Psychiatric Morbidity and Other Factors Affecting Treatment Adherence in Pulmonary Tuberculosis Patients

As the overall prevalence of TB remains high among certain population groups, there is growing awareness of psychiatric comorbidity, especially depression and its role in the outcome of the disease. The paper attempts a holistic approach to the effects of psychiatric comorbidity to the natural history of tuberculosis. In order to investigate factors associated with medication nonadherence among patients suffering from tuberculosis, with emphasis on psychopathology as a major barrier to treatment adherence, we performed a systematic review of the literature on epidemiological data and past medical reviews from an historical perspective, followed by theoretical considerations upon the relationship between psychiatric disorders and tuberculosis. Studies reporting high prevalence rates of psychiatric comorbidity, especially depression, as well as specific psychological reactions and disease perceptions and reviews indicating psychiatric complications as adverse effects of anti-TB medication were included. In sum, data concerning factors affecting medication nonadherence among TB patients suggested that better management of comorbid conditions, especially depression, could improve the adherence rates, serving as a framework for the effective control of tuberculosis, but further studies are necessary to identify the optimal way to address such issues among these patients.


Introduction
Tuberculosis (TB) is a chronic infectious multisystemic disease caused by mycobacterium tuberculosis [1] and is one of the leading causes of mortality worldwide [2][3][4]. The World Health Organization (WHO) has estimated that 2 billion people, almost a third of the world's population, have latent TB [5,6]. Every year about eight million people develop this disease, and some three million die of it, over 95% of these from developing countries [7,8]. In 2005 the highest rates per capital were from Africa (28% of all TB cases), and half of all new cases were from six Asian countries, namely, Bangladesh, China, India, Indonesia, Pakistan, and the Philippines [9,10].
Beginning in 1985, a resurgence [11][12][13][14] of TB was observed, primarily in certain groups, including the homeless [15], those who are HIV seropositive [16], individuals with a history of alcohol or drug abuse [17], and immigrants from a country in which TB is endemic [18].
Many recipients of psychiatric services possess one or more of these risk factors [19,20], and, consequently, TB may be overrepresented in this population. Conversely, psychiatric illness may develop subsequent to TB infection, and mood disorders seem to be particularly common in TB patients compared with those with other medical diagnoses [21][22][23][24].
The World Health Organization's (WHO) goal of tuberculosis control remains elusive [25,26], and this failure has been blamed on numerous factors such as inadequate emphasis on human dimension of tuberculosis control [27][28][29] which includes nonadherence with medication and results in multidrug resistance and therapeutic failure [30,31].
The purpose of this study is to investigate factors associated with medication nonadherence among patients suffering from tuberculosis with emphasis on psychopathology as a major barrier to treatment adherence [32,33].
The literature indicates that psychiatric comorbidity [34] before and after tuberculosis onset, psychological issues such as stigma [35], isolation [36], sense of social support [37], helplessness [38], and other psychological reactions to the We reviewed the reference section of all (64) retrieved articles in order to locate additional publications not found in our initial search disclosure of the diagnosis [39] as well as medication sideeffects [40], all adversely affect the treatment adherence.
On the other hand, studies report high prevalence rates of psychiatric comorbidity among patients with drug-resistant tuberculosis [40] and that prevalence of depression significantly correlates with severity and duration of the disease [41,42].
The causal relationships between mental disorders and tuberculosis are complex. Severe mental disorders are associated with high risk of tuberculosis acquisition and transmission [43] and with poorer adherence to anti-TB treatment. Conversely, diagnosis with tuberculosis increases risk of psychiatric comorbidity.
Only by taking these observations together along with the fact that the prevalence of tuberculosis rises in specific groups [179] especially among individuals who are more likely to be psychologically distressed than the general population, such as homeless, immigrants, and HIV patients, does a complete picture emerge, and researchers conclude that in order to increase the cure rates of tuberculosis psychiatric, comorbidity must be firstly identified and treated [82].

