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Anger Experiences Among Hepatitis C Patients: Relationship to Depressive Symptoms and Health-Related Quality of Life

Received January 19, 2006; revised March 14, 2006; accepted March 20, 2006. Center for Liver Diseases and Dept. of Psychiatry; Inova Fairfax Hospital; MidAtlantic Permanente Medical Group, Falls Church, VA. Send correspondence and reprint requests to Zobair M. Younossi, M.D., M.P.H., Center for Liver Diseases at Inova Fairfax Hospital, 3289 Woodburn Rd., Suite 375, Annandale, VA 22003-6800.
e-mail: zobair.younossi{at}inova.com
© 2007 The Academy of Psychosomatic Medicine

ABSTRACT

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The authors examined anger among hepatitis C (HCV) patients and its relationship to health-related quality of life (HRQL) and depression. Eighty-seven HCV patients who received pegylated interferon-alpha_2b and ribavirin were included. Patients’ mean age was 48 years; 42% were women, and 60% were white. Patients experienced moderate anger while undergoing HCV treatment. Angry feelings increased during treatment in some domains, specifically, Control Over Anger and Angry Reaction. Greater anger was associated with more depression and poorer HRQL. Findings point to the importance for physicians to screen for a wide range of neuropsychiatric side effects of interferon, including anger.

INTRODUCTION

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The deleterious effects of hepatitis C (HCV) on functional health, well-being, and health-related quality of life (HRQL) have been well documented.^1–3 These issues become especially important for patients receiving an interferon-based regimen. Interferon-alpha causes a variety of neuropsychiatric side effects, ranging from irritability and anger to the symptoms of anxiety and depression. To date, only a few studies have investigated the experience of anger among HCV patients.^4–9 There is some evidence that anger-hostility increases during interferon-alpha⁷ and cytokine therapy.⁸ One study found that almost one-third of HCV patients in the sample experienced anger during interferon-alpha treatment,⁴ and another study found that HCV patients had greater anger than patients with chronic non-liver diseases.⁹ This article is the first to examine how anger feelings and experiences change sequentially over the course of antiviral therapy in relationship to both medical and psychological variables, and HRQL.

METHOD

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The study cohort consisted of 87 patients with chronic hepatitis C (CH–C), who received a regimen of pegylated interferon-alpha_2b and ribavirin. Before the initiation of treatment and during treatment, patients were asked to complete questionnaires that assessed their experiences with anger and depressive symptoms, HRQL, and demographic characteristics, at the beginning of each office visit. Clinical data were also collected. Patients were all informed of possible side effects of treatment, so that any attribution bias was consistent among the group. Anger data collected at nine time-points were used for analyses: before antiviral therapy began, at Weeks 4, 12, 24, 36, and 48 of treatment, and 4, 12, and 24 weeks after completion of therapy. This protocol was approved by the Institutional Review Board.

Measures
Anger
The State–Trait Anger Expression Inventory (STAXI–2),^10,11 which measures the experience, expression, and control of anger, was administered to patients. State-Anger measures emotional state at a given time-point and captures feelings ranging from mild irritation to intense rage. The STAXI–2 has a 15-item scale that measures overall state-anger, as well as three state subscales: feeling angry (internal experience of anger), feeling like expressing anger verbally (intensity of feelings related to verbal expression of anger), and feeling like expressing anger physically (intensity of feelings about physical expression of anger). Respondents were asked to indicate the extent to which they had these feelings presently, with item response options ranging from 1: "not at all" to 4: "very much."

Trait-Anger within the STAXI–2 assesses an individual’s disposition to feeling angry over time and in different situations. Ten items quantify an overall trait measure, as well as subscales of angry temperament, a disposition to being angry without provocation, and angry reaction, which measures the frequency with which one feels angry in frustrating or negative situations.

The STAXI–2 also measures anger expression and anger control. Anger-Expression is conceptualized into two components: outward expression, meaning expression of anger toward other people or objects, and inward expression, which is the suppression of feelings of anger. Anger-Control also has two components: inward control, which involves suppression of angry feelings by calming down when angry; and outward control, meaning control over angry feelings by preventing expression of anger toward others. In addition to these four subscales, an Overall Anger-Expression scale may be calculated.

Higher scores on each of the STAXI–2 scales reflect greater anger. The exception is that lower scores on the inward and outward control of anger scores equate to greater anger (i.e., less control over anger).

Health-Related Quality of Life (HRQL)
We administered the Short-Form 36 (SF–36) Health Survey (general health measure) and the Chronic Liver Disease Questionnaire (CLDQ), HCV Version.

