Psychosomatics 44:104-112, April 2003
© 2003 The Academy of Psychosomatic Medicine
A Prospective Study of Neuropsychiatric Symptoms Associated With Interferon- -2b and Ribavirin Therapy for Patients With Chronic Hepatitis C
Eric Dieperink, M.D.,
Samuel B. Ho, M.D.,
Paul Thuras, Ph.D., and
Mark L. Willenbring, M.D.
Received April 18, 2002; accepted Aug. 5, 2002. From the Veterans Affairs Medical Center, Minneapolis; and the Departments of Psychiatry and Medicine, University of Minnesota, Minneapolis. Address reprint requests to Dr. Willenbring, Department of Psychiatry (116A), VA Medical Center, One Veterans Dr., Minneapolis, MN 55417; Mark.Willenbring{at}med.va.gov (e-mail).
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ABSTRACT
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The purpose of this study was to systematically describe the neuropsychiatric side effects of treatment with interferon- -2b (INF-) and ribavirin in patients with chronic hepatitis C as well as to compare different instruments used to measure these side effects. Fifty-five patients with chronic hepatitis C were prospectively followed for 24 weeks and assessed with seven neuropsychiatric symptom measures and one quality of life scale. Of 42 patients treated with INF- and ribavirin, 11 (26%) were receiving psychiatric treatment at baseline. They scored higher on all rating scales at baseline and became more symptomatic during treatment. Of the 31 patients (74%) not in psychiatric care at baseline, 15 (48%) required treatment for neuropsychiatric symptoms, and seven (23%) met criteria for major depression during INF- therapy. The control group of 13 untreated subjects showed little change over the 24-week period. All symptom scales were highly intercorrelated, suggesting that use of one is sufficient for monitoring symptoms.
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INTRODUCTION
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Chronic infection with the hepatitis C virus is one of the most common causes of advanced liver disease. The number of patients with cirrhosis, liver failure, and hepatocellular carcinoma due to chronic hepatitis C is increasing, and currently chronic hepatitis C is the leading indication for liver transplantation.1–3 Treatments utilizing interferon--2b (INF-) have the potential to alter the course of chronic hepatitis C and prevent complications.4,5 Recent advances in therapy with pegylated INF- have significantly improved treatment outcome.6 Unfortunately, many severely ill patients are not receiving INF- because of concerns regarding neuropsychiatric side effects.7
Depression is commonly observed in patients receiving INF-, and suicides have occurred.8,9 Published reports indicate that 15%–40% of patients develop depressive symptoms during therapy.7 However, the incidence, time course, severity, need for psychiatric intervention, and predictive factors for depressive symptoms have not been systematically described. Previous studies have used various symptom scales administered at different time points, making results difficult to compare. Patients with histories of psychiatric and substance use disorders are frequently excluded from INF- treatment,10 so little is known about their neuropsychiatric symptom response and tolerance of treatment.
Furthermore, it is not clear how best to monitor or screen for neuropsychiatric symptoms in patients treated with INF-, nor has an optimal treatment approach been determined. A particularly important question is whether all patients should be treated with antidepressants or whether treatment should be symptom based. Answering these questions is essential if these patients are to have access to treatment.
This paper describes a prospective study of patients with chronic hepatitis C who were treated with INF- and ribavirin. Our objectives were to describe the course of neuropsychiatric symptoms during treatment and to compare different instruments for their measurement. We also sought to determine what proportion of patients required initiation of antidepressant treatment and how patients already receiving psychiatric treatment at baseline responded to hepatitis therapy.
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METHOD
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Subjects
Fifty-five patients seen in a chronic hepatitis C clinic were recruited for the study between May 1999 and May 2001 from VA Medical Centers in Minneapolis and Milwaukee. Institutional review boards approved the study, and subjects gave informed consent. Forty-two patients received INF-, 3 million units subcutaneously three times a week, and ribavirin 1000–1200 mg/day orally (Rebetron, Schering-Plough, Kenilworth, N.J.) according to McHutchinson et al.11 The control group consisted of 13 patients who had declined treatment with INF- and ribavirin, wanted to delay treatment, or for whom INF- monotherapy had failed.
