SIR—Interferon-α (IFN-α), the most effective treatment for chronic hepatitis by virus C (HCV), induces depression, anxiety, and fatigue.1, 2, 3 We report here that depression and anxiety have different time courses compared to fatigue, and that patients experiencing more severe fatigue are less likely to respond to IFN-α by clearing the virus.
We studied all patients who started pegylated IFN-α (pegIFN-α-2b, 1.5 μg/kg, weekly, s.c.) and ribavirin (400 mg, b.d.) between February and July 2001: n=29, 23 males and six females; 23 Caucasians; mean (SD) age 43±7 years; 16 virus genotype 1, 13 virus genotype non-1. All subjects were HCV RNA positive, with histological evidence, by liver biopsy, of moderate or severe HCV-related injury. Treatment lasted 24 weeks for genotype non-1, and 48 weeks for genotype 1. In all, 18 patients (64%; one subject was lost to follow-up) were identified as sustained virologic responders, as indicated by serum HCV RNA undetectable (<100 copies/ml, Roche Amplicor System) at 24 weeks after the end of treatment. Approval was received from Kings College Hospital Research Ethics committee.
To monitor psychiatric adverse effects and quality of life, four self-report questionnaires were administered at baseline, weekly for the first 4 weeks of treatment, and four-weekly thereafter until the end of therapy: the Beck Depression Inventory (BDI),4 the Stait and Trait Anxiety Inventory (STAI),5 Chalder's Fatigue Questionnaire (CFQ);6 and three items from the SF-36 (physical role limitation, emotional role limitation, and physical function).7 At baseline, the scores were: BDI, 12±9; STAI (added scores), 87±21; CFQ, 16±5; and SF-36 (added scores), 242±77. Nine patients (31%) described a previous psychiatric history and were all included in the study; four patients were taking an antidepressant at baseline and continued with this throughout the treatment. The results of the questionnaires during the treatment were modeled as a polynomial function of time, generating curves fitted through all available points, describing both courses over time and changes from baseline using summary measures.
During the treatment, depression and anxiety increased linearly with time (depression: t(26)=4.3, P<0.001; anxiety: t(26)=3.1, P=0.004). Therefore, we used the slopes of the regression lines as summary measures. At 24 weeks, the estimated increases were 4.5 on the BDI (95% CI: 2.4–6.6) and 8.6 on the STAI (3.0–14.3). In contrast, fatigue increased, and quality of life decreased, predominantly during the first 8 weeks of treatment, while the curves remained relatively flat at later time points (fatigue: t(25)=3.3, P=0.003; quality of life: t(25)=−7.4, P<0.001). Therefore, we used the differences between 8 weeks and baseline as summary measures. At 8 weeks, the estimated increase in the CFQ was 3.5 (1.3–5.7), and the estimated decrease in the SF-36 was 117.8 (85.1–150.5). Of note is that Capuron et al8 examined patients treated with IFN-α for malignant melanoma, and also found that fatigue (with anorexia and pain) appears earlier than depression and anxiety. However, we are the first to describe that the reduction in quality of life follows the course of the fatigue, rather than that of depression or anxiety. Interestingly, better quality of life at baseline predicted a larger reduction in quality of life during the treatment (P=0.046).
Baseline mental state did not predict virologic response (all P-values >0.5), but changes in mental state did. Specifically, the 10 patients who did not respond had had greater deterioration in all four psychological variables during the treatment. This reached statistical significance for fatigue: the CFQ increase at 8 weeks was 7.4 in nonresponders and only 2.3 in responders (CI for the difference: 1.1–9.1; P=0.016). This result is particularly striking as the fatigue was measured months before the time in which the viral response was measured. Moreover, this was not due to a difference in virus genotypes in responders vs nonresponders, as changes in mental state were not associated with virus genotype (all P-values >0.5). Although these are preliminary findings in a small sample, our findings are consistent with the work by Raison et al9 in a similar sample, showing that patients who developed a greater increase in depressive symptoms during pegIFN-α-2b and ribavirin treatment were less likely to show virologic response at the end of the treatment. As Raison et al9 suggest, a persisting or less responsive virus could cause worse fatigue and depression by inducing inflammation and immune activation. However, it is also possible that the worse fatigue or depression and the lack of response are both associated with a third factor, for example, MHC class II genotypes regulating the immune response. Finally, patients who experience worse fatigue and depression could be less compliant with therapy, and future studies should measure plasma concentrations of the antiviral agents to clarify this point.
It is of note that Loftis et al10 described results that are apparently in contrast with our work and the work by Raison et al.9 In fact, they found that depression is associated with increased virologic response to (nonpegylated) IFN-α and ribavarin treatment.10 An important difference in the study by Loftis et al10 is that all patients who reached a threshold for depression were started on antidepressant treatment; in our study, and in the study by Raison et al,9 the antidepressant treatment was dictated by clinical judgment of patient's distress. This ‘assertive’ approach explains the high rate of patients receiving antidepressants in the study by Loftis et al: 13 out of 39 subjects (33%),10 vs three out of 29 (10%) in our study, and five out of 60 (8%) in our previous study on a different sample using similar clinical guidelines.1, 2, 3 It is possible that the antidepressant treatment—rather that the depression—explains the better virologic response rate, as the antidepressant treatment may allow better compliance and prevent reductions in the doses of IFN-α and ribavarin. We believe that clarifying the mechanisms by which IFN-α induces psychopathological symptoms will help understanding not only the predictors of the psychiatric outcome but also the predictors of the therapeutic outcome.
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Maddock, C., Landau, S., Barry, K. et al. Psychopathological symptoms during interferon-α and ribavirin treatment: effects on virologic response. Mol Psychiatry 10, 332–333 (2005). https://doi.org/10.1038/sj.mp.4001634
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