Psychiatric Comorbidity Among Hepatitis C–Positive Patients

Hepatitis C is a major public health problem in the United States with current estimates suggesting that 4 million people are infected with this virus. Approximately 75%–85% of infections become chronic, 60%–70% of patients develop persistent active liver disease, and 10%–20% develop cirrhosis (1–7). Hepatitis C now accounts for 8,000 to 10,000 deaths annually and in the year 2000 will likely kill more people than HIV infection (7–11).

Neuropsychiatric conditions are frequently associated with hepatitis C infection. Intravenous drug (IVD) use is a major route of transmission for the virus and now accounts for the majority of new cases of hepatitis C developing in the United States (7, 11–13). Hepatitis C infection has been detected in 50%–80% of patients who use IVDs (7, 11, 14–16). Patients with alcohol dependence also have hepatitis C seropositivity rates that are higher than the general population; 4.8% versus 1%–2%, respectively (17). Furthermore, hepatitis C infection has been detected in up to 46% of patients with alcoholic liver disease even when patients with other risk factors (i.e., IVD use, blood transfusions) have been excluded (18).

Depressive and anxiety symptoms have been reported to be common in patients with untreated hepatitis C infection (6, 15, 19–21). Kraus et al. (22) and Dwight et al. (23) found that 22.4%–28% of patients with untreated hepatitis C were depressed. Lee et al. (24) demonstrated that antidepressant treatment is warranted in the majority of the depressed hepatitis C patients. Singh et al. (10) reported elevated rates of anxiety and depression in patients with end-stage liver disease due to hepatitis C. Prevalence rates for other psychiatric symptoms in hepatitis C-infected patients have not been well studied.

Treatment of hepatitis C is also complicated by a variety of neuropsychiatric symptoms. Currently, interferon-α (IFN-α), with or without ribavirin (RBV), is the only well-established treatment for hepatitis C (1, 9, 24). Neuropsychiatric side effects develop in a substantial percentage of patients who undergo IFN-α therapy (7, 20, 21, 26, 27). Fatigue, irritability, depression, anxiety, psychosis, cognitive dysfunction, and delirium may all complicate IFN-α therapy (7, 10, 21), and these side effects often limit the dose or result in a discontinuation of this medication.

Although several reports have documented the frequency of psychiatric symptoms in patients with hepatitis C infection (7, 10, 19–21), the prevalence rates of DSM-based psychiatric disorders have not been established. Patients with severe mental illnesses often engage in behaviors that place them at high risk for hepatitis C infection (7, 10, 28–33) and it is therefore likely that these disorders are common among hepatitis C-infected individuals.

The present study represents an initial effort to define the prevalence of psychiatric disorders among patients with hepatitis C infection. A retrospective chart review was conducted to identify all DSM-IV-based psychiatric disorders in patients with hepatitis C infection at the Salem, Virginia, Veterans Affairs Medical Center. Psychiatric disorders were independently confirmed based on symptoms reported in the chart, and the frequency of each disorder is presented.

Methods

Subjects

A computer search was conducted to identify all patients with a positive hepatitis C antibody by enzyme immunoassay (EIA) from March 7, 1991, to March 27, 2000, at the Veterans Affairs Medical Center, Salem, Virginia. A total of 761 hepatitis C seropositive individuals were identified. Patients who had received treatment for hepatitis C were excluded, and 400 untreated individuals were randomly selected for inclusion in the chart review.

Procedure

One of two clinical investigators (SY or MR) reviewed each medical record for demographic information (age, gender, race, marital status, combat status, sexual orientation) as well as symptoms of DSM-IV-based psychiatric disorders. Only the diagnoses that could be independently confirmed by the reviewing clinicians were included in the data analysis. To confirm DSM-IV psychiatric disorders, the clinician investigator reviewed individual symptoms recorded in the patient’s medical record and compared them with a checklist of DSM-IV criteria. All DSM-IV criteria were used to establish diagnoses. In this way, DSM-IV diagnoses were confirmed independently of those established by the treating physician. The prevalence rates of past and present psychiatric diagnoses were tabulated and presented as a single frequency. Some psychiatric diagnoses have been grouped together to form diagnostic categories in order to simplify the presentation of this data.

Results

Ninety-seven percent (297/306) of the hepatitis C-positive sample were men and 3% (9/306) were women. Patient ages ranged from 34 to 86 with a mean age of 48 years. Sixty percent (184/306) of patients were white and 40% (122/306) were African American. Approximately 50% (152/306) of patients were divorced or separated, 31% (97/306) were married, and 19% (57/306) were single.

