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Emotional Distress During Interferon--2B and Ribavirin Treatment of Chronic Hepatitis C

Received July 2, 2001; revision received Jan. 24, 2002; accepted Feb. 13, 2002. From the Departments of Internal Medicine and Psychiatry and the Consortium for Health Outcomes Innovation and Cost-Effectiveness Studies, University of Michigan Medical School, Ann Arbor. Address reprint requests to Dr. Fontana, 3912 Taubman Center, Ann Arbor, MI 48109-0362; rfontana{at}umich.edu (e-mail).

ABSTRACT

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The aim of the study was to describe the use of the Brief Symptom Inventory in characterizing the type and severity of emotional distress in 26 patients with chronic hepatitis C who were receiving interferon--2B and ribavirin. The 6-month actuarial incidence of neuropsychiatric toxicity, determined by physician interview, was 58%. Significant differences in mean depression, anxiety, and somatization Brief Symptom Inventory T scores were noted in the 15 patients with clinically apparent neuropsychiatric toxicity compared to the 11 patients without neuropsychiatric toxicity. Because of its brevity and simplicity, the Brief Symptom Inventory may prove to be a useful adjunct to clinician assessment in detecting and monitoring emotional distress during interferon- treatment of chronic hepatitis C.

INTRODUCTION

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Interferon- and ribavirin combination therapy in patients with chronic hepatitis C is expensive, inconvenient, and associated with a multitude of side effects.^1,2 In large, randomized controlled trials, medication side effects led to dose reductions or early discontinuation of antiviral therapy in 40% of treated patients.^3,4 The majority of interferon-induced side effects are dose dependent and readily detected through laboratory and clinical monitoring.^1,2 However, interferon--induced neuropsychiatric toxicity is frequently insidious in onset and not readily detected with standard clinical monitoring.^5,6 Mood disorders during treatment may be potentially serious; both attempted and completed suicide have been reported.^7,8

Mood survey instruments to detect and monitor neuropsychiatric toxicity in patients with chronic hepatitis C should be brief, reliable, and easily scored and interpreted by non-mental-health-care personnel.⁹ Furthermore, mood assessment instruments should detect psychiatric symptoms at an early reversible stage. The primary aim of this study was to determine the use of the Brief Symptom Inventory in characterizing the type and severity of emotional distress in 26 consecutive patients with chronic hepatitis C who were receiving interferon- and ribavirin. We hypothesized that patients with clinically apparent neuropsychiatric toxicity, as determined by physician interview, would have higher Brief Symptom Inventory scores than those without neuropsychiatric toxicity. Secondary aims of this study were to determine the relationship of health-related quality-of-life scores with the development of clinically apparent neuropsychiatric toxicity.

METHOD

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Study Design
Twenty-six consecutive patients with chronic hepatitis C who were participating in a clinical trial of interferon--2B and ribavirin at a single center were recruited.¹⁰ All patients underwent a screening medical history and physical examination. All patients were older than 18 years, had elevated serum alanine aminotransferase levels, and had not been taking their previous antiviral treatment for a minimum of 3 months. Patients with detectable HIV antibody or hepatitis B surface antigen, active substance abuse, or severe or poorly controlled medical or psychiatric disorders were excluded, according to National Institutes of Health consensus conference guidelines.¹¹ Written informed consent was obtained, according to institutional review board guidelines.

Subjects were randomly assigned to receive either a high dose of interferon--2B and ribavirin for 12 weeks followed by a standard dose of interferon--2B and ribavirin for 36 weeks, or a standard dose of interferon--2B and ribavirin for 48 weeks.¹⁰ All subjects underwent standard laboratory and clinical monitoring every 4 weeks through week 48 of treatment and during posttreatment follow-up through week 72. A sustained virological response was defined as undetectable hepatitis C virus RNA at follow-up week 72.

