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Psychosomatics 47:93-107, March-April
doi: 10.1176/appi.psy.47.2.93
© 2006 Academy of Psychosomatic Medicine
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Review

Hepatitis C Treatment for People With Severe Mental Illness

Lisa A. Mistler, M.D., Mary F. Brunette, M.D., Bryan J. Marsh, M.D., Robert M. Vidaver, M.D., Ravi Luckoor, M.D., and Stanley D. Rosenberg, Ph.D.

Received May 7, 2004; revised June 16, July 28, 2004; accepted March 31, 2005. From Dartmouth Medical School, Hanover NH and New Hampshire Hospital, Concord, NH. Send correspondence and reprint requests to Lisa A. Mistler, M.D., at the New Hampshire Hospital Unit C, 36 Clinton St., Concord, NH 03301. e-mail: Lisa.A.Mistler{at}dartmouth.edu
© 2006 The Academy of Psychosomatic Medicine


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 CONCLUSIONS
 REFERENCES
 
Over 4 million people in the United States are chronically infected with hepatitis C virus (HCV), and, if untreated, over 20% of these will progress to more serious disease. Persons with severe mental illness (SMI) have markedly elevated rates of HCV infection, but treatment of persons with SMI and HCV has been controversial. Effective antiviral treatment is available, but side effects include depression and other neuropsychiatric symptoms. This article reviews the available data on neuropsychiatric side effects of interferon (IFN) treatment, discusses the limitations of the current research, and makes recommendations regarding HCV treatment in persons with SMI.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
CONCLUSIONS
 REFERENCES
 
The hepatitis C virus (HCV) is a common chronic blood-borne infection, with an estimated prevalence of 1.8% in the United States population. Moreover, an estimated 20% of persons with severe mental illness (SMI)1–3 are infected. Approximately 20% of chronically infected individuals will develop cirrhosis, and approximately 3% will develop hepatocellular carcinoma. The most common transmission risks for persons with SMI are drug-use behaviors and sexual behaviors related to drug use.3–6

The current standard for the medical treatment of chronic active HCV infection is a weekly injected pegylated version of interferon alpha-2b, with daily, oral ribavirin.7–10 Of patients infected with Genotypes 2 and 3, 76%–82% achieve sustained virologic response, as do 50% of patients with Genotype 1.11,12 Higher doses of interferon-alpha cause more effects,11,12 most commonly headache, nausea, fever, muscle aches, and fatigue. The most serious side effects are hematologic abnormalities, which occur in up to 20% of patients.11,13 Tolerance to the common side effects occurs over weeks, and dangerous side effects are managed with dose-reduction. Discontinuation of IFN is most commonly attributed to fatigue.14

NIH Consensus Guidelines indicate that persons with substance use disorders, mental illness, or HIV should be considered for hepatitis treatment on a case-by-case basis. However, most trials of both alpha- and pegylated interferon excluded clients with SMI because of concerns regarding potential psychiatric, cognitive, and other common side effects.15–17 Emerging studies now suggest that persons with SMI can tolerate treatment and that neuropsychiatric side effects are, in some cases, preventable, and, in most cases, treatable. Severe neuropsychiatric side effects due to IFN are uncommon and reversible.

Interferon Side Effects
IFN is a potent inducer of proinflammatory cytokines. Cytokines cause a variety of changes in the brain that lead to symptoms similar to major depression (anhedonia, reduced activity, listlessness, hyperalgesia, altered sleep, altered appetite, and poor memory).18 IFN-induced major depressive disorder (MDD) is classified as a substance-induced MDD by current diagnostic standards.19

To clarify the risk of developing IFN-MDD in patients treated for HCV infection, we surveyed the literature on depression side effects associated with IFN treatment (Table 1). We include studies of at least 10 patients that utilize at least two time-points to assess mood symptoms or IFN-MDD over time. The strongest evidence regarding whether IFN causes mood side effects comes from studies using comparison groups, a design used by only four published prospective studies.20–23 The studies provide mixed evidence for whether IFN is associated with higher rates of mood problems. In two studies that used measures targeting depressive symptoms specifically, mean depression scores on self-report measures were higher in the IFN-treated groups.21,24 In the study by McDonald and colleagues,25 a structured interview was also used, and very high rates of IFN-MDD (62.9%) were found. However, this small patient group was unique in that patients were later found to have high rates of co-occurring, untreated HIV infection. In two studies that did not use ideal measures of depression, the prevalence of depressed mood or depression scores were not different between treated and untreated patients.20,22