The frequencies of past and present psychiatric diagnoses are presented in Table 1. The following disorders have been grouped together: 1) substance abuse and dependence as “substance use disorders”; 2) depressive disorders other than major depression as “other depressive disorders”; 3) mood disorders other than depressive and bipolar disorders as “other mood disorders”; 4) anxiety disorders other than PTSD as “other anxiety disorders”; 5) personality disorders other than antisocial and borderline personality disorders as “other personality disorders” and 6) psychotic disorders other than schizophrenia and schizoaffective disorders as “other psychotic disorders.” The diagnostic category for other depressive disorders included patients with depressive disorder not otherwise specified (NOS) and dysthymia. “Other mood disorders” included patients with mood disorder NOS and substance-induced mood disorder; “other anxiety disorders” included patients with anxiety disorder NOS, generalized anxiety disorder, and panic disorder with and without agoraphobia; “other personality disorders” included patients with personality disorder NOS and those with paranoid, schizotypal, and dependent personality disorders. Patients with psychotic disorder NOS and substance-induced psychotic disorder were included as “other psychotic disorders.”

As illustrated in Table 1, substance use disorders were quite common in this patient population. Alcohol use disorders were the most common psychiatric disorders encountered in this study, occurring in 86% (262/306) of these patients. Alcohol use disorders were frequently accompanied by other substance use disorders, with 60% (183/306) of patients meeting criteria for polysubstance use diagnoses. Common drugs of abuse included cocaine, marijuana, phencyclidine (PCP), heroin, benzodiazepines, amphetamines, and lysergic diethylamine (LSD). Approximately 28% (87/306) of patients in this sample had a history of IVD use, with cocaine or heroin being the most commonly used intravenous substances.

Mood, anxiety, and personality disorders were also common in this population, each occurring in 26%–34% of patients (see Table 1). Major depressive disorder was the most common single psychiatric diagnosis other than substance use disorders, with 23% (70/306) of patients suffering from this condition. PTSD and antisocial personality disorder were also common, occurring in 19% (69/306) and 16% (50/306) of patients, respectively. Psychotic disorders as a group occurred less frequently than several other diagnostic categories, but a significant minority of patients were diagnosed with these conditions. Over 95% (292/306) of these psychiatric disorders were diagnosed prior to the diagnosis of hepatitis C infection.

Discussion

The results of this study suggest that a variety of psychiatric disorders are common in patients with untreated hepatitis C infection. As expected, substance use disorders were the most frequently encountered conditions, with alcohol abuse or dependence occurring in 86% of our patients. Polysubstance abuse and dependence were also quite common, occurring in well over 50% of patients. However, only 28% of our population had a history of IVD use. One might have expected the prevalence of IVD use in this study to be higher than 28%, particularly in light of the findings from Cheung (34) suggesting that IVD was a risk factor in 81% of veterans with hepatitis C. Furthermore, data from Alter (2) and the Centers for Disease Control and Prevention (35) suggest that in the general population approximately half of all new hepatitis C infections result from IVD use. Certainly patients with histories of IVD use may not have been forthcoming about these behaviors. However, the low rate of IVD use in this patient sample may also reflect a relatively low prevalence of IVD use in the base population from which this study sample was derived. The Salem, Virginia, Veterans Affairs Medical Center serves a small city (population approximately 250,000) and surrounding rural communities in southwest Virginia, and there are no major urban centers in the catchment area. Consequently, the prevalence of IVD use in our base population may be less than what would be expected in a major metropolitan area, such as that among veterans from suburban northern California in the data reported by Cheung (34).

Several psychiatric conditions other than substance use disorders were also common in this study. Between 26% and 34% of hepatitis C-positive patients in this study met criteria for mood, anxiety, or personality disorders, while 1 in 6 suffered from a psychotic disorder. These prevalence rates are substantially higher than the lifetime prevalence rates for these same disorders in the general population (36). Prior research in this area (7, 10, 22–28, 37, 41, 42) has also indicated that psychopathology other than substance use may be prevalent in hepatitis C-infected patients. Several reports (7, 10, 22–28, 37) suggest high prevalence rates of depressive and anxiety symptoms in hepatitis C-positive patients. Other studies (21, 41, 42) using DSM-III-R criteria report the prevalence of depressive disorders in patients with hepatitis C to be 22.4%–28%. These prevalence rates for depressive disorders are quite similar to those found in our current study. However, our current study used DSM-IV criteria and assessed the prevalence of all major Axis I psychiatric disorders rather than just depressive disorders.

