The authors have declared that no competing interests exist.
Conceived and designed the experiments: XJH YYY. Performed the experiments: XJH JHX. Analyzed the data: XJH JW. Contributed reagents/materials/analysis tools: JHX JW. Wrote the paper: XJH YYY.
Antidepressants are effective in treating interferon-α/ribavirin (IFN-α/RBV)-associated depression during or after treatment of chronic hepatitis C (CHC). Whether antidepressant prophylaxis is necessary in this population remains under debate.
Comprehensive searches were performed in Medline, Embase, Cochrane Controlled Trials Register and PubMed. Reference lists were searched manually. The methodology was in accordance with the 2009 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) Statement.
We identified six randomized, double-blind, placebo-controlled trials involving 522 CHC patients treated with pegylated (PEG)-IFN-α plus RBV. The antidepressants used were escitalopram, citalopram, and paroxetine, which are selective serotonin reuptake inhibitors (SSRIs). The rates of depression (17.9% vs. 31.0%, P = 0.0005), and rescue therapy (27.4% vs. 42.7%, P<0.0001) in the SSRI group were significantly lower than those in the placebo group. The rate of sustained virological response (SVR) (56.8% vs. 50.0%, P = 0.60) and drug discontinuation (18.7% vs. 21.1%, P = 0.63) in the SSRI group did not differ significantly to those in the placebo group. In terms of safety, the incidence of muscle and joint pain (40.8% vs. 52.4%, P = 0.03) and respiratory problems (29.3% vs. 40.1%, P = 0.03) were lower, but the incidence of dizziness was significantly higher (22.3% vs. 10.2%, P = 0.001) in the SSRI group.
Prophylactic SSRI antidepressants can significantly reduce the incidence of PEG-IFN-α/RBV-associated depression in patients with CHC, with good safety and tolerability, without reduction of SVR.
Globally, hepatitis C virus (HCV) has become one of the leading causes of chronic liver diseases and affects >170 million people
However, IFN-α-based therapy is associated with an approximately 70% incidence of mild to moderate depressive syndromes
Although some studies have reported that antidepressants are effective in treating IFN-α/RBV-associated depression during or after treatment of CHC
Consequently, the aim of this meta-analysis was to evaluate the efficacy and safety of pretreatment with antidepressants to prevent IFN-α/RBV-associated depression in patients with CHC treated with antiviral therapy in randomized, double-blind, placebo-controlled trials.
Two authors performed a literature search on Medline (1966 to March 2013), PubMed (updated to March 2013), Embase (1980 to March 2013), and Cochrane Controlled Trials Register (Cochrane Library Issue 1, 2013) using the keywords “hepatitis C AND interferon AND depression”. A manual search of publications and manual review of major journals in internal medicine, gastroenterology, hepatology, and infectious diseases (2000–2012) were also performed. This meta-analysis was conducted and reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) Statement issued in 2009
Inclusion criteria were: (1) study population with CHC; (2) antiviral regime was IFN-<alpha>/RBV combination therapy; (3) studies that reported data for outcomes at the end of treatment and follow-up period; (4) studies with full text; and (5) English studies. Exclusion criteria were: (1) non-randomized controlled trials (RCTs); (2) non-prophylaxis studies with pretreatment with antidepressants before antiviral therapy; (3) studies about human immunodeficiency virus, hepatitis B virus or other virus co-infections; and (4) studies about organ transplantation.
Two investigators independently evaluated each study, each of whom was blinded to the other. Any discrepancy was resolved through discussion. Extracted information included study characteristics (first author, study location, and year); patient baseline characteristics (sex, risk factors, baseline HCV RNA, HCV genotype, body mass index, and percentage with fibrosis and cirrhosis); and antidepressant and antiviral regimens. Outcomes included: total number of patients; number of patients with IFN-associated depression at the end of treatment; number of patients with sustained virological response (SVR) at the end of follow-up (defined as undetectable HCV RNA at the end of follow-up); total number of patients with treatment discontinuation; number of patients with serious adverse events; number of patients with dose reduction due to adverse events; and number of patients who received antidepressant rescue treatment.