Instruments
The 21-item Structured Interview Guide for the Hamilton Depression Rating Scale,12 the Beck Depression Inventory,13 the Zung Self-Rating Depression Scale,14 the Inventory to Diagnose Depression,15 the Positive and Negative Affect Scale,16 the Profile of Mood States,17 the Multidimensional Fatigue Inventory,18 and the Medical Outcomes Study 36-item Short-Form Health Survey Quality of Life Scale19,20 were administered at baseline and at 4, 8, 12, and 24 weeks. The untreated control group was administered the same scales at three time points: at baseline and at 12 and 24 weeks.
Treatment
Antidepressant therapy was recommended for patients not already receiving psychiatric care at baseline if the Hamilton depression scale score was greater than 20, or if neuropsychiatric symptoms such as irritability, emotional lability, and fatigue threatened continuation of INF- therapy, even if the Hamilton depression scale score was 20 or less. Sertraline, 50 mg/day, was the recommended treatment, but that could be changed at the discretion of the treating psychiatrist.
Data Analysis
Patients were divided into four groups for data analysis: those who had been receiving psychiatric treatment before beginning INF-/ribavirin treatment (N=11); those for whom antidepressant treatment was recommended during INF- therapy (N=15); those receiving INF- therapy who did not require treatment for neuropsychiatric side effects (N=16); and the untreated control group (N=13).
Groups were compared on descriptive variables by using analysis of variance for continuously distributed measures and chi-square analyses for categorical variables. Analyses of group differences, changes over time, and group-by-time interactions were conducted by using a mixed general linear model.21 Mixed regression models are advantageous in analyses of repeated-measures data because of their ability to manage missing data. Group membership, time, and group-by-time interactions were modeled as fixed effects. The covariance structure was modeled as autoregressive. Comparisons for the three treatment groups were conducted at baseline and at 4, 8, 12, and 24 weeks; the untreated control group was measured only at baseline and at 12 and 24 weeks. Logistic regression was used to evaluate demographic and background variables as predictors for a recommendation of treatment. All available data for patients were used in the statistical analysis. Of the 42 patients who started INF-/ribavirin treatment, 93% (N=39) completed data for week 4, 76% (N=32) for week 8, 83% (N=35) for week 12, and 69% (N=29) for week 24. Of the 13 patients in the untreated control group, 85% (N=11) completed 12-week data, and 69% (N=9) completed week 24 data. Of all 55 patients, 13 (24%) did not complete the 24 weeks of the study; 11 patients did not show up, and two patients moved. Only 10% (N=4 of 42) of patients did not complete at least a 6-month course of INF- therapy. One patient died at week 16 due to a cardiac event, two patients had a drug or alcohol relapse, and one patient stopped treatment because of intolerable depressive and flu-like symptoms.
Response to hepatitis C antiviral therapy included end-of-treatment virologic response, defined as a negative test for the presence of virus in the serum in the last week of therapy. A sustained virologic response was defined as a negative test for virus 6 months after the last dose of INF-.
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RESULTS
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Subject Characteristics
Most patients (98%, N=54) were men, their mean age was 47 years (SD=4.81), 48 (87%) were Caucasian, six (11%) were African American, and one (2%) was Native American. Most (95%, N=52) had at least a high school education, 16 (29%) were employed full-time, and 22 (40%) were disabled. Thirty-eight (69%) were single or divorced, 19 (35%) had annual incomes of $20,000–$39,999, and 29 (53%) had annual incomes below $20,000. No significant differences were found between groups for these measures.
Clinical characteristics of the study group are shown in Table 1. Of the 42 subjects who received INF-/ribavirin treatment, 11 (26%) were receiving psychiatric care at baseline, primarily for mood disorders or posttraumatic stress disorder (PTSD); nine were taking antidepressants, and two were taking mood stabilizers. Many of the 31 subjects not in psychiatric treatment at baseline also had histories of mood disorders, PTSD, a suicide attempt, or traumatic brain injury. More than one-half (N=9 of 13) of the untreated control subjects were receiving psychiatric care at baseline.