Search Strategy.
Using the terms "tuberculosis and mental illness, " "anxiety and depression in tuberculosis, " "risk factors for nonadherence to tuberculosis treatment, " and "psychiatric and antitubercular drugs, " we searched Medline and using the terms "mental illness stigma and tuberculosis, " "mental illness primary care and tuberculosis, " and "tuberculosis nonadherence and psychosocial factors, " we searched PubMed. Articles were restricted to English, and publication dates were from 1950 to 2012. This yielded 355 articles. However, after excluding 38 articles that focused on TB without attention to mental health, 24 articles on mental health outside the context of TB and another 121 irrelevant and 73 extra specialized articles outside our primary focus, 94 articles were found, but 82 were kept for review, after excluding common articles. Then, 34 articles with publication dates older than 5 years were sent to Scholar Google in order to check their citation indexes. With this method, we located 53 additional articles with publication dates during the last 5 years. We reviewed the reference section of all (135) retrieved articles in order to locate additional publications not found in our initial search (Consort diagram- Figure 1).
We reviewed each article, noting date of publication, key results, and conclusions and then assigned the articles to different categories according to our primary focus.
Firstly, we reviewed the past medical literature, from an historical perspective. Then, we theorized upon issues regarding the complex interrelation and interaction between psychiatric disorders and tuberculosis, followed by accumulated data and results from clinical studies indicating prevalence rates of psychiatric comorbidity and specific psychological reactions and disease perceptions in tuberculous patients. Afterwards, we performed a review of the literature on psychiatric disorders in patients receiving antituberculosis drugs, possibly resulting in comorbid states as well as in treatment interruption which compromises treatment efficacy leading to cases of high-grade drug resistance. Tuberculosis Research and Treatment 3 Table 1: Categories of psychiatric conditions in TB patients. (1) Psychiatric conditions arising after TB are diagnosed (as reactions to the medical illness or a direct physiological consequence of the illness)-according to DSM-IV: (i) adjustment disorder, (ii) mood disorders (e.g., major depression), (iii) anxiety disorders (e.g., PTSD, acute stress disorder, and GAD), (iv) somatoform disorders (e.g., pain disorders and neurasthenia), (v) delirium and other cognitive disorders, (vi) personality change due to a general medical condition. Differential diagnosis in this category is necessary between a psychosocial issue and a diagnosable mental disorder.
( 3) Preexisting psychiatric disorders potentially increasing risk of TB and risk of progression from latent TB infection to active TB (e.g., substance related disorders, psychotic disorders, mood disorders, and psychological factors affecting medical condition).
(4) Coexisting psychiatric disorders exacerbated by TB, without necessarily being etiologically related but complicate the diagnosis and management and can alter its course (e.g., specific phobia).
Comorbidity as a result of commonly shared risk factors for the development of a variety of psychiatric disorders and TB (e.g., substance related disorders and low socioeconomic status).
Finally, we summarized factors affecting treatment adherence, and we concluded that management of psychiatric complications, especially depression which is more prevalent in tuberculosis, is necessary and possible without compromising antituberculosis treatment.

Results
The literature review yielded in sum 135 articles: 4 on epidemiology, 3 on the past medical literature, 59 on results from clinical studies on psychiatric comorbidity in TB patients, 12 on psychological reactions and disease perceptions, 28 on psychiatric disorders in patients receiving anti-TB drugs, 17 on factors affecting medication nonadherence, and 12 on interactions involving TB medications and psychiatric medications. The overall citations are many more since we reviewed the reference section of these retrieved articles.

Psychiatry and Tuberculosis
4.1. A Review of the Literature. The psychological aspects of tuberculosis have always been a topic of interest over the centuries [180][181][182] and the association of tuberculosis and mental illness became a subject of statistical analysis as early as 1863 [183]. Clouston analyzed the deaths from tuberculosis in an Edinburgh asylum, after comparing figures from La Salpetriere and a New York state asylum and raised the question if conditions of living in asylums favor the development of tuberculosis or there is a special relationship between tuberculosis and insanity. Later, studies [184] in New York state hospitals indicated that prevalence rates of tuberculosis, diagnosed by X-rays findings, increased with the length of time between first admission and the X-ray survey, emphasizing the role of the contagious factor [185].
Concerning psychopathology of tuberculosis, Jacobson firstly observed that some tuberculous patients are euphoric and appear totally unaware of the gravity of their illness [186]. This clinical observation was later rejected by other studies [187,188]. When attempting to describe the personality of tuberculous patients some writers implied that the number of neurotics among them was greater than the number encountered among the general population [187][188][189], but figures are lacking. When figures do come up, Day [190] believed that 30% of patients he observed in an English sanatorium were "ill of mind, " Breuer [191] reported that for 34% of his patients, tuberculosis was "psychologically determined, " and Forster and Shepard [192] found that 31% of tuberculous patients in Cragmor Sanatorium were suffering from an "abnormal mental state. " Bobrowitz [193] mentioned that from 20% to 50% of patients of the Otisville Sanatorium in New York leave against advice mainly for psychological reasons and Ashmore and Bell [194] found that among veterans tuberculous patients who left against advice in their first year of treatment, chronic alcoholism, psychopathy, and ignorance, all played a part. Also, tuberculous patients have been psychoanalyzed by Jelliffe and Evans [195] who concluded that they were "childish, selfish, self-centered, irritable, dissatisfied, and ungrateful. " Wittkower and Todd [196] described the various states of mind in these patients: "constructive resignation and indifference, depression and anxiety, defiance and ultra-cheerfulness, resentment and apathy. " Scattered through the literature, there are numerous reports suggesting that the natural history of tuberculosis is modified under the influence of emotional factors, and Hartz [197] noted that "an individual may react to life situations with an anxiety state or other personal behavior in such a way as to interfere with healthy living, and these reactions may thereby become a most significant factor in the onset and course of clinical tuberculosis. "

Theoretical Considerations.
There have been times when the high incidence of tuberculosis in mental illness was interpreted to mean that perhaps tuberculosis may cause mental 4 Tuberculosis Research and Treatment   56% in the control group were found to have psychiatric problems/anxiety state was most common in the control group (57%). The prevalence of psychiatric illness was higher in females than males, high between 15 and 44 years (91%) and more in the low socioeconomic group, illiterates, and semiliterates; more in housewives, unskilled workers, and large and joint families. Higher psychiatric morbidity was observed in chronic, far-advanced and resistant tuberculosis patients.  The degree of neuroticism correlated significantly with scores on subscales of DAQ. Higher neuroticism showed higher psychosocial dysfunctioning. Denial of problem was seen more in controls.
The differences between the two groups were statistically significant. The tuberculosis patients were receiving treatment from two DOTS centres in East Delhi, and the controls were from the same locality.
A valid illness behavioral profile of these patients to be used as an adjuvant to the implementation of the revised tuberculosis control programme.
Furin (2001) [76] A retrospective record review of 60 patients who had received individualized therapy for MDR-TB.
Defined using DSM-IV criteria.
Depression was the most frequent baseline finding, occurring in 38.3% of the patient population and alcoholism in 3.3%.
Side effects of medication include: depression newly diagnosed in 18.3% patients after a median of 8.5 months, anxiety in 11.7%, and psychotic symptoms in 10%.

