De novo depression and anxiety disorders and influence on adherence during peginterferon-alpha-2a and ribavirin treatment in patients with hepatitis C
Drug Abuse and Psychiatry Department, Hospital del Mar and Grup de Recerca Clínica en Farmacologia Humana i Neurociències, Unitat de Recerca Farmacològica, Institut Municipal d’Investigació Mèdica, Barcelona
Drug Abuse and Psychiatry Department, Hospital del Mar and Grup de Recerca Clínica en Farmacologia Humana i Neurociències, Unitat de Recerca Farmacològica, Institut Municipal d’Investigació Mèdica, Barcelona
Dr R. Solà, Liver Section, Hospital del Mar, C/ Passeig Marítim 25-29, 08003 Barcelona, Spain. E-mail: email@example.com
Background Depression and anxiety have been associated with interferon treatment and low treatment adherence.
Aim To study the incidence and associated risk factors of depressive and anxiety disorders during pegylated interferon plus ribavirin and treatment adherence in a prospective cohort of 176 patients with chronic hepatitis C patients.
Methods Patients were interviewed at baseline using the Structured Clinical Interview for DSM-IV Mental Disorders and the Patient Health Questionnaire and the Hospital Anxiety and Depression Scale were completed. Both questionnaires were completed also after 4, 12 and 24 weeks of treatment.
Results De novo depressive and/or anxiety disorders were diagnosed in 53 (36%) patients, in whom antidepressants and/or anxiolytics were administered. Higher baseline depression-subscale score (OR = 27.8, 95% CI = 2.82–333), primary education level (OR = 3.1, 95% CI = 1.40–7.03) and being an immigrant (OR = 3.2, 95% CI = 1.12–9.47) were predictors of psychiatric disorders during anti-viral therapy. The percentage of patients with good adherence was lower in those with depression and/or anxiety (79% vs. 90%, P <0.04). Only one patient (1%) discontinued treatment because of a major depressive episode. Depression and/or anxiety disorders had no effect on attainment of sustained virological response.
Conclusion Early detection and treatment of depressive and anxiety disorders favours good adherence to anti-viral treatment in hepatitis C.
Chronic infection with hepatitis C virus (HCV) is a major public health problem that affects about 3% of the world’s population.1, 2 Twenty per cent of HCV-infected patients develop cirrhosis and between 1% and 4% liver cancer.3, 4 In fact, chronic hepatitis C is currently the main cause of chronic liver disease and the leading indication for liver transplantation in Western countries.5
Interferon (IFN) was the first effective treatment for hepatitis C and when given in combination with ribavirin (RBV), the rate of sustained virological response (SVR) increased from 10% to more than 50%.6, 7 However, IFN therapy is associated with important psychiatric adverse effects, including sadness, anhedonia, fatigue, anxiety, irritability, anorexia, impaired concentration, insomnia and suicide ideation or its attempts.6 In many patients, these adverse effects are the main reason for poor treatment adherence,6, 8 as well as a major reason for excluding HCV-infected patients from potentially curative anti-viral therapy.4, 9, 10 The effect of psychiatric symptoms during anti-viral therapy, particularly depressive symptoms, on the likelihood of viral response is unclear.11, 12 The presence of depressive symptoms prior to IFN treatment seems to play a role as a risk factor for inducing depression during therapy,13–16 but the occurrence of anxiety disorders before and during IFN treatment has been little investigated.17 On the other hand, a previous study in which HCV genotype as a risk factor for depression was evaluated, no association was observed.18
Recently, treatment with pegylated IFN (PegIFN) in combination with RBV has become the standard of care for patients with chronic hepatitis C. Pegylation involves the addition of a polyethylene glycol molecule to IFN-alpha. It is a process that increases its half-life, allows once-a-week administration, improves anti-viral efficacy and may have less psychiatric side effects.12, 19 Nevertheless, only a few studies have prospectively assessed the frequency and time-course of depressive syndromes during treatment with PegIFN and RBV using validated psychiatric assessment tools, and anxiety syndromes have been analysed.18, 20
Several studies and case reports have shown that antidepressants, especially selective serotonin reuptake inhibitors (SSRI), are useful in ameliorating IFN-induced depression.21–23 Furthermore, it has been suggested that antidepressants can also prevent psychiatric adverse effects in patients with melanoma treated with IFN24 as well as in patients with hepatitis C.25 Two recent studies showed that SSRI treatment cannot prevent induced-depressive episodes but can ameliorate the symptomatology.26, 27 Therefore, successful medical treatment of chronic hepatitis C requires the detection and management of depression both before and during treatment, and an understanding of risk factors for IFN-induced depression.28, 29
The aims of this study were to evaluate in a prospective naturalistic cohort of patients with chronic hepatitis C receiving PegIFN alpha-2a and RBV, the incidence, time at onset, associated risk factors and treatment of depression and anxiety disorders and anti-viral treatment adherence.