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TABLE 1. Clinical Characteristics of Chronic Hepatitis C Patients Treated With INF- and Ribavirin, by Psychiatric Treatment Requirements, and an Untreated Control Group of Chronic Hepatitis C Patients
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A history of psychoactive substance use was common; about one-half of the group reported lifetime alcohol dependence, and a similar proportion reported lifetime drug dependence. Past-year alcohol use was significantly more common in the group receiving psychiatric treatment at baseline ( 2=4.88, df=1, p<0.03). This group also reported more tobacco use and illicit drug use in the past year, but group differences were not statistically significant.
A sustained virologic response to INF- and ribavirin therapy was found in 12/42 (29%) of patients. No significant group differences in response rate were observed (Table 1).
Neuropsychiatric Symptoms
All measures were highly intercorrelated, and especially so with the Beck Depression Inventory at all time points. Pearson correlations (r) ranged from 0.41 to 0.96; 89% were greater than 0.60, and 44% were greater than 0.80. Data for baseline and week 8, the time point of greatest group difference, are shown in Table 2. Data for other time points and subscores are available from the authors. It is notable that scales purportedly measuring different symptoms, such as the Multidimensional Fatigue Inventory, Short-Form Health Survey, and Beck Depression Inventory, all demonstrated similar patterns. Therefore, we will report symptom pattern data only for the Beck Depression Inventory. The Inventory to Diagnose Depression determines whether diagnostic criteria for major depression are met, a qualitatively different type of information, so its results are also reported.
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TABLE 2. Correlations Between Neuropsychiatric Measures at Baseline and at Week 8 Among Chronic Hepatitis C Patients Treated With INF- and Ribavirin
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Baseline Measurements
Patients for whom no psychiatric treatment was required and those for whom antidepressant psychiatric treatment was recommended had similar low scores, reflecting their lack of significant baseline symptoms. The subjects receiving psychiatric treatment at baseline and the untreated control group patients also had similar scores, demonstrating moderate psychiatric distress. Significant differences were found between the no psychiatric treatment required group and both the subjects receiving psychiatric treatment at baseline (F=21.48, df=1, 39, p<0.001) and the untreated control group (F=23.20, df=1, 41, p<0.001). Significant differences were also found between the group for which antidepressant psychiatric treatment was recommended and both the subjects receiving psychiatric treatment at baseline (F=8.28, df=1, 24, p=0.008) and the untreated control group (F=8.91, df=1, 24, p=0.006).
Inventory to Diagnose Depression results showed a similar pattern (Table 3). No patients in the group requiring no psychiatric treatment or the group for which antidepressant psychiatric treatment was recommended met criteria for major depressive disorder at baseline, whereas almost half of the subjects receiving psychiatric treatment at baseline and the untreated control groups did (2=15.53, df=3, p=0.001).
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TABLE 3. Inventory to Diagnose Depression Scores Over 24 Weeks for Chronic Hepatitis C Patients Treated With INF- and Ribavirin, by Psychiatric Treatment Requirements, and an Untreated Control Group of Chronic Hepatitis C Patients
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Course of INF- Therapy
Subjects receiving psychiatric treatment at baseline entered hepatitis C treatment with substantial neuropsychiatric symptom levels that worsened. As seen in Figure 1, their scores were significantly higher across the study period than those of patients for whom antidepressant psychiatric treatment was recommended (t=2.64, df=39, p=0.01) or patients who received no psychiatric treatment (t=5.35, df=39, p<0.001). At baseline, five (46%) of 11 patients met criteria for major depressive disorder. During treatment three additional patients met criteria for major depressive disorder, but by week 24 only three (27%) of 11 met criteria for major depressive disorder (Table 3). In spite of these high symptom levels, all but one patient in this group completed a 6-month course of INF-/ribavirin therapy. Treatment was discontinued after relapse of his substance use disorder at 12 weeks.
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FIGURE 1. Beck Depression Inventory Scores Over 24 Weeks for Chronic Hepatitis C Patients Treated With INF- and Ribavirin, by Psychiatric Treatment Requirements, and an Untreated Control Group of Chronic Hepatitis C Patients
aPatient scored >20 on the Hamilton depression scale or neuropsychiatric side effects (e.g., irritability, emotional lability, fatigue) threatened continuation of INF- therapy.
bSignificant difference between the group receiving psychiatric treatment at baseline and the no psychiatric treatment required group at all time points (p<0.01).
cSignificant difference between antidepressant psychiatric treatment recommended group and the no psychiatric treatment required group at all time points (p<0.01).