The number and type of medical comorbidities, defined as medical conditions requiring active treatment, were determined before treatment.¹² Subjects receiving medications for a mood disorder at study enrollment were classified as having an active medical comorbidity. All subjects completed a self-administered questionnaire detailing patient demographics, risk factors for acquiring chronic hepatitis C, and substance abuse history. Subjects with alcoholism or alcohol dependence were defined as those reporting a history of inpatient hospitalization, formal alcohol rehabilitation, or counseling for excessive alcohol consumption. Alcohol abuse was defined as individuals reporting affirmatively to one of the four CAGE questions in the past.¹³

Neuropsychiatric Toxicity
Neuropsychiatric toxicity during treatment was defined through physician interview as clinically significant psychiatric symptoms, such as depressed mood or anxiety, that impaired daily functioning or worsening of preexisting symptoms that required further intervention. Formal DSM-IV diagnostic criteria for neuropsychiatric toxicity were not employed. The assessing physician was an experienced clinician who was unaware of Brief Symptom Inventory scores. Stepwise interventions for neuropsychiatric toxicity included administration of adjuvant medications, such as antidepressants and/or interferon- dose reduction. Interventions for patients with severe neuropsychiatric toxicity included referral to a mental health professional for further assessment or early discontinuation of interferon- and ribavirin.

Brief Symptom Inventory
The Brief Symptom Inventory was self-administered every 4 weeks through week 48 and at week 72 of follow-up. The Brief Symptom Inventory is a 53-item survey of mental health status that generates nine psychiatric symptom subscales and three summary scores.^14,15 Brief Symptom Inventory subscales include somatization, obsessive compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. The Global Severity Index, a summary index of global emotional distress, is calculated by summing the responses to all completed items and dividing by the total number of completed items. Subjects with a subscale or Global Severity Index T score 63 (i.e., in the 90th percentile) were defined as having clinically significant emotional distress.^16,17

Health-Related Quality of Life
Health-related quality of life was assessed at treatment weeks 0, 4, 12, 24, and 72 with the modified SF-36 (Hepatitis Quality of Life Questionnaire, QualityMetric Inc., Lincoln, R.I.).¹⁸ The eight SF-36 subscale scores, as well as the physical and mental health summary scores, were compared to those of healthy comparison subjects in the U.S. population. The role emotional and mental health subscales, as well as the physical and mental health summary scores, were compared among patients with and without neuropsychiatric toxicity.

Data Analysis
Statistical analyses were performed with SAS and SPSS for Windows (SAS Institute, Cary, N.C.; SPSS, Inc., Chicago). Descriptive statistics were calculated and reported as means and standard deviations unless otherwise indicated. At each study visit, patients were categorized as demonstrating clinically apparent neuropsychiatric toxicity ("with neuropsychiatric toxicity") or no evidence of neuropsychiatric toxicity ("without neuropsychiatric toxicity"). The cumulative incidence of neuropsychiatric toxicity during the first 24 weeks of treatment was calculated by using the Kaplan-Meier method. Univariate analyses of clinical predictors of neuropsychiatric toxicity were performed by using chi-square analysis, Fisher's exact tests for categorical variables, and Student's t tests for continuous variables. Repeated-measurement analysis of variance (ANOVA) was performed to examine the effect of neuropsychiatric toxicity on selected Brief Symptom Inventory subscale T scores (anxiety, depression, and somatization), Global Severity Index T scores, and selected SF-36 scores (physical and mental health summary scores, role emotional, and mental health subscales). In addition, 95% confidence intervals were calculated on the difference between mean scores for the patients with and without neuropsychiatric toxicity. For each of the selected SF-36 and Brief Symptom Inventory scores, the effects of time, the presence of neuropsychiatric toxicity, and their interactions were examined. Although the interaction and time effects were not significant, the time effect was kept in the model to control for time. When we compared patients with and without neuropsychiatric toxicity, the Bonferroni-adjusted result was the same as the unadjusted result since there was only one comparison.

RESULTS

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Patient Group
Compensated cirrhosis was present in three patients (11.5%); 14 (53.8%) met criteria for a past history of alcoholism or alcohol abuse (Table 1). Eighteen patients (69.2%) reported active medical comorbidities that required ongoing treatment or monitoring, including arthritis (N=5), depressed mood (N=5), hypertension (N=4), headaches (N=4), gastroesophageal reflux (N=3), diabetes mellitus (N=2), valvular heart disease (N=2), abdominal pain (N=2), anxiety (N=1), glaucoma (N=1), and essential tremor (N=1).

