Hepatitis C virus (HCV) infects more than 4 million Americans and is the leading cause of liver failure leading to transplantation.1 Approved treatments include interferon, either with or without ribavirin, and produce moderate success if patients undergo the full dose of medications.
Many factors affect whether patients undergo a full course of treatment, in the past, most clinical trials excluded participants with psychiatric comorbidity, especially opiate dependence and affective disorders. This contributed to the exclusion of many patients with diagnoses of substance dependence and major psychiatric disorders such as affective disorders, anxiety disorders, and psychotic disorders. Patient psychiatric adverse events to treatment, patient collaboration with the treatment team, and psychiatric comorbidities are the most common factors that contribute to treatment exclusion. This article examines these factors and recommends an assessment strategy that addresses the psychiatric complexities to facUitate their inclusion into treatment for HCV.
Comprehensive hepatitis C program algorithm used at the Cincinnati VA Medical Center.
INTERFERON TREATMENT AND PSYCHIATRIC SYMPTOMS
Sixty percent to 85% of HC V-seropositive patients have a chronic active infection.' Interferon, with or without ribavirin, is the only treatment approved by the Food and Drug Administration for chronic HCV infection. While interferon treatment is fraught with a high number of adverse events, to do nothing is not a secure alternative. Although many patients are asymptomatic, others report feelings of depression, abdominal pain, fatigue, joint pain, and other symptoms.2,3 The virus often produces a progressive infection that sometimes is oncogenic. There is evidence that quality of life (as measured by the SF-36) is worse for patients with HCV who are unaware of the diagnosis compared to standard population controls and that it worsens when the diagnosis is confirmed and communicated to patients.4
Management of physical complaints and adverse events becomes a major task for the HCV clinicians.1 The length of antiviral treatment ranges from 24 weeks for HCV genotype 2 to 48 weeks for genotype 1 . Failure to clear the virus at 24 weeks usually results in cessation of antiviral treatment. Work-ups may drag on for weeks, and many hepatologists require a liver biopsy.
While pegylated interferon has a longer half-life and may be superior to interferon-alfa in producing sustained viral responses (SVR), it produces higher blood levels of interferon, which increases the report of some adverse events. Inclusion of ribavirin brings improved SVR but more adverse events. Some of these adverse events can be treated symptomatically, some are inconvenient but tolerable, and others are potentially serious and require careful monitoring.
Treatment adherence is important because the treatment for HCV is expensive, lengthy, and requires collaboration between clinicians and patient. There is some evidence that treatment compliant patients (defined as taking 80% of antiviral medications and keeping 80% of the clinic appointments) have an improved outcome compared to earlier dropouts and noncompliant patients.1
Onset of severe psychiatric problems can result in premature discontinuation of interferon treatment. Consequently, one of the most controversial adverse events during interferon treatment is depression. It is controversial because of the scarcity of psychiatrists involved with HCV clinics, the uncertainty of who is at high risk, the ambiguity about its course, the unreliability of some of the patients, and the tension around the proper management of depression.
Mania induced by interferon treatment for HCV also has been reported, as well as serious depression or suicide. There is growing evidence that in some cases, prophylactic treatment with antidepressants can minimize serious depression syndromes and facilitate completion of interferon treatment.5
RISKS OF PSYCHIATRIC COMORBIDITY
Alcohol dependence is a common comorbid condition with HCV thai must be managed to avoid premature treatment 0termination and to maximize SVR.1 Some studies report approximately 20% of the alcoholics also have HCV.6
Alcohol use with chronic HCV is routinely discouraged because it increases the viral count by reducing the efficacy of the immune system and because it may induce greater progression of liver disease. Furthermore, alcohol dependence is commonly associated with erratic behavior and deficits in self-care. Alcoholics may miss appointments, skip medication doses, eat little or have an unbalanced diet, sleep less, and hold other people accountable for their own shortcomings.
