Prevention of interferon-alpha associated depression in psychiatric risk patients with chronic hepatitis C *

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1 Journal of Hepatology 42 (2005) Prevention of interferon-alpha associated depression in psychiatric risk patients with chronic hepatitis C * Martin Schaefer 1, *, Markus Schwaiger 1, Andrea S. Garkisch 1, Maurice Pich 1, Axel Hinzpeter 1, Ralf Uebelhack 1, Andreas Heinz 1, Florian van Boemmel 2, Thomas Berg 2 1 Department of Psychiatry, Charité University Medicine Berlin, Campus Charité Mitte, Schumannstr. 20/21, D Berlin, Germany 2 Department of Gastroenterology and Hepatology, Charité University Medicine Berlin, Campus Charité Virchow, Augustenburger Platz 1, D Berlin, Germany See Editorial, pages Background/Aims: Interferon-alpha (IFN-a) induced depression is a major limitation for the treatment of chronic hepatitis C, especially for patients with psychiatric disorders. We prospectively studied the efficacy of a pre-emptive treatment with the antidepressant citalopram to prevent depression during hepatitis C treatment with pegylated IFNa-2b plus ribavirin. Methods: 14 HCV infected patients with psychiatric disorders received a prophylactic medication with citalopram (20 mg/day) before and during therapy with IFN-a. The incidence of major depression was compared with 22 HCV infected patients with psychiatric disorders (group B; nz11) and without psychiatric risk factors (group C; nz11), who underwent IFN-a treatment without a pre-emptive antidepressant therapy. Depression was diagnosed by DSM-IV criteria. Results: Pre-treatment of psychiatric patients with citalopram significantly reduced the incidence of major depression during the first 6 months of antiviral treatment as compared to the two control groups (group A 14% vs. 64% and 55% in group B and C; log-rank 6.89; dfz2; PZ0.032). Patients who developed symptoms of major depression during IFN therapy could also be improved by antidepressive treatment. Conclusions: Our open label pilot study, though small, clearly indicates that IFN alpha induced depression in psychiatric risk patients can be ameliorated by both the use of antidepressants as well as by intensive psychiatric care. However, larger, double blind placebo controlled trials in other patient populations are required to confirm these preliminary findings. q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Hepatitis C; Interferon-alpha; Depression; Antidepressants; SSRI; Drug addiction 1. Introduction One of the most important neuro-psychiatric side effects of interferon-alpha (IFN-a) during treatment of chronic Received 17 May 2004; received in revised form 11 January 2005; accepted 26 January 2005; available online 2 April 2005 * The authors have declared that they received funding from the drug company involved in order to carry out their research. * Corresponding author. Tel.: C ; fax: C address: martin.schaefer@charite.de (M. Schaefer). hepatitis C virus (HCV) infection is the induction of episodes of major depression and suicidal thoughts [1,2]. In such cases, treatment must be interrupted or at least reduced. On the other hand, adherence to IFN-a therapy is essential to achieving a sustained virological response. Thus, improvement of IFN-a therapy s side effects should lead to a higher compliance rate among patients and have the best antiviral efficacy [3]. However, several reports indicate that IFN-a can also worsen pre-existing affective or schizophrenic disorders [4 6]. This led to the conclusion that patients with psychiatric disorders have an increased risk of developing severe neuropsychiatric complications /$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi: /j.jhep

2 794 M. Schaefer et al. / Journal of Hepatology 42 (2005) during IFN-a treatment, e.g. severe depression and suicidal thoughts. From that it was recommended that HCV-infected patients suffering from severe and uncontrolled psychiatric disorders should not be treated with IFN alpha therapy. Recent investigations showed growing evidence, that besides hormonal and cytokine changes, diminished serotonergic neurotransmission might be involved in the pathoetiology of IFN-associated depressive mood changes [2,6]. Reduced tryptophan levels, increased activity of the indoleamine-2,3-dioxygenase (IDO) and lower activities of serum peptidases, have been associated with an increased risk of developing depressive mood changes during IFN-a treatment [7 11]. Therefore, the application of selective serotonin reuptake inhibitor (SSRI s) seems to be a logical therapeutic strategy for acute treatment or prevention of IFN-associated depression [12 20]. Indeed, the present clinical guidelines in the United States for the management of interferon associated depression during HCV-therapy include evaluating patients for current or past depression, treating depressive symptoms prior to antiviral treatment and conducting close monitoring [21]. At present, however, only one prospective controlled trial has been performed investigating the efficacy of an antidepressant pretreatment for the prevention of depression induced by standard IFN-a- 2b in patients with malignant melanoma but without psychiatric disorders [22]. In contrast, no prospective controlled data is available, focusing on the efficacy of a prophylactic antidepressant treatment with patients, who receive antiviral treatment with pegylated interferons because of a chronic hepatits C infection. We, therefore, investigated in an open, prospective and controlled trial, whether a pre-emptive treatment with the SSRI citalopram can prevent major depression during treatment with pegylated interferon-alpha-2b in HCV-infected patients with psychiatric disorders. 