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TABLE 1. Baseline Characteristics of 26 Patients With Chronic Hepatitis C Who Participated in a 48-Week Study of Interferon--2B and Ribavirin Treatment

Thirteen subjects (50%) received a high dose of interferon--2B and ribavirin for the first 12 weeks of treatment, and 13 subjects received a standard dose of interferon--2B and ribavirin. Ten (38.5%) of the 26 subjects completed 48 weeks of antiviral therapy, and seven (26.9%) had a sustained virological response (Figure 1). Ten patients were virological nonresponders at either week 12 or 24 and had treatment stopped, according to study protocol. Six patients had treatment prematurely discontinued during the first 24 weeks of treatment because of side effects, including severe neuropsychiatric toxicity⁴ and gastrointestinal intolerance.²

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FIGURE 1.  Flowchart of 26 Patients With Chronic Hepatitis C Who Participated in a 48-Week Study of Interferon--2B and Ribavirin Treatment

Neuropsychiatric Toxicity
The cumulative incidence of clinically apparent neuropsychiatric toxicity during the first 24 weeks of treatment was 58% (by Kaplan-Meier analysis). Neuropsychiatric toxicity was observed in 15 patients after a median of 28 days of antiviral therapy (range=7–168). Selective serotonin reuptake inhibitors were used in seven subjects with either anxious or depressive symptoms, and nefazodone was used in eight subjects with depressive symptoms, insomnia, and irritability. Seven subjects experienced severe neuropsychiatric toxicity after a median of 28 days of antiviral therapy (range=7–112), leading to premature discontinuation of study medications⁴ and/or psychiatric referral.⁶

The mean duration of antiviral therapy administered to subjects with clinically apparent neuropsychiatric toxicity was similar to that of subjects without neuropsychiatric toxicity (mean=28.3 weeks, SD=18.2, versus mean=28.4 weeks, SD=17.0, respectively). However, interferon- dose reductions were more commonly required in patients with clinically apparent neuropsychiatric toxicity than in patients without neuropsychiatric toxicity (six of 15 [40.0%], versus one of 11 [9.1%]). Ribavirin dose reductions were also more commonly required in patients with clinically apparent neuropsychiatric toxicity than in patients without neuropsychiatric toxicity (seven of 15 [46.7%], versus one of 11 [9.1%]). However, the sustained virological response rate was similar in patients with and without neuropsychiatric toxicity (three of 15 [20.0%], versus four of 11 [36.4%]).

Brief Symptom Inventory Scores
Before treatment, clinically significant emotional distress, defined by a Global Severity Index T score of 63, was noted in two (7.7%) of the 26 patients. Baseline mean Brief Symptom Inventory subscale T scores were consistently higher in the patients who developed clinically apparent neuropsychiatric toxicity than in those without neuropsychiatric toxicity (Table 2). Between-group comparisons of the 15 patients with neuropsychiatric toxicity and the 11 patients without neuropsychiatric toxicity demonstrated notable differences in mean Global Severity Index and depression T scores (Figure 2 and Figure 3). In addition, significant between-group differences were noted in obsessive-compulsive, anxiety, and somatization T scores (p<0.0001) (data not shown). Group differences in mean Brief Symptom Inventory subscale and Global Severity Index T scores were apparent by week 4 of treatment in the patients with neuropsychiatric toxicity and persisted through week 24. With repeated-measures ANOVA, the Global Severity Index, depression, anxiety, and somatization T scores were significantly greater in the patients with neuropsychiatric toxicity than in the patients without neuropsychiatric toxicity through week 24 (p<0.0001). Global Severity Index T scores tended to improve at posttreatment follow-up week 72 but remained higher than pretreatment Global Severity Index T scores in some patients (data not shown).

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TABLE 2. Brief Symptom Inventory T Scores for Patients With Chronic Hepatitis C, With and Without Clinically Apparent Neuropsychiatric Toxicity, Before Interferon--2B and Ribavirin Treatment

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FIGURE 2.  Global Severity Index T Scores for 15 Patients With and 11 Patients Without Clinically Apparent Neuropsychiatric Toxicity During the First 24 Weeks of Interferon--2B and Ribavirin Treatmenta aT scores adjusted for time were significantly different between groups (95% CI=–21.41 to –11.16) (p<0.0001, repeated-measures ANOVA). The numbers of patients with clinically apparent neuropsychiatric toxicity are noted at each time point.