10
Tuberculosis Research and Treatment The SSRS results of subjective and objective supports and total score of social supports of the tuberculosis group * → were significantly higher than those of the control group/. * were much lower than those of the control group.

MINI-International Neuro
Psychiatric Interview Scale.
46% of psychiatric morbidity, majority is depressive disorders (36%) followed by anxiety disorders (24%)/comorbidity of depressive and anxiety disorders in 16% of patients. 31% psychiatric morbidity in patients admitted in medical wards [47] psychiatric morbidity of 20% in their study of two general medical wards [48]. Depressive disorders are more in lower socioeconomic groups, patients with longer duration of tuberculosis illness, who stayed in hospital for longer duration and patients receiving non-RNTCP drugs. Anxiety disorders are more in lower educated group, tuberculosis associated with complications and patients with longer hospital stay.

12
Tuberculosis Research and Treatment      and alcohol misuse.
The prevalence of PTSD symptoms was 29.6%.
Factors that predicted PTSD symptoms were poverty, residing in an urban area, psychological distress, suicide attempt, alcohol and/or drug use before sex, unprotected sex, TB-HIV coinfected, and the number of other chronic conditions.

18
Tuberculosis Research and Treatment Eighty-two of the patients had tuberculosis.
The incidence rate of tuberculosis was significantly higher than that of the general population for both male and female schizophrenic patients.
Lopez (1994) [19] 43 psychiatric patients at a general hospital at time of discharge.
19% were PPD positive at time of discharge, with 2 patients requiring a course of isoniazid prophylaxis.
Saez (1996) [12] 85 men discharged to community living by the on-site mental health program between 1990 and 1992, in NY.
All HIV-positive men, PPD-positive or inconclusive and all had active TB.  Tuberculosis is a disease both of individual and society and patients' first reactions to the diagnosis were tension/anxiety (30%), loss of interest/depression (26%), denial (6%), could not explain how they felt (20%), and only 18% were hopeful of cure.
Rajeswari [109] The initial reaction of patients to the disclosure of the diagnosis was worry (50%) and suicidal thoughts (9%).
Deribew [92] People with perceived stigma may have a low self-image and be socially isolated which may predispose them to common mental disorders. Jaggarajamma [110] Perceived stigma which refers to the fear of discrimination or acceptability was higher than enacted stigma, which refers to actual discrimination or acceptability.
Courtwright [111] The most common cause of TB stigma is the risk of transmission from TB infected individuals to susceptible community members but also because of its association with HIV, poverty, low social class, malnutrition, or disreputable behavior. Also, TB stigma had a more significant impact on women and on poor or less-educated community members, which is especially concerning given that these groups are often at higher risk for health disparities [112]. TB stigma may, therefore, worsen preexisting gender-and class-based health disparities, and it is perceived to increase TB diagnostic delay and treatment nonadherence [37,113].
Naidoo [38] People who have a lifelong or infectious disease and who have limited social, psychological, and economic resources find it extremely difficult to maintain a reasonable quality of life and that helplessness [114] and depression have a negative influence on adherence to treatment.
Marra [115] There are numerous aspects of active TB that may lead to a reduction in the quality of life, such as prolonged therapy with multiple, potentially toxic drugs that can lead to adverse reactions in a significant number of patients. Also, there is considerable social stigma associated with active TB leaving the individual feeling shunned and isolated from their friends and families, and there is a lack of knowledge regarding the disease process and its treatment which may contribute to feelings of helplessness and anxiety. illness or that mental illness forms a strong predisposition to tuberculosis [198].
The literature suggests the mutual influence and relationship between physical and mental illness, and many studies report the nature and prevalence of comorbid physical illness with severe mental disorders [199]. Research in this direction is mainly concerned with studying physical morbidity among psychiatrically ill individuals [200], but studies to delineate psychiatric profile of physically ill persons [201,202] have also received attention.
Medical illness and chronic disease create multiple burdens for patients, including the necessity to deal with pain, suffering, reduced quality of life, premature mortality, financial costs, and familial emotional trauma [110]. The risk factors for mental health problems are complex [203]. Presence of medical illness [204], stigma, and discrimination [92] are major determinants of mental disorders, especially mood and anxiety disorders. Usually, the more serious the somatic disease, the more probable will be, to be accompanied by mood and/or anxiety symptoms of variable severity [86]; conditions arising after the somatic disease is diagnosed. Failure to manage such mental health problems increases the patients' probability of suffering from complications, even lethal.
The lifetime prevalence of mood disorder in patients with chronic disease is from 8.9% to 12.9%, with a 6-month prevalence of 5.8% to 9.4% [205,206]. According to findings from worldwide research, 20% of patients with somatic disease suffer from major depression [207,208].
In patients with pulmonary disease in particular, functionality may be severely impaired due to chronic psychogenic and somatic pain [209], frequent hospital admissions, and dependency from medical and nursing personnel. The observed higher prevalence of depression and anxiety in patients with chronic pulmonary disease [210]-compared to other chronic diseases-may be explained within this context.