2. Methods Overall, 36 patients with a chronic hepatitis C infection gave their informed consent to participate in this prospective trial and the study was approved by the institutional ethical board of the Charité University Medicine Berlin Inclusion and exclusion criteria Inclusion criteria were a detectable serum HCV-RNA level (AMPLI- COR w, Roche Diagnostics, Branchburg, NJ) for more than 6 months and elevated alanine aminotransferase (ALT O30 U/L, normal!24 U/L). General exclusion criteria were the presence of other liver diseases, Child B or C cirrhosis, severe cardiac or neurological diseases, co-infection with hepatitis B or HIV, presence of hepatocellular carcinoma as evaluated by ultrasound and alpha-fetoprotein, autoimmune disorders, a neutrophil count below 1500 per cubic millimetre, and a platelet count below 75,000 per cubic millimetre. Psychiatric exclusion criteria were any antidepressant therapy in the last 3 months before antiviral treatment was initiated, and the need for any type of psychiatric medication. Thus, patients with the need for prophylactic or long-term medication, including antidepressants, mood-stabilizers or antipsychotics were not included in the trial. Patients with schizophrenia, bipolar disorder, exacerbated personality disorder, dementia or any other organic brain disease were also excluded. Further psychiatric exclusion criteria were ongoing drug abuse (with the exception of a controlled methadone substitution treatment) and a present abuse of alcohol or benzodiazepines. Drug abuse was controlled prior and during the trial by randomized urine testing Patients (treatment groups) Patients were carefully evaluated by an experienced psychiatrist. Psychiatric disorders were diagnosed using the standardized clinical interview for DSM-IV diagnosis. According to the result of the psychiatric evaluation, patients were distributed into three groups. Group A: patients with the clinical indication of an antidepressant treatment due to current mild to moderate depressive symptoms (nz14). These patients suffered from affective disorders (recurrent depressive episodes) with or without personality disorders and drug addiction. Group B (psychiatric control group): patients with psychiatric disorders but without a clinical need for a present antidepressant treatment (did not present depressive symptoms at baseline or during the last 3 months; nz11). Group C (non-psychiatric control group): patients with chronic hepatitis C in whom a history of psychiatric disorders or drug addiction was carefully excluded (nz11). Psychiatric diagnoses of the patients in group A and B according DSM-IV criteria are listed in Table 1. In most of the patients, the psychiatric diagnose was not verified until they came to our outpatient-clinic. The duration of psychiatric illness (first clinical relevant symptoms or treatment because of drug dependence or psychiatric problems) was estimated according to information received directly from the patients or attending physicians. The mean duration of illness was 4.1G2.2 years in group A and 3.9G1.7 years in group B. Most of the patients reported, that they had no continuous psychiatric treatment in the last 2 years including psychopharmacologic support. Table 1 Psychiatric diagnoses of patients from Group A and B according to DSM-IV criteria Psychiatric diagnoses Group A (nz14) (with citalopram n (%) Affective disorder 4 (29) 2 (19) Affective disorder and 1 (7) 0 (0) personality disorder Affective disorder and methadone 2 (14) 0 (0) substitution treatment Affective disorder, personality 1 (7) 1 (9) disorder and former drug addiction Affective disorder, personality 5 (36) 1 (9) disorder and methadone substitution treatment Personality disorder and former 0 (0) 3 (27) drug addiction Personality disorder and 0 (0) 3 (27) methadone substitution treatment Schizoaffective disorder and 1 (7) 0 (0) former drug addiction Schizoaffective disorder, personality disorder, and former drug addiction 0 (0) 1 (9) Group B (nz11) (no citalopram n (%) The combined diagnoses of the patients are listed. No patient received a psychiatric medication, i.e. antidepressants, mood stabilisers or antipsychotics, during the last 3 months before antiviral treatment with IFN-a was initiated. Both schizoaffective patients had a history of only schizodepressive episodes without schizomanic episodes.

