Copyright ©The Author(s) 2015.
World J Hepatol. Jul 28, 2015; 7(15): 1921-1935
Published online Jul 28, 2015. doi: 10.4254/wjh.v7.i15.1921
Table 1 Hepatitis C and pain related diagnoses
Whitehead et al[13]8224Retrospective chart reviewClinical data, diagnoses, and medical historyPain and SUD diagnoses were common among HCV patients, and opioids were frequently prescribed
Morasco et al[14]49Subjective assessmentClinical interview, medical records BDI-II, SDS, HRQOL SF-36Psychosocial variables, particularly depression severity, account for variance in pain intensity and pain functioning
Rogal et al[17]1286Retrospective cohort studySelf-report, symptom checklist and medical recordThere is a high prevalence of pain and opioid use in patients with chronic liver disease
Morasco et al[15]119Subjective assessmentTLFB, self-report; MPI, BDI-II, PCS, CPSS, CPCI, SCIDBiopsychosocial factors significantly affected pain severity and pain interference in patients with HCV
Table 2 Hepatitis C and psychiatric comorbidities
Lehman et al[20]120Subjective assessmentBDI-II, ASI, PCL, AUDIT, medical recordsClinically significant levels of depression anxiety, PTSD and alcohol-related problems were observed in patients with HCV
Fireman et al[19]293Prospective assessmentAUDIT-C, BDI-IIPsychiatric and substance use disorders are highly prevalent among veterans with chronic HCV
Rowan et al[21]62Subjective assessmentHRQOL SF-36Psychosocial factors, especially depression, are strong indicators of impaired HRQOL for HCV-infected Veterans
Bini et al[41]4084Prospective cohort studyEligibility for IFN therapy based on medical chart review of psychiatric and SUDsThe majority of veterans were not considered suitable candidates for HCV treatment because of substance use disorders, psychiatric disease, and comorbid medical disease
Mikocka-Walus et al[10]139Cross-sectional assessmentHADS, SCL-90, HRQOL SF-12, disease severity assessmentsPatients with HCV had significantly higher prevalence of depression and lower HRQOL than patients with IBD and IBS, and the general population
Nelligan et al[22]881Subjective assessmentBDI-II; medical recordsRates of depression are high among veterans with HCV and persist among those with antidepressant prescriptions
Weinstein et al[11]878Retrospective chart reviewClinical and demographic data, medical historyIndividuals with HCV have a higher prevalence of depression than HBV and NAFLD patients and the general population
Table 3 Neuropsychiatric side effects of interferon and interferon-induced depression
Fried et al[32]-Retrospective literature reviewPEGIFN-α-2a and 2b with RBV, IFN-α -2b/RBVAcross studies, depression occurred in 22% of those treated with PEGIFN-α-2a/RBV, 31% with PEGIFN-α-2b/RBV and 30%-34% of those treated with standard IFN treatment (PEGIFN-α-2b/RBV)
Fried et al[33]1121Randomized clinical trialPEGIFN-α-2a/RBV, IFN-α-2b/RBV, PEGIFN-α-2aPatients treated with PEGIFN-α-2a plus RBV or placebo had a lower incidence of depression than those treated with IFN-α-2b plus RBV (22% and 20% vs 30%)
Loftis et al[16]-Retrospective literature reviewIFN-α, IFN-β, and IFN-γSymptoms of depression induced by IFN therapy is common and can limit the treatment utility, often necessitate discontinuation of IFN treatment or the use of psychopharmacologic agents. Depression is also a suspected side effect of therapy with IFN-β and IFN-γ; however, the association has not been as convincingly confirmed
Hauser et al[34]-Retrospective literature reviewIFN-αNeuropsychiatric side effects such as depression, may develop as a result of IFN therapy and lead to lower HRQOL, dose reductions or discontinuation
Raison et al[35]162Longitudinal assessmentPEGIFN-α-2bModerate to severe depressive symptoms occurred frequently during PEGIFN/RBV treatment and was predicted by baseline depression scores and higher doses of RBV
Inder et al[37]1Retrospective case reportIFN-α-2a/RBVSuicide attempt occurred during IFN-α treatment, improvements were only seen with drug discontinuation. Following re-challenge with combination therapy, patient again experienced suicidal ideation
Loftis et al[18]32Prospective cohort studyPEGIFN-α-2a and 2b/RBVIFN therapy results in a significant increase in depressive symptoms over time, with neuro-vegetative and somatic symptoms of depression increasing more than other depressive symptoms
Table 4 Antiviral treatment response rates in patients with psychiatric and substance use disorders comorbidities