The reasons for the frequent cooccurrence of psychiatric disorders and medical illnesses could be that the first represents reactions to illnesses and treatment or that they are a direct physiological consequence of the illness or complications of treatments (INH-induced psychosis) [83,134].
Also, psychiatric disorders may coincide with medical illnesses, without being etiologically related to them, but they complicate the diagnosis and management and can alter their course. For diagnostic purposes, it is often difficult to determine if the vegetative symptoms of depression or somatic symptoms of anxiety are evidences of the psychiatric disorder or symptoms of medical disease, or both.
Another reason for the frequent comorbidity is that there are commonly shared risk factors [19] for the development of a variety of psychiatric and medical disorders (smoking [211], low socioeconomic status [93], etc.).
Tuberculosis is a classic example of a disease with both medical and social dimensions, characterized by its close relation to poor socioeconomic conditions [110]. Increased risk [1,105] of acquiring active disease occurs with alcoholism, smoking, intravenous drug abuse, diabetes mellitus, Isoniazid and ethambutol Peripheral neuropathy is associated with the use of isoniazid In approximately 17% of patients using doses of 300 mg daily and lower frequency to the use of ethambutol [118] Isoniazid and ethambutol The optic neuritis manifests with reduced visual field or acuity or color vision Uncommon during the use of isoniazid and ethambutol/is related to generally at high doses or prolonged use [118] Isoniazid The behavioral disorders, changes in the rhythm of sleep, reduced memory, and psychosis have been described for the use of isoniazid. Seizures and coma are described by the excessive intake of isoniazid.  The incidence of isoniazid-associated psychosis is rare [131] Isoniazid A patient who developed a psychotic disorder after 4 months of isoniazid prophylaxis for a positive tuberculosis tine test. His symptoms resolved within 2 weeks of discontinuing the isoniazid. [132] Primary antituberculosis (anti-TB) drugs Out of 1149 patients with established tuberculosis who initially received anti-TB therapy neuropsychiatric manifestations were observed during the initial phase of therapy.
In 0.7% of TB patients [133] 22 Tuberculosis Research and Treatment Has been reported in 1%-2% of patients taking shorter courses of the drug, with higher rates reported with prolonged treatment [134] Ethionamide A patient being treated with streptomycin, isoniazid, pyrazinamide, ethionamide, and prednisolone developed an acute psychotic reaction and died after jumping from a second floor window. It is probable that the reaction was precipitated by the ethionamide.
A case report [135] Ethambutol Dizziness, disorientation, and auditory and visual hallucinations developed after seven days of therapy. Following discontinuation of anti-TB agents, the psychiatric symptoms subsided. When the patient was challenged with EMB, the same psychiatric symptoms recurred, but resolved again after discontinuation of EMB. EMB may be associated with mania, confusion, and psychosis.
A case report [136] Fluoroquinolones Have been implicated in rare occurrences of psychosis, depression, suicidal ideation, delirium, and nightmares. CNS toxicity occurs in 1%-4.4% of patients but with serious adverse occurring in less than 0.5% of patients.
A case of a woman who experienced an acute psychosis secondary to ciprofloxacin administration, which resolved on cessation of therapy. Two cases of organic psychosis, induced by ofloxacin. 8861 patients receiving ciprofloxacin were assessed worldwide, and 138 cases presented with various neurological adverse reactions.
[137] [138] [139] [140] Ofloxacin or ciprofloxacin In a retrospective study conducted by the authors, 4189 reports of consultant psychiatric examinations were analyzed. In 29 patients, the suspicion of psychopathological ADR during treatment with ofloxacin or ciprofloxacin was documented. Psychopathological findings included delirious states, paranoid, depressive and manic syndromes, agitation, sleep disturbances, and stupor. In elderly patients, delirious and paranoid syndromes were predominant, whereas affective disturbances occurred more often in younger patients.
Reported psychiatric disturbance in 0.7% of 4189 individuals treated with either ofloxacin or ciprofloxacin. [141] Cycloserine Severe psychiatric manifestations-including hallucinations, anxiety, depression, euphoria, behavioral disorders, and suicidal ideation and/or attempts. Psychiatric symptoms appear most likely to present within the first 3 months of treatment.
Have been reported to occur in 9.7%-50% of individuals receiving CS. HIV infection, and other factors. The above-mentioned risk factors are very prevalent in psychiatric populations and increase risk of progression from latent TB to active TB [104]. Patients suffering from pulmonary tuberculosis are reported to have psychiatric disorders like depression [212], anxiety, psychosis [83], and also many psychosocial problems [37,213] like increased smoking [74], increased alcohol consumption [87], divorce, and isolation from the family [36]. However, it is important to draw the line between a psychosocial issue and a diagnosable mental disorder in order to address the effective interventions which necessitate different knowledge and skills [214].
Psychopathology may be a very important negative factor to treatment adherence [169] for patients with somatic disease, and nonadherence to treatment is a major setback for effective tuberculosis control in the community, possibly responsible for the appearance of drug-resistant TB which is caused by inconsistent or partial treatment of the disease [215] and probably responsible for nonadherence with latent TB therapy, which may increase risk of progression from Table 6: Clinically significant drug-drug interactions involving TB medications and psychiatric medications.

