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Hepatitis C infection, antiviral treatment and mental health: A European expert consensus statement

Published:August 09, 2012DOI:https://doi.org/10.1016/j.jhep.2012.07.037

      Summary

      Mental health problems frequently occur in chronic infection with the hepatitis C virus (HCV) and during antiviral treatment with pegylated interferon-alpha (PegIFNα) and ribavirin. Depression is one of the most important complications during antiviral treatment of chronic hepatitis C infection. However, an increased prevalence of depression, fatigue, and cognitive disturbances has also been reported in untreated HCV-positive patients. Patients with psychiatric disorders or drug addiction also have an increased risk of HCV infection. Furthermore, because of possible drug–drug interactions, new antivirals administered together with PegIFNα and ribavirin may complicate psychiatric side effect management, even if no specific psychiatric adverse events are known so far for these new drugs.
      The European liver patient’s organization (ELPA) organised a European expert conference to review the literature and develop expert recommendations for the management of mental health problems in HCV infected patients.
      This paper results from the output of the 2011 EASL meeting and subsequent dialogue with patient groups and relevant experts in Europe. It summarises the current knowledge of HCV infection and the brain; prevalence, course, and neurobiology of IFN-α associated psychiatric side effects; possible risk factors for IFN-α associated depression and suicide attempts; psychiatric management of HCV infected patients before and during antiviral treatment; prevention of IFN- α associated psychiatric side effects; and psychiatric aspects of the new antivirals.
      The summarised current knowledge about mental health changes before and during antiviral treatment should improve interdisciplinary management of HCV infected patients.

      Keywords

      Introduction

      An estimated 170 million people are infected with the hepatitis C virus (HCV) worldwide. HCV infection is the most frequent cause of chronic hepatitis and an important risk factor for liver cirrhosis and hepatocellular carcinoma. There is an increased prevalence of psychiatric co-morbidity in patients with chronic HCV infection and emerging evidence suggests that mental health problems may be associated with the infection itself, possibly mediated by an effect on the central nervous system (CNS). In addition, antiviral combination therapy with PegIFNα and ribavirin is often associated with significant psychiatric side effects, such as depression, fatigue, insomnia, anxiety, cognitive disturbances [
      • Dieperink E.
      • Willenbring M.
      • Ho S.B.
      Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a review.
      ,
      • Schaefer M.
      • Engelbrecht M.A.
      • Gut O.
      • Fiebich B.L.
      • Bauer J.
      • Schmidt F.
      • et al.
      Interferon alpha (IFNalpha) and psychiatric syndromes: a review.
      ] or suicide attempts, which represent the worst possible complication of severe depressive syndromes [
      • Sockalingam S.
      • Links P.S.
      • Abbey S.E.
      Suicide risk in hepatitis C and during interferon-alpha therapy: a review and clinical update.
      ]. Mental health problems during antiviral treatment have a strong impact on quality of life, may reduce treatment compliance and are risk factors for treatment failure [
      • Raison C.L.
      • Borisov A.S.
      • Broadwell S.D.
      • Capuron L.
      • Woolwine B.J.
      • Jacobson I.M.
      • et al.
      Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction.
      ,
      • Schafer A.
      • Wittchen H.U.
      • Seufert J.
      • Kraus M.R.
      Methodological approaches in the assessment of interferon-alfa-induced depression in patients with chronic hepatitis C – a critical review.
      ,
      • Leutscher P.D.
      • Lagging M.
      • Buhl M.R.
      • Pedersen C.
      • Norkrans G.
      • Langeland N.
      • et al.
      Evaluation of depression as a risk factor for treatment failure in chronic hepatitis C.
      ]. Research over recent years has sought to increase knowledge about the frequency, course, and pathophysiology of mental health problems during chronic HCV infection and antiviral therapy with PegIFNα and ribavirin. Different management strategies for the acute treatment or for the prevention of psychiatric problems have been developed to avoid dose reduction or treatment discontinuation. However, to date there has not been an international, interdisciplinary consensus regarding the current knowledge of mental health problems during HCV infection and treatment-related psychiatric problems. At the 2011 EASL meeting, the European liver patient’s organization (ELPA) initiated a European expert consensus conference to review the current available scientific data on HCV and treatment-related psychiatric effects, in order to produce recommendations for the psychiatric management of patients before, during and after hepatitis C treatment.

      Methods

      The European expert consensus group consisted of four hepatologists, five clinical psychiatrists and/or neurobiologists, from Europe, and a member of ELPA. Consensus was based on current available clinical trials and other evidence published in the English language to March 2011, and the clinical experience of the consensus group. The following questions were discussed: (1) Does a chronic HCV infection affect the brain? (2) What is known about the prevalence, course, and neurobiology of IFN-α associated psychiatric side effects? (3) What are the risk factors for IFN-α associated depression and suicide attempts? (4) What should be done with HCV infected patients before antiviral treatment is started? (5) What is known about possible management of psychiatric problems during antiviral treatment? Can IFN-α -associated psychiatric side effects be prevented? (6) How will new antivirals influence psychiatric side effects of IFN-α and patients management? The Delphi-technique, requiring agreement of at least 80% of the group was employed. The level of evidence and recommendations follows the EASL system adapted from the GRADE system [
      EASL Clinical Practice Guidelines
      Management of hepatitis C virus infection.
      ] (Table 1). Results from the consensus meeting were additionally presented in two international symposia (EASL conference, Berlin, 2011 and INHSU, Brussels, 2011) and further discussed together with professionals and patients. Subsequent important publications that significantly influenced the recommendations were further discussed in the group and included in this final version of the paper.
      Table 1Evidence grading (adapted from the GRADE system)
      EASL Clinical Practice Guidelines
      Management of hepatitis C virus infection.
      .