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TABLE 1. Incidence of Depressed Mood and Major Depressive Disorder in Patients Treated With Interferon Alpha



Table 1 also lists 13 uncontrolled, prospective studies designed to assess IFN side effects. In six prospective studies using researcher measures to report IFN-MDD prevalence, IFN-MDD occurred in 19.2%–45% of IFN-treated HCV or cancer patients.26,27 One of these studies reported that depressive scores increased,28 and, in another, structured clinician interviews showed mood symptoms to be decreased.29

Seven studies utilizing self-report measures of depression show a wide range of mood changes. In the only clinical trial to use a standardized self-report measure of depression, Bernstein et al.14 assessed 448 HCV patients with the Beck Depression Inventory and found that 18% of HCV patients developed mild depressive symptoms, and an additional 15.7% developed moderate-to-severe IFN-MDD. Three other studies found IFN-MDD in 25.9%–33% of patients,30–32 whereas two found depression symptoms in only 5.2%33 to 9.5%,34 and two reported no change in depressive symptoms over time or no new diagnoses of IFN-MDD.35,36 In summary, studies using researcher-administered measures designed to assess depression showed that about one-third of persons experienced IFN-MDD, whereas studies using self-report measures reported a wide range, from 0% to 33%.

Industry-funded IFN trials use physician report, rather than more rigorous researcher measures, to assess depressive side effects, and tend to exclude persons with psychiatric symptoms or history. Seven prospective clinical trials of IFN (in HCV or cancer patients)13,37–42 reported that approximately one-fourth (9%–40%) of IFN-treated patients experienced mood symptoms (not IFN-MDD), a much higher rate than the low rates reported in retrospective studies (0.9%–2.2% of HCV or melanoma patients).43,44 A recent trial of intramuscular pegylated IFN (dosed weekly) suggests that depressed mood occurs less often with this medication than the old type of oral IFN-alpha (20% versus 30%).38

Rate of withdrawal from IFN treatment due to mood changes is another indicator of the burden of mood changes. Notably, retrospective studies of HCV-infected psychiatric patients report that only 6%–18% of patients withdrew from IFN treatment for any reason.45,46 Withdrawal due to depressive symptoms in other studies (Table 1) ranges widely, from 0.04%13 to 21.6%,39 and up to 45%, in a small sample of melanoma patients.46 Many prospective studies document suicidal thoughts in small numbers (0.33%–3.4%) of IFN-treated patients,14,40,43 but higher rates have been reported in intravenous drug users with HCV (19.2%47). Two studies26,29 reported that suicidal thoughts were reduced, rather than elevated, after 3 months of IFN treatment. Retrospective studies and large retrospective surveys report suicide attempts in 2 of 11,241,48 3 of 2,575,26 and 2 of 987 patients;44 others report completed suicides: 1 in 72139 and 2 in 2,575.26

Clinical lore suggests that higher doses and longer length of IFN treatment lead to worse mood problems,43 but evidence from prospective studies and clinical trials does not support this contention.22,26,32,41,42,49,50 The evidence is also mixed as to whether mood symptoms peak early (e.g., 2–6 weeks)21or later (e.g., 3–6 months).31 Changes in mood and cognition tend to occur weeks or months after treatment, in contrast to changes in energy, appetite, and psychomotor speed, which occur within days.28,29,31,40,51 Neither social support nor gender appear to be related to the development of depression.24,52,53 Moreover, depression symptoms usually resolve rapidly when treated with antidepressant medication or when the IFN is discontinued.24,40

Little research has addressed the question of whether previous psychiatric illness increases the likelihood of developing psychiatric symptoms during IFN treatment. Although two groups 45,54 documented that 82%–94% of persons with significant psychiatric disorders were able to complete IFN treatment without "clinical problems," no research has systematically studied IFN treatment and side effects in persons with severe psychiatric disorders such as schizophrenia and bipolar disorders. Other studies included persons with psychiatric disorders and monitored them over time. In 7 of 10 prospective studies, baseline depressive symptoms predicted the development of MDD during IFN treatment.28,45,46,52,55,56 In contrast, four other studies found that previous history of depressive disorder did not predict the development of depression symptoms.27,33,36 Two retrospective studies found that a history of psychiatric illness or neurologic illness40,57 was associated with psychiatric or neurologic symptoms during treatment.

