INT J TUBERC LUNG DIS 8(6):749759 2004 IUATLD

Psychiatric issues in the management of patients with multidrug-resistant tuberculosis

P. Vega,* A. Sweetland, J. Acha, H. Castillo, D. Guerra, M. C. Smith Fawzi, S. Shin
* Neuropsychiatric Service, Department of Medicine, Ministry of Health, Lima, Socios En Salud, Lima, Department of Health and Social Sciences, Universidad Peruana Cayetano Heredia, Lima, Peru; Program in Infectious Disease and Social Change, Department of Social Medicine, Harvard Medical School, Boston, Division of Social Medicine and Health Inequalities, Brigham and Womens Hospital, Boston, Massachusetts, USA SUMMARY
I N T R O D U C T I O N : Psychiatric issues present a challenge in the treatment of patients with multidrug-resistant tuberculosis (MDR-TB). Both baseline psychiatric disorders and development of psychiatric complications related to anti-tuberculosis drugs and psychosocial factors require aggressive management. S E T T I N G : A community-based non-governmental health organization in Lima, Peru. O B J E C T I V E : To review the literature for psychiatric complications associated with anti-tuberculosis medications, to describe the incidence and prevalence of depression, anxiety and psychosis among individuals receiving MDRTB therapy, and to detail the management approach used in this cohort. M E T H O D S : A retrospective case series was performed among the rst 75 patients to receive individualized MDRTB therapy in Lima, Peru, between 1996 and 1999. R E S U L T S : Baseline depression and baseline anxiety were observed in respectively 52.2% and 8.7% of this cohort. Most individuals with baseline depression experienced improvement of depressive symptoms during the course of TB therapy. The incidence of depression, anxiety and psychosis during MDR-TB treatment was 13.3%, 12.0% and 12.0%, respectively. While the majority of individuals with depression, anxiety and psychosis required psychiatric pharmacotherapy, cycloserine was successfully continued in all but one case. C O N C L U S I O N : Psychiatric comorbidities are not a contraindication to MDR-TB therapy. Management of psychiatric complications is possible without compromising anti-tuberculosis treatment. K E Y W O R D S : multidrug-resistant tuberculosis; psychosis; depression; anxiety; cycloserine; Peru; review

MORE THAN 50 YEARS after the advent of effective therapy, tuberculosis (TB) remains one of the leading causes of adult deaths in the world, disproportionately affecting people in poor countries.1 Individuals at highest risk for exposure and illness are thus precisely those with the least means to overcome the disease. Furthermore, drug-resistant strains are contributing increasingly to a global public health disaster. In a survey performed in 2000, multidrugresistant TB (MDR-TB) was identied in each of the 72 countries surveyed.2 Current estimates indicate that 273 000 new MDR-TB cases occur each year.3 Although recently removed from the list of high-burden countries,4 Peru continues to have one of the highest rates in the Americas, with 15% of reported cases, despite representing only 3% of the population.5 By denition, MDR-TB refers to strains of Mycobacterium tuberculosis that are resistant to at least isoniazid (INH) and rifampicin, the two most powerful

anti-tuberculosis agents. Second-line anti-tuberculosis drugs, including cycloserine (CS), the uoroquionolones, ethionamide/prothionamide (ETH), kanamycin/ amikacin, capreomycin and para-aminosalicylic acid, are generally weaker and more toxic than rst-line agents. For this reason, prolonged therapy (1824 months) and frequent adverse reactions are signicant challenges to successful treatment of MDR-TB patients, particularly in resource-poor settings. Management of these side effects is complicated by the fact that discontinuation of the drug or treatment interruption may compromise treatment efcacy, especially in cases of high-grade drug resistance. Rather than suspending the suspected agent, which may be one of few therapeutic resources available to treat the infection, medical providers are required to develop strategies to aggressively manage the symptoms through secondary medications and other biosocial interventions. While adverse effects associated with MDR-TB

Correspondence to: Ms Annika Sweetland, Socios En SaludSucursal Per, Avda Merino Reyna 575, Carabayllo, 06 Lima, Peru. Tel: ( 51) 1-612-5200. Fax: ( 51) 1-547-2121. e-mail: asweetland@pih.org Article submitted 22 July 2003. Final version accepted 23 November 2003.

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treatment may be managed effectively,6,7 certain side effects require special attention. In particular, psychiatric complications, such as anxiety, depression, and psychosis, can greatly impact patient quality of life, as well as physicians attitudes toward MDR-TB therapy. Successful control of psychiatric symptoms is therefore crucial not only for favorable patient outcome, but also for patients overall well-being and physicians comfort with managing MDR-TB therapy. The most commonly reported management strategy to control psychiatric symptoms is to remove the offending agent.810 However, a few published reports describe management strategies that avoid the discontinuation of the drug, for example lowering the dose or simultaneously administering antidepressant or antipsychotic therapy.1113 The use of B6 supplementation to prevent neurotoxicity associated with ETH, INH and CS has also been advocated. Similar protective effects may be observed with psychiatric symptoms induced by these medications.10,1417 Psychiatric complications have been associated with anti-tuberculosis therapy since the 1950s.18,19 Although signicant psychiatric symptomatology has been most commonly associated with CS and INH, other drugs implicated at the case report level include ETH, ethambutol (EMB) and the uoroquinolones. Severe psychiatric manifestationsincluding hallucinations, anxiety, depression, euphoria, behavioral disorders, and suicidal ideation and/or attemptshave been reported to occur in 9.750% of individuals receiving CS.14,1927 CS-associated neurotoxicity is likely due to diminished central nervous system (CNS) production of -aminobutyric acid (GABA) caused by inhibition of glutamic decarboxylase and facilitated by effective penetration of the blood-brain barrier.28 In the majority of these cases, the drug was discontinued, with rapid recovery of mental status and no recurring symptoms. Psychiatric symptoms appear most likely to present within the rst 3 months of treatment.22,24,26,29 Increased risk of CNS toxicity may be associated with supratherapeutic levels of CS,30 concomitant use of ETH,31 INH,31 or uoroquinolones,32 and ethanol ingestion.27 Less commonly, INH has been associated with neuropsychiatric side effects, including depression, irritability, obsessive-compulsive neurosis, and attempted suicide.810,3336 In the Boston Collaborative Drug Surveillance Program performed in 1974, more than 35% of adverse effects associated with INH were psychiatric in nature, with an incidence of 1.9%.37 Similarly, in Peru, severe psychiatric syndromes associated with INH occurred in approximately 1.0% of tuberculosis cases between 1991 and 1999.38 Pallone, Goldman and Fuller performed a review of the literature on INH-induced psychosis in 1993.39 They found that the most common psychiatric symptoms associated with INH were delusions, generally presenting after approximately 4 weeks of taking the drug, and