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FIGURE 3.  Depression T Scores for 15 Patients With and 11 Patients Without Clinically Apparent Neuropsychiatric Toxicity During the First 24 Weeks of Interferon--2B and Ribavirin Treatmenta aT scores adjusted for time were significantly different between groups (95% CI=–17.25 to –8.52) (p<0.0001, repeated-measures ANOVA). The numbers of patients with clinically apparent neuropsychiatric toxicity are noted at each time point.

Health-Related Quality of Life
Baseline physical health and mental health summary scores of the entire group were significantly lower than those of healthy comparison subjects in the population (data not shown). During the first 24 weeks of treatment, the mean physical and mental health summary scores of the 15 patients with neuropsychiatric toxicity were lower than those of the 11 patients without neuropsychiatric toxicity (p<0.0001, repeated-measures ANOVA) (data not shown). However, more striking differences were noted in the role emotional and mental health subscale scores over time in the two patient groups (p<0.0001, repeated-measures ANOVA) (Table 3). During posttreatment follow-up, role emotional and mental health subscale scores tended to improve in both groups of patients, although they remained lower in patients who had experienced neuropsychiatric toxicity during treatment than in the patients without neuropsychiatric toxicity.

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TABLE 3. SF-36 Role Emotional Scores for Patients With Chronic Hepatitis C, With and Without Clinically Apparent Neuropsychiatric Toxicity, During Interferon--2B and Ribavirin Treatmenta

Predictors of Neuropsychiatric Toxicity
Exploratory univariate analysis revealed that mean subject age, antiviral treatment regimen, presence of alcoholism or abuse, history of intravenous drug use, mean SF-36 mental health summary scores, and mean Global Severity Index T scores were not different in patients with and without neuropsychiatric toxicity. However, the patients who developed clinically apparent neuropsychiatric toxicity were significantly more likely to be female, to have a baseline mood disorder requiring treatment, and to have active medical comorbidities (p<0.05). In addition, pretreatment SF-36 physical health summary scores were significantly lower in the patients who developed neuropsychiatric toxicity (p=0.04).

DISCUSSION

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Neuropsychiatric toxicity is a common and potentially serious side effect of antiviral therapy for chronic hepatitis C.^5,6 The clinical manifestations of interferon--induced neuropsychiatric toxicity are protean but include a predominance of affective symptoms, including depression, anxiety, and irritability.^5,8 Neuropsychiatric toxicity can be difficult to distinguish from the somatic side effects of interferon- and ribavirin treatment, such as fatigue and weakness.^3,4 In addition, neuropsychiatric toxicity can appear early on, with subtle changes in mood and interpersonal relationships, or later in the course of treatment. Although patients with chronic hepatitis C with underlying psychiatric illness may be at a greater risk of developing neuropsychiatric toxicity, studies have failed to demonstrate reliable predictors of neuropsychiatric toxicity during antiviral treatment, and patients without a history of psychopathology may develop severe neuropsychiatric toxicity.^7,8

Our data demonstrate that 15 (57.7%) of 26 patients with chronic hepatitis C developed clinically apparent neuropsychiatric toxicity, as determined by physician interview, during the first 24 weeks of antiviral therapy. Patients with clinically apparent neuropsychiatric toxicity were more likely to require both interferon- and ribavirin dose reductions during treatment than patients without neuropsychiatric toxicity. Although the number of patients evaluated was small, the greater likelihood of female patients and those with active medical comorbidities to develop neuropsychiatric toxicity is consistent with previous studies.^19–21 The lack of an association of neuropsychiatric toxicity with the use of high doses of interferon- was unexpected in light of the dose-dependent nature of interferon--induced neuropsychiatric toxicity and may be due to the small number of patients completing treatment.²