3 M. Schaefer et al. / Journal of Hepatology 42 (2005) Treatment regimen All patients received a combination therapy using pegylated IFN-a-2b (1.5 mg/kg per week s.c.) plus ribavirin ( mg/day orally according to body weight). The duration of antiviral therapy was 24 weeks for genotypes 2 (nz2) and 3 (nz6) and 48 weeks for genotypes 1 (nz27) and 4 (nz1). Group A patients received an antidepressive therapy with citalopram (20 mg per day per os), starting 2 weeks before the beginning of antiviral treatment. No pre-emptive anti-depressive treatment was applied for patients in group B and C Psychiatric evaluation during treatment Patients were intensively followed in the psychiatric outpatients clinic over a treatment period of 6 months. All patients were seen by hepatologists and psychiatrists bi-weekly during the first 8 weeks and then once a month. Mental status was continuously monitored. Major depressive episodes during interferon-alpha treatment were diagnosed by clinical assessment according to DSM-IV criteria. In addition, we used the Montgomery Asberg Depression Scale (MADRS) for the quantitative evaluation of depressive mood changes before and during antidepressive treatment. In order to avoid interviewer bias resulting from the lack of a double-blinded setting, the diagnosis of major depressive episodes and MADRS scores were evaluated by one senior psychiatrist who was blinded to the antidepressant pre-treatment as well as to the psychiatric history of the patients. At each visit, patients were additionally screened for suicidal thoughts, irritability, sleeping disturbances, lack of concentration and craving for drugs or alcohol Management of major depressive episodes In case of major depressive episodes, patients were seen weekly by a senior psychiatrist. Patients without concomitant antidepressant medication (group B and C) who developed depression during antiviral therapy received citalopram 20 mg/die with the option of further increase of the daily dosage in case of non-response after 3 weeks of treatment. We started with the same dosage to be able to compare the efficacy of 20 mg citalopram regarding prevention and acute treatment of IFN-alpha associated depression. Therapeutic response was monitored with the MADRS before citalopram treatment and after 3 weeks. Patients in group A, who developed a major depressive episode although they had a concomitant treatment with citalopram (20 mg/day), received an additional treatment with mirtazapine (30 60 mg/day). This different type of antidepressive regimen was chosen in such instances when a patients did not respond to citalopram and also by considering our clinical experience that increase of citalopram dosage is less effective for the treatment of IFNalpha induced depression than the application of another antidepressive drug as mirtazapine which has as a dual action by enhancing serotonergic as well as noradrenergic neurotransmission. This approach may increase the probability to receive a response even in case of non-response to the SSRI citalopram. Beside the antidepressant treatment, only zopiclon or zolpidem was allowed in case of sleeping disturbances for a period of 14 days or lormetazepam in case of acute anxiety or agitation Statistical analysis The incidence of depression during IFN-a treatment in the three groups was compared by means of the log-rank test. Survival curves are displayed with Kaplan Meier plots. Kruskal Wallis test was used for non-parametric and ANOVA was used to compare parametric data. T-test (two tailed) was used for comparison of the MADRS scores between group A and B after antidepressant treatment. 