The SF–36¹² consists of 36 items, measuring general health status in eight domains: Physical Functioning, Role Limitations: Physical, Bodily Pain, General Health Perceptions, Vitality, Role Limitations: Emotional, Mental Health, and Social Functioning. Each scale has scores ranging from 0 to 100. The SF–36 is also divided into summary scores for Mental and Physical components. The Mental Health summary component score ranges from 10 to 74, and the Physical Health summary component ranges from 8 to 73. Higher scores on each scale indicate greater HRQL. The SF–36 has good validity and reliability in chronic-disease samples, including CH-C.^1,2,13

The CLDQ-HCV is a liver disease-specific HRQL instrument, consisting of 29 items reflecting four domains: 1) Emotional Functioning; 2) Systemic Symptoms; 3) Activity; and 4) Worry. Response options for each item range from 1: "all of the time" to 7: "none of the time." Scores on these subscales also range from 1 to 7. An overall CLDQ score is also calculated (range: 1–7). Higher scores on each CLDQ scale reflect greater HRQL. This instrument is valid and has good test–retest reliability.^14–16

Depressive symptom level
To measure depressive symptoms, the Center for Epidemiologic Studies Depression Scale (CES–D)¹⁷ was administered to patients. This 20-item scale is a reliable and valid measure for screening depressive symptoms in CH-C populations.¹⁸ Summary scores range from 0 to 30, with higher scores indicating greater depressive symptoms. Although the continuous measure of CES–D was used in multivariate analyses, for descriptive purposes, scores were divided into low/mild depressive symptoms (<16) and moderate/high depressive symptoms (16), consistent with previous designations.¹⁷

Patients’ clinical and laboratory data at baseline as well as during treatment and at follow-up were also collected.

Statistical Analysis
Descriptive data on the STAXI–2, including reliability coefficients, were assessed, and 12 predictors of anger were examined: body mass index (BMI: 30 versus >30); HCV RNA level (<850,000 versus 850,000); alanine transaminase (ALT) level (<40 versus 40); genotype (Genotype 1 versus Other); whether the patient had cirrhosis, history of alcoholism, history of depression, or depressive symptoms; whether the patient was taking an antidepressant or antianxiety medication; gender; age; and race (white, black, other race). Personal and clinical factors predicting anger at baseline were examined with ordinary-least-squares (OLS) regression. Next, we analyzed the experience of how anger changed over the course of antiviral therapy. Paired-sample t-tests were utilized to examine changes in anger between each pair of time-points. Finally, the relationship between anger and HRQL was assessed by use of bivariate correlations. All statistically significant relationships summarized below were significant at p <0.05.

RESULTS

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Clinical data, demographic characteristics, and baseline HRQL scores are summarized in Table 1. Table 2 provides the baseline means, standard deviations (SDs), and alpha reliability values for each anger subscale. All subscales had acceptable-to-high reliability; the only exception was that the Outward Expression of Anger scale had relatively low reliability (=0.62).

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TABLE 1. Baseline Descriptive Statistics (N=87)

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TABLE 2. Descriptive Data for Anger Subscales

Predictors of Anger
OLS regression was used to examine predictors of anger scales. Depressive symptoms and race were the two most consistent statistically significant predictors of anger scores. Greater depressive symptoms were associated with less inward control of anger (23.3 [SD: 5.8]) for those with CES–D >16, versus 25.1 (SD: 4.7) for those with CES–D 16; p <0.05) and with higher scores on angry reaction (11.0; [3.5] versus 6.9 [2.7]; p <0.05) and trait-anger scales (19.0 [4.4] versus 14.9 [4.1]; p <0.05). Black patients had significantly higher scores (p <0.05) on the scales tapping physical expression of anger (7.6 [5.7]), verbal expression of anger (7.7 [5.8]), the overall anger-state scale (22.7 [16.3]), and feeling angry (7.5 [5.0]), as compared with white patients (5.1 [0.5], 5.2 [1.0], 15.8 [2.4], and 5.5 [1.2], respectively) and patients of another race (5.0 [0.0], 5.2 [0.7], 15.7 [1.8], and 5.5 [1.2], respectively). White patients and those of another race had similar mean scores on these four anger scales. Of the three racial groups, whites had the lowest inward-expression scores (13.7 [3.9]), whereas black patients (15.3 [8.0]) and individuals of other racial groups (16.0 [4.2]) had similar, higher average scores.