In summary, the strongest research suggests that mild-to-moderate depression symptoms occur in 20%–40% of IFN-treated patients, whereas severe IFN-MDD occurs in fewer than 10%. Depression symptoms at the time of treatment initiation increase the likelihood of developing depression during IFN treatment, but, as will be discussed later in this article, the depressive symptoms that develop during IFN treatment appear to be treatable with antidepressant medication.

Other Neuropsychiatric Symptoms Induced by IFN
Anxious mood has been reported in up to one-fourth (7.4%–28.1%) of untreated HCV patients49,58–61 and in about one-fifth (2.0%–16%) of IFN-treated HCV patients.27,31,42 Two prospective studies reported an increase in anxiety symptoms over time during IFN treatment,42,46 whereas another reported a reduction in the number of patients with anxious mood.31 In a retrospective study, only 1.4% of 943 treated HCV patients were diagnosed with IFN-induced anxiety disorder, and all were able to complete IFN treatment.62 IFN-induced anxiety appears to be mild and uncommon.

Few data are available to inform clinicians about the risk for other psychiatric symptoms, such as mania or psychosis, or whether persons who live with SMI are at risk for illness exacerbation. Several groups found good tolerability of IFN treatment in SMI patients45,54 and low rates of treatment-discontinuation in psychiatric patients,27,45,63 but two retrospective studies found increased neurologic or psychiatric symptoms in psychiatric patients.40,57 Case reports document that mania and psychosis occur in small numbers of IFN-treated patients,26,64–69 but no prospective studies carefully assess their incidence in persons with psychiatric disorders.

IFN treatment may induce cognitive impairment (e.g., in memory and concentration), in addition to the cognitive problems associated with untreated HCV infection, which have been reported in up to 50% of HCV patients.59,60 Formal prospective neuropsychological testing in treated individuals, compared with control subjects, offers the most accurate measure of the prevalence and type of cognitive changes with IFN treatment. However, only three small studies prospectively assessed cognitive functioning with neuropsychological testing in IFN-treated patients (Table 2).20,35,50 The only prospective, randomized, controlled trial of IFN treatment using neuropsychological testing (in melanoma patients) found no differences in measures of concentration or memory between persons taking IFN and control subjects.20 A small, uncontrolled, prospective study of IFN-treated HIV patients showed no change in cognitive functioning over time.35 In contrast, Capuron and colleagues49 showed slowing of cognitive performance, which started after days of treatment and correlated with depression symptoms after 1 month of treatment. An uncontrolled prospective study of HCV patients found that 34% of 56 patients experienced decreased cognitive functioning, which correlated with EEG changes, but not with depression scores.70 The results of two prospective studies using self-report measures, which document subjective changes in memory and concentration, also conflict,53,71 but up to 30% of patients reported problems with concentration. Three other prospective studies used unstructured clinical assessments. One reported the development of cognitive problems in 13% of IFN-treated patients with cancer,72 and two reported delirium in about 5% of patients with cancer or chronic viral infections.29,33,40,72 Similarly, a cross-sectional study using neuropsychological testing found that cancer patients treated with IFN experienced more problems in cognitive speed, verbal memory, and executive functioning than untreated cancer patients.73 Three case series (N=46) further documented problems with memory, concentration, slowing, and delirium.29,74 Renault et al.32 and Adams et al.73 reported that delirium and cognitive changes were associated with a history of or current cerebral insult, such as brain injury or metastases. Cognitive problems resolved with discontinuation of medication44,70 or treatment with antidepressant medication.46,75


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TABLE 2. Cognitive Side Effects of Interferon Treatment



Summary of IFN-Induced Cognitive Changes
Problems with cognitive functioning have been reported in patients with chronic HCV infection, but evidence of IFN-induced cognitive decline is mixed and mostly limited to small, uncontrolled studies. The best research to-date suggests that use of moderate-dose IFN to treat persons with HCV is unlikely to cause significant cognitive problems in the majority of persons who do not have a history of previous cerebral insult. Further studies of cognitive side effects of IFN treatment of HCV patients are needed.

