is an open-access article distributed under the terms of the \u003Ca rel=\"license\" href=\"http:\u002F\u002Fcreativecommons.org\u002Flicenses\u002Fby\u002F4.0\u002F\" target=\"_blank\"\u003ECreative Commons Attribution License (CC BY)\u003C\u002Fa\u003E. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\u003C\u002Fp\u003E\n\u003Cp\u003E\u003Cspan\u003E*Correspondence:\u003C\u002Fspan\u003E Martie Van Der Walt, \u003Ca id=\"encmail\"\u003EbWFydGllLnZhbmRlcndhbHRAbXJjLmFjLnph\u003C\u002Fa\u003E\u003C\u002Fp\u003E\n\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\n\u003C\u002Fdiv\u003E",menuHtml:"\u003Cul class=\"flyoutJournal\"\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h1\"\u003EAbstract\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h2\"\u003EIntroduction\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h3\"\u003EThe Interaction Between Tuberculosis and Depression\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h4\"\u003EPast Wisdom, Tuberculosis, and Melancholia\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h5\"\u003EThe Development of Antituberculotics\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h6\"\u003EIsoniazid, Serendipity, and the First Antidepressant\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h7\"\u003EDevelopment of New Antituberculotics\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h8\"\u003EEvolution of Antidepressants\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h9\"\u003EThe Impact of the Digital ERA\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h10\"\u003EDiscussion\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h11\"\u003EConclusion\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h12\"\u003EAuthor Contributions\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h13\"\u003EFunding\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h14\"\u003EConflict of Interest\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h15\"\u003EAcknowledgments\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003Cli\u003E\u003Ca href=\"#h16\"\u003EReferences\u003C\u002Fa\u003E\u003C\u002Fli\u003E\r\n\u003C\u002Ful\u003E\r\n"},files:[{name:"EPUB.epub",fileServerPackageEntryId:g,type:{code:ar,name:ar}},{name:as,fileServerPackageEntryId:"fpsyt-12-617751\u002Ffpsyt-12-617751.pdf",type:{code:p,name:p}},{name:as,fileServerPackageEntryId:g,type:{code:p,name:p}},{name:"fpsyt-12-617751.xml",fileServerPackageEntryId:"fpsyt-12-617751\u002Ffpsyt-12-617751.xml",type:{code:"NLM_XML",name:"XML"}},{name:"Provisional PDF.pdf",fileServerPackageEntryId:g,type:{code:p,name:p}}]},currentArticlePageMetaInfo:{title:at,link:[{rel:"canonical",href:au}],meta:[{hid:v,property:v,name:v,content:av},{hid:aw,property:aw,name:"title",content:at},{hid:ax,property:ax,name:v,content:av},{hid:ay,name:ay,content:"non-communicable disease,History,Isoniazid,Psychiatry,antidepressant,Treatment,multidrug resistance,policy,syndemic,Depression,Tuberculosis"},{hid:az,property:az,name:"site_name",content:w},{hid:aA,property:aA,name:C,content:"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=1200&f=png\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F617751\u002Ffpsyt-12-617751-HTML\u002Fimage_m\u002Ffpsyt-12-617751-g001.jpg"},{hid:aB,property:aB,name:"type",content:"article"},{hid:aC,property:aC,name:"url",content:au},{hid:aD,name:aD,content:"summary_large_image"},{hid:aE,name:aE,content:"12"},{hid:aF,name:aF,content:o},{hid:aG,name:aG,content:w},{hid:aH,name:aH,content:E},{hid:aI,name:aI,content:F},{hid:aJ,name:aJ,content:_},{hid:aK,name:aK,content:"617751"},{hid:aL,name:aL,content:"English"},{hid:aM,name:aM,content:H},{hid:aN,name:aN,content:"non-communicable disease; History; Isoniazid; Psychiatry; antidepressant; Treatment; multidrug resistance; policy; syndemic; 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Psychiatry","1664-0640",void 0,"The Tuberculosis-Depression Syndemic and Evolution of Pharmaceutical Therapeutics: From Ancient Times to the Future",18,9,12,1920,"por-journal.com",7,"escubed.org",1918,"fipp","https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002F6AABBF14-F784-4D3A-922AAF7C5C78EEB0\u002Fwebimage-5702571E-9A2B-4ABE-A1E051BF419C941A.png","science","neurology","22C10171-81B3-4DA6-99342F272A32E8BB","jpg","2022-06-27T10:00:51Z","fpsyt",68,"journal_field","10.3389\u002Ffpsyt.2021.617751","\u003Cp\u003EThe interplay between tuberculosis and depression has been problematic since the humoralists. Over the centuries similarities in disease management have transpired. With the advent of isoniazid chemotherapy, transformation of tuberculosis patients from morbidly depressive to euphoric was noted. Isoniazid was thereafter widely prescribed for depression: hepatotoxicity ending its use as an antidepressant in 1961. Isoniazid monotherapy led to the emergence of drug resistant tuberculosis, stimulating new drug development. Vastly increased investment into antidepressants ensued thereafter while investment in new drugs for tuberculosis lagged. In the 21st century, both diseases independently contribute significantly to global disease burdens: renewed convergence and the resultant syndemic is detrimental to both patient groups. Ending the global tuberculosis epidemic and decreasing the burden of depression and will require multidisciplinary, patient-centered approaches that consider this combined co-morbidity. The emerging era of big data for health, digital interventions and novel and repurposed compounds promise new ways to treat both diseases and manage the syndemic, but absence of clinical structures to support these innovations may derail the treatment programs for both. New policies are urgently required optimizing use of the current advances in healthcare available in the digital era, to ensure that patient-centered care takes cognizance of both diseases.\u003C\u002Fp\u003E",8,"History","Martie","Tuberculosis Platform, South African Medical Research Council","South Africa",1103481,"Karen H.",368476,"Lawrence","United States",8132,"Francisco",388360,{},91,"Psychopharmacology","psychopharmacology","EPUB","fpsyt-12-617751.pdf","Frontiers | The Tuberculosis-Depression Syndemic and Evolution of Pharmaceutical Therapeutics: From Ancient Times to the Future","https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fpsychiatry\u002Farticles\u002F10.3389\u002Ffpsyt.2021.617751\u002Ffull","The interplay between tuberculosis and depression has been problematic since the humoralists. 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