History of depression and taking an antidepressant/antianxiety medication at the beginning of therapy had only small relationships with patients’ anger scores. Patients with a history of depression and who were taking an antianxiety/depression medication also scored significantly higher (p <0.05) on the angry-reaction scale (8.1 [2.9] and 8.1 [3.0] versus 6.3 [2.3] and 5.9 [2.0] among those without a previous history of depression and who were not taking a medication) and the overall trait measure of anger (16.6 [4.4] and 16.3 [3.9] versus 14.1 [3.6] and 13.4 [2.9], respectively). Anger scores did not vary by HCV RNA level, history of alcoholism, genotype, cirrhosis, BMI, ALT level, gender, or age.

Changes in Anger Scores
Table 3 presents average anger scale scores (SD) for each treatment week. To highlight changes in anger, scores for the scales that had significant changes over the treatment regimen are depicted in graphs. To simplify the findings, only those relationships that were statistically significant are described below.

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TABLE 3. Mean (SD) Anger Scores by Week

Inward expression of anger scores did not fluctuate much during antiviral therapy. Scores at Follow-Up Week 12 were lower than scores at the beginning of treatment (baseline and Week 4) and the second half of therapy (Week 36; p <0.05). Baseline outward expression of anger scores were greater than the scores at Weeks 12 and 36 (p <0.05). Outward anger-expression scores also declined from the final week of treatment (Week 48) to Week 4 of follow-up (p <0.05). There were no other statistically significant differences in inward and outward expression of anger scores.

Again, lower scores on the inward and outward control over anger scales reflect greater display of anger. Patients’ scores on inward control of anger increased from baseline to the end of the treatment regimen (higher scores at Treatment Week 48 and Follow-Up Weeks 4 and 24, as compared with baseline; p <0.05). Inward control of anger scores were higher at Follow-Up Weeks 4 and 24, as compared with mid-treatment (Weeks 4, 12, and 24; p <0.05; Figure 1).

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FIGURE 1.  Anger Control and Summary Scores Throughout Treatment and Follow-Up Weeks 4–24

Patients’ scores on the scale measuring outward control of anger also differed over the treatment regimen (Figure 1). Outward Control of Anger scores tended to be higher after antiviral therapy was completed than during the treatment regimen, meaning that individuals had less outward control over their anger during antiviral therapy (Follow-Up Week 4 and 24 scores were higher than scores at Weeks 4, 12, 24, and 36; p <0.05). Outward Control of Anger scores were similar at baseline and during treatment.

As shown in Figure 1, scores on the overall STAXI Index (which takes into consideration the four measures of anger-control and anger-expression) were greater at baseline and the first half of treatment (Weeks 4, 12, and 24) than at Week 48 of treatment and the initial period after completion of antiviral therapy (Follow-Up Weeks 4 and 12; p <0.05). Anger scores were higher during antiviral therapy and declined after treatment was finished.

Regarding State-Anger, t-tests indicated that patients’ scores on the scales of overall state anger, feeling angry, and verbal and physical expression of anger did not change across the course of treatment or after treatment was completed (the one exception was that Week 4 scores differed from Follow-Up Week 24 on the Feeling Angry scale; p <0.05). Very few patients exhibited any verbal or physical expression of anger.

Turning to Trait-Anger, the overall trait scale did not vary much over the course of treatment. The exception was that baseline scores were higher than at Treatment Week 4 and at Follow-Up Week 4 (p <0.05). Angry-temperament scores overall decreased from baseline and the completion of antiviral therapy (i.e., baseline scores were higher than scores at Week 48 of treatment and Follow-Up Weeks 4 and 12; p <0.05) but did not fluctuate during treatment. Angry-reaction scores fluctuated over the course of treatment (Figure 2), being higher at baseline than the first half of treatment (Weeks 4, 12, and 24; p <0.05) but did not differ from the second half of treatment and follow-up period. Furthermore, scores at the final week of treatment were higher than in the first half of treatment (Weeks 4, 12, and 24; p <0.05). Angry-reaction scores also increased from the end of treatment (Week 48) to the weeks after treatment completion (p <0.05).

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FIGURE 2.  Anger-Reaction Scores Throughout Treatment and Follow-Up Weeks 4–24

Relationship Between Anger and HRQL
Relationships between SF–36 scores, CLDQ scores, and anger scores were assessed with bivariate (Pearson) correlations. Although inward and outward control over anger, trait-anger, and angry reaction were correlated with several HRQL scales, the overall anger-expression index, outward and inward expression of anger, and angry temperament were associated with only a few HRQL scales. State-Anger and its subscales tapping physical and verbal expression of anger and feeling angry were not related to HRQL.