Alcohol intoxication often changes priorities and motivation, leading to use of other substances of abuse. Alcohol use can induce mood disorders and physical problems. The guilt and shame commonly associated with out-of-conrrol drinking can lead to lying and denial, which blocks effective collaboration. All of these can threaten to undermine the effectiveness of interferon treatment.
Because depression is an important adverse event of interferon treatment and because alcohol can induce depressive syndromes, it is important to differentiate what type of depression is present.7 Major depression often requires medication or psychotherapy before remission is achieved.
Alcohol -induced depression, on the other hand, is commonly encountered and is treated by sobriety. After heavy daily drinking for a number of weeks, substance-induced depression remits over 2 to 4 weeks of abstinence. Interferon-induced depression can be treated by stopping interferon or by adding an antidepressant. A detailed discussion of the treatment of depression in HCV can be found in the article by Loftis and Hauser in this issue (page 385). These are quite different strategies and may involve cessation of antiviral treatment. Surreptitious drinking often implies an impaired treatment alliance and may predict a poor prognosis for the patient.
While patients with major depression have a higher risk of suicide, active drinkers have a very high risk (60- to 120fold increase) of suicide compared to the general population.7 Alcohol-induced depression, while easily treated, still has a suicide risk that should not be dismissed. Alcoholics also have a much higher prevalence of affective disorders than the general population, which requires observation and active treatment.8 The National Comorbidity Study found men had a 24% co-occurrence of major depression and 1 1% dysthymia, while women had a 48% co-occurrence of major depression and 21% dysthymia.9
Anxiety is not generally a major risk in the treatment of HCV, but it is a common threat to quality of life among alcoholics.8 The National Comorbidity Study revealed an increased rate of anxiety disorders among alcoholics. Men had a 19% prevalence of social phobia and 14% occurrence of simple phobia; in contrast, women had a 30% prevalence of each.
In a small quality-of-life study, Hunt et al.3 found anxiety symptoms decreased 1 month after treatment was initiated, which suggests HCV patients had some anticipatory anxiety regarding treatment. Furthermore, patients' anxiety levels almost returned to baseline levels within 6 months of treatment and 6 months post-treatment. However, anxiety levels were not higher man baseline as a result of treatment.
The major risk for substance use disorders is relapse to active use of alcohol, drugs, or both. It is not a common problem, but it also is not rare. In our clinic, 11 of the first 92 patients treated for HCV relapsed while being monitored; however, most of the relapses occurred after treatment was stopped, and only five patients discontinued treatment because of the relapse.10
Although relapse is not always a cause to discontinue interferon treatment, relapse can threaten the completion of interferon treatment in several ways. Relapse can lead to uncooperative behavior caused by excessive consumption of alcohol or drugs, failure to keep appointments, or missed medication doses. Considerable research has shown that alcohol consumption causes more liver fibrosis in patients with HCV, possibly in a doserelated manner.11 Recurrent needle use with intravenous drug users is usually a cause to discontinue interferon, and Sylvestre et al. 12 have reported on the lack of response to interferon treatment if interferon is continued in such cases.
Mood, Anxiety, and Psychotic Disorders
Institutionalized psychiatric patients have a higher than average rate of HCV. In Japan, Sawayama et al.13 found 10% of neuropsychiatrie patients were HCV antibody positive compared to 1.5% of matched controls. Length of hospitalization, age, gender, and being shaved by a barber with a common razor at the hospital were all associated with higher risk ofHCV.
Rosenberg et al.,14 in a multisite prevalence study conducted in the eastern United States, reported an overall positive HCV rate of 16% among 931 patients, with the rate increasing to 25% in large metropolitan areas and decreasing to 10% in rural areas. Of this group, two thirds had psychotic disorders and 28% had affective disorders.
Forty-two percent of these patients had comorbid substance dependence disorders, 26% with alcohol use and 26% with drug use disorders. However, 75% of the HCV-positive group had used needles for drug use in the past. Most of the remaining HCV-positive patients met at least one of the Centers for Disease Control and Prevention (CDC) risk factors, with only two of 1 22 having no risk factors.
