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The Effect of Pegylated Interferon-_2b and Ribavirin on Posttraumatic Stress Disorder Symptoms

Received January 25, 2006; revised August 15, 2006; accepted August 30, 2006. From the Depts. of Psychiatry and the Hepatitis C Resource Center at the VA Medical Center; Univ. of Minnesota Medical School; and the Dept. of Medicine, VA San Diego Healthcare System and the Univ. of California, San Diego. Send correspondence and reprint requests to Dr. Eric Dieperink, VA Medical Center (116A), Dept. of Psychiatry, One Veterans Dr., Minneapolis, MN 55417. e-mail: Eric.Dieperink{at}med.va.gov
© 2008 The Academy of Psychosomatic Medicine

ABSTRACT

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BACKGROUND: Patients with chronic psychiatric diagnoses have a prevalence of chronic hepatitis C (HCV) approximately 11 times higher than the general American population. Posttraumatic stress disorder (PTSD) is particularly common among HCV patients. OBJECTIVE: The authors describe the effect of treatment with pegylated-interferon-_2b (IFN) and ribavirin for patients with HCV on their posttraumatic stress disorder (PTSD) symptoms. METHOD: Sixteen patients with HCV and combat-related PTSD were followed for 24 weeks and assessed with self-report measures of PTSD, hostility, and depression. RESULTS: Depression and Resentment scores significantly increased in five patients treated with IFN and ribavirin, but no significant differences were found in PTSD scores when compared with 11 control patients. CONCLUSION: The results suggest that patients with PTSD and HCV can be safely treated with anti-viral therapies when they are given appropriate psychiatric care.

Key Words: Interferon • PTSD

INTRODUCTION

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The hepatitis C virus (HCV) is the most common blood-borne infection in the world, and nearly 2% of Americans are infected with the virus.¹ In a recent study, veterans who used the Veterans Administration (VA) for health care were found to have an approximate HCV prevalence rate of 5.4%, with Vietnam-era veterans having the highest rate, at 11%.²

Patients with chronic psychiatric diagnoses have a prevalence of HCV approximately 11 times higher than the general American population.³ Not only is HCV common among psychiatric patients, but HCV patients frequently have psychiatric problems. Posttraumatic stress disorder (PTSD) is particularly common among HCV patients. El-Serag et al.,⁴ in a large study of 33,824 veterans with HCV, found that 33.5% were diagnosed with PTSD. In two smaller studies, 19% and 20.8% of consecutive HCV patients were found to have PTSD.^5,6 Although there are no data regarding the rates of PTSD in HCV patients in community settings, it is likely that they approximate the rates seen in the VA. First of all, similar to studies of VA HCV patients, community-setting studies show high rates of psychiatric problems, including anxiety, depression, and substance-use disorders.⁷ Also, because intravenous drug use is the most frequent route of HCV transmission, trauma-related psychiatric disorders such as PTSD are likely to be common among patients with HCV, given the high rates of traumatic events associated with substance use.^8,9

Finally, when patients are not systematically screened for PTSD, it often goes unrecognized. In a VA study, Lehman and Cheung found that 56% of HCV patients who screened positive for PTSD did not have chart diagnoses of this disorder.⁵ In a multicenter, community, primary-care study in patients without HCV, Rodriguez et al.¹⁰ found that 48% of patients with PTSD had gone unrecognized.

Effective treatment for HCV with interferon (IFN) and ribavirin eradicates the virus in 40%–50% of patients with genotype 1 and approximately 80% of patients with genotype 2 or 3.^11,12 Successful treatment of HCV is associated with decreased liver fibrosis, cirrhosis, and possibly liver cancer.^13–16 However, many patients do not receive antiviral therapy because of concerns about the neuropsychiatric side effects of IFN. Flu-like symptoms are the most common side effects of IFN; close to 50% of patients experience depressive symptoms, but irritability and anxiety symptoms are also common, occurring in 24%–47% of patients.¹⁷ Currently, psychiatric and substance-use disorders are cited as a main reason for exclusion from antiviral therapy.^18–20 Although few data are available, it is likely that patients with PTSD are excluded from antiviral therapy because of concerns about the possibility of increased irritability, hostility, and sleep disturbance, as well as worsening depression and anxiety. Recently, Rifai et al.²¹ reported that 39% of a veteran cohort was excluded from antiviral therapy because of the presence of psychiatric problems, including PTSD.

Despite the likely high rates of traumatic events as well as PTSD in patients with HCV, only one case report has investigated the effects of interferon (nonpegylated) and ribavirin on PTSD symptoms. Maunder et al.²² reported the emergence of PTSD symptoms in three patients treated with interferon-_2b and ribavirin. To our knowledge, no studies are available regarding the effects of interferon and ribavirin on patients with current PTSD diagnoses and symptoms. Therefore, we prospectively studied patients with chronic hepatitis C and combat-related PTSD who were treated with IFN and ribavirin and compared them with similar patients who were not treated with antiviral therapy. Our objectives were to describe the course of PTSD symptoms during treatment and to determine whether the hyperarousal symptoms of PTSD were most apt to change during therapy. We hypothesized that hyperarousal symptoms would be most likely to change, given that irritability and sleep difficulties associated with IFN are common.¹⁷ We also sought to determine whether PSTD symptoms change independently of depressive symptoms.