Dalgard et al[31]27Longitudinal assessmentIFN-α-2aRate of reinfection was not significantly different among IVDUers treated for HCV as compared to non IVDUers despite reinitiation of injection drug use in 33% of IVDUers
Loftis et al[27]39Prospective cohort studyIFN-α-2b/RBVGender, past history of MDD, and past history of SUD were not significantly associated with response rates
Backmund et al[47]18Longitudinal assessmentIFN-α-2a, IFN-α-2a/RBVIVDUers can be reinfected after treatment for HCV infection, but the reinfection rate is minimal and should not jeopardize the potential benefit for most patients
Chainuvati et al[40]647Retrospective database reviewEligibility/treatment rates for Interferon therapyTherapy completion and SVR rates are similar among Veterans with and without psychiatric or SUDs, challenging the perception that adherence is worse as a result of psychiatric co-morbidities
Anand et al[42]4061Longitudinal assessmentIFN-α-2b/RBVPatients with and without mild to moderate alcohol use had comparable completion and SVR rates to antiviral treatment
Hauser et al[38]55Retrospective chart reviewPEGIFN/RBV, IFN/RBVPeople with MDD had completion and SVR rates similar to those without psychiatric illness. Patients with MDD can be safely and effectively treated with antiviral therapy provided that they are on antidepressant medications during antiviral therapy
Huckans et al[43]60Retrospective chart reviewPEGINF/RBV, IFN/RBVPatients with schizophrenia experience similar rates of psychiatric symptoms on and off antiviral therapy
Grebely et al[48]58Prospective longitudinal follow upIFN-α-2b/RBV, PEGIFN-α-2a, PEGIFN-α-2bRate of reinfection following treatment for HCV infection among current and former IVDUers engaged in a multidisciplinary program is low
Table 5 Antidepressant treatment of interferon-induced depression
Gleason et al[54]15Open-label clinical trialCitalopramIFN-induced MDD in patients with HCV may be effectively and safely treated with citalopram
Hauser et al[24]39Prospective cohort studyCitalopram and buproprion33% of patients receiving IFN therapy develop IFN-induced MDD. There were no differences in age, gender, past history of MDD, or substance use between those who became depressed and those who did not. Of those who developed IFN-induced depression most responded to antidepressant treatment allowing continuation of antiviral therapy. Also the group who developed IFN-induced depression had significantly higher baseline BDI scores than the group who did not develop IFN- induced depression
Loftis et al[27]-Various antidepressantsIFN-α, IFN-β, and IFN-γDepression induced by IFN therapy is common and can limit treatment utility and necessitate discontinuation of antiviral treatment. However, the use of psychopharmacologic agents allows treatment continuation
Angelino et al[36]-Various antidepressantsIFN-αTreatment with IFN may provoke episodes of depression however, several standard treatments for depression can mediate these symptoms, suggesting that depression may not be a barrier to effective treatment
Gleason et al[55]18Open-label clinical trialEscitalopramIFN-induced MDD in patients with HCV may be effectively and safely treated with escitalopram
Table 6 Antidepressant prophylaxis
Angelino et al[36]-Retrospective literature reviewCitalopram; fluvoxamineProphylactic antidepressants might be well-considered for patients with a family history of - or previous episodes of - depression
Schaefer et al[57]33Prospective clinical trialCitalopramPre-treatment of psychiatric patients with citalopram significantly reduced the incidence of IFN-induced MDD during the first 6 mo of antiviral treatment
Raison et al[59]61Double-blind, placebo-controlled clinical trialParoxetineData support the use of antidepressant pre-treatment in HCV patients with elevated depressive symptoms at baseline
Morasco et al[58]33Double-blind, placebo-controlled clinical trialParoxetineA prophylactic approach to reduce IFN-α-induced depression may not be indicated in patients with HCV
Galvão-de Almeida et al[56]-Retrospective literature ReviewCitalopram, paroxetine, escitalopramAntidepressant prophylaxis may blunt the magnitude of depressive symptoms in HCV patients and raise the rates of treatment completion in those with psychiatric diagnosis
Morasco et al[60]39Double-blind, placebo-controlled clinical trialCitalopramCitalopram is not superior to placebo in preventing IFN-induced MDD
Table 7 Telaprevir