among patients of an average age of 35 years (range 1753). They summarize risk factors as receiving a dose above 5 mg/kg; age 50 years or older; comorbid disease including diabetes mellitus, hepatic insufciency, alcoholism, and hyperthyroidism; and past psychiatric history. Several mechanisms have been proposed to account for INH-associated toxicity. INH may act as an monamine oxidase (MAO) inhibitor; alternatively, psychiatric effects may be caused by INH-induced pyridoxine deciency, with subsequently diminished production of norepinephrine, serotonin, dopamine, and GABA.39 Further review has uncovered several more case reports detailing psychotoxic reactions to INH with similar observations.13,4043 Several case reports associate the use of ETH with occurrence of depression, anxiety, psychosis, and suicide.9,14,4446 The mechanism for INH and ETH neurotoxicity is likely the same.37 EMB may also be associated with mania,47 confusion,15,31 and psychosis,48 although the mechanism for this effect is unknown. Finally, the uoroquinolones have been implicated in rare occurrences of psychosis,49,50 depression,51 delirium,52,53 and nightmares.54 A large-scale retrospective study by Hollweg et al. reported psychiatric disturbance in 0.7% of 4189 individuals treated with either ooxacin or ciprooxacin.55 In this study, while elderly individuals were more likely to experience delirium or paranoia, younger individuals had greater rates of depressive and manic syndromes. Underlying hepatic or renal dysfunction, concomitant antibiotics or immunosuppressants, and baseline psychiatric disorders or psychosocial stressors, were identied as risk factors for quinolone-associated psychiatric disturbance. In addition to drug toxicity, psychosocial factors contribute to psychiatric complications during MDRTB therapy, and consequently patients adherence to these regimens. Two early reports on sanatorium care discuss several emotional aspects associated with TB, including depression, anxiety, and suicidal ideation.56,57 Considering that these reports pre-date the development of effective antibiotics for the treatment of TB, it is apparent that psychiatric complications occur even in the absence of drug therapy. Some of the psychosocial issues that are often prominent concerns of individuals with MDR-TB include: social stigma and discrimination; fear and guilt associated with infectious risk; the socio-economic and psychological burdens of living with a chronic, life-threatening illness; increased dependence on others; multiple treatment failures and being told in health centers that no further therapy was available; losing family members to the disease; and concomitant poverty. The impact of social stigma has been examined with regard to other infectious diseases, such as the human immunodeciency virus and the acquired immune-deciency syndrome (HIV/AIDS), the impact of which include

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depression, low self esteem, and shame.5861 Fear of infection is one of the factors contributing to social stigma, which may produce social isolation, diminished marriage prospects, limited social support, and result therefore in the denial of diagnosis and consequent rejection of treatment.62,63 Despite the fact that TB infection is not necessarily associated with specic risk behaviors, TB patients are still generally held responsible for their illness and blamed for not taking better care of themselves.63 Further, poverty alone has been demonstrated to have a clear association with increased risk for mental illness.64 Several authors have described how these psychosocial factors complicate adherence to drug regimens, and emphasize the importance of attention to mental health needs to ensure positive treatment outcomes.62,63,65,66 Adherence is especially important in the case of MDR-TB, as this is often a patients last treatment option; failure to complete this treatment leads to a high rate of fatality, in addition to ongoing transmission of highly drug-resistant strains. Despite such challenges, a community-based initiative in Lima, Peru, has demonstrated successful outcomes in treating MDR-TB patients,67 in part through comprehensive management of psychiatric side effects and psychosocial factors.63 One of the fundamental components of this program has been the aggressive management of adverse reactions using protocols and community-based outreach to minimize the need for treatment interruption or discontinuation of antituberculosis drugs.68,69 Here, we describe the incidence, characteristics, and management of psychosis, depression, and anxiety occurring among patients receiving individualized treatment for MDR-TB in Lima, Peru.

METHODS
Study population All patients had documented MDR-TB and were enrolled in treatment between 1 August 1996 and 31 January 1999 through collaborative effort between two non-governmental organizations (Partners In Health and Socios En SaludSucursal Per) and the Peruvian Ministry of Healths National Tuberculosis Program (NTP). The catchment area included three districts of Northern Lima (Carabayllo, Comas and Independencia), a shanty town hosting roughly 762 000 people in 1997 with high rates of poverty, violence, unemployment, and mental illness.7073 In addition, through active case nding, this area was identied as a hot spot for the disease in Peru, with estimated TB rates higher than the national incidence.74 Treatment protocol All patients were referred by the NTP for suspicion of MDR-TB based on history of treatment failure or household contact with a known MDR-TB patient.

Comorbidities, including psychiatric conditions, were not a contraindication to treatment. Written informed consent was obtained from all patients and one family member prior to initiating therapy. Multidrug resistance was conrmed by conventional or BACTEC methods performed by the Massachusetts State Laboratory Institute on sputum specimens.74 Individualized therapy was based on each patients resistance pattern. Of note, individuals with resistance to INH only at low concentrations received high-dose INH (900 mg twice a week) as part of their regimens. Pyridoxine (150300 mg/day) was administered with MDR-TB regimens. All patients participated in an unstructured clinical interview with a psychiatrist to screen for baseline psychiatric disorders prior to initiation of individualized therapy. Patients received treatment under the auspices of the Peruvian NTP: community-based directly observed therapy delivered in health centers and in patients houses by community health workers.75,76 All treatment was provided to patients free of charge. Patients were evaluated at least once a month by an NTP physician trained in the management of MDR-TB. These evaluations included screening for psychosis, depression, and anxiety. Patients were additionally assessed for any side effects identied by health care workers. Patients with psychiatric symptoms were referred to a psychiatrist at the physicians discretion. The psychiatrist used clinical criteria based on DSM-IV77 to diagnose psychiatric syndromes. In general, symptoms were managed according to protocols that were developed by the physicians trained at Socios En Salud in the management of MDR-TB (see Appendices 1 and 2). Anti-depressants, anxiolytics, anti-psychotics, and psychotherapy were prescribed by both primary MDR-TB physicians and psychiatrists, and provided free of charge. Study design and data collection A case series with a retrospective chart review was conducted among all patients who had initiated individualized treatment between 1 August 1996 and 31 January 1999. All patients had completed treatment at the time of chart review. The follow-up period for all patients who were still alive was at least 18 months after completion of treatment. All charts were reviewed by a physician trained in the management of MDR-TB, then all cases with suspected new onset of psychiatric disorders were further reviewed by the treating psychiatrist. The case denition of psychosis was based on DSM-IV criteria by a physician.77 Categorization of depression was based on DSM-IV criteria by a psychiatrist, and included the following diagnoses: major depressive disorder, dysthymia, adjustment disorder with depressed mood, and substanceinduced mood disorder with depressive features. The diagnosis of anxiety was also based on DSM-IV criteria for generalized anxiety disorder or substance-

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induced anxiety disorder by a psychiatrist. Other variables extracted from the chart review for all patients included age, sex, drugs in the individualized regimen, number of previous treatment regimens, treatment outcome, baseline psychiatric illness using DSM-IV criteria according to a psychiatrist, history of alcohol or drug abuse, hypothyroidism (before or during treatment), HIV, diabetes mellitus, and malnutrition. The charts of all cases of psychiatric disorders were reviewed in more detail with respect to timing and duration of presentation of symptoms, clinical management, and treatment outcome. Statistical analysis The following risk factors were analyzed for association with incidence of depression, psychosis or anxiety: sex; age; baseline depression; education level; unemployment; marital status; presence of dependent children; presence of TB household contacts; presence of household contacts who died of TB; hypothyroidism; presence of comorbidities (i.e., diabetes, HIV, malnutrition, history of alcoholism or drug abuse); history of institutionalization (i.e., incarceration or extended hospitalization) or homelessness; receipt of medications associated in the literature with psychiatric side effects (i.e., CS, INH, EMB, ETH, uoroquinolones); and CS dose. Multivariable analysis for occurrence of each side effect was also performed using a multiple regression model including all variables associated with a P value 0.05 or an odds ratio (OR) 2.0 on univariate analysis. All data were entered in Microsoft Excel 97 (Microsoft Corporation, Seattle, WA, USA); all statistical analysis was performed using SAS, version 8.2 (SAS Institute, Cary, NC, USA). Reported P values were based on two-sided Fishers exact tests, or for continuous variables, t-tests or, if non-parametric, the Wilcoxon test. For binary variables, ORs with 95% condence intervals (95%CIs) were also calculated.

Table 1 Prevalence and incidence of psychosis, depression and anxiety among MDR-TB patients
Prevalence prior to MDR-TB therapy (n 69) n (%) Psychosis Depression Anxiety 0 (0) 36 (52.2) 6 (8.7) Persistent symptoms among those with baseline diagnosis n (%) 0 (0) 12/36 (33.3) 3/6 (50.0) Incidence during MDR-TB therapy (n 75) n (%) 9 (12.0) 10 (13.3) 9 (12.0) Prevalence during MDR-TB therapy n (%) 9 (12.0) 22 (29.3) 12 (16.0)

MDR-TB multidrug-resistant tuberculosis (dened as resistance to at least isoniazid and rifampicin).

the onset of depression and anxiety was more variable. For both depression and anxiety, the mean time of presentation was 7.3 months, with a range of 117 and 216 months, respectively. Table 2 summarizes the demographic and clinical characteristics of this cohort and has been described in more detail elsewhere.67 MDR-TB regimens included CS in all but one case, with a median daily dose of 1000 mg. Twenty-ve patients (33.3%) received high doses of INH, 52 (69.3%) received ETH, 11 (14.7%) received EMB, and 72 (96.%) received a uoroquinolone. While the occurrence of psychiatric complications during MDR-TB therapy was not signicantly associated with adverse treatment outcome, there was a trend toward increased risk of default among individuals who developed psychosis (OR 6.0, 95%CI 0.942.3). Risk factors and management of psychiatric complications

RESULTS
Baseline characteristics, incidence of psychiatric complications, and treatment outcomes Between August 1996 and January 1999, 75 patients initiated treatment. Charts were available and reviewed for all cases. The baseline prevalence, as well as incidence during treatment of psychosis, depression and anxiety, are summarized in Table 1. Of note, roughly half of the cohort had a baseline diagnosis of depression, including three individuals who also had a co-existing anxiety disorder. None had baseline psychosis. During the course of MDR-TB therapy, 10 (13.3%) patients developed depression, nine (12.0%) developed anxiety disorders, and nine (12%) experienced psychosis. While psychosis tended to occur earlier in MDR-TB treatment (mean 3.6 months, range 18),