3. Results The major clinical parameters of all patients are given in Table 2. The three groups did not differ significantly regarding age or gender, although the control group without a psychiatric disorder tended to be older compared to the psychiatric groups A and B. Overall, MADRS scores at baseline were significantly higher in the psychiatric groups compared to the non-psychiatric controls with the highest values in group A Prevention of IFN-alpha induced major depression During the 6 month period of IFN-a treatment, major depression was diagnosed by clinical assessment according to DSM-IV criteria in 15 out of 36 patients (42%). While the incidence of major depression in group B (64%) and the control patients (group C) (55%) did not differ significantly, psychiatric patients with citalopram pre-treatment (group A) developed significantly fewer depressive episodes (14%) during the treatment period (95% confidence interval, ; log-rank test, dfz2, PZ0.032; Fig. 1). Group differences became significant after 4 months of treatment (c 2 Z6.417, dfz2; PZ0.040; Kruskall Wallis test) and remained also significant after 6 months (c 2 Z7.052, dfz2; PZ0.029; Kruskall Wallis test). Table 2 Base-line characteristics Data Psychiatric patients Controls F-or c 2 value df P value Group A (citalopram (NZ14) Group B (no citalopram (NZ11) Group C (no citalopram (NZ11) Age 41G5.9 40G G8.0 FZ a Gender (male) 64% (9) 64% (7) 55% (6) c 2 Z b History of drug 64% (9) 81% (9) 0% (0) c 2 Z b,c addiction HCV genotype 1 or 4 57% 73% 100% c 2 Z b MADRS at baseline 13.8G G G5.1 FZ a,d Data are given as meangstandard error. Abbreviations: MADRS, Montgomery Asberg Depression Scale, IFN-a, pegylated interferon-a-2b. a Univariate ANOVA with Bonferroni post hoc-test. b Kruskal Wallis test. c Group A compared to group B and group C. d Between group A and group C.

4 796 M. Schaefer et al. / Journal of Hepatology 42 (2005) percentage of patients without depression % log-rank p= months of treatment group A (with SSRI) group B (without SSRI) controls (without SSRI) Fig. 1. Effect of antidepressant pre-treatment with citalopram on the development of depression during Hepatitis C treatment with pegylated Interferon-alpha 2b and Ribavirin in patients with psychiatric diagnosis. Kaplan Meier analysis of the percentage of psychiatric patients with citalopram (Group A) and without citalopram (Group B) and the controls (non-psychiatric, without citalopram) who were free of major depression. The comparison of the curves between group A to group B and C shows a significant difference in the development of depression. Overall, 2 patients in group A, 7 patients in group B and 6 patients in group C developed a major depressive episode during interferon-treatment. However, none of the psychiatric patients had to discontinue interferon-treatment or had to be admitted to a psychiatric hospital due to suicidal thoughts Treatment of IFN-alpha induced major depression Those patients without antidepressant pre-treatment who developed depression during therapy with IFN-a (nz13; 7 in group B and 6 in group C) received citalopram 20 mg/day while the two affected patients in group A were treated with mirtazapine at doses between 30 and 60 mg/day in addition to the concomitant therapy with citalopram. Quantitative changes of depressive symptoms were assessed with the MADRS before and after 3 weeks of antidepressant treatment. Mean MADRS scores during major depression were significantly higher in group A (35.0G2.8) and B (26.42G5.1) compared to group C patients (22.5G4.1; FZ 5.701, dfz2, PZ0.018; univariate ANOVA with Bonferroni post hoc-test). During the first 3 weeks of antidepressant therapy, the mean MADRS scores decreased significantly from 26.0G5.9 to 12.1G5.1 (TZ9.304, dfz15, P!0.001). The mean improvement was 55%G 20.1 (range %). Overall, 86% (nz13/15) of the patients did response (defined as 40% improvement of the MADRS scale after 3 weeks of antidepressant therapy). No differences were seen between group B and C (response in 6/7 patients in group B and 6/6 patients in group C). However, even the non-reponders (one patient in group A and B, respectively) still showed a 30% decrease of MADRS scores after 3 weeks of antidepressant treatment. Interestingly, MADRS values after 3 weeks of antidepressant treatment did not differ significantly between group A (15.5G4.9), group B (10.8G4.3) and group C patients (12.3G6.2) (FZ0.621, dfz2, PZ0.554). Thus, the decrease of MADRS scores was positively