      Results and recommendations

      HCV and the brain

      Psychiatric co-morbidity has been reported to occur frequently in patients with chronic HCV infection, with a higher incidence of depressive symptoms, bipolar symptoms, anxiety, fatigue, psychotic symptoms, alcoholism, and drug abuse (Fig. 1). Cognitive disturbances have also been frequently reported [
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      • Heeren M.
      • Arvanitis D.
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      Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy.
      ,
      • Forton D.M.
      • Hamilton G.
      • Allsop J.M.
      • Grover V.P.
      • Wesnes K.
      • O’Sullivan C.
      • et al.
      Cerebral immune activation in chronic hepatitis C infection: a magnetic resonance spectroscopy study.
      ,
      • Hilsabeck R.C.
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      ,
      • Lowry D.
      • Coughlan B.
      • McCarthy O.
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      Investigating health-related quality of life, mood and neuropsychological test performance in a homogeneous cohort of Irish female hepatitis C patients.
      ,
      • Weissenborn K.
      • Krause J.
      • Bokemeyer M.
      • Hecker H.
      • Schuler A.
      • Ennen J.C.
      • et al.
      Hepatitis C virus infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy.
      ].The higher rate of psychiatric disorders in HCV infected populations may be related to a higher risk of HCV infection in psychiatric patients but may also be the consequence of a direct or indirect effect of HCV on the central nervous system (CNS). Whilst the prevalence of HCV infection in the European general population is approximately 2%, the prevalence in psychiatric populations has been found to be between 6.7% and 8.5%; patients with intravenous drug abuse have the highest risk, with a prevalence between 30% and 98% [
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      ]. This is related to increased high risk behaviour, such as intravenous drug abuse, but also to other risk factors such as long-term hospitalisation [
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      ].
      Figure thumbnail gr1
      Fig. 1Increased prevalence of psychiatric co-morbidity in HCV infected populations. Prevalence rates of psychiatric diseases in HCV infected patients were obtained from several publications and mean and standard deviation for prevalence rates were calculated for each disease. Results are based on 10 studies for major depression [
      • El Serag H.B.
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      Psychiatric disorders among veterans with hepatitis C infection.
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      ,
      • Dwight M.M.
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      • Larson A.M.
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      ,
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      • Almeida A.G.
      • Bressan R.A.
      • Lacerda A.L.
      • De-Oliveira I.R.
      • et al.
      High frequency of unrecognized mental disorders in HCV-infected patients.
      ,
      • Butt A.A.
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      Comorbid medical and psychiatric conditions and substance abuse in HCV infected persons on dialysis.
      ,
      • Golden J.
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      ,
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      ], 7 studies for anxiety disorders [
      • El Serag H.B.
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      ,
      • Kraus M.R.
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      ,
      • Dwight M.M.
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      • Larson A.M.
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      ,
      • Batista-Neves S.C.
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      • Almeida A.G.
      • Bressan R.A.
      • Lacerda A.L.
      • De-Oliveira I.R.
      • et al.
      High frequency of unrecognized mental disorders in HCV-infected patients.
      ,
      • Golden J.
      • O’Dwyer A.M.
      • Conroy R.M.
      Depression and anxiety in patients with hepatitis C: prevalence, detection rates and risk factors.
      ,
      • Yovtcheva S.P.
      • Rifai M.A.
      • Moles J.K.
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      Psychiatric co-morbidity among hepatitis C-positive patients.
      ,
      • Lehman C.L.
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      ], 6 studies for bipolar disorder [
      • El Serag H.B.
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      • Rabeneck L.
      Psychiatric disorders among veterans with hepatitis C infection.
      ,
      • Butt A.A.
      • Khan U.A.
      • McGinnis K.A.
      • Skanderson M.
      • Kent K.C.
      Co-morbid medical and psychiatric illness and substance abuse in HCV-infected and uninfected veterans.
      ,
      • Butt A.A.
      • Evans R.
      • Skanderson M.
      • Shakil A.O.
      Comorbid medical and psychiatric conditions and substance abuse in HCV infected persons on dialysis.
      ,
      • Lim J.K.
      • Cronkite R.
      • Goldstein M.K.
      • Cheung R.C.
      The impact of chronic hepatitis C and comorbid psychiatric illnesses on health-related quality of life.
      ,
      • Yovtcheva S.P.
      • Rifai M.A.
      • Moles J.K.
      • Van der Linden B.J.
      Psychiatric co-morbidity among hepatitis C-positive patients.
      ,
      • Fireman M.
      • Indest D.W.
      • Blackwell A.
      • Whitehead A.J.
      • Hauser P.
      Addressing tri-morbidity (hepatitis C, psychiatric disorders, and substance use): the importance of routine mental health screening as a component of a comanagement model of care.
      ], 7 studies for schizophrenia [
      • El Serag H.B.
      • Kunik M.
      • Richardson P.
      • Rabeneck L.
      Psychiatric disorders among veterans with hepatitis C infection.
      ,
      • Butt A.A.
      • Khan U.A.
      • McGinnis K.A.
      • Skanderson M.
      • Kent K.C.
      Co-morbid medical and psychiatric illness and substance abuse in HCV-infected and uninfected veterans.
      ,
      • Butt A.A.
      • Evans R.
      • Skanderson M.
      • Shakil A.O.
      Comorbid medical and psychiatric conditions and substance abuse in HCV infected persons on dialysis.
      ,
      • Nguyen H.A.
      • Miller A.I.
      • Dieperink E.
      • Willenbring M.
      • Tetrick L.
      • Durfee J.M.
      • et al.
      Spectrum of disease in U.S. veteran patients with hepatitis C.
      ,
      • Yovtcheva S.P.
      • Rifai M.A.
      • Moles J.K.
      • Van der Linden B.J.
      Psychiatric co-morbidity among hepatitis C-positive patients.
      ,
      • Fireman M.
      • Indest D.W.
      • Blackwell A.
      • Whitehead A.J.
      • Hauser P.
      Addressing tri-morbidity (hepatitis C, psychiatric disorders, and substance use): the importance of routine mental health screening as a component of a comanagement model of care.
      ], 9 studies for alcohol abuse [
      • El Serag H.B.
      • Kunik M.
      • Richardson P.
      • Rabeneck L.
      Psychiatric disorders among veterans with hepatitis C infection.
      ,
      • Butt A.A.
      • Khan U.A.
      • McGinnis K.A.
      • Skanderson M.
      • Kent K.C.
      Co-morbid medical and psychiatric illness and substance abuse in HCV-infected and uninfected veterans.
      ,
      • Dwight M.M.
      • Kowdley K.V.
      • Russo J.E.
      • Ciechanowski P.S.
      • Larson A.M.
      • Katon W.J.
      Depression, fatigue, and functional disability in patients with chronic hepatitis C.
      ,
      • Batista-Neves S.C.
      • Quarantini L.C.
      • Almeida A.G.
      • Bressan R.A.
      • Lacerda A.L.
      • De-Oliveira I.R.
      • et al.
      High frequency of unrecognized mental disorders in HCV-infected patients.
      ,
      • Butt A.A.
      • Evans R.
      • Skanderson M.
      • Shakil A.O.
      Comorbid medical and psychiatric conditions and substance abuse in HCV infected persons on dialysis.
      ,
      • Lim J.K.
      • Cronkite R.
      • Goldstein M.K.
      • Cheung R.C.
      The impact of chronic hepatitis C and comorbid psychiatric illnesses on health-related quality of life.
      ,
      • Nelligan J.A.
      • Loftis J.M.
      • Matthews A.M.
      • Zucker B.L.
      • Linke A.M.
      • Hauser P.
      Depression co-morbidity and antidepressant use in veterans with chronic hepatitis C: results from a retrospective chart review.
      ,
      • Nguyen H.A.
      • Miller A.I.
      • Dieperink E.
      • Willenbring M.
      • Tetrick L.
      • Durfee J.M.
      • et al.
      Spectrum of disease in U.S. veteran patients with hepatitis C.
      ,
      • Yovtcheva S.P.
      • Rifai M.A.
      • Moles J.K.
      • Van der Linden B.J.
      Psychiatric co-morbidity among hepatitis C-positive patients.
      ], 7 studies for other drug use [
      • El Serag H.B.
      • Kunik M.
      • Richardson P.
      • Rabeneck L.
      Psychiatric disorders among veterans with hepatitis C infection.
      ,
      • Butt A.A.
      • Khan U.A.
      • McGinnis K.A.
      • Skanderson M.
      • Kent K.C.
      Co-morbid medical and psychiatric illness and substance abuse in HCV-infected and uninfected veterans.
      ,
      • Dwight M.M.
      • Kowdley K.V.
      • Russo J.E.
      • Ciechanowski P.S.
      • Larson A.M.
      • Katon W.J.
      Depression, fatigue, and functional disability in patients with chronic hepatitis C.
      ,
      • Butt A.A.
      • Evans R.
      • Skanderson M.
      • Shakil A.O.
      Comorbid medical and psychiatric conditions and substance abuse in HCV infected persons on dialysis.
      ,
      • Nelligan J.A.
      • Loftis J.M.
      • Matthews A.M.
      • Zucker B.L.
      • Linke A.M.
      • Hauser P.
      Depression co-morbidity and antidepressant use in veterans with chronic hepatitis C: results from a retrospective chart review.
      ,
      • Nguyen H.A.
      • Miller A.I.
      • Dieperink E.
      • Willenbring M.
      • Tetrick L.
      • Durfee J.M.
      • et al.
      Spectrum of disease in U.S. veteran patients with hepatitis C.
      ,
      • Yovtcheva S.P.
      • Rifai M.A.
      • Moles J.K.
      • Van der Linden B.J.
      Psychiatric co-morbidity among hepatitis C-positive patients.
      ], and 5 studies for fatigue [
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      ,
      • Barkhuizen A.
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      ,
      • Kenny-Walsh E.
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      ,
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      ].
      There is also evidence that HCV infection itself may be directly associated with psychiatric symptoms, independent of pre-existing psychiatric disorders. Stigmatisation and the fact that patients have to cope with a chronic infectious disorder increase the risk of depression and anxiety [
      • Schafer A.
      • Scheurlen M.
      • Felten M.
      • Kraus M.R.
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      ]. A relationship between duration of HCV infection and severity of depressive symptoms or anxiety has been reported [
      • Kraus M.R.
      • Schafer A.
      • Csef H.
      • Scheurlen M.
      • Faller H.
      Emotional state, coping styles, and somatic variables in patients with chronic hepatitis C.
      ]. Furthermore, major depression has been reported to occur more frequently in HCV than in HBV infected patients, independent of drug or alcohol abuse, suggesting a specific association between HCV infection and the development of depression [
      • Carta M.G.
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      ]. Fatigue, which is the commonest symptom in HCV infection, is unrelated to the severity of liver disease and occurs more frequently in HCV than HBV infected patients; it also improves after successful antiviral treatment [
      • Cacoub P.
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      ]. Fatigue may be the greatest determinant of reduced health-related quality of life in HCV infection [
      • Foster G.R.
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      ]. Cognitive impairment has been reported in HCV infected patients with only minimal liver disease, independent of psychiatric co-morbidity or addiction disorder [
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      Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy.
      ,
      • Lowry D.
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      • McCarthy O.
      • Crowe J.
      Investigating health-related quality of life, mood and neuropsychological test performance in a homogeneous cohort of Irish female hepatitis C patients.
      ,
      • Forton D.M.
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      ]. A small study showed that patients who were successfully treated for HCV had less cognitive impairment than HCV-positive patients [
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      ].
      A number of studies now support the hypothesis that HCV directly or indirectly induces biological changes in the CNS, which may result in psychiatric symptoms. Studies using proton magnetic resonance spectroscopy showed changes in the cerebral choline/creatine ratio [
      • Forton D.M.
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      ], in the N-acetylaspartate/creatine ratio [
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      • Hecker H.
      • Schuler A.
      • Ennen J.C.
      • et al.
      Hepatitis C virus infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy.
      ], in the Myo-inositol/creatine ratio [
      • Forton D.M.
      • Hamilton G.
      • Allsop J.M.
      • Grover V.P.
      • Wesnes K.
      • O’Sullivan C.
      • et al.
      Cerebral immune activation in chronic hepatitis C infection: a magnetic resonance spectroscopy study.
      ], and in choline, creatine, N-acetylaspartate, and N-acetyl-aspartyl-glutamate concentrations [
      • Bokemeyer M.
      • Ding X.Q.
      • Goldbecker A.
      • Raab P.
      • Heeren M.
      • Arvanitis D.
      • et al.
      Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy.
      ], suggesting an altered metabolism consistent with cerebral immune activation. Reduced dopamine transporter and serotonin transporter binding has also been reported in HCV patients, that was associated with cognitive dysfunction [
      • Weissenborn K.
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      • Tillmann H.
      • et al.
      Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment.
      ]. Moreover, a recent PET study using PK11195, a peripheral benzodiazepine receptor ligand, has shown increased caudate nucleus binding in HCV patients, consistent with microglial activation [
      • Grover V.P.
      • Pavese N.
      • Koh S.B.
      • Wylezinska M.
      • Saxby B.K.
      • Gerhard A.
      • et al.
      Cerebral microglial activation in patients with hepatitis C: in vivo evidence of neuroinflammation.
      ]. The mechanism and significance of these findings have not been defined but there is accumulating virological data to suggest that HCV may penetrate into the CNS and replicate, possibly at a very low level [
      • Fishman S.L.
      • Murray J.M.
      • Eng F.J.
      • Walewski J.L.
      • Morgello S.
      • Branch A.D.
      Molecular and bioinformatic evidence of hepatitis C virus evolution in brain.
      ,
      • Fletcher N.F.
      • Wilson G.K.
      • Murray J.
      • Hu K.
      • Lewis A.
      • Reynolds G.M.
      • et al.
      Hepatitis C virus infects the endothelial cells of the blood–brain barrier.
      ,
      • Forton D.M.
      • Karayiannis P.
      • Mahmud N.
      • Taylor-Robinson S.D.
      • Thomas H.C.
      Identification of unique hepatitis C virus quasispecies in the central nervous system and comparative analysis of internal translational efficiency of brain, liver, and serum variants.
      ,
      • Wilkinson J.
      • Radkowski M.
      • Laskus T.
      Hepatitis C virus neuroinvasion: identification of infected cells.
      ,
      • Wilkinson J.
      • Radkowski M.
      • Eschbacher J.M.
      • Laskus T.
      Activation of brain macrophages/microglia cells in hepatitis C infection.
      ]. Putative biological pathways have been proposed by which hepatitis C might lead to psychiatric symptoms but causality has not been clearly demonstrated and more data are needed, particularly to evaluate reversibility with successful antiviral treatment.
      Figure thumbnail fx4

