Martin Schaefer

Hepatitis C treatment in “difficult-to-treat” psychiatric patients with pegylated interferon-alpha and ribavirin: Response and psychiatric side effects†

We investigated and compared the results of treating the chronic hepatitis C (HCV) infection of different groups of psychiatric‐risk patients and controls with pegylated interferon alpha (pegIFN‐α) plus ribavirin. Seventy patients were prospectively screened for psychiatric disorders. Seventeen patients without psychiatric diseases or drug addiction (controls), 22 patients with psychiatric disorders, 18 patients who had received methadone substitution treatment and 13 patients who were former drug users were treated with pegIFN‐α plus ribavirin. Sustained virological response (SVR), adherence, and psychiatric side effects (using the Montgomery‐Asberg Depression Rating Scale and the Brief Psychiatric Rating Scale) in the groups were compared. An SVR was found in 58.6% of all patients: 58.8% of the controls, 50% of psychiatric patients, 72.2% of methadone patients, and 53.8% of former drug users. Methadone‐substituted patients and former drug users had significantly higher dropout rates. Scores for neither depressive nor psychotic symptoms differed significantly between groups during treatment. However, the controls had lower pretreatment scores, followed by a significant higher increase to maximum scores. A stepwise logistic regression model showed that only genotype, not group (control, psychiatric, methadone, or former drug abuse), type of psychiatric diagnosis (affective disorder, personality disorder, or schizophrenic disorder), depression scores before and during treatment, change in depression score, antidepressive treatment, sex, or liver enzymes before treatment, was associated with SVR. Conclusion: In an interdisciplinary treatment setting psychiatric diseases and/or drug addiction did not negatively influence psychiatric tolerability of and antiviral response rate to HCV treatment with pegIFN‐α and ribavirin. (HEPATOLOGY 2007.)

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

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 patients 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.

Recommendations for the management of hepatitis C virus infection among people who inject drugs

In high income countries, the majority of new and existing hepatitis C virus (HCV) infections occur among people who inject drugs (PWID). In many low and middle income countries large HCV epidemics have also emerged among PWID populations. The burden of HCV-related liver disease among PWID is increasing, but treatment uptake remains extremely low. There are a number of barriers to care which should be considered and systematically addressed, but should not exclude PWID from HCV treatment. The rapid development of interferon-free direct-acting antiviral (DAA) therapy for HCV infection has brought considerable optimism to the HCV sector, with the realistic hope that therapeutic intervention will soon provide near optimal efficacy with well-tolerated, short duration, all oral regimens. Further, it has been clearly demonstrated that HCV treatment is safe and effective across a broad range of multidisciplinary healthcare settings. Given the burden of HCV-related disease among PWID, strategies to enhance HCV assessment and treatment in this group are urgently needed. These recommendations demonstrate that treatment among PWID is feasible and provide a framework for HCV assessment and care. Further research is needed to evaluate strategies to enhance testing, linkage to care, treatment, adherence, viral cure, and prevent HCV reinfection among PWID, particularly as new interferon-free DAA treatments for HCV infection become available.

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

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 patients 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.

Recommendations for the Management of Hepatitis C Virus Infection Among People Who Inject Drugs

In the developed world, the majority of new and existing hepatitis C virus (HCV) infections occur among people who inject drugs (PWID). The burden of HCV-related liver disease in this group is increasing, but treatment uptake among PWID remains low. Among PWID, there are a number of barriers to care that should be considered and systematically addressed, but these barriers should not exclude PWID from HCV treatment. Furthermore, it has been clearly demonstrated that HCV treatment is safe and effective across a broad range of multidisciplinary healthcare settings. Given the burden of HCV-related disease among PWID, strategies to enhance HCV assessment and treatment in this group are urgently needed. These recommendations demonstrate that treatment among PWID is feasible and provides a framework for HCV assessment, management, and treatment. Further research is needed to evaluate strategies to enhance assessment, adherence, and SVR among PWID, particularly as new treatments for HCV infection become available.

Correlation between sICAM-1 and depressive symptoms during adjuvant treatment of melanoma with interferon-α

Interferon-alpha (IFN-alpha) treatment is frequently complicated by symptoms of depression. The mechanism by which peripherally administered IFN-alpha enters and modulates the central nervous system remains unclear. The cell adhesion molecule ICAM-1 is involved in the regulation of blood-brain barrier (BBB) permeability. ICAM-1 expression was shown to increase during IFN-alpha treatment and recently the expression of ICAM-1 on vascular endothelial cells in the brain was found to be correlated with the development of depression. We therefore hypothesized that soluble ICAM-1 may be involved in the development of IFN-alpha associated depression. In a prospective study, serum levels of soluble ICAM-1 (double sandwich ELISA test) and symptoms of depression (SDS) were measured in 48 patients with malignant melanoma before and during adjuvant IFN-alpha treatment. Both, depression scores and the serum levels of sICAM-1 significantly increased after three months of IFN-alpha treatment compared to baseline levels (p < .001). Patients who developed depression (SDS-index scores > or = 50) after three months of treatment had higher sICAM-1 levels compared to non-depressed patients. Furthermore, sICAM-1 levels were positively correlated with SDS values (r = .367, p = .018). Our data provides evidence for an association between the induction of sICAM-1 and the development of symptoms of depression during IFN-alpha treatment, possibly by enhancing BBB-permeability.

Current schizophrenia drugs: efficacy and side effects.