The overall anger-expression index was related to several scales, including the Mental Health summary scale (r = –0.35), overall CLDQ (r = –0.29), activity (r = –0.29), systemic symptoms (r = –0.25), and general health (r = –0.24). Patients with greater inward expression of anger had lower scores on the pain (r = –0.34), activity (r =–0.27) and systemic symptom (r = –0.25) scales. Outward expression of anger was only correlated with the Mental Health summary scale (r = –0.26). Inward and outward control-of-anger scales were associated with the following HRQL scales: the Mental Health summary scale (r=0.38 and 0.29, respectively), Mental Health subscale (r=0.33 and 0.25), general health (r=0.21 and 0.24), vitality (r=0.30 and 0.27), overall CLDQ (r=0.32 and 0.25), and activity (r=0.27 and 0.27). Inward expression of anger was only correlated with emotion (r=0.29) and social functioning (r=0.25).

The trait-anger scale was correlated with overall CLDQ and the four CLDQ subscales (correlations ranged from –0.24 for Worry to –0.36 for Overall CLDQ). Angry reaction was related to overall CLDQ and its four subscales (relationships range from –0.23 for Worry to –0.41 for Overall CLDQ) but not to any SF–36 scale. Angry temperament, in contrast, was only associated with the SF–36 Mental Health subscale (–0.21).

Thus, greater trait-anger and less inward and outward control of anger were moderately correlated with lower CLDQ. Although trait, control, and expression of anger were related to some SF–36 subscales, none of the anger scales were related to the Physical Health SF–36 summary scale, Physical Functioning, and Physical and Emotional Role Limitations.

DISCUSSION

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This is the first systematic assessment of an important neuropsychiatric side effect of interferon-alpha, anger, by use of a standardized questionnaire. Using the broad-based STAXI–2 scale to measure HCV patients’ anger revealed that HCV patients’ experiences with anger varied depending on the subscale assessed. State-anger (including the verbal and physical expression of anger), angry temperament, and inward and outward expression of anger did not vary much before, during, and after therapy. Measures of trait-anger did not tend to change much over the course of treatment, which is not surprising, given that trait-anger is a personality dimension and tends to be stable over time. On the other hand, HCV patients exhibited less control over their anger while receiving interferon-alpha treatment, and angry-reaction scores fluctuated over the course of treatment.^19,20

Examination of factors relating to greater anger revealed a link between anger and depressive symptoms. This provides further support for the importance of monitoring HCV patients receiving interferon for subtle changes in irritability and anger. These symptoms may be predictive of development of more serious interferon side effects (depression), which can be treated proactively. Conversely, depression and irritability, which may be captured by the STAXI–2, are interrelated and mandate careful examination of depression itself before interferon treatment is initiated. Research with other patient populations has also documented the negative effects of irritability on quality of life, suggesting that irritability and anger may be broader indicators of depression.²¹ Furthermore, antidepressant treatment in patients without interferon treatment has been demonstrated to reduce such anger experiences. Additional research is needed to further identify how anger, irritability, and depressive symptoms are related.

Our study also provided evidence for an association between anger and HRQL. Patients experiencing anger not only had more depressive symptoms, but they also had significant impairment of their HRQL. This HRQL impairment was documented both by generic and disease-specific HRQL instruments. These findings highlight the moderate relationship between trait-anger and anger control and expression and several domains of HRQL. Interestingly, state-anger and HRQL were not correlated.

In summary, our study is the first systematic assessment of anger, depression, and HRQL in patients with HCV receiving an interferon-based regimen. Because the STAXI–2 has been previously used mostly with adolescent populations^22,23 and patients with serious psychiatric problems,^24,25 more research is needed to test the psychometric properties of the STAXI–2 scales among patients with hepatitis C (using larger samples) and other illnesses. This study again highlights the importance of assessing for the entire spectrum of interferon-induced neuropsychiatric side effects, which are the most important predictors of patients’ HRQL.²⁶ Future research on the efficacy of proactive treatment of these neuropsychiatric side effects is needed to determine whether any intervention can improve patients’ well-being and their adherence to antiviral regimen. Also, research should further investigate how other common side effects of interferon therapy, such as impaired sleep, may also affect anger, irritability, depression, and HRQL.

ACKNOWLEDGMENTS

 
This research was partially supported by grants from the Liver Outcomes Research Fund; Inova Health Systems Foundation; and Amgen, Thousand Oaks, CA.

REFERENCES

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Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Dan, A. A. Articles by Younossi, Z. M. Search for Related Content PubMed Citation Articles by Dan, A. A. Articles by Younossi, Z. M. Depression Syndromes Secondary to General Medical Disorders

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