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Psychosomatics 48:405-411, September-October 2007
doi: 10.1176/appi.psy.48.5.405
© 2007 Academy of Psychosomatic Medicine
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Hepatitis C in Schizophrenia: Screening Experience in a Community-Dwelling Clozapine Cohort

Oliver Freudenreich, M.D., Rajesh T. Gandhi, M.D, Jared P. Walsh, B.A., David C. Henderson, M.D., and Donald C. Goff, M.D.

Received September 2, 2005; revised May 26, 2006; accepted June 13, 2006. From the Massachusetts General Hospital Schizophrenia Program, the Division of Infectious Diseases and Partners AIDS Research Center; the Division of Psychiatry and Medicine, and Harvard Medical School, Boston, MA. Send correspondence and reprint requests to Oliver Freudenreich, M.D., MGH Schizophrenia Program, Freedom Trail Clinic, 25 Staniford St., Second Floor, Boston, MA 02114. e-mail: ofreudenreich{at}partners.org
© 2007 The Academy of Psychosomatic Medicine


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 REFERENCES
 
Hepatitis C virus (HCV) infection occurs in up to 20% of patients with chronic mental illnesses. To determine the prevalence of hepatitis C in a diagnostically well-defined sample, the authors screened all schizophrenia outpatients in a clozapine clinic (N=98) for HCV antibodies. Eight patients were positive for hepatitis C antibodies (antibody-positive prevalence: 8.2%); of those, 50% had detectable viral loads (viremia-positive prevalence: 4.1%). Screening for HCV infection should be considered for outpatients with schizophrenia. However, clinical experience treating HCV in schizophrenia patients is limited; in this cohort, 2 years after screening, no patient had received interferon/ribavirin treatment.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 REFERENCES
 
Hepatitis C virus (HCV) is estimated to affect almost 2 out of every 100 Americans.1 This amounts to 4 million infected Americans, of which 2.7 million have chronic viremia. Hepatitis C is the most common reason for liver transplantation in the United States. An estimated 10,000 people die each year from causes related to hepatitis C infection. This means that more people die from hepatitis C than from AIDS.2

The most important risk factor for HCV infection is current or past injection drug use (IDU).3 Because hepatitis C may be clinically silent for many years, screening for HCV is advised for high-risk populations such as injection drug users (IDUs). Screening is potentially beneficial because it allows patients who are found to have HCV to seek treatment that can eradicate the infection. Successful treatment eliminates the risk of transmission to other people, and it prevents the consequences of chronic hepatitis C infection, such as hepatocellular carcinoma, liver cirrhosis, and liver failure.

A significant minority of patients with schizophrenia have comorbid IDU or other high-risk behaviors that place them at risk for HCV infection. Estimates of hepatitis C infection in cohorts of patients with mental illnesses, including schizophrenia, have ranged from 8.5% to 19.6%.4,5 The NIMH/Veterans Administration (VA)-sponsored Rosenberg study5 was the first study to comprehensively assess the medical morbidity from human immunodeficiency virus (HIV), HCV, and HBV (hepatitis B virus) in a variety of settings, not just in inpatient or defined-treatment settings chosen for convenience of sampling. Nine hundred thirty-one severely mentally ill in- and outpatients from four geographically different regions underwent serological testing for the aforementioned infections; the rates for HIV, HCV, and HBV were 3.1%, 19.6%, and 23.4%, respectively. In a quality-improvement project, Al Jurdi and colleagues6 found that 10.5% of inpatients with psychosis were positive for hepatitis C. This is similar to the prevalence rate of 6.2% reported by Nakamura and colleagues for schizophrenia inpatients in Japan.7 One study from the United States reported a much higher prevalence rate: 20.3% in 535 chronically hospitalized psychiatric patients.8 In a study of 4,644 patients with schizophrenia treated in the Veterans Affairs (VA) system, 47.5% of patients were screened for hepatitis C (the VA has been at the forefront of the fight against hepatitis C and actively supports systematic screening of high-risk populations); 9.9% of patients with schizophrenia were antibody-positive for hepatitis C.9 In a survey of 141 patients with schizophrenia from a cohort in Baltimore, MD, the majority (70%) reported that they had been tested for HIV, but only a minority (12%) were certain they had been screened for HCV.10 This points to a lack of awareness of hepatitis C among patients and providers, since HIV and HCV share common risk factors.