Assessment of the methodological quality of the trials was based on the Jadad composite scale
The statistical analyses were conducted and Forest plots were generated using RevMan 5.2.3 (Nordic Cochrane Center, Rigshospitalet, Copenhagen, Denmark). The primary endpoints were the rate of incidence of depression and the rate of SVR. The secondary endpoints were the rate of drug discontinuation or withdrawal, rate of antidepressant rescue treatment, and the rate of adverse events. For the calculation of risk ratios (RRs), patients assigned to prophylactic antidepressant treatment were compared with those assigned to placebo in the same trial. The RRs were calculated along with their respective 95% confidence intervals (CIs) and presented for each individual study. Statistical heterogeneity between trials was evaluated by the χ2 and I2 tests, with significance being set at P<0.10. In the absence of significant heterogeneity (P>0.10), the fixed-effect method was used to combine the results. When heterogeneity was confirmed (P≤0.10), the random-effect method was used, and sensitivity analyses and meta-regressions were performed with study characteristics to evaluate potential sources of heterogeneity. Stratified analyses were performed using the variables found to be statistically significant in the meta-regressions. Any potential publication bias was evaluated by inspecting funnel plots and the Begg–Mazumdar test
Of the 871 articles found after initial searching,
Study | Status of CHC | Status of Depression | Measures for Depression Assessment |
Morasco BJ |
>18 years old, eligible for IFN/RBV therapy. | Exclusion criteria: hypersensitivity to paroxetine, active delirium, current major depressive disorder, bipolar disorder, a schizophrenia-spectrum disorder, and a substance use disorder within the last six months. | DSM-IV (SCID) HAM-D |
Raison CL |
18–65 years old, Exclusion criteria: other liver disease, unstable cardiovascular, endocrinologic, haematologic, renal or neurologic disease. | Exclusion criteria: history of schizophrenia or bipolar disorder, diagnosis of major depression or substance, abuse/dependence within 6 months of study entry. | SCID MADRS |
Diez-Quevedo C |
18–65 years old, ≥16 months of persistent elevated ALT. Exclusion criteria: other liver disease, unstable cardiovascular, endocrinologic, haematologic, renal, autoimmune, neurologic disease, Co-infection with HBV, HIV, neutrophil count<1500,platelet count <70,000 per µl, hemoglobin<12 g/dl in men and <11 g/dl in women, non reliable contraception in women. | Exclusion criteria: history or current diagnosis of schizophrenia or bipolar disorder, dementia; the presence, within 2 months of study entry, of drug, or alcohol abuse, symptomatic mental disorders(including major depressive disorders, dysthymia, and anxiety disorders other than specific phobias),the use of any psychiatric medication(patients were only allowed to maintain treatments with benzodiazepines at constant dosages). Zolpidem was used for insomnia when needed. | DSM-IV |
De Knegt RJ |
18–70 years old, Exclusion criteria: presence of contra-indications, for anti-viral therapy, abnormal values for thyroid stimulating hormone. | Exclusion criteria: a concurrent psychiatric axis I diagnosis, concurrent use of psychotropic drugs, a history or other evidence of severe illness or malignancy and any other condition which would make the patient unsuitable for the study. | M.I.N.I. DSM-IV MADRS BDI SCL-90 |
Morasco BJ |
≥18 years old, eligible for antiviral therapy. | Exclusion criteria: ongoing depression or active psychotic symptoms during the previous 3 months, substance abuse in the previous 6 months, medical comorbidities that could interfere with treatment, or current antidepressant use. | DSM-IV (SCID) MADRS |
Schaefer M |
>18 years old, treatment-naive patients, serum HCV RNA levels ≥1000 IU/mL. Exclusion criteria: pretreatment with IFN or immunotherapy, other chronic infection, or an autoimmune or severe somatic comorbid condition. | Exclusion criteria: a lifetime diagnosis of an affective disorder, drug abuse in the past 12 months, treatment with antidepressants during the past 3 years, or a history of any other axis I disorder. | DSM-IV (SCID) MADRS |
HBV: Heptatitis B virus, HIV: Human Immunodeficiency Virus, DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, M.I.N.I: Mini-international Neuropsychiatric Interview, SCID: Structured Clinical Interview for DSM–IV; MADRS: Montgomery–Asberg Depression Rating Scale, BDI: Beck Depression Inventory, SCL-90:Symptom Check List-90.