Potential Mechanisms of Neuropsychiatric Side Effects
Using brain imaging, EEG, and assays of hormones and peptides, studies in animals and humans show significant changes during treatment with IFN-alpha, pointing to potential mechanisms by which this medication causes changes in mood and cognition. One PET76 and two EEG56,70 studies showed IFN-induced frontal lobe changes in the brain associated with change in incentive or ability to perform cognitive, verbal, or motor tasks. IFN-alpha may induce a toxic encephalopathy (delirium), which interferes with frontal lobe functioning, particularly when the medication is delivered in high doses or to persons with previous brain injury. When the medication is used in low or moderate doses, subjective or milder objective cognitive changes can occur, possibly related to the IFN-induced depressive disorder75 or milder encephalopathy.70

IFN-induced depressive symptoms and disorders are thought to be due to cytokine-induced abnormalities in the hypothalamic-pituitary-axis, neurotransmitter systems, or other mechanisms.77 In cancer patients who develop IFN-MDD, ACTH and cortisol were increased.78 In animals, serotonin metabolism was altered after IFN treatment, shunting tryptophan away from serotonin production.75 In IFN-treated humans, serum 5-HT and plasma tryptophan were reduced, and serum kynurenine was increased,26 suggesting that IFN induces depression through catabolism of tryptophan to kynurenine, resulting in lowered serotonin levels. This hypothesis is supported by the effectiveness of serotonin-reuptake inhibitors in treating IFN-MD.46 Also, studies in animals and humans showed that IFN depleted dopamine, slowed metabolic activity in the prefrontal cortex, and increased activity in the putamen and globus pallidus, similar to the abnormalities of Parkinson's disease.79 These changes in the frontostriatal areas correlated with IFN-induced psychomotor slowing, fatigue, and anhedonia, suggesting that dopaminergic agents may reduce slowing; however, these agents have not been formally tested in IFN-treated humans.

Prevention and Treatment of Neuropsychiatric Side Effects
Education, assessment, monitoring, and medication treatments are important aspects of the management of neuropsychiatric side effects of interferon (IFN).38,45,80–83 Education before treatment is recommended for helping clients anticipate and manage side effects,80 and patients must be assessed at baseline and monitored regularly and frequently for neuropsychiatric symptoms.

Table 3 summarizes studies on the impact of antidepressant treatment on IFN-MDD; these include one randomized, placebo-controlled trial of prevention,46 three open-treatment trials,14,30,84 and four treatment case reports.85–88 One controlled study reported that pretreatment with antidepressant medication dramatically reduced the development of IFN-MDD.46 Uncontrolled studies using antidepressants to treat newly-emerged IFN-MDD report improvements in 73.3%–90% of patients.14,30,84 Four case reports (N=21) also report improvement in depression and anxiety symptoms with antidepressant medication.56,85,86,88 One study71 reported that mood and cognitive symptoms responded to antidepressants, whereas fatigue and anorexia did not. Naltrexone treatment resulted in improvement in cognition and emotional symptoms in five of nine IFN-treated CML patients.89


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TABLE 3. Antidepressant Treatment of Depression in the Context of Interferon-Alpha Treatment



In summary, small, uncontrolled studies suggest that antidepressant treatment of IFN-MDD (including related cognitive problems) is effective, but larger controlled studies are needed, and the mechanisms of the medication's impact on IFN-MDD are still unclear.75 It is currently recommended that persons with depression symptoms at baseline should be offered antidepressant medication and that IFN treatment should be delayed until symptoms abate. Also, pretreatment with antidepressants may prevent the development of IFN-MDD46 in persons without baseline symptoms, but some experts recommend waiting to use antidepressant medications until depression side effects emerge.84 If IFN treatment-emergent depressive symptoms are severe or a patient elects to avoid medication treatment of them, IFN discontinuation may be necessary. Case reports also suggest that IFN-induced mania and psychosis also respond to IFN discontinuation.68,69