Patients and methods
Selection of patients
Between January 2004 and September 2005, all consecutive patients with chronic hepatitis C starting treatment with PegIFN and RVB in the Hepatology Units of two acute-care teaching hospitals in Barcelona (Spain) were eligible. Exclusion criteria were language or cognitive difficulties, the presence of other liver diseases, co-infection with hepatitis B or the human immunodeficiency virus, hepatocellular carcinoma assessed by ultrasonography and alpha-fetoprotein levels, autoimmune disorders, a neutrophil count of <1.5 × 109/L and a platelet count of <75 × 109/L. In addition, patients whose baseline assessment showed the presence of major psychiatric disorders other than affective disorders (such as psychotic disorders) were offered psychiatric treatment but were not enrolled in the study. Patients with a history of substance abuse were required to be abstinent for at least 6 months prior entry into the study. The study protocol was approved by the institutional review board of the participating hospitals. All subjects signed an informed consent form.
The study used a prospective cohort design. All patients were interviewed at baseline using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I)30 and both the Patient Health Questionnaire (PHQ)31 and the Hospital Anxiety and Depression Scale (HADS) were completed.32 Then, the treatment was started in patients with PegIFN alpha-2a (180 μg s.c. weekly) and RBV (800–1200 mg p.o. daily) for 24 or 48 weeks according to HCV genotype. After 4, 12 and 24 weeks of treatment, all patients completed again the PHQ and the HADS questionnaires.
If at any point during the study, a patient showed clinically relevant anxiety or depressive symptoms as detected by PHQ or a HADS anxiety or depression score of 11 or greater, he/she was referred to a senior psychiatrist on the same day. The psychiatrists, after a full clinical assessment, either confirmed or not the presence of a depressive or anxiety disorder on the basis of DSM-IV criteria using the anxiety or depression SCID module and decided on the need for drug treatment. Neither PegIFN nor RBV was stopped nor were the doses reduced before psychiatric consultation. Good adherence to PegIFN and RBV treatment was defined as when the patient did not need to stop or when the patient received at least 80% of the total dosage of both drugs.33 Sustained virological response was evaluated 24 weeks after completion of PegIFN and RBV treatment.
All participants were assessed at baseline using the SCID-I to assess current and past history of psychiatric disorders. Likewise, two self-administered questionnaires were used. (i) the Spanish validated version of the PHQ,34 an instrument designed for the screening of depressive and anxiety disorders in primary care and other medical settings, as well as bulimia nervosa, binge eating disorder and alcohol abuse or dependence. PHQ allows establishing a current DSM-IV diagnosis of any depressive episode, a panic syndrome and a generalized anxiety syndrome. This screening questionnaire has shown good psychometric properties to detect depressive and anxiety disorders in medical settings. The overall accuracy (88%), sensitivity (87%) and specificity (88%) of the Spanish version are similar to the original English version of the PHQ in primary care patients.31 Kappa values of 0.74 were found between PHQ diagnosis and those of an independent mental health professional.34 (ii) The Spanish validated version of HADS35 is a self-administered questionnaire including 14 items scored on a 4-point Likert scale split into two subscales of depression and anxiety. This questionnaire was especially designed for the evaluation of anxiety and depression in medical patients.