Study | Study design | SSRI | Anti depression regime | Antiviral regime | Sample size (AD/control) | Quality Score |
Morasco BJ |
multi-center, double-blind, placebo-controlled. | Paroxetine | 4 weeks of prophylaxis, subsequent 24–48weeks of administration. | genotype-based dose of PEG-IFN-α2a,2b or IFN-α, weight-based dose of RBV. | 14/19 | 4 |
Raison CL |
multi-center, double-blind, placebo-controlled. | Paroxetine | 2 weeks of prophylaxis, subsequent 24 weeks of administration. | PEG-IFN-2α, 2b or IFN-α, RBV according to treating Physicians. | 28/33 | 4 |
Diez-Quevedo C |
multi-center, double-blind, placebo-controlled. | Escitalopram | 2 weeks of prophylaxis, subsequent 14 weeks of administration. | PEG-IFN-α2a,180 mg/w, RBV 800–1200 mg. | 66/63 | 4 |
De Knegt RJ |
multi-center, double-blind, placebo-controlled. | Escitalopram | 2 weeks of prophylaxis, subsequent 24 weeks of administration. | genotype-based dose of PEG-IFN-α2a, weight-based dose of RBV. | 40/39 | 4 |
Morasco BJ |
double-center, double-blind, placebo-controlled. | Citalopram | 2 weeks of prophylaxis, subsequent 24–48weeks of administration. | genotype-based dose of PEG-IFN-α. guideline-based dose of RBV. | 19/20 | 4 |
Schaefer M |
multi-center, double-blind, placebo-controlled. | Escitalopram | 2 weeks of prophylaxis, subsequent 24–48weeks of administration. | genotype-based dose of PEG-IFN-α2a,weight-based dose of RBV. | 90/91 | 5 |
SSRI: selective serotonin reuptake inhibitor; study quality was evaluated on the 7-item Jadad scale, with a range of 0–5.
All six trials provided data about the rate of PEG-IFN-α/RBV-associated depression. The SSRI group included 252 patients with a rate of depression of 17.9%, while the placebo group included 261 patients with a rate of depression of 31.0%. The test for heterogeneity of the data obtained a P value of 0.27, thus the hypothesis of homogeneity was achieved. An estimated RR of 0.58 (95% CI: 0.43–0.79) was obtained after the data were pooled, and a significant effect on the rate of depression was found for the prophylaxis of SSRIs to prevent PEG-IFN-α/RBV-associated depression in patients with CHC (P = 0.0005) (
End-points | No. of patients with available data | SSRI group (No./%) | Placebo group (No./%) | P for homogeneity/Model | Exact RR (95%CI) | P |
Rate of depression | 428/Escitalopram and citalopram | 37/17.2 | 69/32.4 | 0.24/Fixed | 0.54 [0.38–0.75] | 0.0003 |
389/Escitalopram | 35/17.9 | 65/33.7 | 0.12/Fixed | 0.54 [0.38–0.76] | 0.0004 | |
94/Paroxetine | 8/19.0 | 14/26.9 | 0.23/Fixed | 0.72 [0.34–1.54] | 0.40 | |
474/Escitalopram and Paroxetine | 43/18.5 | 77/32.0 | 0.17/Fixed | 0.58 [0.43–0.80] | 0.0007 | |
Rate of SVR | 327/Escitalopram andCitalopram | 93/57.4 | 90/54.5 | 0.34/Fixed | 1.05 [0.87–1.27] | 0.60 |
288/Escitalopram | 86/59.4 | 80/55.2 | 0.25/Fixed | 1.09 [0.90–1.33 ] | 0.38 | |
321/Escitalopram and Paroxetine | 93/59.2 | 82/50.0 | 0.05/Random | 1.20 [0.80–1.79] | 0.39 | |
Rate of discontinuation | 428/Escitalopram and Citalopram | 34/15.8 | 30/14.1 | 0.28/Fixed | 1.12 [0.71–1.77] | 0.61 |
388/Escitalopram | 31 | 25 | 0.22/Fixed | 1.22 [0.75–1.99] | 0.43 | |
94/Paroxetine | 14/33.3 | 26/50.0 | 0.71/Fixed | 0.66 [0.40–1.09] | 0.10 | |
483/Escitalopram and Paroxetine | 45/18.9 | 51/20.8 | 0.19/Fixed | 0.95 [0.67–1.35] | 0.78 | |
Rate of reception of rescue therapy | 389/Escitalopram | 56/28.6 | 87/45.1 | 0.05/Random | 0.62 [0.50–0.77] | <0.0001 |
SSRI: selective serotonin reuptake inhibitor.