      Prevalence, course, and neurobiology of interferon-α-induced neuropsychiatric side effects

      Prevalence

      Depression is a common side effect of IFN-α treatment. Overall, depression during IFN-α treatment develops in 30–70% of the treated patients. This prevalence rate depends on the methods of assessment (i.e., diagnostic interview, clinical evaluation, self-reports, observer-rated scales), the time of evaluation and the severity of depression. For instance, it is estimated that mild to moderate depression develops in 45–60% of the patients treated with IFN-α, moderate to severe depression in 15–40%, and major depression in 15–45% [
      • Schaefer M.
      • Engelbrecht M.A.
      • Gut O.
      • Fiebich B.L.
      • Bauer J.
      • Schmidt F.
      • et al.
      Interferon alpha (IFNalpha) and psychiatric syndromes: a review.
      ,
      • Raison C.L.
      • Borisov A.S.
      • Broadwell S.D.
      • Capuron L.
      • Woolwine B.J.
      • Jacobson I.M.
      • et al.
      Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction.
      ,
      • Kraus M.R.
      • Schafer A.
      • Csef H.
      • Scheurlen M.
      Psychiatric side effects of pegylated interferon alfa-2b as compared to conventional interferon alfa-2b in patients with chronic hepatitis C.
      ,
      • Musselman D.L.
      • Lawson D.H.
      • Gumnick J.F.
      • Manatunga A.K.
      • Penna S.
      • Goodkin R.S.
      • et al.
      Paroxetine for the prevention of depression induced by high-dose interferon alfa.
      ,
      • Raison C.L.
      • Demetrashvili M.
      • Capuron L.
      • Miller A.H.
      Neuropsychiatric adverse effects of interferon-alpha: recognition and management.
      ,
      • Schaefer M.
      • Schmidt F.
      • Folwaczny C.
      • Lorenz R.
      • Martin G.
      • Schindlbeck N.
      • et al.
      Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups.
      ,
      • Schaefer M.
      • Hinzpeter A.
      • Mohmand A.
      • Janssen G.
      • Pich M.
      • Schwaiger M.
      • et al.
      Hepatitis C treatment in “difficult-to-treat” psychiatric patients with pegylated interferon-alpha and ribavirin: response and psychiatric side effects.
      ]. Treatment options such as standard vs. pegylated (PEG) IFN-α, types of PegIFNα2a vs. 2b and associated ribavirin do not seem to have a significant influence.
      In addition to depression, IFN-α is also associated with the occurrence of a wide range of other neuropsychiatric symptoms (Table 2). Fatigue represents probably the most prominent side effect as it develops in up to 80% of the patients. Sleep alterations, irritability, anxiety, and cognitive disturbances may occur in up to 50% of the patients. In contrast, mania, and psychosis represent more rare adverse events of IFN-α treatment, developing in up to 3% of the patients. Finally, whereas suicidal thoughts have been reported in up to 10% of the patients undergoing IFN-α therapy, case reports of suicide or suicidal attempts remain only anecdotal. The incidence of depression and impaired quality of life appears greater in IFN-α treatment of HCV infection compared to treatment of chronic hepatitis B infection [
      • Marcellin P.
      • Lau G.K.
      • Zeuzem S.
      • Heathcote E.J.
      • Pockros P.J.
      • Reddy K.R.
      • et al.
      Comparing the safety, tolerability and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alpha-2a.
      ].
      Table 2Prevalence of IFN-α associated side effects. (
      • Davis J.M.
      • Weaver J.A.
      • Kohut M.L.
      • Colbert L.H.
      • Ghaffar A.
      • Mayer E.P.
      Immune system activation and fatigue during treadmill running: role of interferon.
      ,
      • McHutchison J.G.
      • Gordon S.C.
      • Schiff E.R.
      • Shiffman M.L.
      • Lee W.M.
      • Rustgi V.K.
      • et al.
      Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group.
      ,
      • Sockalingam S.
      • Abbey S.E.
      • Alosaimi F.
      • Novak M.
      A review of sleep disturbance in hepatitis C.
      ,
      • Zeuzem S.
      • Feinman S.V.
      • Rasenack J.
      • Heathcote E.J.
      • Lai M.Y.
      • Gane E.
      • et al.
      Peginterferon alfa-2a in patients with chronic hepatitis C.
      ,
      • Constant A.
      • Castera L.
      • Dantzer R.
      • Couzigou P.
      • de Ledinghen V.
      • Demotes-Mainard J.
      • et al.
      Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms.
      ,
      • Kraus M.R.
      • Schafer A.
      • Faller H.
      • Csef H.
      • Scheurlen M.
      Psychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy.
      ,
      • Martin-Santos R.
      • Diez-Quevedo C.
      • Castellvi P.
      • Navines R.
      • Miquel M.
      • Masnou H.
      • et al.
      De novo depression and anxiety disorders and influence on adherence during peginterferon-alpha-2a and ribavirin treatment in patients with hepatitis C.
      ,
      • Fontana R.J.
      • Bieliauskas L.A.
      • Lindsay K.L.
      • Back-Madruga C.
      • Wright E.C.
      • Snow K.K.
      • et al.
      Cognitive function does not worsen during pegylated interferon and ribavirin retreatment of chronic hepatitis C.
      ,
      • Horikawa N.
      • Yamazaki T.
      • Izumi N.
      • Uchihara M.
      Incidence and clinical course of major depression in patients with chronic hepatitis type C undergoing interferon-alpha therapy: a prospective study.
      ,
      • Hosoda S.
      • Takimura H.
      • Shibayama M.
      • Kanamura H.
      • Ikeda K.
      • Kumada H.
      Psychiatric symptoms related to interferon therapy for chronic hepatitis C: clinical features and prognosis.
      ,
      • Dieperink E.
      • Ho S.B.
      • Tetrick L.
      • Thuras P.
      • Dua K.
      • Willenbring M.L.
      Suicidal ideation during interferon-alpha2b and ribavirin treatment of patients with chronic hepatitis C.
      ,
      • Evon D.M.
      • Ramcharran D.
      • Belle S.H.
      • Terrault N.A.
      • Fontana R.J.
      • Fried M.W.
      Prospective analysis of depression during peginterferon and ribavirin therapy of chronic hepatitis C: results of the Virahep-C study.
      ,
      • Yu M.L.
      • Dai C.Y.
      • Lee L.P.
      • Hsieh M.Y.
      • Hou N.J.
      • Huang J.F.
      • et al.
      Outcome of chronic hepatitis C patients who required early termination of pegylated interferon-alpha plus ribavirin combination therapy.
      ,
      • Fattovich G.
      • Giustina G.
      • Favarato S.
      • Ruol A.
      A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon.
      ,
      • Janssen H.L.
      • Brouwer J.T.
      • van der Mast R.C.
      • Schalm S.W.
      Suicide associated with alfa-interferon therapy for chronic viral hepatitis.
      ,
      • Renault P.F.
      • Hoofnagle J.H.
      • Park Y.
      • Mullen K.D.
      • Peters M.
      • Jones D.B.
      • et al.
      Psychiatric complications of long-term interferon alfa therapy.
      )

      Time course

      Dimensional analyses of symptoms developing during IFN-α treatment have revealed differential time courses for the neuro-vegetative/somatic vs. mood/cognitive symptoms. Neurovegetative and somatic symptoms, including fatigue, decreased appetite, pain, and gastrointestinal disorders, develop at early stages of treatment, usually as soon as the first weeks of therapy [
      • Capuron L.
      • Gumnick J.F.
      • Musselman D.L.
      • Lawson D.H.
      • Reemsnyder A.
      • Nemeroff C.B.
      • et al.
      Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions.
      ]. These symptoms appear in a majority of patients treated with IFN-α and they remain persistent during the whole duration of treatment. Mood and cognitive symptoms, including depressive symptoms, anhedonia, memory disturbances and concentration problems, develop in a smaller proportion of patients (15–50%) and at later stages of treatment, usually after week 4 of therapy, with a greater intensity of depressive symptoms after week 8 [
      • Musselman D.L.
      • Lawson D.H.
      • Gumnick J.F.
      • Manatunga A.K.
      • Penna S.
      • Goodkin R.S.
      • et al.
      Paroxetine for the prevention of depression induced by high-dose interferon alfa.
      ,
      • Capuron L.
      • Gumnick J.F.
      • Musselman D.L.
      • Lawson D.H.
      • Reemsnyder A.
      • Nemeroff C.B.
      • et al.
      Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions.
      ,
      • Capuron L.
      • Miller A.H.
      Immune system to brain signaling: neuropsychopharmacological implications.
      ]. Most neuropsychiatric side effects appear between weeks 10 and 24 of IFN-α treatment and some of them may persist until the end of antiviral therapy [
      • Hadziyannis S.J.
      • Sette Jr., H.
      • Morgan T.R.
      • Balan V.
      • Diago M.
      • Marcellin P.
      • et al.
      Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.
      ,
      • Reichenberg A.
      • Gorman J.M.
      • Dieterich D.T.
      Interferon-induced depression and cognitive impairment in hepatitis C virus patients: a 72 week prospective study.
      ]. Whilst most of the neuropsychiatric effects resolve with treatment cessation, cases of persistent, recurring or new developing symptoms have been described [
      • Gohier B.
      • Goeb J.L.
      • Rannou-Dubas K.
      • Fouchard I.
      • Cales P.
      • Garre J.B.
      • et al.
      Hepatitis C, alpha interferon, anxiety and depression disorders: a prospective study of 71 patients.
      ,
      • Nickel T.
      • Sonntag A.
      • Backmund M.
      • Pollmacher T.
      Depression during therapy with interferon alpha – how long should an antidepressant treatment last?.
      ].