TB medications Psychiatric medications Interactions References
Isoniazid, in therapeutic dose Was found to inhibit markedly plasma, but not platelet, MAO. [149] Drug that inhibits monoamine oxidase SSRIs or TCAs.
Is contraindicated because of the potential to induce serotonin syndrome [150] No reports of serotonin syndrome induced by combining SSRIs and isoniazid are published. [151] Isoniazid Phenytoin and carbamazepine selected benzodiazepines (valium and others) Valproate Haldol.
Isoniazid can cause increased phenytoin and carbamazepine serum concentrations and toxicity. Isoniazid inhibits metabolism of selected benzodiazepines. Inhibition of monoamine oxidase and histaminase by Isoniazid can cause significant drug-food interactions. isoniazid has a biphasic effect of inhibition-induction on one cytochrome P450 isozyme, CYP2E1 and increases hepatic and CNS valproate toxicity and haldol toxicity.
Are metabolized by similar mechanisms. Hepatic cytochrome P450 (CYP) enzymes are largely responsible for metabolism of isoniazid, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. While it has not been definitively established which isoenzymes are implicated in the metabolism of isoniazid, CYP2E1, CYP1A2, CYP2C9, CYP2C19, and CYP3A are inhibited to varying degrees by isoniazid. CYP2C19 and CYP3A were inhibited potently by isoniazid in a concentration-dependent manner. Both enzymes were inhibited approximately 40% by doses in the therapeutic range. Isoniazid induced competitive inhibition of CYP2D6 and weak noncompetitive inhibition of CYP2E1. [154] Isoniazid Paroxetine is metabolized primarily by CYP2D6.
CYP2D6 is affected negligibly by isoniazid. The potential for drug interactions would appear to be minimal. [24] Isoniazid Citalopram appears to be metabolized primarily by CYP2C19 and/or CYP3A4.
CYP3A3/4 is inhibited by isoniazid increased potential for drug interactions. [161,162] [ [161][162][163] 24 Tuberculosis Research and Treatment Reduces their levels. [164] Rifampin Nortriptyline A case report Higher than expected doses of nortriptyline were required to obtain a therapeutic drug level while the patient was receiving rifampin. [165] latent TB to active TB. Additionally, psychiatric disorders may hinder adaptation to chronic disease conditions, and it is known that adaptation is a crucial survival factor in chronic diseases [216]. Temporal and causative associations determine possible distinct categories of psychiatric conditions in TB patients (presented in Table 1).

Results from Clinical Studies
Research has shown that people infected with TB are more likely to develop mental and psychological problems than people not infected with the disease [217,218]. To be afflicted with pulmonary, tuberculosis is a unique and painful experience in the biopsychosocial history of an individual, and the emergent stress contributes to psychiatric morbidity [59].
Depression, posttraumatic stress disorder (PTSD), and acute stress disorder are the most common stress-related conditions of TB patients [36,219]. Reactions to the stressful situation brought about by the illness negatively affecting an individual's ability to work, in conjunction with social and respiratory isolation [220], lowered self-esteem, fear of spreading the illness to others, helplessness brought out by incapacitation due to chronic illness, and social stigma attached to this illness, are all plausible causes that one can postulate for depression and anxiety. Dependence on alcohol and other drugs could be the response to anxiety and depression [59].
The psychiatric morbidity of patients is considered to be a psychogenic reaction of neurotically predisposed people to their special situation and awareness that they are suffering from a severe and dangerous illness [221].
Prevalence studies (Table 2) reporting mean depression and anxiety rates of 46%-72% establish the need to address mental disorders in TB care [214].
Conversely, individuals with chronic mental illnesses present a series of risk factors that predispose them to extensive medical comorbidities [102,222]. Prevalence rates of tuberculosis among psychiatric patients are presented in Table 3, indicating that programs serving people with severe mental illness should regularly screen participants for TB infection and evaluate them for chemoprophylaxis in order to avoid the risk of developing active TB.