Hézode et al[73]334Phase 2 randomized clinical trialTelaprevir PEGIFN/RBVHCV genotype 1 - treatment naïveTelaprevir groups had significantly higher rates of SVR than PEGIFN/RBV alone. Depression occurred in 20%-23% of patients and was not significantly different across groups
McHutchison et al[68]115Randomized clinical trialTelaprevirHCV genotype 1 - previous non-responders to PEGINF/RBVRe-treatment with telaprevir was more effective than PEGIFN-α/RBV alone. Depression occurred in 11%-17% of participants
Zeuzem et al[69]663Phase III randomized clinical trialTelaprevir, PEGIFN- α-2a/ RBVHCV genotype 1 - previous non responders, partial responders and relapsersTelaprevir in combination with PEGIFN/RBV significantly improved rates of SVR and, as compared with PEGIFN/RBV alone showed no increase in neuropsychiatric side effects
Kumada et al[72]1126Multicenter randomized clinical trialTelaprevir, PEGIFN-α-2b/RBVHCV genotype 1 - treatment naiveTriple therapy with telaprevir-based regimen resulted in higher SVR with shorter duration. Depression was not listed as an adverse event
Sherman et al[74]540Randomized clinical trialTelaprevir PEGIFN-α-2a/RBVHCV genotype 1 - treatment naïveCombination therapy with telaprevir for 24 wk was non inferior to standard therapy for 48 wk. Fifty-three percent of patients experienced psychiatric symptoms
Table 8 Boceprevir
Kwo et al[77]520Two part randomized clinical trialBoceprevirchronic HCV genotype 1 - treatment naïveBoceprevir has the potential to double the SVR rate compared with standard treatment alone. Insomnia was the only psychiatric illness documented
Bacon et al[75]403Placebo controlled, randomized clinical trialPEGIFN-α-2b/RBV boceprevir, PEGIFN-α-2b/RBVRetreatment of patients with chronic HCV genotype 1 infectionBoceprevir resulted in significantly higher rates of SVR. Significant onset of depression was not indicated
Poordad et al[76]1097Double blind, placebo controlled randomized clinical trialBoceprevir PEGIFN-α-2b/RBVChronic HCV genotype 1 - treatment naïveBoceprevir significantly increased the rates of SVR. Insomnia was the only psychiatric condition identified as an adverse event
Table 9 Simeprevir
Fried et al[80]338Phase 2b double blind, placebo controlled randomized clinical trialSimeprevir PEGIFN-α-2a/RBVTreatment-naıve patients with HCV genotype 1 infection.Simeprevir in combination with PEGIFN/RBV significantly improved SVR rates and shortened therapy duration. Depression occurred in 10.4% of patients on simeprevir and 18.2% on standard treatment
Zeuzem et al[79]396Placebo controlled, randomized clinical trialSimeprevir, PEGIFN-α-2a/RBVpatients with HCV genotype-1 infection previously treated with PEGIFN/RBV12, 24, or 48 wk simeprevir with 48 wk PEGIFN/RBV significantly increased rates of SVR and was generally well tolerated. Depression occurred in 2/396 simeprevir patients
Jacobson et al[81]394Phase 3, randomized, double blind, placebo controlled multicenter clinical trialSimeprevir, PEGIFN-α-2a/RBVTreatment naïve patients with HCV genotype 1Simeprevir with PEGIFN-α-2a/RBV shortens therapy without worsening the adverse event profiles associated with PEGIFN
Manns et al[82]257Phase 3 multicenter randomized, placebo controlled clinical trialSimeprevir PEGIFN-α-2a or 2b/RBVTreatment-naive patients with HCV genotype 1 infectionAddition of simeprevir to PEGIFN-α-2a or PEGIFN-α-2b plus RBV improved SVR without worsening the known adverse events associated with peginterferon
Kumada et al[83]79Open label non comparative multicenter trialSimeprevir PEGIFN-α-2b/RBVHCV genotype 1 - treatment-naïve or had previously received IFN-based therapySimeprevir combined with PEGIFN-α-2b/RBV was effective across both groups. One patient in the control group receiving standard therapy alone discontinued due to grade 2 depression
Table 10 Sofosbuvir
Kowdley et al[86]316Multicenter, open label, phase 2 clinical trialSofosbuvir-2a PEGIFN-α-2a/RBVHCV genotype 1 - non-cirrhotic treatment-naive, patientsSVR occurred in 90% of patients treated with sofosbuvir and PEGIFN/RBV for 12 wk. Depression occurred in 8%-16% of patients across all groups but was not a primary reason for discontinuation
Lawitz et al[87]147Two-cohort, phase 2, placebo controlled, clinical trialSofosbuvir PEGIFN/RBVTreatment-naive patients with genotype 1-3 HCV infectionSVR occurred in 90% of patients treated with sofosbuvir and PEGIFN/RBV and the side effects profile was similar to that of PEGIFN/RBV and did not include depression. Depression was not a significant adverse event in this study