      Neurobiology

      Recent advances have been made in the identification of mechanisms leading to neuropsychiatric toxicity in patients treated with IFN-α. Whilst multiple mechanisms have been proposed, this section will focus on two major aetiological pathways, corresponding respectively to alterations in monoamine metabolism and impaired neuroendocrine function. Experimental studies have shown that IFN-α is able to alter the synthesis, transport system, and turnover of monoamines [
      • Kamata M.
      • Higuchi H.
      • Yoshimoto M.
      • Yoshida K.
      • Shimizu T.
      Effect of single intracerebroventricular injection of alpha-interferon on monoamine concentrations in the rat brain.
      ,
      • Kitagami T.
      • Yamada K.
      • Miura H.
      • Hashimoto R.
      • Nabeshima T.
      • Ohta T.
      Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood–brain barrier.
      ,
      • Sato T.
      • Suzuki E.
      • Yokoyama M.
      • Semba J.
      • Watanabe S.
      • Miyaoka H.
      Chronic intraperitoneal injection of interferon-alpha reduces serotonin levels in various regions of rat brain, but does not change levels of serotonin transporter mRNA, nitrite or nitrate.
      ,
      • Shuto H.
      • Kataoka Y.
      • Horikawa T.
      • Fujihara N.
      • Oishi R.
      Repeated interferon-alpha administration inhibits dopaminergic neural activity in the mouse brain.
      ]. Moreover, recent data indicate that immune mediators, including IFN-α, induce significant alterations in enzymatic pathways involved in the metabolism of major neurotransmitters, including serotonin, dopamine, and norepinephrine [
      • Capuron L.
      • Schroecksnadel S.
      • Feart C.
      • Aubert A.
      • Higueret D.
      • Barberger-Gateau P.
      • et al.
      Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: role in neuropsychiatric symptoms.
      ,
      • Neurauter G.
      • Schrocksnadel K.
      • Scholl-Burgi S.
      • Sperner-Unterweger B.
      • Schubert C.
      • Ledochowski M.
      • et al.
      Chronic immune stimulation correlates with reduced phenylalanine turnover.
      ,
      • Widner B.
      • Ledochowski M.
      • Fuchs D.
      Interferon-gamma-induced tryptophan degradation: neuropsychiatric and immunological consequences.
      ]. These alterations involve the activation of the enzyme indoleamine-2,3-dioxygenase (IDO), which leads to the degradation of tryptophan into neurotoxic pathways [
      • Widner B.
      • Ledochowski M.
      • Fuchs D.
      Interferon-gamma-induced tryptophan degradation: neuropsychiatric and immunological consequences.
      ,
      • Byrne G.I.
      • Lehmann L.K.
      • Kirschbaum J.G.
      • Borden E.C.
      • Lee C.M.
      • Brown R.R.
      Induction of tryptophan degradation in vitro and in vivo: a gamma-interferon-stimulated activity.
      ], and impairment in the metabolism of tetrahydrobiopterin (BH4), the co-factor of tyrosine hydroxylase [
      • Widner B.
      • Ledochowski M.
      • Fuchs D.
      Interferon-gamma-induced tryptophan degradation: neuropsychiatric and immunological consequences.
      ,
      • Byrne G.I.
      • Lehmann L.K.
      • Kirschbaum J.G.
      • Borden E.C.
      • Lee C.M.
      • Brown R.R.
      Induction of tryptophan degradation in vitro and in vivo: a gamma-interferon-stimulated activity.
      ].
      Another mechanism underlying the neuropsychiatric effects of IFN-α involves changes in neuroendocrine function. In support of this notion, acute IFN-α administration in patients with malignant melanoma was found to stimulate the hypothalamo–pituitary–adrenal (HPA) axis, leading to a rapid increase in the secretion of the adrenocorticotropic hormone (ACTH) and cortisol [
      • Capuron L.
      • Raison C.L.
      • Musselman D.L.
      • Lawson D.H.
      • Nemeroff C.B.
      • Miller A.H.
      Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy.
      ]. Interestingly, this increased HPA axis reactivity to the acute administration of IFN-α was associated with the development of major depression at later stages of IFN-α treatment [
      • Capuron L.
      • Raison C.L.
      • Musselman D.L.
      • Lawson D.H.
      • Nemeroff C.B.
      • Miller A.H.
      Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy.
      ]. When IFN-α was delivered chronically, however, the activation of the HPA axis was not apparent anymore. Consistent with this data, IFN-α treatment for 12 weeks in patients with hepatitis C was found to be associated with a flattening of the diurnal ACTH and cortisol slopes [
      • Raison C.L.
      • Borisov A.S.
      • Woolwine B.J.
      • Massung B.
      • Vogt G.
      • Miller A.H.
      Interferon-alpha effects on diurnal hypothalamic–pituitary–adrenal axis activity: relationship with proinflammatory cytokines and behavior.
      ]. This effect may be related to impairment in corticosteroid receptor signalling, as inflammatory cytokines were found to disturb glucocorticoid receptor (GR) translocation and function, likely to be associated with GR resistance in relevant cell types [
      • Pace T.W.
      • Miller A.H.
      Cytokines and glucocorticoid receptor signaling. Relevance to major depression.
      ,
      • Pariante C.M.
      • Pearce B.D.
      • Pisell T.L.
      • Sanchez C.I.
      • Po C.
      • Su C.
      • et al.
      The proinflammatory cytokine, interleukin-1alpha, reduces glucocorticoid receptor translocation and function.
      ].
      Figure thumbnail fx5

      Risk factors for IFN-α induced depression or suicide

      Predicting the occurrence of psychiatric adverse effects is an important area of clinical research, as ultimately it could lead to prophylactic interventions only in those at risk. Clinical, genetic, and biomarker predictors have all been proposed. The following chapter will focus on ‘baseline factors’ that are measurable before starting IFN-α.

      Clinical risk factors

      Studies have demonstrated that patients with higher levels of baseline depressive symptoms have higher depression scores during IFN-α treatment, and hence are more likely to develop clinically significant depression. This has been shown for both viral hepatitis [
      • Raison C.L.
      • Borisov A.S.
      • Broadwell S.D.
      • Capuron L.
      • Woolwine B.J.
      • Jacobson I.M.
      • et al.
      Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction.
      ,
      • Gohier B.
      • Goeb J.L.
      • Rannou-Dubas K.
      • Fouchard I.
      • Cales P.
      • Garre J.B.
      • et al.
      Hepatitis C, alpha interferon, anxiety and depression disorders: a prospective study of 71 patients.
      ,
      • Pariante C.M.
      • Landau S.
      • Carpiniello B.
      Interferon alfa-induced adverse effects in patients with a psychiatric diagnosis.
      ] and cancer [
      • Capuron L.
      • Ravaud A.
      • Miller A.H.
      • Dantzer R.
      Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferon-alpha cancer therapy.
      ]. A personal history of major depression has also been found to be a risk factor, although this may be due to higher depressive baseline scores, rather than a specific effect [
      • Raison C.L.
      • Borisov A.S.
      • Broadwell S.D.
      • Capuron L.
      • Woolwine B.J.
      • Jacobson I.M.
      • et al.
      Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction.
      ]. Despite this, studies have demonstrated that patients with a pre-existing psychiatric diagnosis can have equivalent outcomes to patients without mental disorders with regard to viral response and treatment interruptions [
      • Schaefer M.
      • Schmidt F.
      • Folwaczny C.
      • Lorenz R.
      • Martin G.
      • Schindlbeck N.
      • et al.
      Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups.
      ,
      • Schaefer M.
      • Hinzpeter A.
      • Mohmand A.
      • Janssen G.
      • Pich M.
      • Schwaiger M.
      • et al.
      Hepatitis C treatment in “difficult-to-treat” psychiatric patients with pegylated interferon-alpha and ribavirin: response and psychiatric side effects.
      ,
      • Pariante C.M.
      • Landau S.
      • Carpiniello B.
      Interferon alfa-induced adverse effects in patients with a psychiatric diagnosis.
      ]. Baseline sleep disturbance is also a risk factor [
      • Gohier B.
      • Goeb J.L.
      • Rannou-Dubas K.
      • Fouchard I.
      • Cales P.
      • Garre J.B.
      • et al.
      Hepatitis C, alpha interferon, anxiety and depression disorders: a prospective study of 71 patients.
      ].

