Depression in chronic hepatitis: the virus, the drug, or the ethnic background?

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Treatment of chronic hepatitis C (CHC) with pegylated interferon (pegIFN) and ribavirin (RBV) can cause or exacerbate depression. Mood disorders including depression, anxiety and irritability are particularly common and are reported in up to 50% of treated patients. Depression can be dose-limiting and lead to dose reductions in 40% and to early discontinuation in up to 20% of treated patients, thus reducing the chance to obtain a sustained virological response. Depression can improve with pegIFN dose reductions and adjuvant medications. The fact that IFN may affect the neuropsychiatric status of patients with or without hepatitis is well known. Cytokines have been shown to alter the metabolism of key monoamines, including serotonin, norepinephrine and dopamine, all of which are believed to play a role in psychopathology (1). Although pro-inflammatory cytokines are too large to freely pass through the blood–brain barrier, several relevant pathways by which cytokine signals can access the brain have been elucidated, including passage of cytokines through leaky regions in the blood–brain barrier, active transport and transmission of cytokine signals by afferent nerve fibres (2).

Against this background, it is surprising that depressions in IFN-treated patients with chronic hepatitis B (CHB) seem to develop less frequently than in patients with CHC. Hepatitis B and C viruses (HBV and HCV) are two clinically distinct but related diseases. In this issue of the journal, Marcellin et al. (3) compared the rates of depression using pooled data from prospective studies of pegIFN α-2a treatment in chronic hepatitis. They compared five studies done in CHC with two in CHB. Differences (HBV vs HCV) were observed in the incidence of serious adverse events (4–5 vs 7–16%), and in treatment withdrawals (6–8 vs 17–33%). The frequency of depression-related events was lower in patients with CHB (4 vs 22%, P<0.001), as was the impact of treatment on health-related quality of life. Stratification of depression-related events in the pegIFN α-2a studies analysed showed that they were less frequent in CHB compared with CHC, irrespective of ethnicity. A higher incidence of depression-related events was reported in Caucasian patients when compared with Asian patients in both CHB and CHC studies, which is consistent with research that shows depression to be sensitive to cultural influences (4). The finding that depression was less frequent in Taiwanese patients with CHC receiving PegIFN/RBV combination therapy (5) underlines the importance of such factors.

While these observations are important to optimize treatment of chronic viral hepatitis with pegIFN, caution has to be applied for the interpretation of the data. Basically, there are three possibilities: (i) there are real differences between the two viruses with respect to psychological factors, (ii) there are differences which may exist even before initiation of treatment and (iii) the methods to measure depression are culture dependent and do not reflect the whole clinical spectrum and impact of depression.

Several observations indicate that there are virus-related differences accounting for the variations of IFN side effects: some studies indicate that HCV, like HIV, may affect the brain directly (6–8), no similar observations were made in HBV-infected subjects. However, the data whether HCV infection plays a role in the development of neuropsychiatric symptoms or affects quality of life are conflicting. HBV and HCV are acquired via different modes of transmission; most patients with CHB in Asia tend to acquire the infection early in life, usually perinatally, while in the Western world the infection occurs later in life by sexual transmission. Thus, the mode of and the age at infection may have an impact on disease perception and its role in daily life. In contrast, many patients with CHC acquire the infection as young adults, many of them by i.v. substance abuse. In a large Italian study (9), the frequency of psychiatric conditions was investigated in a large number of patients with CHB, CHC and controls. The psychiatric diagnosis was formulated by means of the Composite International Diagnostic Interview Simplified according to DSM-IV criteria. A higher lifetime prevalence of major depressive disorder was observed among CHC compared with CHB or controls, but this association was independent of treatment with IFN-α and was not influenced by substance or alcohol abuse. In contrast, anxiety disorders did not appear to be associated with CHC. Health-related quality of life (HRQOL) was significantly impaired in veterans with CHC, but comorbid depression was independent of CHC and was associated with both lower physical and mental components of HRQOL (10).

Pre-existing psychiatric conditions may contribute to drug tolerance. As part of the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial, depression and cognition were investigated at the start and during retreatment. Although the majority of patients had normal Beck depression inventory (BDI)-II scores, 30% of the lead-in patients were receiving either an anxiolytic or antidepressant medication at baseline (11). This study was conducted in mostly Caucasians from North America, where public awareness for depression is high. This study also showed that methods to assess depression may have an impact on the findings. One-third of the patients perceived themselves depressed but had normal test results using BDI-II. Perception of depression in other parts of the world may be different. In a Turkish study, no significant difference was observed in the rate of psychiatric diagnosis between hepatitis B and hepatitis C patients. Both groups were significantly different from the control group on all subcategories of quality of life criteria. Psychiatric morbidity (mainly depression) was the major variable on lowering HRQOL. HRQOL was significantly decreased in patients with psychiatric morbidity (12). In a German study (13), the depressogenic nature of IFN-α treatment was described only in a subset of vulnerable individuals. It may be possible to clinically predict these vulnerabilities in initially euthymic subjects. BDI at 1 month was predicted by baseline BDI. Controlling for baseline BDI scores, categorical major depression was predicted by combined high baseline neuroticism and low agreeableness. Similar observations were made by us (14). Unfortunately, the methods of how depression was assessed in the pivotal registration trials of pegIFNs in CHB and CHC are not given. It is also unclear whether and how depression was evaluated at baseline.

Ethnic origin may not only affect how well a drug is tolerated, but also how emotional problems are perceived by the patients, their relatives and their treating physicians. Because most patients in the CHB trials were Asians, and in the CHC trials Caucasians, perception of depression may induce a major bias. In a study in Egypt, no significant reduction of HRQOL was found in patients chronically infected with HCV compared with uninfected, contemporaneous controls. This may be explained in part by a lower morbidity among patients chronically infected with HCV in rural Egypt and a higher morbidity among uninfected controls as compared with those of Western studies, as well as a lack of awareness of hepatitis C serological status (15). Even in Caucasians, active injecting drug users' knowledge about the serological status of chronic HCV infection had an impact on HRQOL while the serological status per se did not negatively affect the HRQOL (16).

Without a standardized evaluation of depression before and on treatment, it cannot be decided whether the virus or the ethnicity will determine the tolerance of antiviral therapy. Nevertheless, all efforts should be made to identify susceptibility of IFN-induced depression before treatment and to select patients who may benefit from antidepressive medication to improve adherence to therapy.

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