Yates corrected chi-squared contingency tests (χ2) and Student’s t-test were used for univariate analysis of categorical and continuous variables, respectively. A logistic multivariate regression model was used to analyse the relationships between risk factors and the presence of depressive or anxiety disorders before or during anti-viral treatment. Variables included in the model were gender, age, immigrant condition, level of education, HCV genotype, advanced liver fibrosis, past history of anxiety or depressive disorders, past history of intravenous drug use, past history of alcohol dependence, baseline anxiety or depressive disorders, baseline HADS scores and use of antidepressants at baseline. Stepwise backward elimination (with P < 0.05 as the criterion of elimination) was used to remove nonsignificant factors. Adjusted odds ratio (OR) and corresponding Wald confidence intervals were calculated using regression coefficients. Changes in HADS scores as a function of time were assessed using repeated-measures analysis of variance employing mixed linear modelling. Data were analysed using the statistical software spss (version 12.0) for Windows (SPSS, Inc., Chicago, IL, USA). It included its module for exact testing. The level of statistical significance considered was 95%.
Table 1 shows socio-demographic characteristics, genotype and psychiatric history of the 176 patients at baseline. Some differences were found between genders and in the immigrant subgroup. Women were older (P =0.002) and had a lower level of education (P =0.02). Men had a higher past prevalence of alcoholism (P =0.003) and opioid (P =0.005) dependence disorders. However, no differences were found in the past history of depressive and/or anxiety disorders. Immigrant patients (n = 33) were from south-eastern Asia (n = 16), Latin America (n = 8), Eastern Europe (n = 7) and Central Africa (n = 2). Immigrant patients were younger (P =0.0002) and 70% had HCV genotype 2/3 (P <0.0001). Immigrant patients had significantly less past history of psychiatric disorders (P =0.05), included less depression disorders (P = 0.03) compared with non-immigrants.
Table 1. Socio-demographic characteristics, genotype and psychiatric history (lifetime psychiatric disorders: SCID-I-DSM-IV) at baseline, before starting the anti-viral treatment
All patients (N = 176)
Men (N = 119)
Women (N = 57)
Immigrant (N = 33)
Non-immigrant (N = 143)
* Total sample with liver biopsy = 140 patients; † Student’s t-test; chi-squared test.
Age, mean (s.d.)
Educational level, N (%)
Employed, N (%)
Immigrant condition, N (%)
VHC genotype, N (%)
Advanced fibrosis*, N (%)
Lifetime psychiatric diagnoses (DSM-IV), N (%)
Depression or anxiety
Some psychiatric disorder
Table 2 shows the figures for current psychiatric disorders according to PHQ at baseline. Before starting anti-viral therapy, 30 (17%) patients had some depressive and/or anxiety disorder. Only three patients had a current major depressive disorder (2%) and one patient had a pure anxiety disorder (1%). No differences were found by gender (men 15% vs. women 22%; P =0.293) or immigrant subgroup (27% vs. 15%; P =0.206).
Table 2. Current psychiatric disorders based on Patient Health Questionnaire (PHQ) at baseline
Current psychiatric disorders
All subjects [N = 176; N (%)]
Men [N = 119; N (%)]
Women [N = 57; N (%)]
Major or minor depression
Anxiety disorders (with/without any depression)
Some depression and anxiety
A past history of alcohol dependence (adjusted OR = 5.0; 95% CI = 1.8–13.2; P =0.002), an HCV genotype other than 1 (adjusted OR = 2.7; 95% CI = 1.1–6.4; P =0.02) and a past history of an anxiety or depressive disorder (adjusted OR = 2.4; 95% CI = 1.0–5.8; P =0.04) were independent risk factors for depressive and anxiety disorders at baseline. Other variables such as gender, age, immigrant condition, level of education, employment status, advanced liver fibrosis and past history of an opioid dependence disorder were not independent predictive factors in the logistic regression model.