Psychosis Among the nine patients (12%) who developed psychosis during treatment, younger age (average 24.1 vs. 29.7 years among those with and those without psychosis, P 0.008) was identied as a risk factor. Furthermore, none of the individuals who developed psychosis were married vs. 36.4% among those who did not de-velop psychosis (P 0.05). In a multivariable analysis, including female sex, age, baseline depression, unmarried status, number of dependent children, and presence of an MDR-TB household contact, no variable was found to be signicantly associated with psychosis. In three (33.3%) cases CS was suspended temporarily, in two (22.2%) the CS dose was decreased, and in one (11.1%) the drug was suspended then resumed at a lower dose (Table 3). It was never necessary to discontinue CS indenitely. No changes in other TB drugs were required. Only one (11.1%) patient was hospitalized due to psychosis, while the rest were managed through close monitoring by community health promoters, nurses, and doctors in the patients homes. All but one individual received antipsychotic drug therapy. Psychotic episodes recurred in two (22.2%) individuals, but were effectively

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Table 2

Baseline characteristics among 75 patients receiving individualized MDR-TB therapy

n (%) Median (range) 26.8 (11.865.1) 37 (49.3) 38 (50.7) 7 (13.2) 46 (86.8) 7 (220) 24 (34) 47 (66) 12 (16.0) 19 (25.3) 14 (18.7) 30 (40.0) 0 (0.0) 0 (07) 58 (77.3) 28 (37.3) 3.0 (08) 6.0 (212) 23 (30.7) 11 (14.7) 9 (12.0) 1000 (7501000) 74 (98.7) 25 (33.3) 52 (69.3) 12 (16.0) 72 (96.0)

Characteristic Age, years Sex Male Female Education level (n 53) Completed elementary school or less Some high school or more Household size (n 70) Marital status Married/living with partner Unmarried (single, divorced, widowed, separated) Occupation Not working Student Homemaker Worker, aside from professional Professional Number of dependent children TB and MDR-TB household contacts Household contacts who died of TB Number of previous treatment regimens Number of drugs to which patient is resistant Comorbidity* Hypothyroidism before or during ITR Prior institutionalization or homelessness Maximum cycloserine dose (mg) Cycloserine Isoniazid (high dose) Ethionamide Ethambutol Fluoroquinolones

* Chronic disease included diabetes mellitus (1), HIV (1), malnutrition (15), and history of alcoholism or drug use (7). MDR-TB multidrug-resistant tuberculosis; TB tuberculosis; ITR individualized treatment regimen; HIV human immunodeciency virus.

managed in both cases. While patients receiving antipsychotic medications at the conclusion of therapy generally continued their use for an additional 3045 days, in only one (11.1%) case was it necessary for the patient to continue taking anti-psychotic medications beyond this window. Psychosis resolved in eight

(88.9%) of the cases, with a median duration of psychotic symptoms of 4 weeks (range 0.7128). Two (22.2%) patients who experienced psychosis abandoned treatment, one (11.1%) of whom was psychotic at the time of default. Of note, three (33.3%) of these cases occurred among sisters in one family.

Table 3

Characteristics and management of psychiatric symptoms (n

75)
Baseline depression with persistent symptomatology (n 12) n (%) 10 (8.3) 0 (0) 0 (0) 6 (50) 2 (16.7) 0 (0) Baseline anxiety with persistent symptomatology (n 3) n (%) 0 (0) 0 (0) 0 (0) 3 (100) 0 (0) 0 (0)

Management Reduced dose of cycloserine Temporary suspension of cycloserine Terminated dose of cycloserine Required psychiatric medications Persistent psychiatric symptoms throughout MDR-TB treatment requiring psychiatric medications Required hospitalization due to psychiatric symptoms
MDR-TB multidrug-resistant tuberculosis.

New psychosis (n 9) n (%) 3 (33.3) 4 (44.4) 0 (0) 9 (88.9) 3 (33.3) 1 (11.1)

New depression (n 10) n (%) 1 (10.0) 0 (0) 0 (0) 8 (80) 1 (10.0) 0 (0)

New anxiety (n 9) n (%) 4 (44.4) 0 (0) 0 (0) 8 (88.9) 3 (33.3) 0 (0)

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Depression Among the 36 (52.2%) patients with baseline depression, two thirds (66.7%) did not require psychiatric attention or medications for depressive symptoms during therapy due to mild symptomatology or remission. Ten (13.3%) patients without baseline symptomatology experienced a new onset of depression during TB therapy; no signicantly associated risk factor was identied on univariate analysis. In a multivariable analysis including number of dependent children, hypothyroidism, and presence of a TB household contact, no variable was identied to be signicantly associated with depression. The dose of CS was lowered in one (10.0%) new case for the duration of treatment; no other modication of TB therapy was made for other patients presenting with depression during treatment. Anti-depressive medications were indicated in 80% of the new cases, although symptoms were generally effectively managed and they were not needed throughout treatment. Finally, no patients in this cohort were hospitalized for depression. Anxiety Of the six (8.7%) patients with baseline anxiety, half (50.0%) had persistent symptoms requiring psychiatric intervention, and one (16.7%) experienced a manic episode. Furthermore, nine (12%) patients had a new onset of anxiety during treatment. Risk factors significantly associated with onset of anxiety during MDRTB treatment were having more dependent children (P 0.007) and a higher average dose of CS (972 mg vs. 884 mg among those with and those without anxiety, P 0.04). Eight of nine patients (88.9%) were receiving CS at the maximum dose of 1000 mg. The multivariable analysis included the following factors: age, married status, number of dependent children, CS dose, TB household contact, and lack of chronic disease. Among these variables, only higher dose of CS (P 0.01) and greater number of dependents (P 0.002) were signicantly associated with occurrence of anxiety. In four (44.4%) cases, the dose of CS was lowered for the duration of treatment; no other changes in anti-tuberculosis therapy were made. While anxiolytic medications were necessary in eight (88.9%) of the nine cases, only three (33.3%) required medications for the duration of treatment. There were no hospitalizations due to anxiety. DISCUSSION
The baseline prevalence of depression observed in our cohort was greater than the prevalence in the general population of Lima, Peru (52.2% vs. 6.7%).71 On the other hand, baseline rates of anxiety and psychosis were comparable to those of the general population of Lima.71 High rates of depression and anxiety among tuberculosis patients have been reported elsewhere,78 and are likely related to social stigma, inad-

