Suicidal ideation during interferon-α2b and ribavirin treatment of patients with chronic hepatitis C

doi:10.1016/j.genhosppsych.2004.01.003

General Hospital Psychiatry

Volume 26, Issue 3, May–June 2004, Pages 237-240

https://doi.org/10.1016/j.genhosppsych.2004.01.003 Get rights and content

Abstract

Psychiatric and substance use disorders affect most patients with chronic hepatitis C and are the most common reasons for exclusion from antiviral therapies. Suicidal ideation (SI) is often cited as a reason to exclude patients from interferon-based treatment or to terminate antiviral treatment that is in progress. This study examines SI in hepatitis C patients untreated and treated with interferon-α2b, a medication commonly associated with depression. Fifty-five subjects with chronic hepatitis C were followed for 24 weeks with three measures of depression, each containing one item assessing SI. A total of 15/55 (27%) subjects reported SI while not on interferon therapy. Of the 42 patients treated with interferon, 18 (43%) endorsed SI at some point during antiviral treatment. However, 17/18 (94%) finished at least a 6-month course of interferon therapy. No subjects attempted suicide. Although SI in some form is common in hepatitis C patients, in most cases it is mild in nature. With adequate support most patients can successfully complete a full course of antiviral treatment.

Introduction

The hepatitis C virus (HCV) infects an estimated 4 million Americans, most of whom become chronic carriers of the disease [1]. Injection drug use is a main route of transmission and patients with substance use or psychiatric disorders are frequently affected by this illness. Several recent studies have shown that HCV patients have high rates of both current and past psychiatric and substance use disorders. In one study, 88% of patients seen at a VA hepatitis C clinic had either a history of a psychiatric or substance use disorder or both [2]. In a large population-based study, el-Serag et al. [3] found that over 86% of 33,824 HCV-infected veterans had a past history of a psychiatric or substance use disorder and approximately 35% had an active or current disorder. In addition to psychiatric disorders associated with HCV, treatment with interferon causes neuropsychiatric symptoms, including depression, and suicides have been reported [4]. Unfortunately, this has led to treatment exclusion of many HCV patients with comorbid psychiatric or substance use disorders. Excluding patients from antiviral therapy is concerning as outcomes have improved dramatically over the past 2–3 years with the addition of ribavirin and pegylated interferon to the current treatment regimen.

Clinicians' reluctance to treat hepatitis C patients who report suicidal ideation (SI) is understandable. Little data are available concerning SI during interferon treatment. Published reports consist mainly of case reports and a survey of European hepatologists of attempted and completed suicides [4]. At the same time, SI is thought to be common in the general population. Increased rates are found in patients with medical conditions but the highest reported rates are found in patients with chronic medical disease and major depression [5]. No data are available on the rate of SI in hepatitis C patients. We previously reported the rates of depression in a group of HCV patients before and during interferon therapy [6]. Here we examine the rate of SI endorsed during this study.

Section snippets

Method

Subjects were 55 veterans recruited in a consecutive manner for this descriptive, observational study. All patients were treated in a chronic hepatitis C clinic at the VA Medical Centers in Minneapolis and Milwaukee May 1999 and May 2001. Institutional review boards at both centers approved the study protocol and all subjects gave written informed consent prior to participation. Forty-two patients received interferon α2b, 3 million U subcutaneously three times per week, along with ribavirin

Results

Almost all subjects, 54 (98%) were men, their mean age was 47 (SD 4.81), 48 (87%) were Caucasian, 6 (11%) were African American, and 1 (2%) was Native American. Fifty-two (95%) had at least a high school education, 16 (29%) were employed full-time, and 22 (40%) were disabled. Thirty-eight (69%) were single or divorced, 19 (35%) had incomes of $20,000–39,999, and 29 (53%) had an income below $20,000. These characteristics did not differ significantly between those who developed SI during

Discussion

Currently, practitioners generally stop interferon treatment if SI arises and many would not offer a course of treatment at all if SI were reported [4]. In this observational study of male veterans with hepatitis C, 27% endorsed SI in some form on standard questionnaires, while not taking interferon. Furthermore, new SI developed during interferon therapy in 26% of patients who received antiviral treatment. In spite of developing SI, most patients were able to complete a 6-month course of

Acknowledgments

This work was supported by the Minneapolis Hepatitis C Resource Center, the Research Service of the Department of Veterans Affairs and an unrestricted grant form Schering-Plough. The following people made substantial contributions to the study: Kristen Phillips, Gunnar Larson, Arnold Valerius, William Townsend.

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Suicidal thoughts can arise from a combination of depressive symptoms, anxiety, agitation, and irritability,46 representing the worst complication of IFN-induced depression.113 The incidence of suicidal ideation in patients with HCV has proven to be higher among those treated with INF-based therapy.116 Neurobehavioral symptoms associated with IFN-based therapy have been reported to reduce HRQoL and compromise compliance, thereby reducing its antiviral efficacy.117–119
Hepatitis C virus (HCV) infection is a global health problem that can results in cirrhosis, hepatocellular carcinoma and even death. HCV infection is 3–20-fold more prevalent among patients with versus without severe mental illness (SMI), such as major depressive disorder, personality disorder, bipolar disorder and schizophrenia. Treatment options for HCV were formerly based on pegylated interferon alpha, which is associated with neuropsychiatric adverse events, and this contributed to the exclusion of patients with SMI from HCV treatment, elimination programmes, and clinical trials. Moreover, the assumption of poor adherence, scant access to healthcare and the stigma and vulnerability of this population emerged as barriers and contributed to the low rates of treatment and efficacy.
This paper reviews the literature published between December 2010 and December 2020 exploring the epidemiology of HCV in patients with SMI, and vice versa, the effect of HCV infection, barriers to the management of illness in these patients, and benefits of new therapeutic options with pangenotypic direct antiviral agents (DAAs).
The approval of DAAs has changed the paradigm of HCV infection treatment. DAAs have proven to be an equally efficacious and safe option that improves quality of life (QoL) in patients SMI.
Knowledge of the consequences of the HCV infection and the benefits of treatment with new pangenotypic DAAs among psychiatrists can increase screening, referral and treatment of HCV infection in patients with SMI.
La infección por el virus de la hepatitis C (VHC) es un problema de salud mundial que puede provocar cirrosis, carcinoma hepatocelular e incluso la muerte. La infección por el VHC es de 3 a 20 veces más prevalente entre los pacientes con enfermedades mentales graves (EMG), como el trastorno depresivo mayor, el trastorno de personalidad, el trastorno bipolar y la esquizofrenia. Las opciones de tratamiento para el VHC se basaban anteriormente en el interferón pegilado alfa, que se asocia con efectos adversos neuropsiquiátricos, y esto contribuyó a la exclusión de los pacientes con EMG del tratamiento del VHC, tanto de los programas de eliminación como de los ensayos clínicos. Además, la mala adherencia terapéutica, el escaso acceso de los pacientes a la asistencia sanitaria y el estigma y la vulnerabilidad de esta población surgieron como barreras y contribuyeron a las bajas tasas de tratamiento y eficacia.
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La aprobación de los AAD ha cambiado el paradigma del tratamiento de la infección por VHC. Los AAD han demostrado ser una opción igualmente eficaz y segura que mejora la calidad de vida (QoL) en los pacientes SMI.
El conocimiento de las consecuencias de la infección por el VHC y los beneficios del tratamiento con los nuevos AAD pangenotípicos entre los psiquiatras puede aumentar el cribado, la derivación y el tratamiento de la infección por el VHC en pacientes con EMG.