Injection drug use (P < .001), crack use (P < .001), and substance use disorders (P < .01) were all significantly related to HCV-positive status. Injection drug use had the highest odds ratio at 3 1 ; the odds ratios for crack use, a history of sexually transmitted diseases, and trading sex for drugs or money were 7, 3.5, and 2.4, respectively. Age, but not ethnicity, also was associated with HCV. Having a history of sexually transmitted diseases and of trading sex for money or drugs were significantly (P < .01) related to HCV.
In an Italian study of 1 180 institutionalized psychiatric patients, Cividini et al. ,5 found nearly 7% with HCV antibody, which was double the incidence of the general population in the region. A diagnosis of psychosis and a history of contact with blood were associated with an odds ratio of 2.6 and 2.1, respectively. In this study, as in previous studies, age was associated with higher HCV seropositive rates, as was length of hospitalization. Those institutionalized included mentally retarded, demented, and psychotic patients. Dementia and psychosis were associated with higher HCV antibody rates (11%) than mental retardation (3%). Seventy-two percent of these psychiatric patients tested positive for HCV-RNA.
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,™ is a multiaxial diagnostic manual that includes primary and secondary psychiatric disorders. The manual summarizes a variety of diagnoses with which the general psychiatrist may not be familiar. Sleep disorders, sexual disorders, learning disabilities, and mental retardation may be some of the diagnoses not routinely used.
Conditions due to a general medical condition can be vague and ill-defined clinically when the cause of the symptoms is not clear. However, a comprehensive assessment before antiviral treatment is initiated can make management during HCV treatment go more smoothly. Figure I (page 370) depicts an algorithm of the comprehensive HCV evaluation program used at our medical center.
Psychiatric Treatment History
Many aspects of prior psychiatric treatment are important for HCV treatment; therefore, identifying current or past psychiatric treatment is critical. A current therapist, whether a psychiatrist, psychologist, or social worker, can be helpful in obtaining a patient's history, corroborating a patient's history, and confirming a patient's response to treatment and the accuracy of a patient's diagnoses.
The frequency of current psychotherapy and pharmacotherapy sessions is also pertinent in planning how to monitor patients with an axis 1 disorder. The use of residential treatment in addition to outpatient sessions can reveal much about the severity of illness, response to crises, social support, and, of course, diagnoses.
Because many patients have alcohol and drug dependence, it is relevant to ask about current employment and use of homeless shelters/homelessness. Not only does this identify some of the homeless patients, but a history of using shelters gives a clue about social supports and degree of social disconnection.
Last but not least are the histories of self-injurious and violent behaviors. Not only are these behaviors ones that could be triggered by interferon adverse events, but they also are associated with intoxicated behavior. High-risk behaviors, such as compulsive gambling, compulsive unprotected sex, impulse control problems, are all relevant to the comprehensive picture of a patient's ability to collaborate with the demanding HCV treatment plan and to ensure that compromising factors are not introduced during treatment (eg, human immunodeficiency virus, sexually transmitted diseases, erratic compliance, vulnerability to incarceration).
PSYCHIATRIC TREATMENT AND OUTCOME
Selection of psychiatric treatment and treatment response are important pieces of the HCV assessment. Assessing patients' prior psychiatric treatment and outcome can assist in this process (Sidebar).
Many patients have illnesses that respond in a partial manner. Despite medication management and supportive counseling, schizophrenics may still hear voices, depressed patients may feel discouraged chronically, and patients with posttraumatic stress disorder often have panic attacks, insomnia, startle reactions, and dysthymia. During HCV treatment, which is in and of itself stressful, it is helpful to know whether psychotherapy was available to patients in the past and whether it was effective. It is also important to know whether there are community case managers who can help monitor patients with schizophrenia at home to ensure patients are taking care of themselves effectively.