equate social support, and the physiologic impact of chronic disease.62,63,66,79 Interestingly, two thirds of those with baseline depression actually experienced an improvement in their depressive symptoms during treatment, presumably as they recovered from tuberculosis and were able to resume important social roles in their family and community. Development of depression during treatment, observed in 13.3% of our cohort, could be inuenced by similar psychosocial forces, as well as drug-related factors. However, a clearer association can be observed between anti-tuberculosis drugs and both anxiety and psychosis: anxiety occurred more frequently among those receiving higher doses of CS, and psychosis responded to temporary suspension of CS and/or reduction of CS dose. Nevertheless, the role of psychosocial factors should not be underestimated. For instance, having more dependent children was a risk factor for anxiety, likely reecting the stress of fullling a caregiving role while sick. Indeed, the combined inuence of polypharmacy and psychosocial factors highlights the need for integrated responses to psychiatric complications, including both pharmacological and psychosocial components. Three main strategies have been used to manage psychiatric complications during MDR-TB therapy in this program. First, community health workers have been crucial in the identication, referral and management of psychiatric disorders. All community health workers are trained to recognize early manifestations of adverse reactions, including psychiatric symptoms. Importantly, they provide direct supervision of psychiatric medications, in addition to emotional support and counselling, for patients and family members. The second strategy has been the use of psychiatric medications in the majority of incident cases, often managed by a psychiatrist. For psychosis, low-dose risperidone has replaced haloperidol as the favored therapy, due to fewer extrapyramidal symptoms associated with long-term use. For depression, serotoninuptake inhibitors, such as sertraline and uoxetine, are well tolerated and effective, with minimal pharmacological interactions. Among anxiolytics, lorazepam offers the advantage of a short half-life, while clonazepam may be appropriate in individuals with concomitant psychotic or depressive symptoms.31 Adequate psychopharmacotherapy has allowed CS to be successfully continued in all but one case, in which CS was suspended only because an adequate regimen remained. Finally, many patients are referred to a psychosocial support group comprised of patients in treatment and cured individuals. This methodology, described elsewhere,63 has been effective in combating the psychosocial impact of the disease, including marginalization and stigma, hopelessness and grieving, as well as contemplation of suicide or treatment default. There are several limitations to this study. First, the

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small sample size limits the analysis of risk factors and effect of psychiatric complications on treatment outcome. A larger cohort will likely be necessary to identify risk factors associated with development of depression and psychosis. Moreover, given the retrospective nature of this study, the incidence of psychiatric complications could be underestimated because of lack of reporting or appropriate diagnosis.

CONCLUSIONS
Baseline prevalence of depression, anxiety, and psychosis in our cohort was 52.5%, 8.7% and 0%, respectively. Nonetheless, the presence of a baseline psychiatric disorder was not a contraindication to MDR-TB therapy nor to the use of CS. Furthermore, individuals with initial depression and/or anxiety often experienced an improvement in their symptoms during the course of MDR-TB treatment. Depression, anxiety and psychosis each occurred in approximately 1213% of our cohort during treatment. Aggressive use of psychiatric medications (in particular for psychosis), in addition to psychosocial support, has permitted successful resolution of symptoms, usually without the need for hospitalization. Compared with other MDR-TB cohorts, our cohort experienced higher or comparable rates of psychiatric complications, and yet discontinuation of medications, in particular CS, occurred less frequently.12,8082 Thus, psychiatric disorders among patients with MDR-TB can be successfully managed without endangering effective MDR-TB therapy. Acknowledgements
The authors wish to thank the Bill & Melinda Gates Foundation, as well as Thomas White, for their generous support. In addition, we would like to thank the Peruvian Ministry of Health for their collaboration, and the community health workers, whose valiant efforts made this work possible. Finally, we wish to thank our patients for the inspiration that they have given us to continue providing high quality TB care for patients living in poverty.

References
1 Benatar S R. Prospects for global health: lessons from tuberculosis. Thorax 1995; 50: 487489. 2 Espinal M A, Simonsen L, Laszlo A, et al. for the World Health Organization/International Union Against Tuberculosis and Lung Disease Global Working Group on Anti-tuberculosis Drug Resistance Surveillance. Anti-tuberculosis drug resistance in the world. Report No. 2. WHO/TB/2000.278. Geneva, Switzerland: WHO, 2000. http://www.who.int/gtb/publications/ drugresistance/ Accessed March 2004. 3 Dye C, Espinal M A, Watt C J, Mbiaga C, Williams B. Worldwide incidence of multidrug-resistant tuberculosis. J Infect Dis 2002; 185: 11971202. 4 World Health Organization. WHO Report 2002. Global tuberculosis control: surveillance, planning, and nancing. WHO/CDS/TB/2002.295. Geneva, Switzerland: WHO, 2002. 5 World Health Organization. Health, a key to prosperity: successful stories in developing countries. WHO/CDS/2000.4. Geneva, Switzerland: WHO, 2002.