      Genetic risk factors

      Both brain- and immune-related genes have been tested in relationship to the onset of the psychopathology induced by IFN-α. The classical genetic risk factor for depression, the s allele of the short/long polymorphism in the serotonin transporter gene, has been found to be associated with depression in two studies [
      • Bull S.J.
      • Huezo-Diaz P.
      • Binder E.B.
      • Cubells J.F.
      • Ranjith G.
      • Maddock C.
      • et al.
      Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment.
      ,
      • Lotrich F.E.
      • Ferrell R.E.
      • Rabinovitz M.
      • Pollock B.G.
      Risk for depression during interferon-alpha treatment is affected by the serotonin transporter polymorphism.
      ] but not in two others [
      • Kraus M.R.
      • Al Taie O.
      • Schafer A.
      • Pfersdorff M.
      • Lesch K.P.
      • Scheurlen M.
      Serotonin-1A receptor gene HTR1A variation predicts interferon-induced depression in chronic hepatitis C.
      ,
      • Su K.P.
      • Huang S.Y.
      • Peng C.Y.
      • Lai H.C.
      • Huang C.L.
      • Chen Y.C.
      • et al.
      Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
      ]. The apolipoprotein E e4, a genetic variant also associated with neuropsychiatric disorders, has been shown to predict more depression, particularly irritability and anxiety during IFN-α [
      • Gochee P.A.
      • Powell E.E.
      • Purdie D.M.
      • Pandeya N.
      • Kelemen L.
      • Shorthouse C.
      • et al.
      Association between apolipoprotein E epsilon4 and neuropsychiatric symptoms during interferon alpha treatment for chronic hepatitis C.
      ]. A number of reports exist of an association between polymorphisms in immune genes and the occurrence of depression [
      • Bull S.J.
      • Huezo-Diaz P.
      • Binder E.B.
      • Cubells J.F.
      • Ranjith G.
      • Maddock C.
      • et al.
      Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment.
      ,
      • Su K.P.
      • Huang S.Y.
      • Peng C.Y.
      • Lai H.C.
      • Huang C.L.
      • Chen Y.C.
      • et al.
      Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
      ,
      • Gochee P.A.
      • Powell E.E.
      • Purdie D.M.
      • Pandeya N.
      • Kelemen L.
      • Shorthouse C.
      • et al.
      Association between apolipoprotein E epsilon4 and neuropsychiatric symptoms during interferon alpha treatment for chronic hepatitis C.
      ]. Interestingly, the T allele of the C/T single-nucleotide polymorphism upstream of IL28B (rs1297860), a well-known predictor of a worse antiviral response, has been shown to be associated with reduced appetite, energy, and sleep complaints, although it did not affect the risk of depression [
      • Lotrich F.E.
      • Loftis J.M.
      • Ferrell R.E.
      • Rabinovitz M.
      • Hauser P.
      IL28B polymorphism is associated with both side effects and clearance of hepatitis C during interferon-alpha therapy.
      ].

      Biomarker risk factors

      There is some evidence that high baseline inflammation predicts the occurrence of IFN-α-induced depression. Three studies have shown that higher baseline levels of some cytokines predict depression: interleukin-6 (in two studies [
      • Prather A.A.
      • Rabinovitz M.
      • Pollock B.G.
      • Lotrich F.E.
      Cytokine-induced depression during IFN-alpha treatment: the role of IL-6 and sleep quality.
      ,
      • Wichers M.C.
      • Kenis G.
      • Leue C.
      • Koek G.
      • Robaeys G.
      • Maes M.
      Baseline immune activation as a risk factor for the onset of depression during interferon-alpha treatment.
      ]), soluble interleukin-2 receptor [
      • Wichers M.C.
      • Kenis G.
      • Leue C.
      • Koek G.
      • Robaeys G.
      • Maes M.
      Baseline immune activation as a risk factor for the onset of depression during interferon-alpha treatment.
      ], interleukin-10 [
      • Wichers M.C.
      • Kenis G.
      • Leue C.
      • Koek G.
      • Robaeys G.
      • Maes M.
      Baseline immune activation as a risk factor for the onset of depression during interferon-alpha treatment.
      ], soluble tumour necrosis factor-receptor-1 [
      • Friebe A.
      • Schwarz M.J.
      • Schmid-Wendtner M.
      • Volkenandt M.
      • Schmidt F.
      • Horn M.
      • et al.
      Pretreatment levels of sTNF-R1 and sIL-6R are associated with a higher vulnerability for IFN-alpha-induced depressive symptoms in patients with malignant melanoma.
      ], and levels of soluble interleukin-6R (sIL-6R) have been found to be correlated with the risk of depression [
      • Friebe A.
      • Schwarz M.J.
      • Schmid-Wendtner M.
      • Volkenandt M.
      • Schmidt F.
      • Horn M.
      • et al.
      Pretreatment levels of sTNF-R1 and sIL-6R are associated with a higher vulnerability for IFN-alpha-induced depressive symptoms in patients with malignant melanoma.
      ]. In addition, lower levels of the anti-inflammatory polyunsaturated fatty acids, docosahexaenoic acid (DHA), predict higher risks of depression [
      • Su K.P.
      • Huang S.Y.
      • Peng C.Y.
      • Lai H.C.
      • Huang C.L.
      • Chen Y.C.
      • et al.
      Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
      ].

      Risk of suicide

      The overall risk of suicidal thoughts or suicide is elevated in patients with untreated chronic HCV infection because of the increased prevalence of intravenous drug use and psychiatric co-morbidity, as standard risk factors for suicide. However, treatment with IFN-α has been reported to be associated with suicidal thoughts and single cases of completed suicides [
      • Sockalingam S.
      • Links P.S.
      • Abbey S.E.
      Suicide risk in hepatitis C and during interferon-alpha therapy: a review and clinical update.
      ]. Nevertheless because most data come from case reports, the relative risk associated with treatment is unknown, although there is no real evidence that a previous psychiatric history is a risk factor [
      • Sockalingam S.
      • Links P.S.
      • Abbey S.E.
      Suicide risk in hepatitis C and during interferon-alpha therapy: a review and clinical update.
      ].
      Figure thumbnail fx6