METHOD

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Subjects
Sixteen patients seen in the chronic-hepatitis clinic were recruited for the study between December 2002 and February 2005 from the VA Medical Center in Minneapolis, MN. The Institutional Review Board approved the study, and all subjects gave written informed consent. Five patients received pegylated interferon-_2b (Peg-Intron; Schering-Plough; Kenilworth, NJ), 1.5 µg/kg subcutaneously once per week, and weight-based ribavirin (800 mg/day–1,200 mg/day) orally, according to VA treatment guidelines.²³ The control group consisted of 11 patients who declined antiviral treatment, wanted to delay treatment, or for whom previous treatment with non-pegylated interferon-_2b and ribavirin (Rebetron; Schering-Plough; Kenilworth, NJ) had failed.

Instruments and Treatment
The following self-report measures were administered at baseline, 4, 8, 12, and 24 weeks: The Beck Depression Inventory (BDI),²⁴ Buss-Durkee Hostility Inventory,²⁵ Mississippi PTSD scale,²⁶ and PTSD Symptom Checklist–Military Version (PCL–M).²⁷ All patients were treated by their usual mental-health providers. A PCL–M score 50 and a Mississippi score >107 are considered consistent with PTSD. The PCL–M also allows for a categorically-based PTSD diagnosis. This is based on meeting "symptomatic" thresholds for the Diagnostic and Statistical Manual–IV (DSM–IV) PTSD categories of re-experiencing, avoidance, and hyperarousal.^28,29 The Buss-Durkee Hostility Inventory has seven subscales: assault, irritability, resentment, indirect hostility, negativism, verbal hostility, and guilt.

Data Analysis
The antiviral treatment group was compared with the control group on descriptive variables by using analysis of variance for continuously-distributed measures and chi-square analysis for categorical variables. Analysis of group differences, changes over time, and group-by-time interaction were conducted with hierarchical linear models by use of SAS 9.1.³⁰

All available data were used for the statistical analysis. Of the five patients who started antiviral therapy, 5/5 completed the measurements at baseline through Week 12, and 4/5 completed all 24 weeks of the study. Of the 11 untreated patients, all completed baseline, 4-, and 8-week measurements; 10/11 completed Week 12, and 9/11 completed all 24 weeks. All five patients treated with antiviral therapy completed a full course of antiviral therapy.

Response to antiviral therapy included end-of-treatment virologic response, defined as a negative test for the virus in the last week of IFN therapy. A sustained virologic response (SVR) was defined as a negative polymerase chain reaction (PCR)-type test for the virus for at least 6 months after the last dose of IFN.

RESULTS

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Subject Characteristics
All patients were male veterans; their mean age was 55 years (standard deviation [SD]: 2.4), 13 patients (81.2%) were white, and 3 (18.8%) were African American (Table 1). All patients were receiving psychiatric care at baseline (before initiation of antiviral therapy) and throughout the study period. All patients were diagnosed with combat-related PTSD by their current psychiatric clinician. At baseline, 13 patients were taking antidepressants (citalopram, sertraline, paroxetine, fluoxetine, and mirtazapine); 9 patients were taking medications for sleep (zolpidem, temazepam, zaleplon, and trazodone); 4 were taking anti-anxiety agents (hydroxyzine, lorazepam, and alprazolam), and 2 were taking antipsychotic medications (quetiapine and olanzapine). No significant group differences were found for these characteristics.

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TABLE 1. Baseline Patient Characteristics (N=16)

Of the five patients treated with IFN and ribavirin, four were genotype 1, and one was genotype 2. Two of the five patients treated with IFN and ribavirin were end-of-treatment responders; one showed a sustained virologic response; and two were virologic non-responders to antiviral treatment.

Baseline Measurements
All patients were highly symptomatic before initiation of antiviral therapy: mean PCL–M was 59.4 (SD: 10.7); mean BDI was 21.5 (SD 11.7), and the mean total Mississippi score was 114.3 (SD: 16.3). Mean overall Buss-Durkee score was 40.9 (SD: 11.9; Table 1). Most patients (13/16; 81%) scored above the PCL–M and Mississippi thresholds for PTSD. All but two patients (88%) met categorical PCL–M scores for the diagnosis of PTSD. The patients who did not meet full criteria at baseline for PTSD had only two of the three DSM–IV symptomatic responses to the avoidance questions; they were symptomatic for the hyperarousal and re-experiencing categories. One of these patients was in the antiviral treatment group, and the other was in the control group. There were no significant differences in scores between the group that received antiviral therapy and the control group.

Course of IFN and Ribavirin Therapy
The antiviral treatment group had moderately high baseline scores on the BDI, and these significantly worsened during treatment (F[1, 59]=8.27; p<0.01). The BDI scores were also significantly worse over the course of antiviral therapy, as compared with the control group, not receiving IFN treatment (F[1, 59]=4.98; p<0.03; see Figure 1).