Treatment of Persons With Severe Mental Illness and Hepatitis C Virus
Despite concerns about the ability of severely mentally ill clients to tolerate side effects and adhere to HCV treatment, the feasibility and safety of treating SMI clients has been demonstrated.54,56,90 Three published studies54,56,91 report good treatment adherence, low drop-out rates, and good side-effect tolerability in psychiatrically impaired patients by using assertive psychiatric management, close monitoring, and adjustment of psychiatric medication to address the psychiatric side effects of antiviral medications. Equal rates of viral response were also reported in persons with mental illness and/or drug addiction. However, additional systematic trials of treatment adherence, side-effect management, and HCV treatment outcome for people with SMI are needed to confirm these observational studies.

Treatment of HCV-Infected Persons With SMI and Comorbid Substance-Use Disorders
Persons infected with HCV are advised to avoid all liver toxins, including alcohol. Although one study showed that heavy alcohol use was correlated with lack of treatment response in methadone patients with HCV, medication nonadherence, rather than toxic effects of alcohol, mediated that lack of response.92 Thus, rather than simply withholding treatment from persons with substance-use disorders, their ability to attend appointments and adhere to medication should be demonstrated before initiation of HCV treatment. Also, integrated dual-disorder treatment is effective for persons with SMI,93 and it should be offered.

Treatment of Patients Co-Infected With HIV
Co-infection with HIV is common in clients with SMI. For example, in a recent study of SMI clients in a large urban area, 15% of all HCV-positive participants were HIV-co-infected, and 67% of those seropositive for HIV were also HCV-positive.94 Although HIV co-infection may complicate the course and treatment of HCV, it also increases the importance of treatment.95 Morbidity and mortality are more common in co-infected groups, as compared with matched HIV- or HCV-mono-infected patients.96,97 HCV treatment is safe and tolerable in co-infected individuals,98,99 but studies to-date do not assess whether treatment outcomes are as good, and co-infected patients may be more likely to develop psychiatric side effects from IFN.24

Co-infected patients with mental illness need the same type of intensive supports and psychiatric assessment that other mono-infected patients need. Taylor et al.99 demonstrated that a nurse and case-manager team can effectively deliver this assessment and support to co-infected patients with mental illness and/or substance-use disorders. However, those prescribing psychotropic medications need to be aware of the potential for interactions between medications used to treat infectious disease and those used to treat psychiatric illness. Psychotropic medications that share the same metabolic pathways as HCV medications should be used judiciously.

Treatment Recommendations for SMI Patients With HCV
Persons with severe mental illness (SMI) who meet medical criteria for hepatitis C virus treatment should be offered HCV treatment if they are able to attend medical appointments, are engaged in psychiatric and substance-abuse treatment, and are willing to be monitored by psychiatric and medical staff. When treating persons with SMI, proper informed-consent processes should be applied. Education about the effectiveness of the treatment and the potential for occurrence of reversible and treatable neuropsychiatric side effects should be provided. SMI patients, like all IFN-treated patients, should be frequently monitored for neuropsychiatric side effects as well as recurrence of substance-abuse and psychiatric-disorder symptoms. SMI patients may require increased support by case-management and therapeutic staff. Antidepressant pretreatment for IFN-MDD should be offered to clients with current or past mood disorders, and other psychopharmacologic interventions should be enhanced as needed.


  CONCLUSIONS

 
TOP
 ABSTRACT
 INTRODUCTION
 CONCLUSIONS
REFERENCES
 
A growing literature documents the neuropsychiatric side effects of interferon treatment for hepatitis C infection, predominantly, mood changes, which are preventable and treatable with antidepressant medications. The bulk of the data come from small studies, most of which did not include persons with severe mental illness. However, the evidence to-date suggests that persons with severe mental illness can be safely and effectively treated for hepatitis C virus infection. Medically eligible persons with SMI should be offered hepatitis C virus treatment. Further research is needed to clarify the risks and benefits of hepatitis C virus treatment in persons with severe mental illness.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 CONCLUSIONS
 REFERENCES
 

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