Over the course of the past decade, the acceptance of several second-generation antipsychotics (SGAs) as effective medication for the treatment of schizophrenia has led to some changes. SGAs have a lower risk of inducing extrapyramidal side effects and tardive dyskinesia compared with first-generation antipsychotics, and have been said to be more successful in long-term treatment and tolerability. They also significantly improve the quality of life of schizophrenic patients. However, during treatment with SGAs other adverse effects can occur, such as weight gain, metabolic changes, sexual dysfunction and QTc-prolongation, significantly affecting the patient’s physical health. Consequently, these side effects might be the reason that a high proportion of patients discontinue treatment with SGAs. Thus, from the authors’ view, optimising individualised treatment implies increasing the efficacy of current schizophrenia drugs. This can be achieved by finding clinical or pharmacogenetic predictors for the most appropriate drug or drug combination, and by improving side-effect management in combination with non-pharmacological interventions in order to increase patients’ quality of life and treatment compliance, possibly resulting in a better long-term outcome.

The Δ32 mutation of the chemokine-receptor 5 gene neither is correlated with chronic hepatitis C nor does it predict response to therapy with interferon-α and ribavirin

Unlike in HIV, homozygosity for a 32-bp deletion (Δ32) of the chemokine receptor 5 (CCR5) gene was recently described in increased frequency in patients with chronic hepatitis C (HCV). Thus, it was speculated that this mutation might be relevant for disease susceptibility and influence the response to antiviral therapy. The present study sought to confirm the association between HCV and the Δ32 mutation of the CCR5 gene and to correlate it with the response to therapy with interferon-α-2a and ribavirin. Sixty-two patients with HCV and 119 healthy unrelated controls were genotyped for the Δ32 mutation. For the correlation between the Δ32 mutation and response to therapy, only patients (n = 59) who completed 6 months of combination therapy as part of a prospective study were evaluated. The Δ32 mutation was not observed in increased frequency in HCV. Furthermore, a significant difference of the HCV load or aminotransferase concentrations was not observed in carriers versus noncarriers of the Δ32 mutation. After stratification for potentially confounding factors such as gender or HCV genotype, a significant difference was also not detected with respect to treatment outcome. These observations argue strongly against a role of CCR5 for susceptibility to HCV infection or response to combination therapy.

Interaction of hippocampal volume and N-acetylaspartate concentration deficits in schizophrenia: A combined MRI and 1H-MRS study

BACKGROUND Volume deficits assessed with magnetic resonance imaging (MRI) and neurochemical dysfunctions (N-acetylaspartate, NAA) diagnosed using proton MR spectroscopy ((1)H-MRS) are reliable observations in the hippocampus of schizophrenic patients. NAA is an important cerebral amino acid in the synthesis pathways of glutamate, which has been implicated as a pathobiological core of schizophrenic symptomatology, of histological alterations and brain volume deficits in schizophrenia. However, the possible interaction between regional NAA reduction and volume deficits has been targeted only marginally in previous investigations. METHODS In 29 schizophrenic patients and 44 control subjects, a multimodal imaging study with (1)H-MRS and MRI volumetry of the left hippocampus was performed on a 3-Tesla scanner. RESULTS Compared to the control group, the hippocampus of the patients exhibited a significant volume reduction and a significant NAA concentration decrease. In schizophrenic patients, but not in healthy controls, a significant negative correlation between hippocampal NAA concentration and volume (r=-0.455, p=0.017) was observed. None of the imaging parameters was associated with clinical parameters. CONCLUSIONS The results argue for a coexistent neurochemical and structural deficit in the hippocampus of schizophrenic patients. The inverse relationship between the two parameters observed in patients only may reflect an interaction of neurochemistry and brain morphology as a pathobiological mechanism in schizophrenia. This observation is compatible with the important role of NAA in the synthesis of excitatory neurotransmitters and the hypothesized role of glutamate for brain morphology. The independence of the measured imaging parameters from clinical parameters is in line with the neurodevelopmental hypothesis of schizophrenia.

Depressive Mood Changes and Psychiatric Symptoms During 12-month Low-dose Interferon-α Treatment in Patients With Malignant Melanoma Results From the Multicenter DeCOG Trial

The purpose of the present study was to evaluate the incidence, spectrum and extent of psychiatric symptoms in patients with malignant melanoma (MM) before and during adjuvant treatment with interferon-alpha (IFN-α). 850 patients with cutaneous MM of ≥1.5 mm tumor thickness received standard low-dose IFN-α 2a in this prospective multicenter trial of the Dermatologic Cooperative Oncology Group (DeCOG). Psychiatric symptoms were evaluated at baseline and after 3, 6, and 12 months with the Beck Depression Inventory (BDI) and the Symptom Check List 90-Revised (SCL 90-R). In all, 282 patients completed all questionnaires. Mean BDI depression scores increased significantly during the first 6 months of IFN-α treatment (P ≤0.001), followed by a mild but not significant decrease. Also mean SCL 90-R scores increased significantly during the first 3 months of adjuvant treatment with IFN-α (P≤0.001) and remained elevated until month 12 (P≤0.001). Only 5% developed BDI scores >10, indicating a clinically significant depressive syndrome and only 1.4% reached a BDI score ≥18, indicating a moderate to severe depressive syndrome. Patients, who dropped-out early from psychiatric reasons, had significantly increased BDI and SCL-90R scores at baseline. Women scored higher in both scales before and during treatment if compared with men. In conclusion, adjuvant treatment with IFN-α was associated with a significant increase of BDI- and SCL 90-R scores. A higher pretreatment depression score was found to be a risk factor for an early drop-out during therapy. Pretreatment screening and an interdisciplinary care of the patients is recommended.