correlated with the MADRS scores levels during IFN-alpha induced depression. All patients who developed depressive episodes and who responded to treatment with citalopram or mirtazapine were kept on antidepressants and finished the HCV treatment successfully Response to antiviral treatment Overall, 50% of the patients had a sustained virological response (SVR), 43% of the patients with genotype 1 or 4 (12/28) and 75% with genotype 2 or 3 (6/8), respectively, 45% (5/11) of the controls (group C), 54% (6/11) of the patients in group B and 43% (6/14) of the pre-treated patients (group A) showed SVR. Differences did not become statistically significant (c 2 Z1.607, dfz2, PZ 0.448). In two patients from the controls (group C) dose of PEG-IFN-alpha-2b was reduced during the first 24 weeks of treatment because of hematological side effects. The daily dose of ribavirin had to be reduced in 5 patients (2 in group A and 3 in group C, respectively). The PEG-IFN-alpha - or ribavirin doses had not to be reduced between the week 25 and 48 in patients with genotype Drop-outs The trial had to be discontinued in 4 patients: three of them developed somatic side effects, the last patient moved to another town. All patients were infected with HCV genotype 1. None of the patients had to stop treatment because of psychiatric side effects. 4. Discussion The study demonstrates for the first time that pre-emptive treatment with citalopram is highly effective in preventing IFN-a associated major depression in HCV-infected patients irrespective of whether they are patients at risk to develop psychiatric complications or not. Thus, the frequency of IFN-a induced major depression could be reduced up to 40% by applying this kind of pre-emptive treatment. A similar observation was made by Musselmann and colleagues who demonstrated, that the therapy with the serotonin reuptake inhibitor paroxetine was very effective in reducing the incidence of major depressive episodes in IFNa treated patients suffering from malignant melanoma [22]. In contrast to current recommendations [21], our observations clearly indicate a general benefit of an antidepressant pre-treatment for all patients treated with IFN-a, irrespective of the presence of psychiatric risk factors. Furthermore, our study also indicates that the frequency of major depression did not significantly depend on whether patients had already suffered from a psychiatric illness or

5 M. Schaefer et al. / Journal of Hepatology 42 (2005) not. From that one is inclined to propose that patients with psychiatric disorders should not be in general excluded from INF-a therapy. In an interdisciplinary setting, we also recently showed that HCV-infected patients with psychiatric disorders or drug addiction can be successfully treated with IFN-a and ribavirin without an increased risk of an exacerbation of their psychiatric disorder [23]. Similarly, Pariante and coworkers reported, that HCV-infected patients with affective or anxiety disorders did not differ in the frequency and severity of symptoms of depression or drop-outs [24,25]. Van Thiel et al. treated HCV-infected patients with severe psychiatric disorders and drug addiction successfully with an IFN-a monotherapy hereby challenging the concept that a history of psychiatric disorders is a contraindication against interferon alpha therapy [26,27]. However, so far, no trial investigated pharmacological strategies to prevent IFN-a associated psychiatric side effects (i.e. depression) in patients with chronic hepatitis C infection. Although the incidence of depression in our collective was rather high, it still is comparable to the data reported by other authors using psychiatric diagnostic criteria [15,22,23,28]. There is this interesting observation that trials reported by psychiatrists showed an incidence of depression during IFNalpha treatment up to 30 60% in contrast non-psychiatricbased trials reporting a frequency of only 20 30% [29,30]. One explanation is, that non-psychiatric trials only realized severe depressive episodes compromising continuation