Psychological Reactions and Disease Perceptions
People believe that tuberculosis occurring in an individual is always an interruption in life, physically, psychologically, economically, and socially. Observations from the early days of the tuberculosis epidemic, before scientific studies, report that after the initial shock from the diagnosis, there is often a brief or prolonged period of denial, followed by resignation and depression, leading to distorted perceptions about the illness. Patients were described to exhibit strong emotions like fear, jealousy, vindictive behavior, anger, noncooperation, guilt, or a sense of shame. Rarely, suicides occurred, especially when the rest of the family tried to segregate the afflicted in a distant institution, or even stooped to a complete abandonment [223]. The scene changed dramatically in the fifties when tuberculosis became highly curable and preventable, assuming that physical, mental, economic, and social trauma had been rendered minimal, even that social stigma had nearly disappeared and needed no attention [109,224].
Unfortunately, stigma is seen to play a huge role in the experience of illness by TB patients, and it is believed that most TB patients even after full recovery from the illness feel the disease can never be completely cured [225]. According to Lawn [226] "patient perception about TB is usually stained, and patients permanently hold negative feelings towards the disease. " Disease-related stigma occurs when individuals with an illness are deemed undeserving of assistance and support from other individuals in the society (Schulte [227]). Over time, certain illnesses, such as TB, have been associated with reduced social status, and these negative reactions may impede coping and recovery [228]. The psychological adjustments to illness by a patient are negatively influenced primarily by the negative perceptions that other people within the society might hold (Fife and Wright [162]).
In other words, TB often has an impact on the physical, social and mental wellbeing of TB patients ( Rajeswari et al. [109]), and another element of this impact is the perception Of the 184, 48% patients were nonadherent. In multivariate analysis, only injection drug was used and homelessness predicted nonadherence.
These data lend support to directly observed therapy in tuberculosis.
Further improvements in the care of persistently nonadherent patients may require more psychosocial services, appropriate facilities for civil detention, and detaining patients long enough to assure completion of treatment.
Burman, 1997 [168] 18% who received outpatient DOT fulfilled one or more criteria for noncompliance. Risk factors for noncompliance were alcohol abuse and homelessness.
Innovative programs are needed to deal with alcoholism and homelessness in patients with tuberculosis.
Erhabor, 2000 [169] The rate of compliance with antituberculosis regimen under directly observed therapy was found to be high (73%). DOT improves the rate of compliance. The only factor that significantly influenced rate of compliance was proximity to the chest clinic. Also, psychopathology could have adversely affected the rate of compliance.
Locating chest units in the existing primary health care facilities will improve the rate of compliance with antituberculosis therapy. More attention should be paid to behavioral aspect of tuberculosis control. Health workers involved in the management of these patients should develop a higher index of suspicion for possible psychopathology.
Manoharam (2001) [74] 66.7% of subjects completed their treatment. Only smoking was found to be associated with poor compliance in univariate analysis The habit of smoking, disregarding own health, and not adhering to treatment instructions may be a reflection of the subject's personality. Felton, 2005 [170] Factors associated with adherence to treatment: patient related factors, provider characteristics, clinic facilities, characteristics of treatment regimens, and disease characteristics. Substance abuse was identified as the only factor that was strongly associated with nonadherence.
Few TB programmes that have explicitly offered patients treatment for substance abuse generally have demonstrated better outcomes than "unexpanded" DOTS programmes.
K. Ito, 2008 [163] Factors were classified into 7 categories; factors related to disbelief and/or prejudice for diagnosis and/or treatment (except factors related to drug adverse effects) were observed in 51.8%, factors related to economical problem in 24.1%, factors related to job or studies in 23.4%, factors related to drug adverse effects in 22.6%, factors related to visiting out-patients departments in 6.6%, psychiatric disease and/or drug abuse in 4.4%, others in 9.5%.
To improve the quality of tuberculosis medical care and services including good and sufficient explanations on TB and how to cure it and proper managements for drug adverse effects and then to expand public economical support for the costs of medicine and travel expenses to medical facilities and to make accessible time and place of the tuberculosis outpatient clinic more convenient and flexible for patients.

26
Tuberculosis Research and Treatment The factors contributing to noncompliance can be grouped into three categories, namely, patient related, health care, and community and treatment factors.
Develop and implement patient-centred interventions that encourage shared decision-making regarding treatment. Provide ongoing (in-service) training to health staff to improve and upgrade their competencies with regard to health education and communication skills. Strengthen patient support and community advocacy programmes aimed at eradicating the stigma associated with the disease. Emphasise the particular needs of individual patients and tailor the role of support systems to their needs. Plan interventions to reduce the influence of poverty and gender on patients and their treatment adherence Husain, 2008 [88] Depression and lack of perceived control over illness in those suffering from tuberculosis are reported to be independent predictors of poor adherence Treating psychological problems in patients with tuberculosis may substantially improve treatment adherence.
Kruk, 2008 [174] The majority of defaulters across the studies completed the 2-month intensive phase of treatment.
New TB chemotherapeutic agents which can reduce the length of treatment have the potential to improve global TB treatment success rates.
Matebesi, [175] Lack of knowledge about TB, nonsustainability of educational campaigns, side effects of drugs, hunger and lack of family support, stigma attached to TB, and health-related factors such as the attitude of health care providers and the long delay in obtaining a diagnosis.
Recommendations are made for the instigation of enhanced education programmes focusing on patients, the community, and health care providers.
Bagchi, 2010 [176] 16% of patients among patients receiving DOTS treatment were nonadherent to the anti-TB therapy.
Smoking during treatment and travel-related cost factors were significantly associated with nonadherence in the newly diagnosed patients, while alcohol consumption and shortage of drugs were significant in the residual groups.
Targeting easier access to drugs, an ensured drug supply, effective solutions for travel-related concerns, and modification of smoking and alcohol-related behaviors are essential for treatment adherence.
Kizub, 2012 [177] Factors related to the patient (lack of means, being a migrant worker, distance to treatment site, poor understanding of treatment, drug use, and mental illness), medical team (high patient load, low motivation, and lack of resources for tracking defaulters), treatment organization (poor communication between treatment sites, no systematic strategy for patient education or tracking, and incomplete record keeping), and health care system and society. of others in the community about TB, which influences the self-perception of TB patients. The self-perception of a TB patient is influenced by the existing health-related beliefs in the community, the culture of the community, which a TB patient lives in, and the expected health behavior of a TB patient by the community. Although patient's perceptions about TB remain largely unknown [72], yet the literature shows a lot of reactions of TB patients to the disclosure of their diagnosis and these reactions included feelings of loneliness, depression, suicidal thoughts, fear, apathy, shock, concern, surprise (in relation to the lack of symptoms), and acceptation [109,115]. The possible reasons for these emotions may be the stigma discrimination and social isolation attached to the disease or "physical rehabilitation, illiteracy, lack of knowledge of TB, or fear of loss of income on account of long duration of treatment. " [109] Studies reporting patients' psychological reactions and disease perceptions about TB are summarized in Table 4.
Evidence also suggests the correlation between susceptibility to tuberculosis and specific personality traits [229], and studies indicate that in a large number of tuberculosis cases emotional conflict appears to inhibit recovery, and major life changes [189] provoke relapses.
Emerging disciplines like psychoneuroimmunology and neuroendocrinology could pave the way to better understanding of the subject and explain how psychological distress may decrease proliferation of lymphocytes and natural killer cell function and provide clues to recovery from disease and prevent relapse [223].