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FIGURE 1.  PCL–M (Posttraumatic Stress Disorder Symptom Checklist–Military Version) Scores During IFN Treatment, Compared With the Control Group

The PCL–M, Mississippi, and Buss-Durkee scores were symptomatic for all patients at baseline but not significantly different between groups. Subjects in the antiviral treatment group became more symptomatic on the PCL–M and the Mississippi scales, significantly so for the PCL–M (F[1, 59]=4.39; p<0.05) when compared with baseline, but the change did not meet significance when compared with the control group (F[1, 59]=3.78; p<0.06); see Figure 2). The PCL–M Avoidance subscale had the largest change when compared with baseline, although this did not meet statistical significance, and all of the subscales (Re-experiencing, Avoidance, and Hyperarousal) did not significantly change in the treatment group when compared with control subjects (F[1, 59]=2.94; p<0.09; F[1, 59]=0.3; p<0.58; F[1, 59]=0.79; p<0.38; for Avoidance, Hypervigilance, and Re-experiencing, respectively.

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FIGURE 2.  Beck Depression Inventory (BDI) Scores During IFN Treatment, Compared With the Control Group

Buss-Durkee Hostility scores were not significantly different at baseline between groups. However, the antiviral treatment group became more symptomatic at Week 4, but over the following 20 weeks, dropped back to baseline levels. Patients in the antiviral treatment group did show a significant increase at Week 4 on the Buss-Durkee Resentment factor when compared with those who were not administered antiviral therapy (t[52] = –2.06; p<0.045), but this factor showed a similar trajectory as the overall Hostility Buss-Durkee score. No other subscales were significantly different between groups over time.

All patients treated with antiviral therapy either increased their antidepressant dose or added an adjunctive medication between Week 4 and Week 16. None of the IFN-treated patients was prescribed a benzodiazepine during antiviral therapy. Two of the five did receive buspirone; one received quetiapine; one received trazodone; both were at low doses and used as a sleeping aid. Of those patients in the control group, only 3/11 (27%) required a change in antidepressant dose during the 24-week study period. The changes occurred between Week 4 and Week 20.

DISCUSSION

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PTSD is common among patients with HCV and may be used as a reason to exclude patients from antiviral therapy.²¹ In this prospective observational study of veterans with PTSD undergoing IFN/ribavirin treatment for chronic hepatitis C, depressive and PTSD symptoms increased during IFN treatment, but global hostility, as measured by the Buss-Durkee scale did not. However, only the Depression and Resentment subscales of the Buss-Durkee changed significantly when compared with the control group. In spite of increased symptoms, all patients who received antiviral treatment finished a full course of antiviral therapy.

Previous studies of the effects of interferon in patients without PTSD suggest that irritability, hostility, and anxiety are common problems associated with antiviral treatment. Between 35% and 47% of patients treated with interferon experience irritability, and at least 10% experience mood lability.^7,17 Furthermore, in the report by Maunder et al.,²² hyperarousal and re-experiencing symptoms were the most prominent of the PTSD symptoms experienced when patients were treated with IFN. Given these previous studies, we expected that the hyperarousal symptoms of PTSD would be the most likely to increase over the course of IFN treatment. However, only the Avoidance PCL–M subscale showed a noticeable increase. None of the PCL–M subscales (Re-experiencing, Avoidance, and Hyperarousal) significantly changed during IFN therapy when compared with the control group. It is possible that these patients did not experience significantly increased PTSD symptoms because they were appropriately treated with both pharmacological and psychotherapeutic treatments.

The BDI showed the most significant change in the treatment group, suggesting that, as previous studies of patients with psychiatric problems have shown,³¹ depressive symptoms may be the most important group of symptoms to monitor during antiviral therapy. Despite the significant increase in depressive symptoms, all patients were able to complete a course of antiviral treatment.

Irritability and hostility are frequently-reported side effects of IFN therapy.¹⁷ In this study, only the Resentment subscale of the Buss-Durkee showed a significant change (at Week 4) compared with the control group. It is possible that Resentment peaks at Week 4 as patients are trying to cope with the onset of a multitude of antiviral medication side effects. Further exploration of the impact of interferon on hostility is warranted in this population.

There are several limitations to the current study. The small, veteran, and predominantly white, male sample make extrapolation to other populations difficult. Larger studies that include women and more ethnically-diverse populations are needed. Also, studies that include patients with non-combat trauma should be included because these patients may follow a different clinical course. The current study suggests that large changes in PTSD symptoms during interferon therapy are unlikely; however, it is possible that, in a bigger study, clinically meaningful PTSD symptoms would become more apparent. Despite the small number of subjects in this study, depression scores did change significantly and in a manner consistent with earlier and larger studies.^31,32 The data suggest that a depression measure, rather than a PTSD measure, is more sensitive to clinical change during antiviral therapy and may serve as a better guide for psychiatric intervention. Finally, given that PTSD and traumatic events are common among HCV patients, this preliminary study suggests that these patients should not be excluded from antiviral therapy because of PTSD alone. However, larger studies are needed to confirm these findings.

REFERENCES

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