of the antiviral therapy. The factors which cause depressive mood changes during IFN-a therapy are still not well understood. Beside changes in the metabolism of serotonin, alteration of the physiological stress response HPA-axis and to some extent, genetic factors, may all play a major role in causing the development of depressive symptoms during IFN-a treatment [31 34].In fact, there is now ample evidence that a blunted (hyper-reactive) HPA-axis is a major factor in the etiopathogenesis of major depression [33]. However, our data strongly support the significance of a central serotonergic deficit and changes in neurotransmission for the development of depression during treatment with interferon-alpha [34 36]. It also can be deduced from our study that citalopram is an effective antidepressive drug for the acute treatment of IFN-a induced depressive symptoms. Patients in both of our control groups B and C who developed the typical symptoms of major depression during IFN-a treatment rapidly responded to a daily dose of 20 mg citalopram and recovered from the severe depressive symptoms. Surprisingly, the administration of various kinds of antidepressants was, up to the present, only demonstrated in open and uncontrolled trials or case reports [13 15,17,19] but certainly deserves to be a more widely used concomitant strategy. Our experience is that the application of antidepressants improves the well being of these patients and helps them to cope with their anxieties [12,22,37]. We also could observe during this study that the frequent presence of a devoted psychiatrist is of importance especially for patients with pronounced depressive symptoms and this may also have some implications regarding the consequent adherence to the applied therapeutic regimes. On this basis we are inclined to explain the observed lack of drop-outs caused by psychiatric side effects. In our trial, weekly dose of pegylated interferon-alpha-2b was only reduced in two patients because of hematological side effects, but in no case because of the development of a major depressive episode. While depressive mood changes during treatment with standard interferons normally disappeared 2 3 weeks after discontinuation of antiviral medication, depressive episodes induced by pegylated interferons persists over weeks to months. Certainly the different half-life of these drugs may be a causative factor in this respect and antidepressant treatment will become even more important for patients treated with pegylated interferons. However, prospective, randomised, controlled and double blinded trials are needed to clarify the question, if a preemptive antidepressant treatment will also protect patients without psychiatric risk factors from IFN-a associated depression. Therefore, data concerning the safety of a concomitant antidepressant therapy and possible influences on viral response to IFN-a treatment has to be generated. Acknowledgements We thank Dr Ziemer, Dr Kluschke, Dr Gölz, Dr Bellmann, Dr Möller, Dr Heyne, Dr Meyer and Dr John (Berlin) for their clinical help. The study was supported in part by an unrestricted grant of ESSEX-Pharma Germany (Shering-Plough) and by the German hepatitis network of excellence (HepNet). Part of the data were presented at the annual meeting of the AASLD in Boston, References [1] Dieperink E, Willenbring M, Ho SB. Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a review. Am J Psychiatry 2000;157: [2] Schaefer M, Engelbrecht MA, Gut O, Fiebich BL, Bauer J, Schmidt F, et al. Interferon alpha (IFNalpha) and psychiatric syndromes: a review. Prog Neuropsychopharmacol Biol Psychiatry 2002;26: [3] McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002;123: [4] Renault PF, Hoofnagle JH, Park Y, Mullen KD, Peters M, Jones DB, et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987;147: [5] Renault PF, Hoofnagle JH. Side effects of alpha interferon. Semin Liver Dis 1989;9: [6] Valentine AD, Meyers CA, Kling MA, Richelson E, Hauser P. Mood and cognitive side effects of interferon-alpha therapy. Semin Oncol 1998;25:39 47.