      Psychosocial management of HCV infected patients before antiviral treatment

      A number of psychosocial issues have been shown to influence quality of life in patients with HCV infection. Strategies to improve psychological adjustment to chronic medical illness, increase social support, reduce stigmatisation, promote lifestyle changes (alcohol use, nutrition, exercise, work) and give information about possible side effects of antiviral therapy, all significantly improve treatment adherence [
      • Silberbogen A.K.
      • Ulloa E.W.
      • Janke E.A.
      • Mori D.L.
      Psychosocial issues and mental health treatment recommendations for patients with hepatitis C.
      ].
      It is generally accepted that a patient’s psychiatric condition should be monitored during PegIFNα therapy, to detect early treatment-related changes. Practice varies from informal clinical assessment to the systematic use of rating scales to formal psychiatric assessment. A number of well validated depression rating scales are available to monitor mood changes, including self-report scales such as the BDI (Beck Depression Inventory), the Z-SDS (Zung Self-Rating Depression Scale), the CES-D (Centre for Epidemiologic Studies Depression Scale), the PHQ-9 (Patient Health Questionnative) or the HADS (Hospital Anxiety and Depression Scale). Clinician-administered scales, performed by experienced and trained professionals, include the HAMD (Hamilton Depression Scale) and the MADRS (Montgomery-Åsberg Depression Scale). All scales can be used to monitor depressive mood changes over time and to quantify the severity of depressive symptoms. However, although cut-offs are used in scientific investigations to define depression, these scales are not diagnostic instruments and a diagnosis of depression should be confirmed by an experienced psychiatrist using the official diagnostic criteria (ICD-10, DSM-IV) [
      • Iannuzzo R.W.
      • Jaeger J.
      • Goldberg J.F.
      • Kafantaris V.
      • Sublette M.E.
      Development and reliability of the HAM-D/MADRS interview: an integrated depression symptom rating scale.
      ,
      • Shafer A.B.
      Meta-analysis of the factor structures of four depression questionnaires: Beck, CES-D, Hamilton, and Zung.
      ].
      Although depression-scales may help detect early depressive mood changes, a specific cut-off or change in total scores has not yet been defined to indicate the optimal time to initiate antidepressant treatment. A subthreshold treatment strategy has been suggested to start antidepressant treatment when scores are increasing, even at low level [
      • Robaeys G.
      • De Bie J.
      • Wichers M.C.
      • Bruckers L.
      • Nevens F.
      • Michielsen P.
      • et al.
      Early prediction of major depression in chronic hepatitis C patients during peg-interferon alpha-2b treatment by assessment of vegetative-depressive symptoms after four weeks.
      ]. However, an evidence base to support this is lacking.
      The arrangements for depression screening will depend on the composition, skills, and experience of each multidisciplinary team, but formal psychiatric referral is recommended in the following situations: the treating physician is unable to manage depression or initial management has failed; the psychiatric situation is complex or uncertain; there is an identified or suspected risk of suicide, alcohol or substance abuse; a complex and difficult social situation; multiple psychotropic drugs are necessary; or psychotherapeutic treatment is required [
      • Raison C.L.
      • Demetrashvili M.
      • Capuron L.
      • Miller A.H.
      Neuropsychiatric adverse effects of interferon-alpha: recognition and management.
      ,
      • Schaefer M.
      Clinical management of interferon-alfa-associated psychiatric side effects during hepatitis C treatment.
      ]. Hospitalisation may be necessary in cases of high suicide risk, lack of response to treatment, psychotic symptoms, psychotic depression, disorientation, and symptoms of delirium. Psychiatric symptoms may improve with treatment, and the continuation of antiviral treatment because of psychiatric complications should be decided on a case by case basis [
      • Loftis J.M.
      • Matthews A.M.
      • Hauser P.
      Psychiatric and substance use disorders in individuals with hepatitis C: epidemiology and management.
      ,
      • Raison C.L.
      • Demetrashvili M.
      • Capuron L.
      • Miller A.H.
      Neuropsychiatric adverse effects of interferon-alpha: recognition and management.
      ,
      • Robaeys G.
      • De Bie J.
      • Van Ranst M.
      • Buntinx F.
      An extremely rare case of delusional parasitosis in a chronic hepatitis C patient during pegylated interferon alpha-2b and ribavirin treatment.
      ,
      • Schaefer M.
      • Mauss S.
      Hepatitis C treatment in patients with drug addiction: clinical management of interferon-alpha-associated psychiatric side effects.
      ].
      The experience of the last 10 years has clearly shown that patients with psychiatric co-morbidity should not necessarily be excluded from IFN-α-based antiviral therapy [
      • Schaefer M.
      • Hinzpeter A.
      • Mohmand A.
      • Janssen G.
      • Pich M.
      • Schwaiger M.
      • et al.
      Hepatitis C treatment in “difficult-to-treat” psychiatric patients with pegylated interferon-alpha and ribavirin: response and psychiatric side effects.
      ,
      • Pariante C.M.
      • Landau S.
      • Carpiniello B.
      Interferon alfa-induced adverse effects in patients with a psychiatric diagnosis.
      ,
      • Schaefer M.
      • Mauss S.
      Hepatitis C treatment in patients with drug addiction: clinical management of interferon-alpha-associated psychiatric side effects.
      ,
      • De Bie J.
      • Robaeys G.
      • Buntinx F.
      Hepatitis C, interferon alpha and psychiatric co-morbidity in intravenous drug users (IVDU): guidelines for clinical practice.
      ,
      • Robaeys G.
      • Buntinx F.
      • Bottieau E.
      • Bourgeois S.
      • Brenard R.
      • Colle I.
      • et al.
      Guidelines for the management of chronic hepatitis C in patients infected after substance use.
      ,
      • Schaefer M.
      • Heinz A.
      • Backmund M.
      Treatment of chronic hepatitis C in patients with drug dependence: time to change the rules?.
      ]. A multidisciplinary approach is recommended with immediate access to specialist management in cases of severe psychiatric symptoms. For patients with drug addiction, treatment in an opiate substitution programme has been reported as the best setting to start antiviral therapy [
      • Schaefer M.
      • Heinz A.
      • Backmund M.
      Treatment of chronic hepatitis C in patients with drug dependence: time to change the rules?.
      ,
      • Mauss S.
      • Berger F.
      • Goelz J.
      • Jacob B.
      • Schmutz G.
      A prospective controlled study of interferon-based therapy of chronic hepatitis C in patients on methadone maintenance.
      ,
      • Reimer J.
      • Haasen C.
      Need-adapted HCV-treatment setting for injection drug users.
      ,
      • Sylvestre D.L.
      Treating hepatitis C in methadone maintenance patients: an interim analysis.
      ]. The decision to offer antiviral therapy should be individualised in current users of illicit drugs or alcohol who are willing to participate in a substance use programme (such as a methadone programme or alcohol support programme) [
      • Schaefer M.
      • Mauss S.
      Hepatitis C treatment in patients with drug addiction: clinical management of interferon-alpha-associated psychiatric side effects.
      ,
      • Schaefer M.
      • Heinz A.
      • Backmund M.
      Treatment of chronic hepatitis C in patients with drug dependence: time to change the rules?.
      ,
      • Ghany M.G.
      • Strader D.B.
      • Thomas D.L.
      • Seeff L.B.
      Diagnosis, management, and treatment of hepatitis C: an update.
      ]. Antiviral therapy is not recommended for patients with major uncontrolled psychiatric illness [
      • Ghany M.G.
      • Strader D.B.
      • Thomas D.L.
      • Seeff L.B.
      Diagnosis, management, and treatment of hepatitis C: an update.
      ].
      Figure thumbnail fx7

      Management, acute treatment, and prevention of IFN-α associated psychiatric problems