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The Beck Depression Inventory scores of patients for whom antidepressant psychiatric treatment was recommended were similar at baseline to those of patients not requiring psychiatric treatment but quickly diverged. At 4 weeks differences were statistically significant (F=5.46, df=1, 25, p<0.03), which continued through week 24 (overall comparison: t=3.07, df=39, p=0.004); Inventory to Diagnose Depression scores showed similar results. Among those for whom antidepressant psychiatric treatment was recommended, the proportion of subjects meeting major depressive disorder criteria rose to 47% (N=7 of 15) compared with 6% (N=1 of 16) for the subjects requiring no psychiatric treatment (2=4.66, df=1, p<0.04). Rates of discontinuation or dropout from INF-/ribavirin treatment were not significantly different between these two groups (N=2 of 15 and N=1 of 16, respectively). The number of patients for whom antidepressant therapy was recommended at 1–4 weeks was nine; at 4–8 weeks, N=3; at 8–12 weeks, N=3. In the antidepressant treatment recommended group, the baseline Beck Depression Inventory score of those who eventually met major depressive disorder criteria (mean=9.0, SD=7.33) was significantly higher than the score of those who did not meet major depressive disorder criteria (mean=4.36, SD=3.82) (F=5.17, df=1, 28, p<0.04).
The untreated control group had baseline Beck Depression Inventory scores similar to those of the subjects receiving psychiatric treatment at baseline but significantly higher scores than those of the antidepressant psychiatric treatment recommended and no psychiatric treatment groups (F=23.2, df=1, 41, p<0.001). According to the Inventory to Diagnose Depression, five (38%) of 13 met criteria for major depression at baseline (Table 3). In contrast to the groups receiving INF-/ribavirin therapy, scores on all measures in this group decreased over the course of the study. No patients in the untreated control group who were not receiving psychiatric care at baseline required psychiatric care during the study.
Prediction of Psychiatric Treatment Recommendation
We examined the sensitivity and specificity of the Beck Depression Inventory and other instruments for predicting eventual psychiatric treatment recommendation or major depressive disorder diagnosis among subjects in the antidepressant treatment recommended and the no psychiatric treatment required groups. The Beck Depression Inventory was 80% sensitive and 67% specific when using a score of 10 or greater, over the first 12 weeks, for predicting whether patients would enter the antidepressant treatment recommended group (Mantel-Haenszel odds ratio=6.67, 95% confidence interval [CI]=1.3–33.7; p<0.03). A Beck Depression Inventory score of 15 or greater, during the first 12 weeks, was 100% sensitive and 83% specific for predicting major depressive disorder. No other measure performed as well as the Beck Depression Inventory.
Logistic regression was performed to evaluate predictors of psychiatric treatment and major depression in patients not receiving treatment at baseline. Factors tested were a history of a suicide attempt, a history of two or more psychiatric diagnoses, a family history of mood disorder, drug and alcohol dependence, and a history of traumatic brain injury. Two factors were significant or nearly significant predictors of membership in the antidepressant treatment recommended group: family history of a mood disorder (odds ratio=10.70, 95% CI=1.26–90.56; p=0.03) and a history of two or more psychiatric diagnoses (odds ratio=9.96, 95% CI=0.793–125.05; p<0.08). Baseline depression, fatigue, or quality of life scores did not predict a treatment recommendation. However, the only predictor of developing major depressive symptoms was an elevated baseline Beck Depression Inventory score (odds ratio=1.60, 95% CI=1.04–2.06; p=0.03). This risk is an incremental increased risk per baseline Beck Depression Inventory point over zero.