We screened a diagnostically well-defined outpatient sample of clozapine-treated schizophrenia patients. Our clinical goal was to identify new cases of chronic hepatitis in order to refer them for treatment with interferon/ribavirin. Here, we report on the prevalence we found in our sample and on some of the clinical issues we encountered. We also selectively review the limited literature on schizophrenia and hepatitis C to make recommendations regarding screening and interferon treatment for patients with schizophrenia. We hope that our report contributes to an increased awareness of the need to incorporate screening for hepatitis C in the treatment plan of outpatients with schizophrenia.

For a general review of hepatitis C and severe mental illness, please see the recent review by Mistler and colleagues.11 An excellent general resource on all aspects of hepatitis C care is the website of the Veterans Affairs National Hepatitis C Program (www.hepatitis.va.gov).


  METHOD

 
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 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 REFERENCES
 
We screened all patients in the Freedom Trail Clinic’s clozapine clinic for the presence of hepatitis C antibodies. No patient (or their guardian) declined testing, which was done for clinical purposes. The Freedom Trail Clinic is located in downtown Boston and serves a typical urban population. Our clozapine clinic accepts referrals from other hospitals and programs in the greater Boston area as well as from our own general-psychiatry clinic. Many of our clozapine-treated patients are at least partially refractory to treatment, and a small subgroup is hospitalized at least once per year for stabilization. Most patients have been on clozapine for many years. About 11% of patients are under guardianship.

Screening took place over a period of 4 months, from October 2003 to January 2004, by use of an enzyme immunoassay test (EIA) to detect hepatitis C antibody (Abbott Laboratories’ HCV EIA 2.0). Positive antibody results were followed up with a qualitative HCV RNA assay, followed by a quantitative HCV RNA assay, if indicated. We also recorded demographics and laboratory values (complete blood-count and liver-function tests) closest to the screening date. Charts of patients identified as HCV-positive were reviewed for risk factors. The study was approved by the responsible Institutional Review Board and received a waiver for informed consent.

Statistical Analysis
We used descriptive statistics to characterize the sample. Depending on the nature of the variable, two-tailed t-tests and Fisher’s exact test were used to compare laboratory values and demographics between hepatitis C-positive and hepatitis C-negative patients. The level of significance was set at 0.05.


  RESULTS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
REFERENCES
 
The study sample consisted of 98 patients; 92 patients were diagnosed with schizophrenia, 6 patients with schizoaffective disorder. The mean age of the cohort was 44.7 years, ranging in age from 21 to 71 years. Three-quarters of the patients were men, one-quarter women; 90% of patients were white. As a given, all patients were treated with clozapine.

Eight patients of the total sample of 98 were positive for hepatitis-C antibodies. This amounts to an HCV antibody-positive prevalence of 8.2%. Of those eight patients, 50% had detectable HCV RNA (HCV viremia prevalence: 4.1%). As compared with hepatitis-C antibody-negative patients, hepatitis-C antibody-positive patients had significantly higher transaminase levels: ALT 38 U/liter (standard deviation [SD]: 29.4) versus 26 U/liter (SD: 14.7; t[96]=2.1; p=0.04); AST 30 U/liter (SD: 18.9) versus 21 U/liter (SD: 7.2; t[96]=2.6; p=0.01). Mean values, however, were not outside the range for normal values for transaminases for our laboratory (ALT: 0–50 U/liter; AST: 0–45 U/liter). Two of the eight patients had mild transaminase elevations that were outside the normal range for our laboratory; both of these patients had HCV viremia. In this small sample, there were no significant demographic differences between seropositive and seronegative patients.

Only one of the eight hepatitis C-positive patient had been known to have hepatitis C, and he was known to be dependent on cocaine, including IDU. For three other patients, "polysubstance abuse" was recorded in the chart, but there was no suggestion that this had included IDU. Four patients had no clear risk factors on chart review.

Although all patients were referred for further testing and treatment, 2 years after the screening, no patient had been treated with interferon.

Should All Patients With Schizophrenia Be Screened for Hepatitis C Infection?
Even in our small cohort, screening detected several previously undiagnosed cases of chronic hepatitis C infection. We found that the rate of hepatitis C seropositivity was increased fourfold in our sample of well-characterized and rather typical schizophrenia outpatients on clozapine, as compared with published estimates for the general population. Many subjects had been long-term patients in our clinic and entered the mental health system before hepatitis C was recognized as a prevalent condition. Hepatitis C virus was only discovered in 1989,12,13 and widespread screening became possible after the first commercial test became available in 1991. Thus, many patients with schizophrenia had entered the treatment setting before the test for HCV was available. Although the incidence of new infections has been decreasing since screening of the blood supply was initiated, undoubtedly, more cases of already-infected patients will be diagnosed in the decades to come.