To study the incidence of psychiatric disorders during anti-viral therapy, patients with depressive or anxiety disorders at baseline (n = 30) were excluded. Table 3 shows new cases of psychiatric disorders according to PHQ during anti-viral treatment. Fifty-three (36%) of patients (n = 146) developed a depressive or anxiety disorder and eight (6%) of them met criteria for a major depressive syndrome. Only two (4%) patients developed an anxiety disorder without a concomitant depressive syndrome. No differences were found between males and females. However, immigrants compared with non-immigrants showed a higher incidence of depressive or anxiety disorders during the treatment, (64% vs. 37%; P =0.005). Figure 1 shows the time onset of the new cases of depression or anxiety syndromes during the first 24 weeks of treatment. Most of the depressive and anxiety syndromes appeared during the first 4 weeks.
Table 3. Psychiatric disorders based on Patient Health Questionnaire (PHQ) during PegIFN and RBV treatment in patients without baseline psychiatric disorders
All subjects [N = 146; N (%)]
Men [N = 100; N (%)]
Women [N = 46; N (%)]
PegIFN, pegylated interferon; RBV, ribavirin.
Major or minor depression
Anxiety disorders (with/without depression)
Some depression and anxiety
During anti-viral treatment, an overall increase in the HADS depression score was found but it was statistically significant only in the group of patients without baseline PHQ anxiety or depressive syndromes (n = 146; Figure 2). On the other hand, an overall decrease in HADS anxiety scores during treatment was shown only in the group of patients with baseline PHQ anxiety or depressive syndromes (n = 30). No change in the group of patients without such baseline syndromes was observed (Figure 3).
The independent risk factors for the development of depressive or anxiety syndromes during therapy in patients without a baseline PHQ depressive or anxiety syndrome (n = 146) were the baseline HADS depression score (adjusted OR = 27.8; 95% CI = 2.82–333; P =0.006), primary education level (adjusted OR = 3.1, 95% CI = 1.40–7.03, P =0.01) and being an immigrant (OR = 3.2, 95% CI = 1.12–9.47, P =0.03). Other variables such as gender, age, HCV genotype, employment status, advanced liver fibrosis, past history of depressive or anxiety disorders, past history of an alcohol or opioid dependence disorder, a baseline HADS anxiety score and baseline use of antidepressants were not independent risk factors in this model.
Patients with depressive or anxiety syndromes were referred for a psychiatric consultation and treated when necessary. At baseline, 30 patients (17%) were receiving antidepressants or anxyolitics: 21 (12%) and 20 (11%), respectively. At week 4 of the treatment, 38 (22%) patients were receiving antidepressants or anxyolitics: 24 (14%) and 27 (15%), respectively. At week 12, there were 60 (34%) patients: 33 (19%) and 43 (24%), respectively. At week 24 there were 50 (28%) patients: 31 (18%) and 35 (20%), respectively. Citalopram (20–40 mg/day) and escitalopram (10–20 mg/day) were the antidepressants used, and dipotassium clorazepat (10–15 mg/day) or alprazolam (0.5–1.5 mg/day) the anxyolitics that were used. There were no gender differences regarding psychopharmacological treatments. Few patients showed antidepressant side effects, mainly slight nausea and headache at the beginning of treatment. None of them discontinued treatment for this reason.
Table 4 shows the relationship between adherence and the incidence of depressive or anxiety syndromes during the treatment with PegIFN and RBV. One hundred and twenty-seven (87%) of 146 patients without depression or anxiety syndromes at baseline showed a good adherence to PegIFN and RBV treatment. Of the remaining 19 patients (12%), the treatment was stopped in six because of adverse events at weeks 13, 17, 20, 24, 28 and 45, respectively. Only one patient who failed to respond to antidepressant treatment had to discontinue anti-viral therapy because of a severe major depressive episode. The remaining five patients dropped out for medical reasons (haematological reasons: four; thyroidal: one). Thirteen patients received <80% of the total dose of at least one of the two drugs (three of PegIFN, seven of RBV and three of both drugs).