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DISCUSSION
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In this prospective observational study of veterans undergoing INF-/ribavirin treatment for chronic hepatitis C, 48% of those patients not in psychiatric care at baseline required treatment for neuropsychiatric side effects, and 23% developed symptoms consistent with major depression. Treatment with a selective serotonin reuptake inhibitor antidepressant was helpful in stabilizing these symptoms and allowing patients to continue hepatitis treatment. This result is consistent with prior case reports and case series reporting that antidepressants are effective in treating neuropsychiatric side effects associated with INF-.22–24
Equally important, about one-half of patients not in psychiatric care at baseline did not develop significant symptoms nor require psychiatric intervention. This strongly suggests that such treatment be based on symptom development rather than routinely prescribed at the outset of hepatitis treatment. The Beck Depression Inventory is an excellent choice for symptom monitoring; it performed well and is easy to administer and score. Monitoring every 2–4 weeks during the first 3 months of hepatitis treatment appears sufficient for identifying patients who may require psychiatric intervention. On the basis of this study, a score of 10 to 15 would indicate the need for clinical evaluation, and a score of 15 or more would strongly suggest that antidepressant treatment be initiated. Furthermore, as higher baseline Beck Depression Inventory scores predicted the development of major depressive disorder symptoms, the data suggest that patients with baseline Beck Depression Inventory scores above 6 may benefit from antidepressant therapy before initiating INF- therapy. Patients should be informed that they may be at greater risk of developing depression, and an individualized decision can be made by patient and clinician. It is probably justified to recommend prophylactic antidepressant treatment to patients with baseline scores above 10.
Patients with histories of psychiatric or substance use disorders represent a large proportion of patients with chronic hepatitis C;25 in this study the proportion was 70%. In spite of this history, and of moderate to severe psychiatric symptom levels during INF- therapy, an overall sustained virologic response rate of 28% was obtained. Furthermore, the response rate was similar across all treatment groups. This response rate is similar to previously published reports in other populations and provides evidence that patients with these problems can complete and benefit from hepatitis treatment and should be not be routinely excluded.11
We previously reported that patients with psychiatric disorders had more adverse events during INF- monotherapy.26 Before and during the current study, we developed a model for collaboration between hepatology and mental health staff. This model included open lines of communication, improved access to identified mental health and addiction treatment practitioners, and standardized methods for monitoring medical and neuropsychiatric symptoms during INF- therapy. It is likely that patients in this study benefited from this integration of care. Integrating medical and psychiatric treatment has shown promise in controlled trials in similar populations.27 This approach requires further study.
Few studies have followed chronic hepatitis C patients not receiving INF-, who may nevertheless experience significant depression and anxiety.28,29 We found these patients to have significant psychiatric symptoms, but these symptoms did not worsen over time. This supports the conclusion that INF- has a measurable effect on neuropsychiatric symptoms and is not due to chronic hepatitis C alone.
Risk factors for depression during interferon therapy have not been well documented. Family history increases the risk of major depression in the general population.30 However, prior studies of chronic hepatitis C patients receiving INF- did not find this association.31,32 In our study, family history predicted a seven-fold increase in likelihood of requiring psychiatric intervention. Hepatitis C patients with a family history of mood disorders should be followed closely for depressive symptoms and treated aggressively if they arise. A prior history of two or more psychiatric diagnoses was also predictive of a need for psychiatric treatment during hepatitis treatment. Multiple psychiatric diagnoses may indicate susceptibility to stressful life events; these patients should also be closely monitored during INF- therapy.
The current study has several limitations. A relatively small and a predominantly male, Caucasian, veteran sample makes extrapolation to other populations difficult. Future studies should include more women, since they may be at greater risk of developing depressive symptoms. Nonveteran patients and members of other ethnic groups should also be studied. Despite these limitations, this study has several key findings that provide useful guidance for treatment providers. First, patients with existing psychiatric disorders and chronic hepatitis C can expect their symptoms to become worse during INF-/ribavirin therapy, but they can successfully complete therapy given appropriate medical and psychiatric care. Second, a significant proportion of initially nondepressed patients will not require antidepressant treatment. Finally, patients' psychiatric symptoms can be effectively monitored during INF- therapy by using a single depression measure.
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ACKNOWLEDGMENTS
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Supported by the Minneapolis VA Hepatitis C Resource Center, the Research Service of the Department of Veterans Affairs, and an unrestricted grant from Schering-Plough.
The authors thank Lori Tetrick, Kristen Phillips, Kulwinder Dua, Gunnar Larson, Arnold Valerius, and William Townsend for their contributions to this study.
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ABSTRACT
INTRODUCTION