Similarly, it is important to know if there is anyone who would notice a relapse to drinking or drug use. We recommend at least 3 months of alcohol sobriety, 6 months of needle-free opiate substitution therapy, and 3 to 6 months of symptom reduction to a socially stable level for anxiety, depression, or psychotic symptoms. A 3- to 6-month symptomfree period also is recommended for behavior disorders (eg, compulsive gambling, compulsive sexuality, intermittent explosive disorder, eating disorders).
For patients with an alcohol or drug problem, information needed includes whether patients were able to achieve sobriety or abstinence, and whether they experienced any relapses. Attendance at Alcoholics Anonymous, Narcotics Anonymous, or alternative support group meetings also is important patient information. For patients with opiate dependence, it should be determined whether methadone, levo-alpha-acetylmethadol (LAAM), or buprenorphine maintenance was used. Finally, the clinician should know whether intravenous drug use was ever discontinued without any relapses.
Psychiatric management algorithm used at the Cinncinnati VA Medical Center's hepatitis C virus clinic.
(CES-D = Center for Epidemiological Study-Depression.)
While most of our HCV patients have a substance use disorder (89%) and an axis I psychiatric disorder (65%),]0 the history of treatment received and the patient's response are essential. Traditionally, this is considered a group that is too risky to treat or in need of very careful monitoring. Therefore, an active therapeutic relationship with frequent visits (at least every other week) and reasonable symptom reduction and stability with treatment for those with a past psychiatric illness are crucial to the success of treatment.
For patients with a past psychiatric illness who are not symptomatic and not currently in therapy, two recommendations are offered: (1) institute prophylactic treatment with an antidepressant, or (2) identify a monitoring mental health professional who can step in if the patient becomes symptomatic. Furthermore, full psychiatric treatment compliance should be observed for an extended period of time (3 to 6 months recently if noncompliant in tiie past).
In addition, collaboration with therapists who have an awareness of HCV treatment risks and who can collaborate during the year of treatment with the HCV team is beneficial. Collaboration means sharing responsibility for the patient and being available and willing to communicate, daily if necessary.
Monitoring refers to regular clinical visits, weekly if symptomatic from the basic psychiatric illness or from interferon-induced changes (or even daily in unusual circumstances) if the HCV team requests this. Monitoring includes frequent meetings, use of medications to optimize response, alcohol and drug screens, mental status examinations, and use of depression symptom screening surveys such as the Hamilton Depression Scale, Beck Depression Inventory, or Center for Epidemiological Study-Depression.
Monitoring for increased depressed mood and suicidal thinking is essential during treatment. While suicides have been reported during HCV treatment, they are uncommon (less than 1 %). The prevalence of suicide in the United States is 18 per 100,000 for men and approximately four per 100,000 for women; these rates increase in elderly whites, especially men.17
Unfortunately, the psychological risks for suicide are depression, alcoholism, and personality disorder, three problems common in this population of HCV patients.17 Having a gun at home is a risk factor, especially for men. Agitated patients are at higher risk than calm patients, and patients who see no other solution are also at higher risk. A history of suicide attempt is a risk factor for completed suicide and should be assessed. In addition, the lethality of the attempt is relevant, ie, did the individual expect to die, or was the attempt made so as to be found right away.17
The neurobiological research on suicide does not show consistent results, with only half of studies showing reduced central nervous system serotonin; however, the theory that low serotonin levels are associated with violent and suicidal behavior remains in the literature. !7 If this has validity, it is relevant since there is evidence that interferon treatment reduces serotonin levels by altering enzyme activity in the catabolic pathways.18
Use of marijuana and hashish is an ambiguous behavior. There is considerable variation in clinicians' willingness to diagnose cannabis use. The main issues are the patient's relapse to other drugs and alcohol, as well as risk-taking behaviors. While there is little evidence that cannabis use impairs liver function or response to interferon treatment, there is clinical experience showing that marijuana use can trigger relapses to cocaine or alcohol use. Furthermore, some crackdependent addicts smoke their crack in joints, making the two drugs interconnected for the user. Alcohol, cocaine, and opiate use are all associated with risky behaviors (including poor self-care behaviors) that reduce immune competency and expose people to co-infections such as human immunodeficiency virus and hepatitis B.