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Close relationships have been reported between sleep alterations and suicidal behaviors, nevertheless few studies used objective measures of sleep. Such objective markers would be interesting in clinical practice to better screen and prevent suicide. We conducted a systematic review and meta-analysis of published studies examining the relationship between sleep markers and suicidal behaviors using PubMed, Cochrane Library, and Web of Science databases. Actigraphy, polysomnography, and nocturnal EEG were considered. The qualitative analysis retained 15 original studies, including 1179 participants (939 with a psychiatric disorder), and 11 studies were included for the meta-analysis. Current suicidal behaviors were associated with a decreased total sleep time (TST) (SMD = −0.35, [95% CI: −0.66 to −0.04], p = 0.026, I² = 39.8%). The evaluation of possible moderators shows that age, gender, and depression scores had no effects on the random effect model. No significant differences were observed regarding sleep efficiency, REM latency, or percentage of REM sleep. In conclusion, among candidate objective markers, decreased total sleep time seems associated with suicidal behaviors and could be easily used to assess suicide risk. Alterations of regular sleep duration should invite healthcare professionals to screen the cause and propose sleep interventions to prevent suicide.
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Stress homeostatic mediators are the most consistently anomalous biomarkers observed in suicide and may therefore point to a common ‘core biology’ of stress susceptibility, and suicidal behaviour. Previously reported meta-analyses have demonstrated aberrant levels of stress cortisol and inflammatory cytokines in suicide patients compared to controls, and significant associations between the stress regulator FK506-binding protein 51 (FKBP5) gene and suicidal behaviour. Although these independent studies were investigated as separate entities in suicide, stress mediators interact in a dynamic system, collectively giving rise to system changes physiologically, and ultimately psychologically and behaviourally. It is therefore important to study the dynamic network these stress mediators. Network meta-analysis allows for the simultaneous comparison of more than two biological mediators, and for comparisons to be made between mediators that have not been directly compared before, using previously reported, pooled meta data. Such network approaches may help study the complex biological phenomena of suicide and may provide better prediction of biological risk of suicidal states.
This study aimed to establish the comparative relationships between key stress mediators in suicidal patients compared to non-suicidal controls using a random-effects network meta-analysis approach.. The key stress mediators included cortisol, six inflammatory markers (interleukin-6 (IL-6), interleukin-4 (IL-4), interleukin-2 (IL-2), tumour necrosis factor-a (TNF-α), interferon (IFN-y) and transforming growth factor β (TGF-β), and the FKBP5 single nucleotide polymorphism (SNP) allele. Data was derived from three previously published meta-analysis. The study population comprised of 1348 suicidal patients, defined as suicide attempters, completers, or patients with severe suicidal ideation, and 1750 non-suicidal controls, defined as healthy controls and psychiatric patients without suicidal ideation or previous attempts.
Pair-wise indirect effects of stress mediators in suicide compared to controls demonstrated that relative to the effect of the FKBP5 risk SNP allele on suicide risk, the magnitude of differences (suicide vs control) for the levels of IL-2 (SMD −0.72; 95% CI, −0.135 to −0.09 and IL-4 (SMD −0.71; 95% CI, −1.34 to −0.08) were significantly smaller (with 95% confidence intervals not crossing the null). The comparative relationships between stress mediators in suicidal behaviour demonstrates that the dynamic stress network relationship is dysregulated in suicide patients when compared to controls.
This model suggests that a genetic stress susceptibility with downstream abnormal cortisol stress axis functioning, together with anomalous interactions between the inflammatory system, may be one of the neurobiological correlates of suicide behaviour. This biological state may leave the individual physiologically susceptible and unable to cope with environmental stressors, which is consistent with the stress-diathesis hypothesis of suicide behaviour.