      Acute psychiatric problems due to IFN-α have a high impact on access to treatment, adherence, and response rates. Between 10% and 14% of the patients discontinue therapy due to a psychiatric adverse event such as fatigue, depression, irritability, and insomnia [
      • Manns M.P.
      • McHutchison J.G.
      • Gordon S.C.
      • Rustgi V.K.
      • Shiffman M.
      • Reindollar R.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.
      ,
      • Fried M.W.
      • Shiffman M.L.
      • Reddy K.R.
      • Smith C.
      • Marinos G.
      • Goncales Jr, F.L.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      ]. Specific psychopharmacological management can successfully treat psychiatric symptoms in patients on IFN-α [
      • Raison C.L.
      • Demetrashvili M.
      • Capuron L.
      • Miller A.H.
      Neuropsychiatric adverse effects of interferon-alpha: recognition and management.
      ,
      • Schaefer M.
      • Mauss S.
      Hepatitis C treatment in patients with drug addiction: clinical management of interferon-alpha-associated psychiatric side effects.
      ,
      • Maddock C.
      • Baita A.
      • Orru M.G.
      • Sitzia R.
      • Costa A.
      • Muntoni E.
      • et al.
      Psychopharmacological treatment of depression, anxiety, irritability and insomnia in patients receiving interferon-alpha: a prospective case series and a discussion of biological mechanisms.
      ]. However, approximately only one third of patients who develop depression during antiviral treatment are correctly diagnosed [
      • Leutscher P.D.
      • Lagging M.
      • Buhl M.R.
      • Pedersen C.
      • Norkrans G.
      • Langeland N.
      • et al.
      Evaluation of depression as a risk factor for treatment failure in chronic hepatitis C.
      ]. Increased education of both treating nurses/physicians and patients is necessary to allow improved early detection of psychiatric symptoms. An ability to distinguish pre-existing mental health issues from IFN-α related effects is important in correctly guiding treatment [
      • Schaefer M.
      • Mauss S.
      Hepatitis C treatment in patients with drug addiction: clinical management of interferon-alpha-associated psychiatric side effects.
      ]. A concomitant and continuous psychotherapeutic support programme has recently been shown to be able to reduce acute psychiatric complications and the need for pharmacological interventions during antiviral therapy [
      • Neri S.
      • Bertino G.
      • Petralia A.
      • Giancarlo C.
      • Rizzotto A.
      • Calvagno G.S.
      • et al.
      A multidisciplinary therapeutic approach for reducing the risk of psychiatric side effects in patients with chronic hepatitis C treated with pegylated interferon alpha and ribavirin.
      ]. In general, psychoeducational programmes, supportive treatment, behavioural or cognitive therapy, may all increase adherence to antiviral therapy, but so far trials are lacking. However, if psychiatric complications are associated with IFN-α treatment, acute pharmacological intervention becomes necessary and psychotherapy should not be offered alone [
      • Raison C.L.
      • Demetrashvili M.
      • Capuron L.
      • Miller A.H.
      Neuropsychiatric adverse effects of interferon-alpha: recognition and management.
      ,
      • Schaefer M.
      • Mauss S.
      Hepatitis C treatment in patients with drug addiction: clinical management of interferon-alpha-associated psychiatric side effects.
      ,
      • Reimer J.
      • Backmund M.
      • Haasen C.
      New psychiatric and psychological aspects of diagnosis and treatment of hepatitis C and relevance for opiate dependence.
      ].
      The pharmacological management of side effects depends on a degree when they occur during treatment (Table 3). Management of sleep disturbance appears important because it is a risk factor for the development of depressive symptoms [
      • Sockalingam S.
      • Links P.S.
      • Abbey S.E.
      Suicide risk in hepatitis C and during interferon-alpha therapy: a review and clinical update.
      ]. In addition to short-term (zolpidem) or long-term hypnotics (zopiclone), some patients might also require benzodiazepines, although the risk of drug dependence must be taken into account. Alternative strategies include the use of sedative antidepressants such as mirtazapine or trimipramine [
      • Schaefer M.
      • Mauss S.
      Hepatitis C treatment in patients with drug addiction: clinical management of interferon-alpha-associated psychiatric side effects.
      ]. Early antidepressant treatment is recommended to prevent the development of severe depression. Uncontrolled studies have shown that different classes of antidepressants are highly effective, especially the selective serotonin reuptake inhibitors (SSRI) (response rates >80%, defined as >40% reduction of depression scale scores) [
      • Gleason O.C.
      • Yates W.R.
      • Philipsen M.A.
      Major depressive disorder in hepatitis C: an open-label trial of escitalopram.
      ,
      • Hauser P.
      • Khosla J.
      • Aurora H.
      • Laurin J.
      • Kling M.A.
      • Hill J.
      • et al.
      A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C.
      ,
      • Kraus M.R.
      • Schafer A.
      • Faller H.
      • Csef H.
      • Scheurlen M.
      Paroxetine for the treatment of interferon-alpha-induced depression in chronic hepatitis C.
      ,
      • Schaefer M.
      • Schwaiger M.
      • Garkisch A.S.
      • Pich M.
      • Hinzpeter A.
      • Uebelhack R.
      • et al.
      Prevention of interferon-alpha associated depression in psychiatric risk patients with chronic hepatitis C.
      ]. In the only prospective, randomised, placebo-controlled trial, citalopram 20 mg od was significantly superior to placebo in reducing depressive symptoms after 2 and 4 weeks [
      • Kraus M.R.
      • Schafer A.
      • Schottker K.
      • Keicher C.
      • Weissbrich B.
      • Hofbauer I.
      • et al.
      Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study.
      ]. The frequency and severity of adverse events due to SSRIs are comparable to those in patients not infected with HCV [
      • Gleason O.C.
      • Yates W.R.
      • Philipsen M.A.
      • Isbell M.D.
      • Pollock B.G.
      Plasma levels of citalopram in depressed patients with hepatitis C.
      ]. Currently available data do not indicate negative long-term effects on virological response or an increase of treatment discontinuation because of side effects of antidepressants [
      • Schaefer M.
      • Schmidt F.
      • Folwaczny C.
      • Lorenz R.
      • Martin G.
      • Schindlbeck N.
      • et al.
      Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups.
      ,
      • Schaefer M.
      • Mauss S.
      Hepatitis C treatment in patients with drug addiction: clinical management of interferon-alpha-associated psychiatric side effects.
      ,
      • Diez-Quevedo C.
      • Masnou H.
      • Planas R.
      • Castellvi P.
      • Gimenez D.
      • Morillas R.M.
      • et al.
      Prophylactic treatment with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind, placebo-controlled trial.
      ,
      • Raison C.L.
      • Woolwine B.J.
      • Demetrashvili M.F.
      • Borisov A.S.
      • Weinreib R.
      • Staab J.P.
      • et al.
      Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C.
      ]. If patients respond to acute pharmacological treatment of IFN-α associated depression, the antidepressant should be continued through antiviral therapy and for 6–12 weeks after discontinuation because persistence or recurrence of depression, suicidal thoughts or cognitive disturbances have been reported after the end of antiviral treatment [
      • Gallegos-Orozco J.F.
      • Fuentes A.P.
      • Gerardo A.J.
      • Perez-Pruna C.
      • Hinojosa-Becerril C.
      • Sixtos-Alonso M.S.
      • et al.
      Health-related quality of life and depression in patients with chronic hepatitis C.
      ,
      • Reichenberg A.
      • Gorman J.M.
      • Dieterich D.T.
      Interferon-induced depression and cognitive impairment in hepatitis C virus patients: a 72 week prospective study.
      ,
      • Gohier B.
      • Goeb J.L.
      • Rannou-Dubas K.
      • Fouchard I.
      • Cales P.
      • Garre J.B.
      • et al.
      Hepatitis C, alpha interferon, anxiety and depression disorders: a prospective study of 71 patients.
      ,
      • Nickel T.
      • Sonntag A.
      • Backmund M.
      • Pollmacher T.
      Depression during therapy with interferon alpha – how long should an antidepressant treatment last?.
      ,
      • Schmidt F.
      • Janssen G.
      • Martin G.
      • Lorenz R.
      • Loeschke K.
      • Soyka M.
      • et al.
      Factors influencing long-term changes in mental health after interferon-alpha treatment of chronic hepatitis C.
      ]. For other IFN- α associated psychiatric complications, no specific trial data are available and symptomatic treatment should be individualised. Fatigue might be ameliorated by antidepressant treatment especially if there are also depressive symptoms [
      • Capuron L.
      • Gumnick J.F.
      • Musselman D.L.
      • Lawson D.H.
      • Reemsnyder A.
      • Nemeroff C.B.
      • et al.
      Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions.
      ]. One prospective and controlled trial showed a positive effect of ondansetron, but data have not been confirmed so far [
      • Piche T.
      • Vanbiervliet G.
      • Cherikh F.
      • Antoun Z.
      • Huet P.M.
      • Gelsi E.
      • et al.
      Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study.
      ]. Single case reports also indicate positive effects of tryptophan or stimulating agents [
      • Schaefer M.
      • Winterer J.
      • Sarkar R.
      • Uebelhack R.
      • Franke L.
      • Heinz A.
      • et al.
      Three cases of successful tryptophan add-on or monotherapy of hepatitis C and IFNalpha-associated mood disorders.
      ,
      • Schwartz A.L.
      • Thompson J.A.
      • Masood N.
      Interferon-induced fatigue in patients with melanoma: a pilot study of exercise and methylphenidate.
      ,
      • Malek-Ahmadi P.
      • Ghandour E.
      Bupropion for treatment of interferon-induced depression.
      ,
      • Martin K.A.
      • Krahn L.E.
      • Balan V.
      • Rosati M.J.
      Modafinil’s use in combating interferon-induced fatigue.
      ]. Because cognitive disturbances might be related to depressive symptoms, antidepressants treatment should be initiated as first line treatment. However, no specific treatment is known for acute or long-lasting cognitive disturbances unrelated to depression. Irritability as symptom of depression and sleep disturbance might respond to antidepressant treatment. However, if irritability is related to mania, antidepressants may exacerbate symptoms, and a case series has suggested that a small dose of antipsychotic medication may help with this symptom [
      • Maddock C.
      • Baita A.
      • Orru M.G.
      • Sitzia R.
      • Costa A.
      • Muntoni E.
      • et al.
      Psychopharmacological treatment of depression, anxiety, irritability and insomnia in patients receiving interferon-alpha: a prospective case series and a discussion of biological mechanisms.
      ]. In any case of manic or psychotic symptoms, confusional state, or suicidal thoughts, patients should immediately be evaluated by an experienced psychiatrist. The decision to dose reduce or discontinue IFN-α treatment should be made by the multidisciplinary team [
      • Sockalingam S.
      • Links P.S.
      • Abbey S.E.
      Suicide risk in hepatitis C and during interferon-alpha therapy: a review and clinical update.
      ,
      • Raison C.L.
      • Demetrashvili M.
      • Capuron L.
      • Miller A.H.
      Neuropsychiatric adverse effects of interferon-alpha: recognition and management.
      ,
      • Schaefer M.
      • Mauss S.
      Hepatitis C treatment in patients with drug addiction: clinical management of interferon-alpha-associated psychiatric side effects.
      ].
      Table 3Strategies for the management of IFN-associated acute adverse events.
      Since the detection of early IFN-α-related depressive symptoms relies on close observation and may be missed, preventive strategies using antidepressants as a pre-treatment may offer the chance to protect patients from the development of clinically relevant depression. The first prophylactic study was conducted in melanoma patients [
      • Musselman D.L.
      • Lawson D.H.
      • Gumnick J.F.
      • Manatunga A.K.
      • Penna S.
      • Goodkin R.S.
      • et al.
      Paroxetine for the prevention of depression induced by high-dose interferon alfa.
      ]. Paroxetine pre-treatment was able to reduce the incidence of major depression and the likelihood of IFN-α withdrawal in patients receiving high-dose therapy with IFN-α. Three open label trials focused on patients with psychiatric risk factors: previous history of IFN-α-induced depression [
      • Kraus M.R.
      • Schafer A.
      • Al Taie O.
      • Scheurlen M.
      Prophylactic SSRI during interferon alpha re-therapy in patients with chronic hepatitis C and a history of interferon-induced depression.
      ], major depressive disorder in remission [
      • Gleason O.C.
      • Fucci J.C.
      • Yates W.R.
      • Philipsen M.A.
      Preventing relapse of major depression during interferon-alpha therapy for hepatitis C – a pilot study.
      ], or pre-existing depression and drug addiction [
      • Schaefer M.
      • Schwaiger M.
      • Garkisch A.S.
      • Pich M.
      • Hinzpeter A.
      • Uebelhack R.
      • et al.
      Prevention of interferon-alpha associated depression in psychiatric risk patients with chronic hepatitis C.
      ]. In all three studies, antidepressants were able to reduce the incidence of IFN-α-induced depression. Six prospective, randomised, placebo-controlled trials have been published up to date [
      • Diez-Quevedo C.
      • Masnou H.
      • Planas R.
      • Castellvi P.
      • Gimenez D.
      • Morillas R.M.
      • et al.
      Prophylactic treatment with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind, placebo-controlled trial.
      ,
      • Raison C.L.
      • Woolwine B.J.
      • Demetrashvili M.F.
      • Borisov A.S.
      • Weinreib R.
      • Staab J.P.
      • et al.
      Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C.
      ,
      • de Knegt R.J.
      • Bezemer G.
      • Van Gool A.R.
      • Drenth J.P.
      • Hansen B.E.
      • Droogleever Fortuyn H.A.
      • et al.
      Randomised clinical trial: escitalopram for the prevention of psychiatric adverse events during treatment with peginterferon-alfa-2a and ribavirin for chronic hepatitis C.
      ,
      • Morasco B.J.
      • Rifai M.A.
      • Loftis J.M.
      • Indest D.W.
      • Moles J.K.
      • Hauser P.
      A randomized trial of paroxetine to prevent interferon-alpha-induced depression in patients with hepatitis C.
      ,
      • Morasco B.J.
      • Loftis J.M.
      • Indest D.W.
      • Ruimy S.
      • Davison J.W.
      • Felker B.
      • et al.
      Prophylactic antidepressant treatment in patients with hepatitis C on antiviral therapy: a double-blind, placebo-controlled trial.
      ,
      • Schaefer M.
      • Sarkar R.
      • Knop V.
      • Effenberger S.
      • Friebe A.
      • Heinze L.
      • et al.
      Escitalopram for the prevention of peginterferon-alpha2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.
      ]. In four of them, antidepressant pre-treatment with paroxetine, citalopram or escitalopram, did not reduce the incidence of IFN-α-induced major depressive episodes or the overall severity of depressive symptoms [
      • Diez-Quevedo C.
      • Masnou H.
      • Planas R.
      • Castellvi P.
      • Gimenez D.
      • Morillas R.M.
      • et al.
      Prophylactic treatment with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind, placebo-controlled trial.
      ,
      • Raison C.L.
      • Woolwine B.J.
      • Demetrashvili M.F.
      • Borisov A.S.
      • Weinreib R.
      • Staab J.P.
      • et al.
      Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C.
      ,
      • Morasco B.J.
      • Rifai M.A.
      • Loftis J.M.
      • Indest D.W.
      • Moles J.K.
      • Hauser P.
      A randomized trial of paroxetine to prevent interferon-alpha-induced depression in patients with hepatitis C.
      ,
      • Morasco B.J.
      • Loftis J.M.
      • Indest D.W.
      • Ruimy S.
      • Davison J.W.
      • Felker B.
      • et al.
      Prophylactic antidepressant treatment in patients with hepatitis C on antiviral therapy: a double-blind, placebo-controlled trial.
      ]. However, the largest trial to date by Schaefer et al. demonstrated a positive effect of escitalopram on the incidence and severity of depression defined by MADRS-score and major depression during treatment in patients without prior psychiatric disorders [
      • Schaefer M.
      • Sarkar R.
      • Knop V.
      • Effenberger S.
      • Friebe A.
      • Heinze L.
      • et al.
      Escitalopram for the prevention of peginterferon-alpha2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.
      ]. A further study by de Knegt et al. found similar positive results, but only investigated single items on depression scales [
      • de Knegt R.J.
      • Bezemer G.
      • Van Gool A.R.
      • Drenth J.P.
      • Hansen B.E.
      • Droogleever Fortuyn H.A.
      • et al.
      Randomised clinical trial: escitalopram for the prevention of psychiatric adverse events during treatment with peginterferon-alfa-2a and ribavirin for chronic hepatitis C.
      ]. In the trial by Raison and colleagues, paroxetine pre-treatment showed a positive prophylactic effect only in the subgroup of patients with mildly elevated baseline depression scores [
      • Raison C.L.
      • Woolwine B.J.
      • Demetrashvili M.F.
      • Borisov A.S.
      • Weinreib R.
      • Staab J.P.
      • et al.
      Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C.
      ]. There were no safety issues or negative effects on virological outcome in any of the studies [
      • Diez-Quevedo C.
      • Masnou H.
      • Planas R.
      • Castellvi P.
      • Gimenez D.
      • Morillas R.M.
      • et al.
      Prophylactic treatment with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind, placebo-controlled trial.
      ,
      • Raison C.L.
      • Woolwine B.J.
      • Demetrashvili M.F.
      • Borisov A.S.
      • Weinreib R.
      • Staab J.P.
      • et al.
      Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C.
      ,
      • Morasco B.J.
      • Loftis J.M.
      • Indest D.W.
      • Ruimy S.
      • Davison J.W.
      • Felker B.
      • et al.
      Prophylactic antidepressant treatment in patients with hepatitis C on antiviral therapy: a double-blind, placebo-controlled trial.
      ,
      • Schaefer M.
      • Sarkar R.
      • Knop V.
      • Effenberger S.
      • Friebe A.
      • Heinze L.
      • et al.
      Escitalopram for the prevention of peginterferon-alpha2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.
      ]. The heterogeneous results in the studies published to date are related to methodological concerns. There were small sample sizes in three studies [
      • Raison C.L.
      • Woolwine B.J.
      • Demetrashvili M.F.
      • Borisov A.S.
      • Weinreib R.
      • Staab J.P.
      • et al.
      Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C.
      ,
      • Morasco B.J.
      • Rifai M.A.
      • Loftis J.M.
      • Indest D.W.
      • Moles J.K.
      • Hauser P.
      A randomized trial of paroxetine to prevent interferon-alpha-induced depression in patients with hepatitis C.
      ,
      • Morasco B.J.
      • Loftis J.M.
      • Indest D.W.
      • Ruimy S.
      • Davison J.W.
      • Felker B.
      • et al.
      Prophylactic antidepressant treatment in patients with hepatitis C on antiviral therapy: a double-blind, placebo-controlled trial.
      ], one trial only evaluated depression during the first 3 treatment months and there were low rates of major depression in placebo-treated patients [
      • Diez-Quevedo C.
      • Masnou H.
      • Planas R.
      • Castellvi P.
      • Gimenez D.
      • Morillas R.M.
      • et al.
      Prophylactic treatment with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind, placebo-controlled trial.
      ], thus reducing the power of the trial to detect differences between groups. The populations studied were also different, with various rates of previous history of psychiatric and addiction disorders. Moreover, future trials should enlarge the pool of symptoms to be targeted (pain, irritability, fatigue, insomnia, and cognitive dysfunction), define the study populations carefully and try to identify subgroups that show real benefit from antidepressant pre-treatment. Beside specific psychotherapeutic interventions [
      • Cuijpers P.
      • van Straten A.
      • Smit F.
      • Mihalopoulos C.
      • Beekman A.
      Preventing the onset of depressive disorders: a meta-analytic review of psychological interventions.
      ], the protective effect of intensive, multidisciplinary management should also be taken into account.
      Figure thumbnail fx8