Jacobson et al[85]240Phase 3 randomized placebo controlled clinical trialsSofosbuvir RBVChronic HCV genotype 2 or 3 previously unable to be treated with IFN, or previously treated with IFN-based therapiesSofosbuvir and RBV was effective at 12 wk for genotype 2 and 16 wk for genotype 3. Premature discontinuation of the study drug due to adverse events was uncommon in all groups. Depression was not a significant adverse event in this study
Gane et al[84]75Open label randomized clinical trialSofosbuvir, RBVHCV genotype 2 or 3 infection. with no response to prior treatment or with no prior treatmentSofosbuvir plus RBV for 12 wk was effective for patients with genotype 1, 2, or 3 infections. Insomnia occurred in 30%-67% of participants across groups and was the only significant psychiatric symptom to develop during treatment
Table 11 Newer medications and interferon free therapies
Pol et al[92]48Double blind parallel group, dose finding phase 2a randomized, placebo controlled clinical trialDaclatasvir PEGIFN-α-2a/RBVHCV genotype 1 - treatment-naive (without cirrhosis)Daclatasvir increases the antiviral potency of PEGIFN/RBV without increasing the side effects profile. Psychiatric adverse events were not significant in this study
Chayama et al[91]10Open label phase 2a clinical trialDaclatasvir asunaprevirChronic HCV genotype 1b - previous null responders to PEGINF/RBVDual therapy with daclatasvir and asunaprevir alone can achieve high rates of SVR in difficult-to-treat patients and has minimal side effects
Herbst et al[90]-Retrospective literature review of phase 1 to phase 3 clinical trialsDaclatasvirAll genotypes; treatment naive and experienced cohortsDaclatasvir has a potent antiviral effect and clinical efficacy across genotypes and in both treatment naive and experienced cohorts with no evidence of psychiatric adverse events
Suzuki et al[94]43Open label phase 2a clinical trialDaclatasvir asunaprevirHCV genotype 1b for patients with limited treatment options including those with complications of depressionDual therapy with daclatasvir and asunaprevir was well tolerated and achieved high SVR rates. The adverse event profile was favorable; no psychiatric abnormalities were reported
Zeuzem et al[88]394Phase 3 placebo controlled randomized clinical trialABT-450 ritonavir (ABT-450/r), ombitasvir (ABT-267) dasabuvir (ABT-333) RBVRetreatment of HCV in patients who were previously treated with peginterferon-ribavirinRates of response to a 12-wk IFN-free combination regimen were more than 95%. Psychiatric adverse events were not reported
Andreone et al[89]179Phase 3 open label randomized clinical trialABT-450, ritonavir, ombitasvir, dasabuvir RBVHCV genotype 1b - treatment experienced patientsABT-450, ritonavir, ombitasvir, and dasabuvir, with or without RBV, produced a high rate of SVR. Both regimens were well tolerated with minimal adverse events
Sulkowski et al[93]167Two part, open label clinical trialDaclatasvir sofosbuvirHCV genotype 1, 2, or 3Daclatasvir plus sofosbuvir was associated with high rates of SVR. Psychiatric problems were not listed as significant adverse events
Afdhal et al[96]865Phase 3, open-label randomized clinical trialLedipasvir sofosbuvir RBVHCV genotype 1 - treatment naiveLedipasvir–sofosbuvir with or without RBV for 12 or 24 wk was highly effective. The most common adverse events were fatigue, headache, Insomnia, and nausea
Lawitz et al[98]100Open label randomized clinical trialSofosbuvir ledipasvir RBVHCV genotype 1 - treatment-naive or previously treated with a protease-inhibitor regimenSofosbuvir-ledipasvir alone or with RBV has the potential to cure most patients with genotype-1. Psychiatric symptoms were not a listed as significant adverse events
Afdhal et al[95]440Phase 3, randomized, open-label clinical trialLedipasvir sofosbuvir RBVHCV genotype 1 - previously treatedTreatment with ledipasvir and sofosbuvir resulted in high rates of SVR. Neuropsychiatric side effects were minimal, but were observed more frequently among groups with the RBV-containing regimen than ledipasvir sofosbuvir alone
Kowdley et al[97]647Phase 3, open label clinical trialSofosbuvir ledipasvirHCV genotype 1 - treatment naiveLedipasvir-sofosbuvir was associated with a high rate of SVR. Adverse events were more common in the group that received RBV. No additional benefit was associated with the inclusion of RBV