However, although we detected new cases, not a single eligible patient received treatment, and one patient became rather unstable psychologically after the discovery of his infection. The reasons for non-treatment were all related to patients’ refusing further work-up or not following up with referrals. Only one patient eventually saw a specialist but refused the liver biopsy, which was recommended to assess the need for treatment. This was the patient who had a period of clinical instability, with several emergency evaluations, after the discovery of his hepatitis C infection. Several patients argued that they would not need treatment because they felt normal. However, our sample may not be representative of all patients with schizophrenia, and less-severe populations might be referred and treated with more success. Our sample was also not representative because all patients were on clozapine, which might bias against interferon treatment. We note, however, that this was not the reason for patients’ not getting treatment.

Despite our failure to enroll patients into treatment for chronic hepatitis, there are several reasons for screening beyond treatment of hepatitis C with interferon/ribavirin. First, screening and discussion about it provides a teaching opportunity about safe sex and drug use, not just for transmission of hepatitis C but also for HIV. Second, a positive screening test can lead to additional tests (e.g., HIV testing), and the discovery of other treatable illnesses. Third, the discovery of chronic hepatitis C may allow the prevention of additional liver damage (e.g., by vaccinating patients for hepatitis A and B) and may motivate patients to engage in treatment for alcohol use.14 And, last, knowing that an individual is viremic can add to protection for caregivers and family.

Therefore, it seems prudent to recommend that patients with schizophrenia who admit to any risk factor be offered testing for hepatitis C, even if treatment is not a likely outcome. The CDC recommends testing high-risk patients.15 Patients who have injected drugs even once are at risk, something that is not always understood by patients who do not consider themselves IDUs if they have ceased using drugs. Persistently elevated ALT levels of unclear origin are clearly an indication for hepatitis C testing, as was the case in two of our four viremic patients. However, up to 30% of patients with HCV infection present with normal ALT values,16 so testing for HCV should be considered in any patient with risk factors for this infection.

We would have missed several cases had we relied on a history of risk factors alone, rather than conducting universal screening. Because patients, when psychotic, might do things they are either ashamed of or simply do not remember, an argument can be made that all patients who have had a psychotic episode should be offered screening. The current cohort of middle-aged patients with schizophrenia might have experimented with drugs in the remote past and simply do not see this as relevant many decades later. In the general public, the greatest number of patients acquires hepatitis C from IDU. Other risk factors include blood transfusions before 1992, body-piercing and tattooing, and sharing of toothbrushes or razors. Intranasal cocaine use is a risk factor, as well (if infected straws are used). Sexual transmission seems to be rare (under 5%), but, nevertheless, possible. Although sexual activity might be reduced in patients with schizophrenia, they are by no means asexual, and some are at higher risk for sexual victimization or exploitation. Vertical transmission is possible, as well.

It should be noted that there is one dissenting opinion regarding screening. The United States Preventive Services Task Force (USPSTF) not only recommends against routine screening for hepatitis-C infection in asymptomatic adults in the general population, but also did not find compelling evidence for or against screening in high-risk populations. This recommendation is based in part on the fact that most who are infected will not develop cirrhosis or other major negative health outcomes.

In sum, even if few patients with schizophrenia move on to receive treatment for hepatitis C at this point, they might still benefit from knowing their hepatitis-C status and from longitudinal monitoring. The CDC suggests treatment for patients "at risk for cirrhosis" and a "watch-and-wait" approach for patients without fibrosis and with normal liver-function tests. In the future, we would hope that better-tolerated treatments for hepatitis C that are not based on interferons (i.e., drugs that directly target HCV viral replication or protein assembly in a fashion similar to current antiretroviral medications for HIV disease) will become available that then could be offered to previously-identified infected patients.

Is Interferon Contraindicated in Patients With Schizophrenia?
Current treatment of HCV is with subcutaneous interferon-alpha in combination with oral ribavirin. Interferon-alpha is a cytokine that initiates events in cells that make them more resistant to viral infections. It does not cross the blood–brain barrier. Interferon-alpha is clinically available as interferon-alpha2a and alpha2b, both in a polyethylene glycol-conjugated formulation ("pegylated"). These formulations have greatly improved the clinical management of HCV infection: interferon has to be given three times per week, whereas the pegylated forms of interferon reduce the injection frequency to once per week. Interferon is renally eliminated and does not have drug interactions with medications commonly used to treat schizophrenia. Ribavirin is a nucleoside analog that depletes intracellular guanosine triphosphate. Similar to interferon, no cytochrome P450 interactions are known.