Four trials reported data on the effect of antidepressants on SVR. The SSRI group included 176 patients with a rate of SVR of 56.8%, while the placebo group included 184 patients with a rate of SVR of 50.0%. The test for the heterogeneity of the data obtained a P value of 0.08, thus the random model was used. An estimated RR of 1.10 (95% CI: 0.78–1.55) was obtained after the data were pooled. Antidepressant prophylaxis had no significant effect on the rate of SVR in patients with CHC (P = 0.60) (
All of the trials reported data on drug discontinuation. The SSRI group included 257 patients with a rate of discontinuation of 18.7%, while the placebo group included 265 patients with a rate of discontinuation of 21.1%. The test for heterogeneity of the data obtained a P value of 0.27, thus the hypothesis of homogeneity was achieved. An estimated RR of 0.92 (95% CI: 0.66–1.29) was obtained after the data were pooled. Antidepressant prophylaxis had no significant effect on the rate of discontinuation in patients with CHC (P = 0.63) (
Four trials reported data on the number of patients receiving rescue therapy. The SSRI group included 215 patients with a rate of rescue therapy of 27.4%, while the placebo group included 213 patients with a rate of rescue therapy of 42.7%. The test for heterogeneity of the data obtained a P value of 0.13, thus the hypothesis of homogeneity was achieved. An estimated RR of 0.63 (95% CI: 0.51–0.78) was obtained after the data were pooled, and a significant effect on the rate of rescue therapy was found (P<0.0001) (
Data for adverse events were extracted from three trials and subjected to meta-analysis (
Adverse events | No. of patients with available data | SSRI group (No./%) | Placebo group (No./%) | Exact RR (95% CI) | ||
Muscle and joint pain | 371(Escitalopram+ Paroxetine) | 75/40.8 | 98/52.4 | 0.63 [0.42, 0.96] | 0.03 | 0.15 |
310(Escitalopram) | 62/39.7 | 74/48.1 | 0.72 [0.46, 1.12] | 0.14 | 0.15 | |
Dizzness | 371(Escitalopram+ Paroxetine) | 41/22.3 | 19/10.2 | 2.65 [1.46, 4.80] | 0.001 | 0.52 |
310(Escitalopram) | 30/19.2 | 15/9.7 | 2.26 [1.16, 4.43] | 0.02 | 0.57 | |
Headache | 371(Escitalopram+ Paroxetine) | 61/33.2 | 72/38.5 | 0.81 [0.53, 1.24] | 0.33 | 0.56 |
310(Escitalopram) | 49/31.4 | 52/33.8 | 0.90 [0.56, 1.45] | 0.67 | 0.90 | |
Fatigue | 371(Escitalopram+ Paroxetine) | 92/50.0 | 102/54.5 | 0.83 [0.56, 1.25] | 0.38 | 0.28 |
310(Escitalopram) | 76/48.7 | 87/56.5 | 0.73 [0.47, 1.15] | 0.17 | 0.42 | |
Sexual dysfunction | 371(Escitalopram+ Paroxetine) | 17/9.2 | 8/4.3 | 2.35 [0.98, 5.65] | 0.06 | 0.83 |
310(Escitalopram) | 13/8.3 | 5/3.2 | 2.70 [0.94, 7.82] | 0.07 | 0.71 | |
Loss of appetite | 371(Escitalopram+ Paroxetine) | 37/20.1 | 36/19.3 | 1.09 [0.65, 1.82] | 0.75 | 0.09 |
310(Escitalopram) | 24/15.4 | 27/17.5 | 0.85 [0.47, 1.55] | 0.60 | 0.12 | |
Sleep disturbance | 371(Escitalopram+ Paroxetine) | 71/38.6 | 85/45.5 | 0.76 [0.50, 1.15] | 0.19 | 0.25 |
310(Escitalopram) | 57/36.5 | 71/46.1 | 0.68 [0.43, 1.07] | 0.09 | 0.26 | |
Influenza-like illness | 371(Escitalopram+ Paroxetine) | 54/29.3 | 64/34.2 | 0.81 [0.51, 1.27] | 0.35 | 0.58 |
310(Escitalopram) | 42/26.9 | 52/33.8 | 0.72 [0.43, 1.19] | 0.20 | 0.87 | |
Skin problems | 371 (Escitalopram+ Paroxetine) | 94/51.1 | 102/54.5 | 0.83 [0.54, 1.29] | 0.42 | 0.30 |
310(Escitalopram) | 89/57.1 | 92/59.7 | 0.90 [0.57, 1.44] | 0.67 | 0.20 | |
Respiratory problems | 371(Escitalopram+ Paroxetine) | 54/29.3 | 75/40.1 | 0.61 [0.40, 0.94] | 0.03 | 0.27 |
310(Escitalopram) | 46/29.5 | 68/44.2 | 0.53 [0.33, 0.85] | 0.008 | 0.78 | |
Hair loss | 371(Escitalopram+ Paroxetine) | 27/14.7 | 33/17.6 | 0.80 [0.46, 1.40] | 0.43 | 0.38 |
310(Escitalopram) | 24/15.4 | 29/18.8 | 0.79 [0.43, 1.43] | 0.44 | 0.17 | |
Anemia | 310(Escitalopram) | 23/14.7 | 22/14.3 | 1.05 [0.56, 1.97] | 0.89 | 0.21 |
Irritability | 310(Escitalopram) | 16/10.2 | 26/16.9 | 0.55 [0.28, 1.08] | 0.08 | 0.68 |
nausea or vomiting | 371(Escitalopram+ Paroxetine) | 66/35.9 | 69/36.9 | 0.97 [0.63, 1.48] | 0.88 | 0.32 |
310(Escitalopram) | 51/32.7 | 56/36.4 | 0.85 [0.53, 1.36] | 0.50 | 0.42 | |