Psychiatric Disorders in Patients Receiving Antituberculosis Drugs
Psychiatric complications have been associated with antituberculosis therapy since the 1950s [116,117,122]. The possible environmental and genetic factors of anti-TB medicationinduced adverse reactions have always been the matter of concern [230]. It is well documented that the risk of adverse reactions increases with age, malnutrition, and history of hepatitis [231,232], human immunodeficiency virus infection, and hepatitis C virus infection [233]. Genetic factors like isoniazid-metabolizing enzyme gene polymorphisms [234] were studied a lot, but these studies also showed inconsistent results. Until now, the comprehensive study for environmental, genetic, clinical, and administrative factors has not been reported. More specifically, adverse reactions concerning neuropsychiatric complications have been reported, mainly with isoniazid (INH) [134,235,236], which is a first line drug and with ethionamide (ETH) [237,238] and cycloserine (CS) [239,240] (both second-line drugs, reserved for patients with drug-resistant tuberculosis) [164,241]. Psychiatric disorders in patients receiving TB medications are presented in Table 5.

Discussion
Nonadherence to therapy by patients has been cited as the principal obstacle in eliminating tuberculosis [242]. Studies indicate that up to half of all of patients with TB do not complete treatment [243], which contributes to prolonged infectiousness, drug resistance [244], relapse, and death [245]. WHO defines "treatment default" (nonadherence) as a treatment interrupted for two consecutive months, and it is well documented that 30% of all patients who are under selfadministered treatment do not adhere to the therapy in the first two or three months.
Different approaches for ensuring medication adherence have been adopted, since 1991, and include Directly Observed Therapy Short Course (DOTS) [246], medication monitors [247,248], and legal action [249,250], (the use of involuntary detention for persistently nonadherent patients as a last resort) resulting in cure rates of >80% and default rates of <10% [251]. A review of articles published from 1966 through 1996 on DOT programs for TB treatment found that treatment completion rates were greater than 90% when therapy was supervised [252,253]. Having a health care worker present to directly observe patients taking each dose of anti-TB medication has been proposed as the best way to ensure adherence to treatment, thereby diminishing the risk of transmission, relapse or reactivation, and drug resistance [254].
However, even with this approach, patient nonadherence to DOT still occurs [255]. One problem cited is that it is difficult to anticipate who will comply with treatment [256]. Various factors such as age, gender [257], alcohol and drug dependence [166], absence of symptoms, adverse effects of drugs, absence of educational programs, quality of communication between patients and health workers [258][259][260], health culture [261], beliefs [262,263], incentives and transportation time [257], and poor economy [264] have been shown to be associated with nonadherence. In sum, social, cultural, and demographic factors [265] (including educational level and treatment literacy [266]), psychiatric illness, including substance abuse [267] (alcohol and drug) in addition to those related to medication and also to the process of health care delivery and most certainly previous history of nonadherence [166] have all been cited as the most important barriers to TB treatment adherence.
The ability to predict poor medication adherence at initiation of treatment and identify patients at greater risk of dropping out could help in dealing with the problem [268]. Recently, a 30-item TB medication adherence scale (TBMAS) with a positive predictive value of 65.5% and a sensitivity of 82.9% was developed and incorporated the latest research in TB specific medication adherence, where predictors for adherence such as patient behavior and patient-provider interaction in TB treatment have been explored. The resulting tool will help TB medical professionals identify not only TB patients with poor adherence but also potential reasons for nonadherence and help them to design and implement targeted interventions to improve adherence [178].
A study that focused on adherence to DOTS, carried out in India, verified the need to focus research on addressing the disease from the perspective of patients and health professionals, who are the essential elements in this process [269]. In the encounter between health professionals and patients, DOTS could be an opportunity for the manifestation of subjectivities and to help patients with tuberculosis to recover their capabilities for life during regular consultations. At the same time, it allows identifying vulnerabilities and needs that can be dealt with, during the process so as to overcome them [270], which points to the need for actions within a multidisciplinary team, according to the biopsychosocial model of health and illness, where adherence is conceived as a process, not of imposition, but rather of exchange and meeting, one that uses the understanding of the context of patients' lives as a trigger to meet social and health needs [271].
The presence of psychopathology has been found to be one of the causes of nonadherence with therapy in chest conditions [32,33].
Not only psychiatric patients are at risk of getting TB infection, as they are often homeless or have unstable housing conditions and lack food and security, but they also frequently fail to comply with treatment for the same reasons [67].
Individuals who are dealing with issues of substance abuse, HIV infection, mental illness, intellectual disability, and are also often homeless/under-housed are at much higher risk of contracting latent TB infection and of developing active TB disease. This increased risk may be explained by the existence of a number of challenges that increase an individual's vulnerability to tuberculosis, such as inadequate access to food, shelter, and income; substandard and overcrowded shelter conditions; forced migration of shelter users; preexisting health conditions (e.g., hepatitis C, compromised immune system); structural and attitudinal barriers to effective health care; problems in the corrections system [272] (i.e., prison conditions); and immigration and refugee issues (e.g., lack of identification to access health care during first few months). These challenges also increase the probability that individuals living in these conditions will be unlikely to adhere with TB treatment.
In an earlier study [71] on a tuberculosis population, it was found that 30.2% of the population had diagnosable mental disorders and none of these were recognized by the clinic staff. Such lack of knowledge can contribute to negative, pessimistic or victim-blaming messages to TB patients [273,274], which fuels patients' distrust and can lead to problematic treatment [161]. The importance of a nonjudgmental, nonblaming stance is often cited as foundational for psychotherapeutic care in TB [275] along with the adoption of more power sharing with TB patients. Specific strategies are also identified, including education to help recognize mental disorder, training in psychotherapeutic strategies [276], and communication skills building.
TB is a chronic illness, and research into chronic illnesses has indicated that psychological factors, particularly depression, and the patients' perceptions about their illness predict poor adherence. In order to maximize the rate of adherence, health workers involved in the management of these patients should develop a higher index of suspicion for possible psychopathology and utilize the available consultation/liaison psychiatric services [169].
Treating psychological problems in patients with tuberculosis may substantially improve treatment adherence.
According to studies, DOTS programmes are more likely to achieve better TB control outcomes if they include interventions aimed at improving diagnosis of alcohol and substance abuse and treating it concurrently with TB, [277,278] and according to DOTS-Plus Guidelines, for MDR-TB patients, all healthcare workers treating drug-resistant TB should closely work with psychiatric services because there is a high baseline incidence of depression and anxiety in these patients, often connected with the chronicity and socioeconomic stress factors related to the disease [279].
According to all studies, irrespective of regional and population differences a common major factor implicating treatment adherence is the presence of psychopathology, especially depression, among tuberculous patients [280], and the high incidence of depression among these patients necessitates effective management [281] in order to improve treatment adherence and overall quality of life of these patients [282]. Results from these studies advocate a more holistic approach [91] to healthcare programs with the inclusion of mental health services in order to provide pretreatment psychiatric assessment and necessary intervention and eventually reduce default rate in tuberculosis control programs [34].
Awareness of adherence is, as a complex behavioral issue, influenced by many factors [283] and lack of a comprehensive and holistic understanding of barriers to and facilitators of, treatment adherence is currently a major obstacle to finding effective solutions [253,284]. Knowledge about the degree that each of these factors correlates with psychopathology, and contributes to nonadherence is lacking, and prospective cohort studies addressing the cause-effect relationship between risk factors and psychopathology could clarify such issues.
Also, studies focused on human dimension [28] and on subjective experiences of health care consumers [285] may provide information on patient experiences of TB treatment adherence which may serve as a tool to better promote treatment and effectuate more patient-centered interventions [286].
Finally, randomized control trials investigating the effects of pharmacological and psychological interventions modified to address not only depression but also issues around adherence to treatment [287] and illness perceptions [288] need to be carried out.
Studies addressing factors affecting treatment adherence in pulmonary tuberculosis patients are presented in Table 7.