Treatment with interferon might have benefits beyond elimination of future liver toxicity. HCV is not only a hepatotropic but also a neurotropic virus, which can be detected in cerebrospinal fluid.17 It is thus possible that some clinical manifestations, like fatigue, cognitive difficulties, and depression are the direct result of the viral infection, not simply the result of immune system activation.18 In patients with schizophrenia, this might be difficult to determine because of negative and cognitive symptoms from the schizophrenic process, itself. If there is an interaction between hepatitis C and cognition, one could argue that this would represent an additional insult to an already-compromised brain and that patients with schizophrenia should therefore receive even more aggressive treatment.

Patients should be excluded from receiving interferon/ribavirin if the risks of treatment outweigh its benefits. However, complicating any such risk/benefit estimation is the fact that the true risk of interferon/ribavirin treatment is not known for patients with preexisting psychotic disorders because such patients were excluded in registration trials.

One obvious concern is the development of psychosis from interferon, with the risk of a full psychotic relapse. However, whereas, in most treatment cohorts, depression and, less frequently, mania have been reported, psychosis (with hallucinations and delusions) is a rather uncommon complication. It is, nevertheless, a possible complication, and the package insert lists psychosis as a possible side effect of interferon. Hoffman and colleagues19 reported on a case-series of four hepatitis C/HIV co-infected patients who developed new-onset psychosis after treatment for HCV; unfortunately, no denominator is given for the treatment trial population. One case report of a patient on methadone maintenance describes the development of psychosis that did not abate after interferon was stopped.20 A retrospective study of 11,241 HCV mono-infected patients at 73 centers in Italy found 9 patients who developed psychosis de-novo while receiving interferon treatment.21 Nozaki and colleagues22 found only four reported cases of psychosis in patients receiving interferon therapy for HCV in their review of the Japanese literature.

Anecdotal reports of interferon given to patients with schizophrenia are reassuring about the safety of this medication in schizophrenia. It is encouraging that one detailed case report of a schizophrenia patient who was followed with serial ratings of a scale for schizophrenia, the Positive and Negative Syndrome Scale (PANSS), found no meaningful fluctuations in observed psychopathology during interferon treatment.23 Schafer and colleagues24 describe the development of depression, but not psychosis, in a stabilized patient with schizoaffective disorder. Similarly, in one diagnostically mixed treatment cohort that included six schizophrenia-spectrum patients, no problems were seen.25 Last, Van Thiel and colleagues26 reported their successful treatment of hepatitis C in 31 consecutive patients with psychiatric comorbidities, including 13 patients with schizophrenia. In this treatment cohort, 29 patients completed 6 months of interferon, and 15 patients (48%) successfully cleared HCV RNA from serum. Worsening mania was the cause for treatment interruption in the two cases that did not finish the 6 months of interferon treatment.

There are several specific unanswered questions relevant to treatment of schizophrenia patients with HCV. Despite reports attesting to the apparent safety of giving interferon to patients with schizophrenia, it remains uncertain whether patients with schizophrenia are more susceptible to interferon effects than patients without schizophrenia. One model of interferon-induced depression suggests that at least part of the clinical picture may result from chemically-induced tryptophan depletion.27,28 In treated schizophrenia patients, tryptophan depletion has very little clinical effect.29 Another unanswered question is whether HCV+ patients on antipsychotic drugs have the same treatment response to interferon. This is a concern because many antipsychotics, including clozapine, affect the immune system.30 Finally, giving interferon/ribavirin to patients on antipsychotics is feasible; however the overlapping bone marrow toxicity of clozapine and HCV treatment is a concern.

What Is the Role of the Psychiatrist If Treatment of Hepatitis C Is Contemplated?
The role of the psychiatrist is threefold: 1) advocating for treatment inclusion if indicated; 2) assessing patient competency; and 3) supporting the medical treatment team in the multimodal assessment and treatment.