6 798 M. Schaefer et al. / Journal of Hepatology 42 (2005) [7] Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M, et al. Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J Clin Psychopharmacol 2002;22: [8] Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 2002;7: [9] Maes M, Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, et al. Treatment with interferon-alpha (IFN alpha) of hepatitis C patients induces lower serum dipeptidyl peptidase IV activity, which is related to IFN alpha-induced depressive and anxiety symptoms and immune activation. Mol Psychiatry 2001;6: [10] Maes M, Bonaccorso S. Lower activities of serum peptidases predict higher depressive and anxiety levels following interferon-alpha-based immunotherapy in patients with hepatitis C. Acta Psychiatr Scand 2004;109: [11] Wichers MC, Maes M. The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. J Psychiatry Neurosci 2004;29: [12] Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, et al. Interferon-alpha-induced changes in tryptophan metabolism. Relationship to depression and paroxetine treatment. Biol Psychiatry 2003;54: [13] Farah A. Interferon-induced depression treated with citalopram. J Clin Psychiatry 2002;63: [14] Gleason OC, Yates WR, Isbell MD, Philipsen MA. An open-label trial of citalopram for major depression in patients with hepatitis C. J Clin Psychiatry 2002;63: [15] Hauser P, Khosla J, Aurora H, Laurin J, Kling MA, Hill J, et al. A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 2002;7: [16] Kraus MR, Schafer A, Scheurlen M. Paroxetine for the prevention of depression induced by interferon alfa. N Engl J Med 2001;345: [17] Kraus MR, Schafer A, Faller H, Csef H, Scheurlen M. Paroxetine for the treatment of interferon-alpha-induced depression in chronic hepatitis C. Aliment Pharmacol Ther 2002;16: [18] Schaefer M, Schmidt F, Amann B, Schlosser S, Loeschke K, Grunze H. Adding low-dose antidepressants to interferon alpha treatment for chronic hepatitis C improved psychiatric tolerability in a patient with schizoaffective psychosis. Neuropsychobiology 2000;42: [19] Schramm TM, Lawford BR, Macdonald GA, Cooksley WG. Sertraline treatment of interferon-alfa-induced depressive disorder. Med J Aust 2000;173: [20] Valentine AD, Meyers CA. Successful treatment of interferon-alphainduced mood disorder with nortriptyline. Psychosomatics 1995;36: [21] Zdilar D, Franco-Bronson K, Buchler N, Locala JA, Younossi ZM, Hepatitis C. interferon alfa, and depression. Hepatology 2000;31: [22] Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001;344: [23] Schaefer M, Schmidt F, Folwaczny C, Lorenz R, Martin G, Schindlbeck N, et al. Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology 2003;37: [24] Pariante CM, Orru MG, Baita A, Farci MG, Carpiniello B. Treatment with interferon-alpha in patients with chronic hepatitis and mood or anxiety disorders. Lancet 1999;354: [25] Pariante CM, Landau S, Carpiniello B. Interferon alfa-induced adverse effects in patients with a psychiatric diagnosis. N Engl J Med 2002;347: [26] Van Thiel DH, Friedlander L, Molloy PJ, Fagiuoli S, Kania RJ, Caraceni P. Interferon-alpha can be used successfully in patients with hepatitis C virus-positive chronic hepatitis who have a psychiatric illness. Eur J Gastroenterol Hepatol 1995;7: [27] Van Thiel DH, Anantharaju A, Creech S. Response to treatment of hepatitis C in individuals with a recent history of intravenous drug abuse. Am J Gastroenterol 2003;98: [28] Capuron L, Raison CL, Musselman DL, Lawson DH, Nemeroff CB, Miller AH. Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry 2003;160: [29] Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358: [30] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales Jr FL, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347: [31] Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301: [32] Gochee PA, Powell EE, Purdie DM, Pandeya N, Kelemen L, Shorthouse C, et al. Association between apolipoprotein E epsilon4 and neuropsychiatric symptoms during Interferon alpha treatment for chronic hepatitis C. Psychosomatics 2004;45: [33] Jones TH, Wadler S, Hupart KH. Endocrine-mediated mechanisms of fatigue during treatment with interferon-alpha. Semin Oncol 1998;25: [34] Abe S, Hori T, Suzuki T, Baba A, Shiraishi H, Yamamoto T. Effects of chronic administration of interferon alpha A/D on serotonergic receptors in rat brain. Neurochem Res 1999;24: [35] Morikawa O, Sakai N, Obara H, Saito N. Effects of interferon-alpha, interferon-gamma and camp on the transcriptional regulation of the serotonin transporter. Eur J Pharmacol 1998;349: [36] Schaefer M, Schwaiger M, Pich M, Lieb K, Heinz A. Neurotransmitter changes by Interferon-alpha and therapeutic implications. Pharmacopsychiatry 2003;36: [37] Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB, et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 2002;26: