Potential conflict of interest: Nothing to report.
We investigated and compared the results of treating the chronic hepatitis C (HCV) infection of different groups of psychiatric-risk patients and controls with pegylated interferon alpha (pegIFN-α) plus ribavirin. Seventy patients were prospectively screened for psychiatric disorders. Seventeen patients without psychiatric diseases or drug addiction (controls), 22 patients with psychiatric disorders, 18 patients who had received methadone substitution treatment and 13 patients who were former drug users were treated with pegIFN-α plus ribavirin. Sustained virological response (SVR), adherence, and psychiatric side effects (using the Montgomery-Asberg Depression Rating Scale and the Brief Psychiatric Rating Scale) in the groups were compared. An SVR was found in 58.6% of all patients: 58.8% of the controls, 50% of psychiatric patients, 72.2% of methadone patients, and 53.8% of former drug users. Methadone-substituted patients and former drug users had significantly higher dropout rates. Scores for neither depressive nor psychotic symptoms differed significantly between groups during treatment. However, the controls had lower pretreatment scores, followed by a significant higher increase to maximum scores. A stepwise logistic regression model showed that only genotype, not group (control, psychiatric, methadone, or former drug abuse), type of psychiatric diagnosis (affective disorder, personality disorder, or schizophrenic disorder), depression scores before and during treatment, change in depression score, antidepressive treatment, sex, or liver enzymes before treatment, was associated with SVR. Conclusion: In an interdisciplinary treatment setting psychiatric diseases and/or drug addiction did not negatively influence psychiatric tolerability of and antiviral response rate to HCV treatment with pegIFN-α and ribavirin. (HEPATOLOGY 2007.)
It is estimated that 170 million people worldwide are infected with the hepatitis C virus (HCV). Although the prevalence in the general population ranges between 1% and 2.4%,1, 2 the prevalence of HCV infection in patients with a chronic psychiatric disorder has been found to be significantly higher—between 6.8% and 8.5%.3, 4 Moreover, between 60% and 98% of intravenous drug users are chronically infected with HCV.5–7
Interferon alpha (IFN-α) is still the only effective treatment for chronic hepatitis C infection. In 1998, 2 studies showed that a combined regimen of IFN-α with ribavirin increased the sustained virological response (SVR) from 10% to 40%.8, 9 The development of pegylated interferons (pegIFN alpha-2a and pegIFN alpha-2b), characterized by a significantly longer half-life that allowed subcutaneous injection only once a week, further significantly improved therapeutic outcome when used in treatment in combination with ribavirin.10–12 SVR rates between 51% and 82% have been reported, depending on the virus genotype.10, 11
Antiviral treatment of chronic hepatitis C with IFN-α is associated with several neuropsychiatric side effects such as fatigue, anhedonia, depression, irritability, cognitive disturbances, mania, psychotic symptoms, delirium syndromes, relapse in alcohol or drug abuse, and even suicidal thoughts.13, 14 Former or current drug abuse and mental disorders are considered risk factors.13, 15–17 In addition, reports of suicide attempts during IFN-α therapy and the risk of reinfection led to the opinion that the use of INF-α is contraindicated for patients with a preexisting mental disorder, ongoing opiate abuse, or methadone substitution.18, 19 As a consequence, most of these patients remain untreated despite fulfilling the medical criteria for antiviral treatment of chronic hepatitis C.17, 20
The arguments for excluding these patients from treatment often do not stem from the results of suitable prospective and controlled clinical studies that included patients who were drug users or had psychiatric disorders.21 We recently demonstrated that psychiatric-risk patients with hepatitis C who were treated with standard interferon alpha plus ribavirin had response and dropout rates and an incidence of new major depressive episodes comparable to those of nonpsychiatric controls.17 So far, no clinical trial has compared these parameters during combination treatment with pegylated interferons and ribavirin. Therefore, we prospectively investigated the treatment of chronic HCV infection with pegylated IFN-α plus ribavirin in groups of patients with different psychiatric risks and compared their outcomes to those of controls, focusing on SVR, adherence, and differentiation as well as quantification of psychiatric side effects.
HCV, hepatitis C virus; IFN, interferon; SVR, sustained virological response.
Patients and Methods
Between 2001 and 2003, a total of 100 patients with a chronic hepatitis C infection were screened for psychiatric disorders and/or drug addiction and were considered for hepatitis C treatment with pegylated interferons and ribavirin. Twenty patients were not eligible for treatment because of ongoing drug or alcohol abuse, acute suicidal thoughts, or an unstable psychosocial situation (homeless, untreated chronic psychiatric disorders, no social support). A long-term psychiatric treatment program and psychosocial support were offered to those patients. Three of the 20 screened control patients were excluded because they did not agree to fill out psychopathological scales or did not comply with psychiatric appointments prior to treatment. Three of the 25 screened psychiatric patients (2 with personality disorders and 1 with combined depression and anxiety disorder), 2 of the methadone patients, and 2 of the patients formerly abusing drugs refused to participate in the trial. So, 70 of the 100 screened patients were included in the study and started on antiviral treatment after informed consent was given. The trial was approved by the ethics committee of the Charité-Universitätsmedizin Berlin, Campus Mitte.
Inclusion and Exclusion Criteria.
The inclusion criteria were detectable serum HCV RNA for more than 6 months (determined with AMPLICOR, Roche Diagnostics, Branchburg, NJ) and elevated (> 30 U/L) alanine aminotransferase (ALT; normal < 24 U/L).
General exclusion criteria were other liver diseases, Child class B or C cirrhosis, severe cardiac or neurological diseases, coinfection with hepatitis B or HIV, hepatocellular carcinoma according to ultrasound and alpha-fetoprotein level, autoimmune disorders, a neutrophil count less than 1,500/cm3, and a platelet count less than 75,000/cm3.
Psychiatric exclusion criteria were ongoing drug or alcohol abuse, recent suicide attempt, and untreated, unstable, or exacerbated psychiatric disorder. Also, homeless patients, patients with dementia or any other severe organic brain disease, and patients unable to give informed consent were excluded. Drug abuse was controlled prior and during the trial by random urine tests.
All patients received combination therapy of pegylated IFN-α-2b (1.5 μg/kg a week subcutaneously; n = 57, 81.4%) or pegylated IFN-α-2a (180 μg/week subcutaneously; n = 13, 18.6%) plus ribavirin (800–1,200 mg/day orally according to body weight). Antiviral therapy lasted 24 weeks for patients with genotypes 2 and 3 and 48 weeks for patients with genotypes 1 and 4.
Pretreatment Management of Patients.
All patients were seen and screened at our hepatological outpatients center 3 times over up to 3 months before antiviral treatment was started. The patients also had at least 3 screening visits in our psychiatric outpatient department. To prepare patients for the treatment, they were given an intensive explanation of possible psychiatric side effects, and if necessary, their psychiatric treatment was optimized or they were started on antidepressant pretreatment. Moreover, patients who did not come to the appointments were defined as unstable or noncompliant and did not start antiviral treatment.
Definitions of Treatment Groups.
Psychiatric disorders and a history of drug disorders were diagnosed using a structured clinical interview for DSM-IV diagnoses (SCID).22 Excluded from the control group was any patient with a history of psychiatric disorders or drug or alcohol abuse. Also excluded were patients who did not report psychiatric disorders but who had used psychotropic medications such as antidepressants or benzodiazepines for more than 3 weeks. Patients with primary psychiatric disorders (affective disorders, schizoaffective disorders, schizophrenia, personality disorders, or anxiety disorders) who had no history of drug addiction made up the psychiatric group. The third group, the methadone group, included patients treated in a methadone substitution program. Patients with a history of drug addiction (heroin, alcohol or other drugs) who assured us that they had not been abusing any illegal drugs or alcohol in at least the last 6 months were separated into a fourth group, the former drug addicts group. Urine tests for drug and alcohol were used to verify that these patients were not currently using, and they had to have negative results in at least 2 subsequent tests. A comorbid psychiatric disorder was not an exclusion criterion for patients with a history of drug addiction and for those receiving methadone substitution treatment.
Most patients with a drug addiction had a psychiatric comorbidity (Table 1). Overall, 20 patients (28.5%) were diagnosed with an affective disorder, 10 (14.3%) with a schizophrenic disorder, and 19 (27.1%) with a personality disorder. In the psychiatric group, 10 patients (45.5%) suffered from an affective disorder, 6 patients (27.3%) had schizophrenia, and 6 patients (27.3%) had a personality disorder diagnosis. Only 3 patients (16.7%) in the methadone-substituted group had no psychiatric diagnosis. Four patients in this group (22.2%) suffered from an affective disorder, 2 patients (11.1%) were diagnosed with a psychotic disorder, and 9 patients (50.0%) had a personality disorder. In the former drug abusers group, only 1 patient (7.6%) had no comorbid psychiatric disorder. Six patients in this group (46.2%) were afflicted with an affective disorder, 2 patients (15.4%) had a psychotic disorder, and 4 patients (30.8%) had a personality disorder. All patients with a chronic psychiatric disorder continued taking or had optimized any preexisting psychotropic medications (antidepressants, antipsychotics) before hepatitis C treatment was started.
Table 1. Patient Characteristics at Baseline
All (n = 70)
Control (n = 17)
Psychiatric (n = 22)
Methadone (n = 18)
Former Drug Abuse (n = 13)
Controls significantly older than methadone-substituted patients and former drug users.
Methadone group had significantly lower virus load (HCV RNA quantitative).
Depressive symptoms before and mood changes during treatment with IFN-α were monitored by an experienced psychiatrist using the Montgomery-Asberg Depression Rating Scale (MADRS).23 Possible psychotic symptoms during antiviral treatment were evaluated with the Brief Psychiatric Rating Scale (BPRS).24 The MADRS measures the severity of a number of depressive symptoms including mood and sadness, tension, sleep, appetite, energy, concentration, suicidal ideation, and restlessness. A score between 7 and 19 was defined as mild depression, a score between 20 and 33 as moderate depression, and a score of more than 33 as severe depressive syndrome. A “major depression” was verified according to DSM-IV criteria by an experienced psychiatrist. For depression before or during treatment, antidepressants were allowed (citalopram 10–40 mg/day as first choice).
SPSS 12.0 was used for statistical analyses. A P value of 0.05 or less was considered significant. The χ2 test was used for between-group comparisons of categorical data. Analysis of variance (ANOVA) with Bonferroni post hoc tests if a significant group effect was found was used for between-group comparisons of normally distributed data. The Kruskal-Wallis H test and Mann-Whitney U tests were used for post hoc analyses of between-group comparisons of data not normally distributed. Changes in psychiatric scores were calculated with repeated-measures ANOVA (in part with between-subject factor) respectively. Friedman tests. If a significant effect was found for the “point of measurement,” t tests with adjusted α respectively. Wilcoxon tests were calculated. A stepwise logistic regression model was used to elucidate the association of sustained response with group membership, different diagnostic groups, severity of depressive symptoms before treatment (MADRS score), differences in depression scores before treatment and after 6 months of treatment, increased depressive score during treatment, ALT level before treatment, age, genotype, and sex.
Sociodemographic data and hepatitis C virus genotype distribution are shown in Table 1. The mean age of the patients was 44 years, and most patients were male. Patients in the control group were significantly older than patients in the methadone-substituted and former drug users groups. Most patients were infected with HCV genotype 1 or 3. More patients in the control and psychiatric groups were infected with genotype 1 than were patients in former drug addicts group. Methadone-substituted patients had a significantly lower virus load than patients in the other groups.
Treatment Response and Adherence
The overall sustained virological response (SVR) was 58.6% (Table 2). Twenty-four weeks after the end of treatment, 44.4% of patients with genotype 1 or 4 and 84% of patients with genotype 2 or 3 were still HCV RNA negative. Between-group comparisons showed no significant differences in end-of-treatment response (EOT), SVR, and ALT during and after treatment, but there was a relatively small number of patients in each group. However, more patients from the methadone-substituted group had an SVR because of the larger number of patients with genotype 3 infection. Interestingly, the former drug addicts had a lower overall response because none of the genotype 1–infected patients developed an EOT or SVR (Table 2).
Ten patients (14.2%) discontinued treatment early. We observed that patients receiving methadone substitution treatment had the highest dropout rate, followed by patients who were former drug users. Reasons for dropping out were psychiatric side effects (n = 5), somatic side effects (n = 2), or noncompliance (n = 3). One third of the dropouts occurred in the first month of treatment, one third between the first and third months, and one third between the third and sixth months.
Changes in Psychiatric Scores
Total score and changes in scores on the psychiatric scales used were evaluated before treatment and after 1, 3, and 6 months of treatment. We further calculated the subgroup means of individual maximum scores and the total increase in each subgroup (subgroup mean of the individual differences between the pretreatment score and individual maximum) and compared mean scores before treatment and after 24 weeks of treatment.
MADRS scores at baseline of the controls were significantly lower than those of all other groups (Table 3). The MADRS scores of all but the methadone-substituted groups increased significantly between baseline and the third treatment month (control group: F = 12.33, df = 3, P < 0.001; psychiatric group: F = 4.54, df = 3, P = 0.006; former drug user group: F = 3.16, df = 3, P = 0.039). However, the control group had the greatest increase (see Fig. 1A). Hence, after 1, 3, and 6 months of antiviral treatment mean score did not differ significantly between the groups. The group maximums after treatment for 1 month (psychiatric group) and after 3 months (control, methadone-substituted, former drug user groups) were significantly higher than pretreatment scores—again except for the methadone-substituted group (control group: F = 2.84, df = 1, P = 0.001; psychiatric group: F = 9.19, df = 1, P = 0.007; former drug user group: F = 12.23, df = 1, P = 0.06). After reaching the maximum, the depression scores decreased in all groups until the sixth treatment month (Fig. 1).
Table 3. MADRS Scores of Subgroups
Former drug abuse
Control/psychiatric.:t = −4.08, df = 37, P < 0.001; Control/methadone: t = −6.26. df = 33, P < 0.001; Control/former drug user:t = −3.33, df = 27, P = 0.003.
BPRS scores (psychotic symptoms) of the control patients were significantly lower than those of all other groups (Table 4). Methadone-substituted patients and former drug users had the highest scores before and during treatment (between-group differences were not significant). However, during antiviral therapy, BPRS scores increased only slightly in most groups (Fig. 1B). Only the controls showed a significant change over time (F = 2.48, df = 3, P = 0.055). BPRS scores after treatment for 1 month (F = 5.48, df = 1, P = 0.033), 3 months (F = 5.15, df = 1, P = 0.038), and 6 months (F = 6.00, df = 1, P = 0.027) were significantly higher than at baseline. In contrast, the changes in the BPRS scores in the psychiatric, methadone-substituted, and former drug users group did not reach significance. Overall, no significant group differences were seen in mean BPRS scores after 1, 3, and 6 months of treatment, in individual maximum scores, and in maximum increases (Table 4).
Table 4. BPRS Scores of Subgroups
Former drug abuse
Control/psychiatric: t = −2.930, df = 37, P = 0.006; Control/methadone: t = −3.505, df = 33, P = 0.001; Control/former drug user: t = −3.312, df = 27, P = 0.003.
Depression Scores and Antidepressive Treatment Before and During Antiviral Treatment
Four patients in the control group (23.5%), 16 patients (72.7%) in the psychiatric subgroup, 16 patients (88.9%) in the methadone-substituted group, and 9 patients (69.2%) in the former drug abuser group had MADRS scores greater than 7, indicating at least a mild depressive mood before antiviral treatment was started. During treatment, 13 patients (76.5%) in the control group reached depressive scores on the MADRS scale: 8 patients (50.9%) with mild depressive symptoms, 3 (18.8%) with moderate depressive symptoms, and 2 (12.5%) with severe depressive symptoms. In the psychiatric group, 15 patients (68.2%) had mild depression, 4 (18.2%) had moderate depression, and 1 (4.5%) had a severe depressive syndrome. Overall, 11 of the methadone-substituted patients (61.1%) showed mild depressive symptoms, and 5 patients (27.8%) showed moderate depressive symptoms. In the former drug abuser group, 9 patients (69.2%) had mild depression, and 3 patients (23.1%) had moderate depression. No significant between-group differences could be found in the incidence of depression during antiviral treatment. However, after the first treatment month, significantly fewer new depressive episodes were observed in the methadone group than in the control patients (χ2 = 4.37, P = 0.037). The type of preexisting psychiatric disorder did not influence the depression rate during IFN-α treatment (70% of patients with an affective or schizophrenic disorder and 78.9% of patients with a personality disorder suffered from depression).
Significantly more patients who were former drug abusers received antidepressants before treatment was started (38.5%, n = 5, stand. Standard residuum = 2.3; P < 0.05). Preemptive treatment with citalopram was provided to 13.6% of the psychiatric patients (n = 3), 11.1% of the methadone-substituted patients (n = 2), and none of the control patients. During treatment, 58.8% (n = 10) of the controls, 68.2% (n = 15) of the psychiatric patients, 66.7% (n = 12) of the methadone-substituted patients, and 53.8% of the formerly drug-abusing patients received antidepressive medication. Overall, 41.2% (n = 7) of the controls, 18.2% (n = 4) of the psychiatric patients, 22.2% (n = 4) of the methadone-substituted patients, and 7.7% (n = 1) of former drug-using patients did not need antidepressants (ADs) before or during treatment. However, the statistical analysis only showed a strong trend toward a lower need for ADs in the controls during IFN treatment (stand. R = −1.6, χ2 = 12.25, df = 6, P = 0.057).
The increase in depression scores did not differ significantly between patients who received antidepressants before antiviral treatment was started and patients who did not take antidepressants before or during treatment with IFN-α (no ADs: MADRS increase = 5.94 ± 2.08; ADs before treatment: 6.78 ± 2.78; P = 0.83). In contrast, patients who needed citalopram during IFN-α treatment showed a higher increase in depressive symptoms (11.82 ± 1.26, P = 0.018 vs. patients not taking ADs).
Only Hepatitis C Genotype, Not Psychiatric Morbidity, Influenced Sustained Virological Response Rate
To detect factors associated with sustained virological response (SVR) rate, a stepwise logistic regression model was used that included the different groups (control, psychiatric, methadone-substituted, and former drug abuse), genotype, sex, ALT before treatment, MADRS score, increase in and maximum MADRS scores, and antidepressive medication as covariates. The only factor found to be relevant was genotype, with patients infected with genotype 2 or 3 having a significantly better chance of achieving an SVR than patients with genotype 1 (Exp. beta: 20.0; CI: 2.42–165.29; P = 0.005). Neither psychiatric variables such as group, depressive score before treatment, overall increase and maximum depression scores, and antidepressive medication nor other factors such as sex or ALT before treatment were found to be associated with response.
Most patients in the methadone-substituted and former drug addicts groups had a comorbid psychiatric condition. Therefore, we calculated the influence of any preexisting psychiatric disease and then separately calculated the effect of specific psychiatric diagnoses (affective, schizophrenic, or personality disorders) on SVR in all patients in our trial. A binary logistic regression model showed that neither a preexisting psychiatric diagnosis in general nor a specific disorder significantly reduced SVR compared to that in patients without any psychiatric disease.
