Of all the patients that hepatologists routinely treat, those with hepatitis C virus (HCV) are those most likely to also be suffering from psychiatric and addictive disorders. The Five-Site Health and Risk Study examined the prevalence of blood-borne infections in persons with severe mental illness and found that 19.6% of the participants were infected with HCV (a figure 11 times the general population rate) and that half of those subjects with both a substance use disorder and a psychiatric disorder were seropositive.1 Persons with psychiatric and addictive disorders often represent a clinically challenging group for non–mental health clinicians, but the psychiatric side effects of current antiviral therapies compound the difficulty. Interferon has been associated with a host of neuropsychiatric effects, most commonly depression but also anxiety, suicidality, mania, and psychosis.2, 3 Faced with such adverse consequences, hepatologists are naturally concerned about providing interferon to persons with a psychiatric history or psychiatric symptoms, and this results in a lower rate of treatment for this population, which ironically is among the cohorts most in need of antiviral therapy.4
Against this epidemiological background, the article by Schaefer et al., “Hepatitis C Treatment in Psychiatric Risk Patients,”5 represents an important study in the field. As the first prospective controlled clinical trial, it provides an even stronger empirical foundation for the findings of other less methodologically rigorous studies showing that patients with HCV and comorbid psychiatric and substance use disorders have comparable sustained viral responses (SVRs) and rates of depression when treated with antiviral therapies. These results further support the development of evidence-based thinking regarding whether mental health disorders should continue to be considered as exclusions for therapy with pegylated interferon and ribavirin.
The 1997 National Institutes of Health Consensus Conference Statement recommends that patients drinking alcohol or using illicit drugs should establish 6 months of abstinence before being considered for antiviral therapy. The document also warns of possible relapse to substance use. A major depressive disorder is considered a contraindication to HCV treatment that must be “carefully considered.”6 Five years later, the National Institutes of Health Consensus Statement marks a major shift in the attitude toward including patients with mental health disorders among those suitable for HCV treatment:
Many patients with chronic hepatitis C have been ineligible for trials because of injection drug use, significant alcohol use, age and a number of medical and comorbid medical and neuropsychiatric conditions. Efforts should be made to increase the availability of the best current treatments to these patients.7
The 2002 document also expands the eligibility of injection drug users for antiviral therapy, indicating that research has demonstrated “feasibility and effectiveness” and pointing out that because injection drug use is the most common risk factor for the transmission of new HCV infections, increased treatment could have a significant public health impact. Collaboration between gastroenterologists and mental health clinicians is encouraged as a means of coordinating treatments for HCV and substance use. Increased access to methadone is particularly encouraged, as is providing HCV therapy for patients with active substance use on a case-by-case basis.7
Despite these expert recommendations, studies since the release of the statement have found that psychiatric and addictive disorders continue to be major obstacles to HCV treatment.4 The most significant import of Schaefer et al.'s work5 with “very difficult to treat patients” is its potential contribution to expanding access to care for precisely those marginalized populations who, despite having a high prevalence of HCV, are considered too high risk for interferon and ribavirin.1 The authors, however, are quick to point out that the key to their success with these challenging patients is the use of a multidisciplinary team. Other studies, including our own work in New Mexico and a recent article by Knott et al.,8 have reinforced the conclusion that safe and effective treatment for mental health patients requires the close collaboration of HCV specialists and psychiatrists.8, 9 The patients in this study were carefully screened and monitored and received extensive education and counseling, an enhancement of the informed consent process that we have also shown to be beneficial to positive outcomes and a reduction in negative effects.10
Schaefer et al.'s research5 also informs decision-making on several other debated aspects of treating psychiatric patients for HCV: the treatment of patients with psychotic disorders, drug use, and current depression or a history of depression. Most previous investigations have focused on depression as the most common psychiatric side effect of interferon and also the most prevalent co-occurring disorder in HCV patients. More serious mental illnesses such as schizophrenia and bipolar disorder have usually been judged to be too high risk for the initiation of antiviral therapy, and patients with these relatively common conditions have almost never been enrolled in research trials and have seldom been given access to HCV treatment, even in academic or public health settings. In a precedent-setting step, psychotic patients only discussed previously in case reports were enrolled in this trial.11 The scales used to measure depression and psychosis, the Montgomery-Asberg Depression Rating Scale and the Brief Psychiatric Rating Scale, respectively, are among the most widely used and psychometrically validated in psychiatric research, enhancing the reliability of the results.12 The work of Schaefer et al. is also unique because it assesses both depressive and psychotic symptoms and demonstrates that neither diagnosis adversely affects SVR or outcome.
The study also adds to the growing debate regarding whether past or current depression is more predictive of the exacerbation or development of a major depressive disorder as a side effect of combined therapy. Early work identified any history of depression as a risk factor. More recent studies have suggested that current depression rather than past mood problems is most predictive.13, 14 Schaefer et al.'s previous research and that of other investigators did not show an increased development of depression during antiviral therapy for patients whose depression scores were higher at treatment initiation.14 The current study also supports a growing body of evidence showing that intervention with a variety of antidepressant agents prior to and during HCV treatment can prevent or attenuate depressive reactions.15
Several methodological caveats are in order when the strength of the results is evaluated. The small sample size of 70 patients increases the likelihood of a type 2 error, and this emphasizes the need to include these groups in further research to replicate particularly those findings that run counter to other sound studies. The authors' conclusion that there is no difference in SVR between controls and patients with mental health diagnoses is stronger than the data in this study can support and requires studies with greater power to be established.
Given these statistical limitations, the study's findings regarding patients with addictions also challenge broadly held assumptions about the unsuitability of this population due to a lack of adherence, risk of relapse, and failure to respond to antiviral therapy. Although previous studies have independently demonstrated SVR and compliance rates for patients on methadone similar to those for patients without substance abuse disorders, the present work also compares methadone patients to former drug users and shows little difference in the outcomes.16
The authors anticipate the future direction of the evolution of HCV treatment for psychiatric groups when citing the limitations of their work due to the exclusion of homeless patients, those with dementia and other organic brain diseases, those with a history of suicide attempts, those with unstable psychiatric disorders, and most significantly those with ongoing drug or alcohol abuse. The high incidence of HCV in these populations and the emerging data on the safety of antiviral treatments in these populations when a multidisciplinary approach is used,9 of which Schaefer et al.'s article5 is an example, also argue for the inclusion of these disadvantaged groups in phase II and III trails for new drugs. Such inclusion is in keeping with the principle of justice as stated in the Belmont Report on research ethics:17 those populations who are disproportionately burdened with a disease should be fairly represented in studies that may eventually benefit the index condition.
Several new molecules for the treatment of HCV are currently under evaluation, but all are being developed with concomitant interferon.18 This means that if individuals with psychiatric and addictive disorders are to receive the benefits of these new medications, hepatologists will still need assurance that patients can be safely and effectively managed and that withholding treatment from them when collaborative care is available is in general not justified. The value of Schaefer et al.'s work5 is precisely in contributing to the growing body of data that challenge hepatologists and mental health professionals to develop new medications and innovative programs that can further widen the door to admit these patients to HCV treatment.