6 Shin S S, Hyson A M, Castaeda C, et al. Peripheral neuropathy associated with treatment for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2003; 7: 347353. 7 Furin J J, Mitnick C D, Shin S S, et al. Occurrence of serious adverse effects in patients receiving community-based therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2001; 5: 648655. 8 Weidorn W S, Ervin F. Schizophrenic-like psychotic reactions with administration of isoniazid. Arch Neurol Psychiat 1954; 72: 321324. 9 Lees A W. Ethionamide and isoniazid in previously untreated cases of pulmonary tuberculosis. Dis Chest 1964; 45: 247 250. 10 Reilly D K. Isoniazid-related CNS toxicity. Drug Ther 1979; 9: 187188. 11 Aceto J N, Covert D F. Observations on cycloserine-isoniazid in pulmonary tuberculosis. Antibiot Med Clin Ther 1960; 7: 705712. 12 Pasechnikov A D, Malinovskaya T Z, Kostornoy O S. Side effects in multiple drug resistant TB treatment in Tomsk Oblast. Moscow, Russian Federation: 17th Russian Congress on Tuberculosis, 2003. 13 Duggal H S, Nizamie S H. Novel antipsychotic drugs and INHrelated psychosis. Aust N Z J Psychiatry 2000; 34: 343344. 14 Johnson D A. Drug-induced psychiatric disorders. Drugs 1981; 22: 5769. 15 Patel A M, McKeon J. Avoidance and management of adverse reactions to antituberculosis drugs. Drug Safety 1995; 12: 1 25. 16 Ministerio de Salud 1995. Actualizacin de la doctrina, normas y procedimientos para el control de la tuberculosis en el Per. Rev Soc Per Tis Neu E T 1996; 40: 1941. 17 Ministerio de Salud. Actualizacin de la doctrina, normas y procedimientos para el control de la tuberculosis en el Per: 2001. Lima, Peru: Ministerio de Salud del Peru, 2001: pp 71 77. 18 Weidorn W S, Ervin F. Schizophrenic-like psychotic reaction with administration of isoniazid. Arch Neurol Psychiat 1954; 72: 321. 19 Lewis W C, Calden G, Thurslan J R, Gibson W E. Psychiatric and neurological reaction to cycloserine in the treatment of tuberculosis. Dis Chest 1957; 32: 172177. 20 Riska N. Tolerance to cycloserine. Scand J Respir Dis 1970; 71 (Suppl): 209216. 21 Stephanopoulos C, Zoumbouloglou H. Clinical tolerance to cycloserine. Scand J Respir Dis 1970; 71 (Suppl): 235238. 22 Dissmann E. Experience with cycloserine. Scand J Respir Dis 1970; 71 (Suppl): 239243. 23 Bethlem N. Results of treatment of pulmonary tuberculosis with cycloserine in association with other drugs. Scand J Respir Dis 1970; 71 (Suppl): 244249. 24 Helmy B. Side effects of cycloserine. Scand J Respir Dis 1970; 71 (Suppl): 220225. 25 Pasargiklian M, Biondi L. Neurologic and behavioral reactions of tuberculosis patients treated with cycloserine. Scand J Respir Dis 1970; 71 (Suppl): 201208. 26 Leston J M, Rey J C, Gonzalez Montaner L J, Grondona A, Zavalla P N. Psychosomatic reactions to cycloserine in the treatment of tuberculosis. Scand J Respir Dis 1970; 71 (Suppl): 231234. 27 Nariman S. Adverse reactions to drugs used in the treatment of tuberculosis. Adverse Drug React Acute Poisoning Rev 1988; 4: 207227. 28 Berning S E, Peloquin C A. Antimycobacterial agents: Cycloserine. In: Yu V L, Merigan J R, Barriere S L, eds. Antimicrobial therapy and vaccines. Baltimore, MD: Williams & Wilkins, 1999: pp 638642. 29 Snavely S R, Hodges G R. The neurotoxicity of antibacterial agents. Ann Intern Med 1984; 101: 92104.