Table 4. Adherence to treatment related to presence of incident depression or anxiety disorders during PegIFN and RBV treatment in patients without baseline psychiatric disorders
All patients [N = 146; N (%)]
PHQ+ [N = 53; N (%)]
PHQ− [N = 93; N (%)]
PHQ+, incident cases of psychiatric disorders during treatment; PHQ−, non-incident cases of psychiatric disorders during treatment; PegIFN, pegylated interferon; RBV, ribavirin.
Adherence to treatment
IFN doses ≥80%
RBV doses ≥80%
Length of treatment ≥80%
Despite the high percentage of good adherence (79%) in those patients with depression or anxiety disorders during the PegIFN and RBV treatment, adherence was significantly worse compared with patients without depression or anxiety syndromes during the treatment (P =0.04). On the other hand, no differences were found in the rate of SVR depending on the presence (n = 53) or absence (n = 93) of depressive or anxiety syndromes during anti-viral treatment in the overall population (57% vs. 67%; P =0.23), in the subgroup of patients with genotype 1 (41% vs. 60%, P =0.09) and in the subset of patients with genotype other than 1 (81% vs. 85%, P =0.76).
We found a high incidence of depression and anxiety syndromes (36%) during PegIFN and RBV treatment. Half of them appeared in the first month and almost all in the first fourth months of anti-viral treatment. These syndromes were predicted by baseline depression scores, low level of education and immigrant condition. Baseline depression scores were associated with past history of alcohol dependence, past history of depressive or anxiety disorders and HCV genotype other than 1. This genotype was more frequent in the immigrant subgroup. Early detection and treatment of depression and anxiety syndromes allowed patients to obtain a good adherence, and high proportion achieved SVR.
In contrast to initial studies indicating that PegIFN-alpha might have less psychiatric adverse effects than conventional IFN,12–16, 19 our findings show that treatment with PegIFN-alpha-2a and RBV is also associated with a high incidence of depressive and/or anxiety syndromes. This may be explained by the screening instruments used for the detection of psychiatric disorders. On the other hand, there are no conclusive results in the literature supporting that a past history of major depressive disorder is a significant risk factor for the subsequent development of depression during IFN treatment.17, 36–42 In agreement with Raison et al.,11 our data indicate that a previous history of major depression contributes to the risk of developing depressive symptoms during anti-viral therapy through an association with elevated baseline depression scores. Likewise, past history of substance abuse (opioid or alcohol dependence) was not predictive of the development of depressive syndromes during treatment in our sample. Finally, as it has been noted in some14, 18, 43 but not in all studies,17, 37, 44, 45 gender did not emerge as a predictor of IFN’s induced depression.
It is believed that most adverse psychiatric IFN effects occur during the first 3 months of treatment,18, 36 but results are not clear.15, 21 Our study shows that most depression and anxiety syndromes induced by anti-viral therapy appeared during the first 4 weeks of treatment (59%) and more than 90% during the first 12 weeks. Nevertheless, it must be considered that we have assessed only the first 24 weeks of anti-viral treatment and that it is possible that an indeterminate proportion of depression or anxiety syndromes may appear later.
