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Chronic hepatitis C, depression and interferon
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Journal of Hepatology
June 2005
Yves Horsmans
Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Avenue Hippocrate, 10 1200 Brussels, Belgium
In this issue of the Journal, two papers are devoted to a major clinical problem associated with the current treatment of chronic hepatitis C (HCV): depression [1,2]. It is important to outline that neuro-psychiatric symptoms are present in relation to the infection independently of any treatment even if definitive conclusions regarding their pathogenesis are for the most part lacking [3]. Cognitive problems associated with HCV infection are increasingly described. It remains still unclear whether the neuropsychologic effects are due specifically to HCV or to processes associated with HCV infection.
Antiviral treatment may be responsible for an increase in their incidence and probably in their importance [4,5]. Since the combination therapy, pegylated interferon-α (IFN) and ribavirin, may induce viral eradication in the majority of patients, it is important to obtain compliance and to limit the occurrence of side effects induced by the treatment [4,5].
First of all, it must be conceded that until now only a limited number of studies have been devoted to the problem of depression. According to these studies, 15–60% of the patients will develop psychiatric side effects during IFN therapy [6,7]. As outlined by Schaefer et al. [1], the highest incidence has been reported when studies are performed by psychiatrists. Moreover, different studies and consensus statements have claimed that antiviral therapy should be withheld in HCV patients having psychosocial contraindications, including depression [8,9,10]. More recently, a very limited number of studies have in contrast illustrated the fact that pre-existing psychiatric disorders should no longer be considered as contraindications to treatment of HCV if an interdisciplinary setting has been put into place [11]. The present study by Schaefer et al. [1] reinforces this last point of view by showing the efficacy of antiviral treatment in a limited number of HCV patients with pre-existing psychiatric disorders without the need of interrupting IFN administration. They also observed the same incidence of major depression between the group with psychiatric disorders and without pre-emptive selective serotonin reuptake inhibitor (SSRI) treatment and the non-psychiatric control group. Moreover, the authors also provide new arguments in favor of starting SSRI before IFN administration in HCV patients. In the group of HCV patients with pre-existing psychiatric disorders, SSRI treatment was able to reduce the incidence of major depression in comparison to the non-SSRI treated group. Some limitations of this study must be outlined: a small number of patients has been included, 43% of the patients in the group treated pre-emptively with SSRI received antiviral drugs for the duration of only 6 months, the follow-up performed by this group of investigators was particularly intensive (bi-weekly visits during the first 8 weeks) suggesting that the effect of SSRI has been reinforced by this kind of heavy follow-up and patients with the most severe forms of psychiatric disorders have been excluded (schizophrenia, dementia, …). Finally, as the incidence of major depression was similar in patients with or without pre-existing psychiatric disorders, the potential need to use SSRI pre-emptively must be investigated in all HCV patients with, however, the concern about potentially unnecessary exposure of patients to SSRI's.
Even if the success rate in the treatment of depression induced by IFN with SSRI is high, the mechanisms of IFN-α-induced depression remain poorly understood. Cai et al. [2] have provided, in this issue of the Journal new insight into potential mechanisms by studying the in vitro effects of IFN on glucocorticoid (GR) receptors and on serotonin 1A (5-HT) receptors as well as the impact of the combination of IFN with a SSRI on these receptors. The role of these receptors has been previously implicated in mechanisms leading to depression [12–14]. Plasma ACTH, cortisol and interleukin-6 concentrations are significantly increased after the first IFN injection in patients who will develop depression and the reduction in serum 5-hydroxytryptophan and serotonin levels is highly correlated to the degree of depression during IFN treatment [12,13]. From a mechanistic point of view, these data are in favor of the use of SSRI in the treatment of IFN- α-induced depression as well as in their prophylactic use. The in vitro data of Cai et al. [2] also reinforces this point by demonstrating that IFN down-regulated GR and 5-HTR1A levels in lymphoid and hepatic cell lines. This down-regulation is decreased by the addition of a SSRI. These in vitro data must find their confirmation in patients since relatively high concentrations of IFN and fluoxetine have been used by Cai et al. [2] to observe these phenomena. Not only the importance of IFN concentration could play a role in these results, but the duration of exposition of the neural cells to the different drugs could also modify the observations made in vitro. It is well known that mechanisms of receptor activation are based on a dose–response curve: the observed effect of a drug is a function of its concentration in the receptor compartment. These drug–receptor interactions and elicited effects are not only true for IFN but also for SSRI. In the case of antagonism that has presently been described between IFN and SSRI, some work has to be performed to elucidate the pattern of antagonism: simple competition, noncompetitive antagonism, allosteric antagonism? The response to this question should permit to refine the indications for prescription of SSRI in HCV patients receiving antiviral therapy.
Since the pharmacokinetics of pegylated IFN's are different from that of standard IFN [15] and since the time of depression occurrence also differs between pegylated and standard IFN [1], it will be important to determine if the mechanisms described by Cai et al. [2] on GR and 5-HTR1A receptors do also apply to pegylated IFN. Studies using cerebral PET Scan, magnetic resonance spectroscopy and/or imaging should contribute to answer this question. An intriguing possibility would be the use of lymphocytes as an indirect predictor of IFN induced depression if, as suggested by several authors, GR and 5-HTR1A receptors on these cells reflect the metabolic process in brain cells [16].
In conclusion, we are now gaining insight into the treatment and the mechanisms of major depressive disorders induced by IFN. These advances should allow for more patients to be treated. Finally, in close collaboration with psychiatrists, these two studies also illustrate the need to focus more attention on this problem.
References
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