The psychiatrist’s role is crucial and is reflected in the CDC’s recommendation to treat the patient comprehensively, with close collaboration between psychiatrist, primary-care physician, addiction specialist, and hepatologist. There is pragmatic appeal to integration of services for patients with the triple challenge of infectious, psychiatric, and substance-use disorders, although the exact nature of integration strategies has yet to be worked out.31 The STIRR model (for Screen, Test, Immunize, Reduce risk, Refer) is an evidence-based intervention package that has been successfully implemented in community settings.32 In this model, a mobile team of specialists delivers the STIRR intervention at the site of mental health care. On a larger scale, an exemplary model of comprehensive care has not only been championed but successfully implemented in the VA system. However, even in such systems, which are set up to provide comprehensive screening, assessment, and care, successful treatment of most patients remains an elusive goal. Rifai and colleagues33 found that only 33% of patients in a VA medical center received treatment after referral to a gastroenterologist for positive HCV antibodies; 21% of referred patients did not attend the specialty consultation. Clearly, much work needs to be done to determine how to engage patients more successfully. The supported medical care (SMC) model combines chronic-illness self-management and enhanced case management.34 It is a conceptual model that addresses both the integration of services and the engagement of patients.

During the initial discussions, psychiatrists can be involved in determining that a patient is competent to agree to or refuse interferon-based treatment, with a full understanding of its risks and benefits. Hepatologists may be more willing to treat patients with schizophrenia if they believe that a patient receives close psychiatric monitoring (i.e., frequent and regular visits with the psychiatrist and routine use of rating scales [such as the Beck Depression Inventory as the preferred rating scale35]) to serially monitor for the emergence of depression, etc. Neuropsychiatric side effects are to be expected in the treatment of hepatitis C, with prevalence rates reported in up to 70% of patients.36 Most reviews of interferon focus on the propensity for inducing depression, but other possible neuropsychiatric syndromes include mood lability, mania, irritability, and cognitive problems, including confusional states,37 as well as the above-reviewed potential for rare psychosis. Constant and colleagues38 have questioned the conceptualization of interferon-induced mood states as mere depressions. In their prospective study of mood changes with interferon, they found that interferon-induced mood syndromes often consisted of an overlap between hypomanic/manic and depressive symptoms, resembling mixed mood states, with rather prominent irritability and anger. These changes were apparent as early as Week 4 after initiation of interferon therapy.

The final decision regarding whether to treat HCV infection takes into account several factors, including viral genotype, degree of fibrosis on liver biopsy, efficacy of interferon/ribavirin, side-effect tolerability, substance use and social situation, and patient preference. Rifai39 proffered a risk/benefit analysis that weighs two main factors: the likelihood of viral clearing (i.e., viral load and genotype) and the likelihood of interferon-induced neuropsychiatric side effects. Although his analysis model provides a good starting-point for a risk/benefit discussion with a patient, each case still needs to be considered individually because we simply do not have the data to predict outcomes with sufficient accuracy in patients with schizophrenia. Other psychiatric variables that might need to be incorporated into future prediction models include social and psychological variables such as the mode of acquisition and the patient’s interpersonal style.40

Summary
We conclude that universal HCV screening of patients with schizophrenia is reasonable, given that prevalence of infection in many cohorts of schizophrenia patients is higher than in the normal population. Although not all patients will be treated with interferon/ribavirin, there are many other potential benefits from diagnosis of asymptomatic HCV infection. The risks of treatment for schizophrenia patients with interferon are not known, but they are not necessarily higher than for other populations (e.g., with comorbid substance use or depression). Where collaborative and comprehensive systems of care have been implemented, previously-excluded patient populations have been successfully treated with interferon.

Although previous HCV treatment guidelines excluded patients with chronic mental illness, current guidelines from the National Institute of Health (NIH) and the Centers for Disease Control (CDC) recommend a more proactive and inclusive approach to hepatitis C treatment. We therefore encourage psychiatrists to be advocates for treatment with interferon if medically indicated unless very specific reasons argue against it.

Several issues in the treatment of hepatitis C in schizophrenia patients remain unresolved. Studies of these issues, and others, are critical to advancing the care of schizophrenic patients with HCV:

  • What is the risk of interferon-induced neuropsychiatric side effects in schizophrenia? What is the spectrum of possible neuropsychiatric effects?
  • What rating scales best capture the possible range of neuropsychiatric and psychiatric changes and longitudinal effects of treatment?
  • When should patients with schizophrenia be excluded from treatment with interferon? Is clozapine treatment an absolute or relative contraindication to interferon treatment?
  • What are the circumstances under which patients with impaired decision-making capacity should be treated with interferon, in cases where assent is given and in cases where treatment is refused?
  • What effects do antipsychotics have on course of hepatitis C infection and response to interferon, given the modifying effects of many antipsychotics on cytokine networks?
  • Does infection with hepatitis C impair brain functioning in patients with schizophrenia over and above the effects of schizophrenia itself?


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 REFERENCES
 

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