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30 Sweetman S. MartindaleThe complete drug reference. 33rd ed. London, UK: Pharmaceutical Press, 2002. 31 Medical Economics Staff, PDR Staff, eds. Physicians Desk Reference 2003. 57th ed. Oradell, NJ: Medical Economics Co, 2003. 32 Yew W W, Wong C F, Wong P C, Lee J, Chau C H. Adverse neurological reactions in patients with multidrug-resistant pulmonary tuberculosis after coadministration of cycloserine and ooxacin. Clin Infect Dis 1993; 17: 289290. 33 Goldman A L, Braman S S. Isoniazid: a review with emphasis on adverse effects. Chest 1972; 62: 7177. 34 Reilly D K. Isoniazid-related CNS toxicity. Drug therapy 1979; 9: 187188. 35 Bhatia M S. Isonizid-induced obsessive compulsive neurosis. J Clin Psych 1990; 51: 387. 36 Madan A, Jain N K, Sharma T N, Sharma D K, Madan R. Attempted suicide following treatment with isoniazid. Tubercle 1989; 70: 147149. 37 Holdiness M R. Neurological manifestations and toxicities of the antituberculosis drugs. Med Toxicol 1987; 2: 3351. 38 Bonilla C, Portocarrero P G, Surez P G, Molero D. Reacciones adversas a frmacos antituberculosos (RAFA) en tratamientos directamente observados (DOTS). Peru 19911999. Tuberculosis en el Per: Informe 1999. Lima, Peru: Ministerio de Salud del Per, 2000: pp 99106. 39 Pallone K A, Goldman M P, Fuller M A. Isoniazid-associated psychoses: case report and review of the literature. Ann Pharmacother 1993; 27: 167169. 40 Ibrahim Z Y, Menke J J. Comment: Isoniazid-induced psychosis. Ann Pharmacother 1994; 28: 1311. 41 Gnam W, Flint A, Goldbloom D. Isoniazid-induced hallucinosis: response to pyridoxine. Psychosomatics 1993; 34: 537 539. 42 Alao A O, Yolles J C. Isoniazid-induced psychosis. Ann Pharmacother 1998; 32: 889891. 43 Bourgeois J A, Zelenko M, Waraich B S. Psychotic disorder associated with isoniazid. Mil Med 1996; 161: 707. 44 Sharma G S, Gupta P K, Jain N K, Shanker A, Nanawati V. Toxic psychosis to isoniazid and ethionamide in a patient with pulmonary tuberculosis. Tubercle 1979; 60: 171172. 45 Lansdown F S, Beran M, Litwak T. Psychotoxic reaction during ethionamide therapy. Am Rev Respir Dis 1967; 95: 1053 1055. 46 Narang R K. Acute psychotic reaction probably caused by ethionamide. Tubercle 1972; 53: 137138. 47 Pickles R W, Spelman D W. Suspected ethambutol-induced mania. Med J Aust 1996; 164: 445446. 48 Hsu C W, Chu K A, Lu T, Lai R S, Lu J Y. Ethambutol-induced psychosis: a case report [abstract]. Zhonghua Yi Xue Za Zhi 1999; 62: 724727. 49 Mulhall J P, Bergmann L S. Ciprooxacin-induced acute psychosis. Urology 1995; 46: 102103. 50 Zaudig M, von Bose M, Weber M M, Bremer D, Zieglgansberger W. Psychotoxic effects of ooxacin. Pharmacopsychiatry 1989; 22: 1115. 51 Feinberg S S. Fluoroquinolone-induced depression. Am J Psychiatry 1995; 152: 954955. 52 Jay G T, Fitzgerald J M. Ciprooxacin-induced delirium. Ann Pharmacother 1997; 31: 252. 53 Fennig S, Mauas L. Ooxacin-induced delirium. J Clin Psychiatry 1992; 53: 137138. 54 Dey S K. Nightmare due to ciprooxacin in young patients. Indian Pediatr 1995; 32: 918920. 55 Hollweg M, Kapfhammer H P, Krupinski M, Moller H J. Psychopathological syndromes in treatment with gyrase inhibitors [abstract]. Nervenarzt 1997; 68: 3847. 56 Todd G S, Wittkower E. The psychological aspects of sanatorium management. Lancet 1948; 254: 4953. 57 Ludwig A O. Emotional factors in tuberculosis. Public Health Rep 1948; 63: 883888.

58 Lang N G. Stigma, self-esteem and depression: psychosocial responses to risk of AIDS. Hum Org 1991; 51: 6672. 59 Ingram D, Hutchinson S A. HIV-Positive women and stigma. Health Care Women Int 1999; 20: 93103. 60 Fife B L, Wright E. The dimensionality of stigma: a comparison of its impact on the self of persons with HIV/AIDS and cancer. J Health Soc Behav 2000; 41: 5067. 61 Lawless S, Kippax S, Crawford J. Dirty, diseased, and undeserving: the positioning of HIV positive women. Soc Sci Med 1996; 43: 13711377. 62 Liefooghe R, Michiels N, Habib S, Moran M B, De Muynck A. Perception and social consequences of tuberculosis: a focus group study of tuberculosis patients in Sialkot, Pakistan. Soc Sci Med 1995; 41: 16851692. 63 Sweetland A, Acha D, Guerra D. Enhancing adherence: the role of group psychotherapy in the treatment of MDR-TB in urban Peru. In: Cohen A, Kleinman A, Saraceno B, eds. World Mental Health Casebook: Social and Mental Health Interventions in Low-Income Countries. New York, NY: Kluwer Academic/Plenum Press, 2002: pp 5179. 64 Patel V, Kleinman A. Poverty and common mental disorders in developing countries. Bull World Health Organ 2003; 81: 609615. 65 Fullilove M T, Young R, Panzer P G, Muskin P. Psychosocial issues in the management of patients with tuberculosis. J Law Med Ethics 1993; 21: 324331. 66 Barnhoorn F, Adriaanse H. In search of factors responsible for noncompliance among tuberculosis patients in Wardha District, India. Soc Sci Med 1992; 34: 291306. 67 Mitnick C, Bayona J, Palacios E, et al. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 2003; 348: 119128. 68 Partners In Health, Harvard Medical School, Bill and Melinda Gates Foundation. A DOTS-Plus Handbook: Guide to the Community-Based Treatment of MDR-TB. Boston, MA: Partners In Health, 2002. 69 Partners In Health/Program in Infectious Disease and Social Change, Harvard Medical School. The PIH Guide to the Medical Management of Multidrug-Resistant Tuberculosis. Boston, MA: PIH/PIDSC, 2003. 70 Instituto Nacional de Estadstica e Informtica. Proyecciones de poblacin por aos calendario segn departamentos, provincias, y distritos (Periodo, 19902002). Lima, Peru: Instituto Nacional de Estadstica e Informtica, 2001. Boletn Especial No. 16: p. 63. 71 Saavedra J E, Instituto Especializado de Salud Mental Honorio DelgadoHideyo Noguchi. Estudio epidemiolgico metropolitano en salud mental 2002. Anales de Salud Mental 2002; 18: 1197. 72 Minobe K, Perales A, Sogi C, Warthon D, Llanos R, Sato T. Prevalencia de vida de trastornos mentales en Independencia. Anales de Salud Mental 1990; 6: 920. 73 Instituto Nacional de Salud Mental Honorio DelgadoHideyo Noguchi. Prevalencia de vida de trastornos mentales en Independencia (Lima, Peru). Anales de Salud Mental 1985; 1: 206222. 74 Becerra M C, Freeman J, Bayona J, et al. Using treatment failure under effective directly observed short-course chemotherapy programs to identify patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2000; 4: 108114. 75 Farmer P E, Bayona J, Shin S, et al. Preliminary results of community-based MDR-TB treatment in Lima, Peru. Int J Tuberc Lung Dis 1998; 2 (Suppl 2): S371. 76 Farmer P E, Walton D A, Becerra M C. International tuberculosis control in the 21st century. In: Friedman L N, ed. Tuberculosis: current concepts and treatment. 2nd ed. Boca Raton, FL: CRC Press, 2000: pp 475496. 77 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994.