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Previous studies have investigated the role of inflammatory markers in suicidality of patients with major depressive disorder (MDD) or panic disorder (PD). However, few studies have investigated associations between serum inflammatory cytokine levels and suicidality. We hypothesized that MDD and PD status might be significantly associated with serum inflammatory cytokines and that we could predict levels of improvement in suicide ideation intensity using serum inflammatory biomarkers in patients with MDD and PD. For this study, 41 patients with MDD, 52 patients with PD, and 59 healthy control (HC) subjects were enrolled. Psychological measurements and serum inflammatory markers such as interleukin (IL) −6, −10, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and C reactive protein (CRP) were examined. A total of five visits were completed during 12 weeks. After controlling for confounding factors, log-transformed IL-6 (ln_IL-6) at baseline (MDD: 0.297 ± 0.626; PD: 0.342 ± 0.723; HC: −0.121 ± 0.858; p = 0.007, >0.0017, 0.05/30) and mean ln_IL-6 (MDD: 0.395 ± 0.550, PD: 0.249 ± 0.544, HC: −0.139 ± 0.622, p = 0.002, >0.0017, 0.05/30) levels were trends towards significantly higher in patients with MDD and PD than in HC. In MDD patients, a higher level of basal ln_TNF-α was a significant predictor of ΔSSI (changes in SSI scores between baseline and week 12) even after controlling for changes of depression symptoms and baseline SSI scores (standardized β = 0.541, p = 0.002 < 0.0028, 0.05/18). In conclusion, we could predict ΔSSI using baseline inflammatory biomarkers for patients with MDD.
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Citation Excerpt :
Reports indicate a pro-inflammatory state associated with suicidal behavior (Brundin et al., 2017). Treatment with interferon alpha has been shown to induce suicidal ideation in patients with hepatitis C (Dieperink et al., 2004). Moreover, increased C-reactive protein (CRP), a marker of systemic inflammation, and pro-inflammatory cytokines have been described in individuals following recent (Gibbs et al., 2016) and remote (Courtet et al., 2015) suicide attempts, (for review see (Black and Miller, 2015)).
One of the main challenges in suicide prevention is the limited understanding of the biological mechanisms underlying suicide. Recent findings suggest impairments in pain processing in acutely suicidal patients. However, little is known about the biological factors that may drive these discrete physiological abnormalities. In this study, we examined plasma peptides involved in analgesic and inflammatory responses and physical pain threshold in acutely suicidal patients.
Thirty-seven depressed patients of both sexes hospitalized for severe suicidal ideation or a recent suicide attempt were characterized clinically including history of suicidal ideation and behavior. Psychological and physical pain, and pressure pain threshold was also measured. Plasma levels of β-endorphin, neurotensin, agouti-related protein (AgRP), C-reactive protein (CRP), adrenocorticotropic hormone (ACTH), and brain-derived neurotrophic factor (BDNF) were run in Milliplex multiplex assays.
The number of lifetime suicide attempts was positively correlated with β-endorphin (r = 0.702; p = 0.007), and neurotensin (r = 0.728, p = 0.007) plasma levels. Higher pain threshold was measured in the suicide attempt group as compared to the suicidal ideation group. Pain threshold was strongly and negatively associated with CRP plasma levels (r = −0.548; p < 0.001). In patients reporting chronic pain, lower AgRP levels and lower pain threshold were observed (t = 4.472; p = 0.001).
Our results suggest that abnormalities in the opioid and neurotensin systems may underlie the increase in pain threshold found in suicide attempters, and possibly risk for suicidal behavior. Targeting pain circuits and systems may provide therapeutic mechanisms for suicide prevention.

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Brief reportSuicidal ideation during interferon-α2b and ribavirin treatment of patients with chronic hepatitis C

Abstract

Introduction

Section snippets

Method

Results

Discussion

Acknowledgments

J Hepatol

Am J Gastroenterol

Gastroenterology

Psychosomatics

Psychosomatics

Neuropsychiatric symptoms associated with hepatitis C and interferon alphaa review

Am J Psychiatry

Brief report
Suicidal ideation during interferon-α2b and ribavirin treatment of patients with chronic hepatitis C