The Brief Symptom Inventory was chosen to monitor and detect emotional distress because of its established reliability and brevity.²² Although the Brief Symptom Inventory has not been validated as a mood survey instrument for patients with chronic hepatitis C, the Brief Symptom Inventory is a sensitive and reliable means of detecting psychopathology.^23,24 During the first 24 weeks of antiviral treatment, significant increases in mean depression, anxiety, and somatization subscale T scores were observed, as expected, in the patients with clinically apparent neuropsychiatric toxicity (Figure 2 and Figure 3). Mean subscale and Global Severity Index T scores became noticeably higher in the patients with neuropsychiatric toxicity by week 4 and then tended to plateau over time. The pattern of higher T scores in the patients with neuropsychiatric toxicity suggests that the patients were developing emotional distress in multiple domains of psychological functioning, as opposed to pure depressive or anxious symptoms. The elevations in somatization T scores were expected in light of the multitude of systemic side effects associated with interferon- and ribavirin therapy. The elevation in mean obsessive-compulsive subscale T scores among the patients with neuropsychiatric toxicity during treatment was unexpected and may reflect compensatory strategies for impaired cognitive function.²⁴ Further prospective studies of cognitive function in large groups of patients receiving antiviral treatment are needed to follow up on these interesting observations and to compare the Brief Symptom Inventory with other validated instruments and with clinician-based assessment.

Although health-related quality of life was expected to decline during treatment, our findings of lower health-related quality-of-life scores predominantly in the patients experiencing neuropsychiatric toxicity during interferon- and ribavirin treatment have not been previously reported, to our knowledge.^25,26 These observations are consistent with other studies demonstrating a strong link between emotional status and health-related quality of life.^27,28 We have previously shown a strong association between SF-36 scores and Brief Symptom Inventory scores in patients with chronic hepatitis C who were not receiving antiviral treatment.²⁹ Although SF-36 scores tended to improve at week 72 of follow-up, the scores remained lower than pretreatment values in some patients. These observations, taken with Global Severity Index data, suggest that residual impairment in emotional and functional status may be encountered in some patients treated with interferon- and ribavirin.^25,26

The patients who developed neuropsychiatric toxicity during treatment tended to have higher pretreatment Brief Symptom Inventory and lower SF-36 scores than the patients without neuropsychiatric toxicity. The lack of statistically significant differences may be due to the small number of patients studied. However, other studies involving larger numbers of patients and using different instruments have also failed to demonstrate a consistent relationship between baseline emotional status and the risk of developing neuropsychiatric toxicity during antiviral treatment.^5,8 As a result, the need to carefully monitor mood status during antiviral therapy is apparent. Our data suggest that monthly monitoring of mood status during the first 12 weeks of treatment may prove useful. However, we should keep in mind that the Brief Symptom Inventory and other self-administered survey instruments are susceptible to response bias. Therefore, the Brief Symptom Inventory and other instruments should be used as adjunctive screening tools for neuropsychiatric toxicity during treatment rather than as replacements for clinical assessment.

In summary, we identified a 58% incidence of clinically apparent neuropsychiatric toxicity during the first 24 weeks of interferon- and ribavirin therapy in 26 consecutive patients with chronic hepatitis C. Emotional distress was multidimensional and likely reflects the heterogeneity of psychiatric symptoms that may not resemble the symptoms of traditional DSM-IV diagnostic disorders. The Brief Symptom Inventory appears to be a simple and sensitive means of detecting and monitoring emotional distress in patients with chronic hepatitis C who are receiving interferon- and ribavirin. However, large prospective studies assessing the use of interventions in patients with abnormal Brief Symptom Inventory scores during treatment are needed. Although the Brief Symptom Inventory and other mood survey instruments will not replace clinical assessment, they may improve the early detection of reversible neuropsychiatric toxicity and allow the maximal dose of antiviral therapy to be safely administered to patients with chronic hepatitis C.

ACKNOWLEDGMENTS

 
Sponsored in part by Schering-Plough, Inc.

REFERENCES

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Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via Google Scholar Articles by Fontana, R. J. Articles by Moyer, C. A. Search for Related Content PubMed Citation Articles by Fontana, R. J. Articles by Moyer, C. A. Syndromes Secondary to General Medical Disorders

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