Gastrointestinal illness | 371(Escitalopram+ Paroxetine) | 45/24.5 | 33/17.6 | 1.55 [0.93, 2.58] | 0.09 | 0.87 |
310(Escitalopram) | 35/22.4 | 24/15.6 | 1.57 [0.88, 2.79] | 0.12 | 0.60 |
SSRI: selective serotonin reuptake inhibitor. Escitalopram+ Paroxetine indicated that one of these two SSRIs was used in one trial and the data on the two SSRIs were meta-analyzed. Escitalopram indicated that data about the antidepressant were meta-analyzed.
We performed this meta-analysis of randomized double-blind placebo-controlled clinical trials to evaluate the efficacy and safety of prophylactic antidepressants to prevent PEG-IFN-α/RBV-associated depression in patients with CHC. The results reveal that preemptive and concomitant therapy with SSRIs can significantly reduce the incidence of PEG-IFN-α/RBV-associated depression in patients with CHC. SSRI interventions were safe, did not negatively decrease SVR, and did not influence the rate of drug discontinuation or withdrawal.
Interferon-α/RBV-associated depression is characteristic of a serotonergic deficiency and changes in the serotonin signaling pathway, which requires the prophylactic administration of SSRIs
The pooled rate of depression in the placebo group was 31.0%, which fell within the 20–40% incidence of depression in patients treated with IFN-α/RBV
With respect to the effect of SSRIs on the SVR, the results varied among the trials, although the trials were of similar design
IFN-α/RBV-associated depression was an important reason for discontinuing antiviral therapy
The lower rates of rescue therapy, muscle and joint pain and respiratory problems in the SSRI group indicated the better safety and tolerability of SSRIs. These results suggest that prophylactic SSRIs reduce the occurrence of these two adverse events associated with PEG-IFN-α/RBV combination therapy in patients with CHC. However, the pooled rate of dizziness was higher in the SSRI group than the placebo group, which was consistent with the results of each separate trial. This reminds clinicians to pay more attention to the occurrence of this adverse event when prophylactic SSRIs are administrated to patients with CHC. Therefore, prophylactic SSRIs did not worsen most adverse events apart from dizziness. Moreover, adverse events (e.g. diarrhea, headache, and sleep disturbance) were not increased as a result of concurrent administration of antiviral therapy and SSRIs. Although it was reported that citalopram could be safely used during IFN treatment in patients with CHC
We need to emphasize that according to our clinical experience and inclusion criteria, the optimal candidates for SSRI prophylaxis are CHC patients with concurrent subsyndromal depression symptoms (such as insomnia and anxiety) or a history of past major depressive disorders and eligibility for PEG-IFN-α/RBV treatment.
There were several limitations to our study. First, only six eligible RCTs were included, and we were limited by data availability. Second, sample sizes in most of the trials were small and included <50 subjects. Third, the possibility of omission of unpublished or ongoing studies still exist, although publication bias was not found according to the funnel plots and the Begg–Mazumdar test. Fourth, possible variation in the definition of depression and severity of depression were present in the studies included in our analysis, although the criteria for diagnosis and severity of depression were similar in all studies. These defects may weaken our results. Further analysis of increased numbers of multicenter RCTs with larger sample sizes are warranted to evaluate comprehensively the true value of prophylactic SSRIs to prevent PEG-IFN-α/RBV-associated depression during antiviral therapy in patients with CHC.
Despite these limitations, our meta-analysis of double-blind, placebo-controlled RCTs shows that prophylactic SSRIs can significantly reduce the incidence of PEG-IFN-α/RBV-associated depression in patients with CHC, with good safety and tolerability and without reduction of SVR.
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