So far only a few trials have investigated treating patients with psychiatric disorders or drug addiction who have hepatitis C with standard IFN-α as monotherapy or in combination with ribavirin (for a review, see Schaefer et al.25). The goal of our trial was to prospectively compare virological response and psychiatric side effects during antiviral HCV treatment with pegIFN-α and ribavirin in psychiatric-risk patients, those with psychiatric disorders and/or drug addiction, with those in a nonpsychiatric control group. Although more than 80% of patients in the methadone-supported and former drug addiction groups had a psychiatric comorbidity, adherence and compliance and incidence of depressive and psychotic symptoms during antiviral combination treatment with pegIFN-α and ribavirin were similar in psychiatric patients, drug addicts, and nonpsychiatric controls. Thus, we could confirm the results of our previous study, which indicated that patients with psychiatric disorders, methadone-treated patients, and patients with a history of drug addiction had response rates and adherence during treatment of chronic hepatitis C with standard IFN-α and ribavirin similar to those of patients in a nonpsychiatric control group.17
Sustained virological response was achieved by 50%–70% of the patients with psychiatric disorders and/or drug addiction. Taking genotype distribution into account, the response rates were comparable to those in our control group and also to those in other trials with nonpsychiatric patients using pegIFN alpha-2a or -2b.11, 26 Only virus genotype was found to significantly influence sustained virological response rate. In contrast, none of the psychiatric-risk factors analyzed negatively influenced SVR. Thus, our data indicate that psychiatric disorders generally are not independent risk factors for increased dropout or reduced response rates to antiviral treatment of chronic hepatitis C. Psychiatric patients were also not at increased risk of worsening depression during antiviral treatment compared to controls. Taking into account that baseline depression and psychotic symptom scores of those in the psychiatric-risk groups were higher than those of the controls, no significant differences were detected during treatment. This was a result of the depressive symptoms of the nonpsychiatric controls showing a significantly greater increase during treatment than those of the nonpsychiatric controls. Although some authors have identified increased depression score at baseline as a risk factor for higher depression score during treatment with standard IFN-α, our data are in line with the results of other controlled trials that did not find differences in changes in depression scores during IFN-α treatment between patients with preexisting depression and nonpsychiatric controls.17, 27–31 One possible explanation for the higher increase in depression scores in the control group might be the smaller number of patients who received antidepressants before antiviral therapy was started. In fact, recent data showed that at least for preexisting depressive symptoms, preemptive treatment with citalopram can decrease the incidence of major depressive episodes during treatment of chronic hepatitis C with pegIFN-α-2b and ribavirin.32
Although the dropout rate of the methadone-substituted patients was the highest in our trial, 72% achieved SVR. Mauss and coworkers recently reported similar response rates to antiviral treatment with pegIFN-α and ribavirin of methadone-substituted patients and controls.33 In that trial, methadone-substituted patients were also more likely to drop out during the first 3 months of antiviral therapy, but no specific psychiatric care was offered.
Current or previous psychosis is still considered as a contraindication for antiviral treatment with IFN-α.34 Exacerbation of psychotic symptoms during HCV treatment with IFN-α has been reported in single cases, especially in patients with a history of abuse of various drugs, including hallucinogens.30, 35 It has to be postulated that these patients have an increased vulnerability to psychotic episodes, which might be further triggered by neurotransmitter changes during treatment with IFN-α.25 In our trial, none of the psychiatric patients with a psychotic disorder or drug addiction had exacerbation of a psychotic condition with hallucinations or delusional thoughts during treatment with peg IFN-α. The observed increase in scores resulted from rather unspecific symptoms. So far only 2 early clinical trials have tested IFN-α as an add-on treatment for patients with schizophrenia. Both trials showed improvement in psychotic symptoms and reduction in the daily dosage of antipsychotic medication needed.36, 37 Nevertheless, we would recommend that patients with psychotic disorders or drug addiction be carefully monitored for the development of psychotic symptoms during IFN-α treatment.
We are aware that conclusions from our trial have to be drawn carefully because of the small study size. In addition, patients were not randomized by age, sex, and genotype, and the psychiatric group was diagnostically heterogeneous. Patients who had ongoing drug or alcohol abuse or who were not in a continuous psychiatric treatment program were excluded. Thus, even in our trial, 20% of the screened patients fulfilled exclusion criteria, and an additional 10% were not included because of refusal to participate or noncompliance during the screening period. As a consequence, we have to emphasize that not all psychiatric patients or patients with drug addiction and psychiatric comorbidity should be treated for their chronic hepatitis C. However, highly motivated patients might be included in an intensive psychiatric care program to prepare them for antiviral treatment and in general should not be excluded from hepatitis C therapy.38
In summary, the data from our prospective, controlled trial provide evidence that treatment of chronic hepatitis C infection with pegylated interferon alpha and ribavirin is possible in different subgroups of “difficult-to-treat” psychiatric patients. However, we would strongly recommend offering interdisciplinary treatment units in order to optimize adherence and response rates and to manage side effects.25