Assessing patients' readiness for change is important (Sidebar). Prochaska19 described five stages that patients go through in making and sustaining lifestyle changes, In the first stage, precontemplation, patients do not think they have a problem that needs changing. In the second stage, contemplation, they are thinking about changing, but not taking action. The third stage is the action phase, while the fourth is maintenance of the changes made in the action phase. The fifth stage is the relapse phase.
Assessing patients' readiness to change is important for the HCV multidisciplinary team in determining how much effort to invest in the treatment alliance initially. Because of the variety and persistence of the side effects, an understanding of and commitment to doing what needs to be done will be necessary. Patients are not always prepared for the intensity of fatigue or the loss of appetite.
Relapse prevention is a routine technique in outpatient substance dependence.20 Obtaining a history of the prior relapses and their triggers are essential (Sidebar). Triggers can be emotional (eg, anger, depression, boredom, excitement) or environmental (eg, people, places, things).
The environmental support is another important part of the assessment. Hepati - tis C disease itself and the symptoms related to the treatment are not easy to cope with alone. Patients need support from their family and environment during the treatment period.
Because treatment can last from 6 months to 1 year and the adverse effects from treatment can incapacitate patients, understanding its socioeconomic impact is an important part of the assessment. Patients' living situations and their the household income should be addressed. Homelessness is a significant problem, as the support network needs to be arranged before the treatment.
The family should understand that the side effects of treatment might be severe enough to incapacitate the patient. If the patient is the breadwinner of the household, alternative plans should be made in the event that the patient is disabled temporarily. These issues can be assessed and anticipated, with the collaboration of social services if available, before the actual treatment is begun.
Family support and the depth of the social network are critical. Patients can be bedridden initially, with fatigue, malaise, and fever. Family or friends need to help with activities of daily living, not to mention transportation to the HCV clinic. The community may have resources to help patients at home, such as home aides and visiting nurses. Involvement in Alcoholics Anonymous is a useful support if patients are newly sober or are active in 12-Step work.
Other studies have recommended a careful psychiatric assessment before initiating antiviral therapy with interferon.21 Cheung and Ahmed advised, "The importance of detailed psychiatric assessment before initiating interferonbased therapy cannot be emphasized too much.21 Patients with mild or well controlled psychiatric disorders who undergo treatment should continue to be monitored closely by a psychiatrist., with or without psychotropic medication."
Zdilar et al.22 recommended a psychiatric assessment in high-risk groups, which includes patients with depression or a history of depression, past psychiatric hospitalization, a history of substance use disorder, or a family history of depression or suicide attempts. They also found a high prevalence of diagnosable anxiety and depression in patients with chrome HCV (57% of 150 patients).
In their study, Yates and Gleason23 reported only 11 of 76 patients with chronic HCV infection had no psychiatric diagnosis. They also recommended a psychiatric evaluation for high-risk patients, which included patients with current depressive symptoms, a history of depression or suicide attempts, prior psychiatric hospitalization, a family history of depression or suicide, or a history of substance use disorder.
There is a growing consensus that high-risk groups include patients with a prior psychiatric diagnosis. Small studies, such as the study conducted by Ho et al., found that HCV patients with any DSM-IV axis I or axis ? diagnosis had more major adverse events requiring intervention or discontinuation of antiviral therapy.24
In our HCV clinic, because more than 90% of patients meet this criterion, we require depression screening for all patients. Figure 2 (page 374) depicts the algorithm for psychiatric referral and assessment. We recommend all patients be evaluated for a stable home and financial situation to ensure that they have supporting resources. In addition, we recommend all patients with a psychiatric history or substance dependence history be monitored symptomatically for breakthrough symptoms or relapse to illness. Evaluations should be thorough enough to aid the monitors in deciding whether severe psychiatric symptoms, should they appear, are primary (a preexisting illness) or secondary (induced by interferon).
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