Treatment of Comorbid Tuberculosis and Depression
Mood disorders seem to be particularly common in TB patients compared with those with other medical diagnoses. Currently, selective serotonin reuptake inhibitors (SSRIs) are recommended as the first-line treatment for depression and tend to be favored over other pharmacologic treatments such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) because of their relatively benign side effect profiles.
Tuberculosis Research and Treatment 29 However, in patients comorbid for TB, concerns have been raised over the potential for drug interactions between various SSRIs and isoniazid, based on the ability of isoniazid to inhibit monoamine oxidase in plasma [289]. Generally, the combination of SSRIs or TCAs with a drug that inhibits monoamine oxidase is contraindicated because of the potential to induce serotonin syndrome [149]. No reports of serotonin syndrome induced by combining SSRIs and isoniazid are published, and, currently, there is insufficient clinical evidence to definitively establish the potential for an adverse interaction between isoniazid and antidepressants [151,153].
At the molecular level, there is evidence that isoniazid and SSRIs are metabolized by similar mechanisms [159]. Hepatic cytochrome P450 enzymes are largely responsible for metabolism of isoniazid, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. While it has not been definitively established which isoenzymes are implicated in the metabolism of isoniazid, CYP2E1, CYP1A2, CYP2C9, CYP2C19, and CYP3A are inhibited to varying degrees by isoniazid [154], and inhibition of these enzymes slows the elimination of coadministered drugs. All SSRIs appear to be metabolized by cytochrome P450 enzymes; however, the pharmacokinetic interactions of each drug are variable, and available evidence indicates that some SSRIs might be a better choice than others for concurrent treatment.
Clinically, significant drug-drug interactions involving TB medications, especially isoniazid and rifampin, and various psychiatric medications are presented in Table 6.

Conclusion
Tuberculosis remains a leading infectious cause of mortality worldwide.
Studies report high rates of depression and anxiety among tuberculosis patients most likely related to social stigma, inadequate social support, and the physiologic impact of chronic disease. The paper integrates information about how these psychosocial factors complicate adherence to drug regimens and emphasizes the importance of attention to mental health needs to ensure positive treatment outcomes. depression was related to the duration of illness, and severity of the disease/excluded