The prevalence of depression and anxiety syndromes found at baseline before initiating anti-viral therapy is in accordance with data from other studies that also used standardized psychiatric interviews.28, 29 A history of a depressive disorder and alcohol dependence was predictive of baseline depressive syndromes. Furthermore, a somewhat unexpected finding in our study was the association of HCV genotype (other than 1) with an increased risk of depression before starting therapy, but not during the anti-viral treatment. It should be noted that the immigrant subgroup of patients had the highest proportion of HCV genotype other than 1, and these patients showed more induced depression than non-immigrants, although a lower percentage of immigrants had history of psychiatric disorders at baseline. To our knowledge, there is one previous study that evaluated HCV genotypes as risk factors for depression, with negative results.18 According to our data, a higher risk for psychiatric disorders during anti-viral therapy was found in patients with baseline increased HADS depression score, history of a depressive disorder or alcohol dependence, and genotype other than 1. It may be speculated whether pre-treatment with antidepressant may be indicated for these patients. Indeed, prophylactic antidepressant treatment has been found to reduce the development of depression effectively in patients receiving a high-dose of IFN-alpha for malignant melanoma24 or chronic hepatitis C,25 and reduce the severity of depressive symptomatology26, 27 according to some preliminary data.
The detailed assessment of psychiatric symptoms as well as early antidepressant or anxyolitic treatment allowed for good treatment adherence. Nevertheless, patients with induced depression or anxiety disorders had significantly less good adherence than those without induced depression or anxiety during the treatment. Although the study of the virological response was not the main purpose, it is interesting to note that SVR did not differ significantly between both subgroups of patients, an observation that has also been seen in a previous study using standard IFN plus RBV.46 This finding suggests that the antidepressants used in this investigation do not reduce the efficacy of anti-viral therapy. Only one patient discontinued the therapy because of a severe major depression. Antidepressants have proven to be useful in the treatment of IFN-induced mood disorders.21, 22 In this study, it was not possible to draw conclusions about its effectiveness, because of the naturalistic use of the antidepressant treatment. Nevertheless, there are two points to be emphasized. First, HADS depression scores along anti-viral treatment did not significantly increase in patients with baseline PHQ anxiety or depressive disorders. This feature was probably because of the fact that most of the patients were receiving antidepressant treatments (19%) during anti-viral therapy. In addition, HADS anxiety scores improved in this group of patients during anti-viral treatment. Secondly, a significant percentage of patients (12%) were treated with antidepressants even before starting PegIFN and RBV treatment. This suggests that levels of depressive or anxiety symptoms might have been even higher in the absence of antidepressant therapy and it might also explain the low incidence of dropouts. Our figures are similar to those from other naturalistic studies15, 21 and extend the efficacy of antidepressants in preventing and treating IFN-associated depressive episodes. However, controlled studies focusing on the efficacy and safety (with regard to virological response and liver function) of antidepressants in the prevention of psychiatric side effects during PegIFN and RBV treatment are needed.
Some limitations of this study have already been discussed, such as the characteristics of the sample, the fact of assessing only the first 24 weeks of anti-viral treatment and the naturalistic use of antidepressants. It should also be noted that a control group of HCV patients without anti-viral treatment cannot be included for ethical reasons. Therefore, the result of random variations in mood across time cannot be discarded. Despite the longitudinal character of the study, the design does not allow to establish a causal relationship between depressive or anxiety syndromes and PegIFN treatment. We cannot rule out other factors such as RBV18 or the appearance of primary or adaptive mood disorders throughout anti-viral treatment. Finally, like most other studies, our research was based at tertiary referral centres. These conditioning factors make it difficult to generalize our results to the general population of chronic hepatitis C patients.
In conclusion, this study supports the need for close cooperation between hepatologists and psychiatrists in patients with hepatitis C undergoing combined anti-viral treatment. Systematic screening for depression and anxiety using validated assessment tools permits early pharmacological interventions and therefore, increases the likelihood to complete a full course of PegIFN and RBV treatment.
Declaration of personal interests: The authors thank Marta Pulido MD, for editing the manuscript and for editorial assistance. Ricard Sola has served as a speaker for Roche and Bristol Meyers, and a consultant for Roche. He has also received research funding from Roche and Gilead. Declaration of funding interests: This study has been supported in part by grants from the Instituto de Salud Carlos III (C03/02) and (GO3/184), Fondo de Investigaciones Sanitarias (FIS PI051875) and (FIS PI052565).