Psychiatric issues in MDR-TB therapy

757

78 Aghanwa H S, Erhabor G E. Demographic/socioeconomic factors in mental disorders associated with tuberculosis in Southwest Nigeria. J Psychosom Res 1998; 45; 353360. 79 Aydin I O, Ulusahin A. Depression, anxiety comorbidity, and disability in tuberculosis and chronic obstructive pulmonary disease patients: applicability of GHQ-12. Gen Hosp Psychiatry 2001; 23: 7783. 80 Goble M, Iseman M D, Madsen L A, Waite D, Ackerson L, Horsburgh C R Jr. Treatment of 171 patients with pulmonary

tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993; 328: 527532. 81 Yew W W, Chan C K, Chau C H, et al. Outcomes of patients with multidrug-resistant pulmonary tuberculosis treated with ooxacin/levooxacin-containing regimens. Chest 2000; 117: 744751. 82 Tahaoglu K, Torun T, Sevim T, et al. The treatment of multidrug-resistant tuberculosis in Turkey. N Engl J Med 2001; 345: 170174.

APPENDICES

Appendix 1 Management of psychosis in individualized MDR-TB therapy (adapted from reference 69). PO per os; IV intravenous; IM intramuscular; TID thrice daily; QD four times daily; BID twice daily.

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Appendix 2 ence 69).

Management of depression in individualized MDR-TB therapy (adapted from referRSUM

Les problmes psychiatriques reprsentent un dfi lors du traitement des patients atteints de tuberculose germes multirsistants (TB-MR). Une prise en charge vigoureuse simpose la fois pour les maladies psychiatriques prexistantes et pour le dveloppement de complications psychiatriques lies aux mdicaments antituberculeux et aux facteurs psycho-sociaux. C O N T E X T E : Une organisation de sant non-gouvernementale base sur la collectivit Lima, Prou. O B J E C T I F : Revue de la littrature concernant les complications psychiatriques associes aux mdicaments antituberculeux, description de lincidence et de la prvalence de la dpression de lanxit et de la psychose parmi les individus traits pour TB-MR et dtails de lapproche de prise en charge utilise dans cette cohorte. M T H O D E S : Une srie rtrospective de cas a t forme par les 75 premiers patients qui ont bnfici dun traitement individualis pour TB-MR Lima, Prou, entre 1996 et 1999.
INTRODUCTION :

On a observ une dpression et une anxit initiales chez respectivement 52.2% et 8.7% des patients de cette cohorte. La plupart des individus ayant eu une dpression initiale ont ressenti une amlioration des symptmes de dpression au cours du traitement de la tuberculose. Lincidence de la dpression, de lanxit et de la psychose au cours du traitement de la TB-MR a t respectivement de 13,3%, de 12,0% et de 12,0%. Alors que la majorit des individus atteints de dpression, danxit et de psychose ont ncessit une pharmacothrapie psychiatrique, on a pu poursuivre avec succs ladministration de cyclosrine dans tous les cas sauf un. C O N C L U S I O N : Les comorbidits psychiatriques ne reprsentent pas une contre-indication au traitement de la TB-MR. La prise en charge des complications psychiatriques est possible sans compromettre le traitement antituberculeux.
RESULTATS :

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RESUMEN
M A R C O D E R E F E R E N C I A : Las complicaciones psiquitricas presentan un desafo en el tratamiento de pacientes con la tuberculosis multidrogo-resistente (TB-MDR). Trastornos psiquitricos de inicio y tambin la presentacin de nuevas complicaciones psiquitricas relacionadas con las drogas anti-tuberculosas y factores psicosociales requieren un manejo agresivo. L U G A R : Una organizacin no-gubernamental basada en la comunidad en Lima, Per. O B J E T I V O : Revisar la literatura para complicaciones psiquitricas asociadas con los medicamentos antituberculosos, describir la incidencia y prevalencia de la depresin, ansiedad y psicosis entre los individuos recibiendo terapia TB-MDR, y resumir con detalle los protocolos de manejo usados con este cohorte. M T O D O S : Una serie retrospectiva de casos fue realizada entre los primeros 75 pacientes que reciban tera-

pia TB-MDR individualizado en Lima, Peru, de 1996 a 1999. R E S U L T A D O S : Depresin y ansiedad de inicio fueron observadas en 52,2% y 8,7%, respectivamente, de este cohorte. La mayora de individuos con depresin de inicio experimentaron una mejora de sntomas depresivos durante el curso de su terapia antituberculosa. La incidencia de depresin, ansiedad y psicosis durante el tratamiento TB-MDR fue de 13,3%, 12,0%, y 12,0%, respectivamente. Aunque en la mayora de individuos con depresin, ansiedad y psicosis requeran psicofrmacos, se logr continuar el uso de cicloserina en todos menos un caso. C O N C L U S I N : Comorbididades psiquitricas no son contraindicacin para terapia TB-MDR. Manejo de complicaciones psiquitrica es posible sin comprometer tratamiento anti-tuberculoso.