The burden of psychiatric illness in patients with hepatitis C infection is of more than academic interest. Early recognition and treatment of psychiatric disorders in hepatitis C-positive patients is important to the course and management of hepatitis C as well as to the psychiatric disorder itself. For instance, hepatitis C patients who continue heavy alcohol use may experience a more progressive hepatitis course (17, 18, 38) and are generally not considered good candidates for IFN-α therapy. Therapy with IFN-α and RBV is rigorous, requiring close follow-up for at least 6–12 months. Active psychopathology may interfere with compliance, rendering these medications ineffective or precipitating adverse reactions. Furthermore, an awareness of underlying psychopathology is important in deciding whether to initiate IFN-α treatment. As noted earlier, this medication precipitates neuropsychiatric side effects (i.e., depression, anxiety, psychiatric symptoms, and cognitive deficits) in a significant proportion of patients, and these side effects often limit the dose or result in discontinuation of IFN-α (7, 10, 21, 25–28, 37, 41). At present it is unclear whether patients with preexisting psychiatric disorders are at increased risk for the neuropsychiatric complications of IFN-α, but practitioners have been cautioned about the use of this medication in patients with underlying psychopathology (10, 19, 21, 25, 27, 39, 40). Consequently, psychiatrists will likely be asked to assess the psychiatric stability of hepatitis C-positive patients prior to the initiation of IFN-α and to provide ongoing management for patients with psychiatric disorders who receive this treatment.

The exact nature of the association between hepatitis C infection and psychiatric disorders has not been fully established and cannot be addressed with a retrospective chart review of this type. However, it is certainly probable that patients with psychiatric disorders are at increased risk for hepatitis C because they engage in high-risk behaviors more often than the general population (29–34). Our data support this notion in that over 95% (292/306) of our patients were diagnosed with psychiatric disorders long before hepatitis C infection was discovered. Alternatively, hepatitis C is a chronic indolent infection that may remain asymptomatic for many years, and our patients may have had undiagnosed hepatitis C infection prior to the development of their psychiatric condition. Furthermore, hepatitis C testing first became widely available in 1992 and only more recently has been widely used. Consequently many patients may have been infected with this virus long before medical science was able to detect its presence. Whether hepatitis C infection has a specific influence on central nervous system function or psychological state prior to development of severe liver dysfunction remains unclear.

There are several limitations to this study. The selection bias inherent in a retrospective chart review of this nature may have led to an overestimation of the true frequency of psychiatric disorders in this study. Patients in this study were selected for hepatitis C testing based on clinical grounds. Consequently it is possible that patients with psychiatric disorders (particularly substance use disorders) were viewed as high risk and preferentially referred for hepatitis C testing. In addition, patients were not independently interviewed and assessed for psychiatric disorders. Therefore, patients with psychiatric symptoms that were not disclosed to their care providers and documented in their medical records would have been missed in our analysis.

Patients in this study were selected from a Veterans Affairs Medical Center population, where a large percentage of patients are male with a high prevalence of psychiatric illness and substance use. The prevalence of psychiatric disorders in a sample of patients from this population might therefore be expected to be higher than the general population.

These limitations notwithstanding, the prevalence of psychiatric disorders is likely to be higher in patients with hepatitis C than the general population given the major routes of transmission for this virus. Our data, along with results from other studies (7, 10, 19–21, 24, 29–33, 41, 42) support this notion. Furthermore, our data suggest that substance use disorders are not the only psychiatric conditions encountered in patients with hepatitis C infection. Depressive, anxiety, personality, and psychotic disorders were all common in these patients.

Our findings have important implications for the management of hepatitis C-positive individuals, particularly in light of the possible influence of psychiatric conditions on the clinical course and treatment of hepatitis C infection. Vigilance for these psychiatric conditions is warranted among practitioners who care for hepatitis C-infected patients, with referral for psychiatric evaluation where appropriate. Likewise, vigilance for hepatitis C is warranted in patients with established neuropsychiatric illnesses. It is also incumbent upon psychiatrists, who will be asked to assess and manage these illnesses, to become familiar with hepatitis C and the implications of the psychiatric comorbidity, which complicate this infection.