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Department of Psychiatry and Psychotherapy, Charité–Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, GermanyDepartment of Psychiatry, Psychotherapy and Addiction Medicine, Kliniken Essen-Mitte, Essen, Germany
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.
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 [
]. 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 [
]. 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 [
] (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)
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 [
Investigating health-related quality of life, mood and neuropsychological test performance in a homogeneous cohort of Irish female hepatitis C patients.
].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% [
]. This is related to increased high risk behaviour, such as intravenous drug abuse, but also to other risk factors such as long-term hospitalisation [
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 [
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.
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.
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 [
]. 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 [
]. 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 [
Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy.
Hepavir, the first observational study of one cohort of patients treated with alpha-2a interferon, monotherapy. Evaluation of asthenia and its social consequences.
]. Cognitive impairment has been reported in HCV infected patients with only minimal liver disease, independent of psychiatric co-morbidity or addiction disorder [
Investigating health-related quality of life, mood and neuropsychological test performance in a homogeneous cohort of Irish female hepatitis C patients.
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 [
], 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 [
]. 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 [
]. 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 [
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.
]. 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.
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% [
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 [
Comparing the safety, tolerability and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alpha-2a.
Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms.
De novo depression and anxiety disorders and influence on adherence during peginterferon-alpha-2a and ribavirin treatment in patients with hepatitis C.
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 [
]. 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 [
]. 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 [
]. Whilst most of the neuropsychiatric effects resolve with treatment cessation, cases of persistent, recurring or new developing symptoms have been described [
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 [
Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood–brain barrier.
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.
]. 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 [
]. These alterations involve the activation of the enzyme indoleamine-2,3-dioxygenase (IDO), which leads to the degradation of tryptophan into neurotoxic pathways [
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 [
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 [
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 [
]. 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 [
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 [
]. 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 [
]. 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 [
Hepatitis C treatment in “difficult-to-treat” psychiatric patients with pegylated interferon-alpha and ribavirin: response and psychiatric side effects.
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 [
Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment.
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 [
Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment.
Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
]. 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 [
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 [
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.
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.
Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
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 [
]. 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 [
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 [
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) [
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 [
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 [
]. 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 [
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 [
Hepatitis C treatment in “difficult-to-treat” psychiatric patients with pegylated interferon-alpha and ribavirin: response and psychiatric side effects.
]. 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 [
]. 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) [
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 [
Psychopharmacological treatment of depression, anxiety, irritability and insomnia in patients receiving interferon-alpha: a prospective case series and a discussion of biological mechanisms.
]. 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 [
]. 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 [
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 [
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 [
]. 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 [
]. 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) [
]. 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 [
]. 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 [
Prophylactic treatment with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind, placebo-controlled trial.
]. 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 [
]. 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 [
]. 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 [
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 [
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 [
]. 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 [
]. 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 [
Prophylactic treatment with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind, placebo-controlled trial.
Randomised clinical trial: escitalopram for the prevention of psychiatric adverse events during treatment with peginterferon-alfa-2a and ribavirin for chronic hepatitis C.
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 [
Prophylactic treatment with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, 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 [
Escitalopram for the prevention of peginterferon-alpha2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.
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 [
Prophylactic treatment with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind, placebo-controlled trial.
Escitalopram for the prevention of peginterferon-alpha2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.
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 [
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 [
]. 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 [
]. 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).
Investigating health-related quality of life, mood and neuropsychological test performance in a homogeneous cohort of Irish female hepatitis C patients.
Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy.
Hepavir, the first observational study of one cohort of patients treated with alpha-2a interferon, monotherapy. Evaluation of asthenia and its social consequences.
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.
Hepatitis C treatment in “difficult-to-treat” psychiatric patients with pegylated interferon-alpha and ribavirin: response and psychiatric side effects.
Comparing the safety, tolerability and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alpha-2a.
Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood–brain barrier.
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.
Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy.
Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment.
Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
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