      New antivirals and IFN-α: Psychiatric side effects and possible interactions

      New antivirals have been developed that directly inhibit HCV. The first substances for clinical use in combination with PegIFNα (2a or 2b) are telaprevir and boceprevir [
      • Lin C.
      • Kwong A.D.
      • Perni R.B.
      Discovery and development of VX-950, a novel, covalent, and reversible inhibitor of hepatitis C virus NS3.4A serine protease.
      ,
      • Malcolm J.R.
      • Liu C.
      • Neilson R.P.
      • Hansen L.
      • Hannah L.
      Global warming and extinctions of endemic species from biodiversity hotspots.
      ,
      • Manns M.P.
      • Foster G.R.
      • Rockstroh J.K.
      • Zeuzem S.
      • Zoulim F.
      • Houghton M.
      The way forward in HCV treatment – finding the right path.
      ,
      • Pawlotsky J.M.
      • Chevaliez S.
      • McHutchison J.G.
      The hepatitis C virus life cycle as a target for new antiviral therapies.
      ]. Triple therapy with new antivirals together with PegIFNα and ribavirin may be associated with an increase of neuropsychiatric side effects or drug–drug interactions. However, currently available data shows that both new antivirals do not have specific neuropsychiatric side effects. For telaprevir, the most common “psychiatric” adverse events are fatigue and insomnia. The most common other adverse events (AEs) are rash, pruritus, headache, nausea, anaemia, diarrhoea, flu-like symptoms, and pyrexia, with the majority being mild or moderate in severity [
      • Golden J.
      • O’Dwyer A.M.
      • Conroy R.M.
      Depression and anxiety in patients with hepatitis C: prevalence, detection rates and risk factors.
      ,
      • Lim J.K.
      • Cronkite R.
      • Goldstein M.K.
      • Cheung R.C.
      The impact of chronic hepatitis C and comorbid psychiatric illnesses on health-related quality of life.
      ]. However, depression was only evaluated in the trial by Hézode et al. [
      • Hezode C.
      • Forestier N.
      • Dusheiko G.
      • Ferenci P.
      • Pol S.
      • Goeser T.
      • et al.
      Telaprevir and peginterferon with or without ribavirin for chronic HCV infection.
      ], with an incidence of 20–22% in all groups. Regarding boceprevir, this treatment appears to be associated with anaemia and disgeusia [
      • Poordad F.
      • McCone Jr., J.
      • Bacon B.R.
      • Bruno S.
      • Manns M.P.
      • Sulkowski M.S.
      • et al.
      Boceprevir for untreated chronic HCV genotype 1 infection.
      ]. No specific additional psychiatric side effects could be observed. Although 2 patients from different groups committed suicide, no specific information about depression was given in this trial. Other AEs effects included nausea, headache, and fatigue, and were observed at similar rates across all groups.
      The treatment of IFN-α-induced AEs during combination triple therapy may be complicated by possible drug–drug interactions. Telaprevir is primarily metabolised by the cytochrome P450 system (CYP3A) whilst boceprevir is catalysed by cytochrome P450-mediated oxidation (strong inhibitor of CYP3A4/5) and ketone reduction. Benzodiazepines such as midazolam, alprazolam or triazolam should not be combined with either of the two new antivirals because of increased blood levels and sedative effects. Carbamazepine and St. John’s wort as strong inducers of the CYP3A4 and should not be combined with telaprevir or boceprevir (reduced blood levels, reduced effects). Citalopram and escitalopram can be combined with the new antivirals, but a lowered blood concentration around 35% was reported for escitalopram with telaprevir. During treatment of sleep disturbances with zolpidem, blood levels can be reduced up to 50%. For antipsychotic treatment, olanzapine, and for antiepileptic therapy, levetiracetam, gabapentine, and pregabalin, are recommended based on the low rate of interactions. Up to date information about possible drug–drug interactions should be considered for in the management of IFN-α side effects (e.g., www.hep-druginteractions.org).
      Figure thumbnail fx9

      Conflict of interest

      Financial support for research and/or speaker fees have been received from the following:
      Crisanto Diez-Quevedo: Roche Farma Spain, Lundbeck; Carmine M. Pariante: Roche, Lilly; Martin Schaefer: Roche Germany, Lundbeck, Janssen, BMS, Astra Zeneka; Astrid Friebe, Lucile Capuron, Sergio Neri, and Achim Kautz: nil; Geert Robaeys: Merck, Janssen; Graham R. Foster: Roche, Merck, BMS, Janssen, BI, Gilead, Novartis, and Chughai; Daniel Forton: Roche, MSD, Bristol-Myers Squibb, Gilead, Janssen.

      Acknowledgements

      We thank ELPA and EASL for their support to organise the expert meeting and to present and discuss the results.

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