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Hepatitis C - A Medical & Psychiatric Disorder HEP C presents significant challenges for patients, physicians and counselors. NYS OASAS is developing a comprehensive approach to assist patients and AOD professionals. This will include targeted educational and information resources. To follow is an overview of the possible psychiatric effects of Hepatitis C infection in patients, as well as psychiatric side effects of medications often prescribed to patients for this disease. Hepatitis C virus (HCV) infection is the most common cause of chronic liver disease in the United States. Approximately 4 million Americans are positive for the HCV antibody; 75% have had a positive HCV RNA test and are chronically infected. Of the chronically infected patients, 15% will develop cirrhosis. Five percent of those with cirrhosis may develop primary cancer of the liver (Hepatocellular Carcinoma). Patients with alcohol and drug abuse present significant medical challenges. However, HCV patients present with a critical psychiatric component that must be recognized and addressed. An Italian study published in Gastroenterolgy in 1996 by Taruschio et al. showed that 36.7% of HCV patients had a psychiatric disorder. Patients with the HCV infection have been found to be more likely to have psychiatric disorders than other viral hepatitis patients. For psychiatric disorders associated with Hepatitis C, etiologies are categorized to understand this co-morbid relationship:
As this breakdown shows, not only is the disease associated with psychiatric co-morbidity, but the treatments are also known to have significant neuropsychiatric adverse effects. HCV and Depression An article by Johnson et al. in the American Journal of Gastroenterology in 1998 compared depressive symptomatology of drug users with HCV who have not received interferon treatment to non-infected substance abusers. It was found that 57.2% of HCV-positive subjects who were using drugs had significant depressive symptoms. This is compared to 48.2% of non-infected substance abusers who showed significant depression. The study concluded that depression associated with interferon treatment might at least, in part, be accounted for by a pre-existing depression, especially in the substance abuser. These studies led to the recommendation that screening for anxiety and depression should occur before starting HCV treatment protocols. Interferon and Psychiatric DisordersInterferon alfa - 2b, as used in HCV treatment protocols, has a mechanism of action that is not completely understood, but appears to work as an antiviral and immunomodulatory agent interfering with viral replication and enhancing the ability of the immune system to recognize and attack the virus. There are many adverse effects seen with the use of interferon which have a medical and psychiatric overlay. It is also important to consider that the interferon therapy may amplify symptoms of an underlying depression. In addition, flu-like symptoms, gastrointestinal distress and alopecia can all have a profound effect on the psyche. The described neuropsychiatric side effects occur in greater than 20% of the interferon treatment population and include:
In the study by Renault, he described psychiatric side effects of interferon fell into three categories:
These symptoms can appear one to three months after starting interferon treatment and can improve in three to four days after decreasing interferon. The symptoms resolved when therapy was stopped. The organic syndromes were seen in patients with the highest doses of interferon; delirium occurred in patients with severe hepatitis who also had previous organic brain injury, organic brain dysfunction or previous alcohol or substance abuse. Why Does One Develop Depression from Using Interferon?The pattern of personality changes suggests that the dysfunction is in the frontal-subcortical area of the brain. There is also a possibility of interference with or changes in the neurotransmitters of the brain, especially serotonin. Research has shown that patients treated with interferon have altered serum levels of tryptophan, a precursor of serotonin. (In fact, the decrease in serotonin could lead to an interferon-induced dementia syndrome.) There may also be an effect of interferon on the serotonin transporter. Clinically, the use of selective serotonin reuptake inhibitors (SSRI), such as Paxil®, have been shown to work on the serotonin transporter level and treat the depression induced by interferon. Duration of treatment with interferon may also play a role in the development and intensity of the depression. Compliance with the medical regimen may be affected if the depression is not aggressively treated. Interferon-induced depression carries substantial risk of suicide with one reported case of suicide after the discontinuation of interferon. Further, interferon side-effects tend to look like opiate-withdrawal symptomatology and one has to investigate the possibility of relapse and the onset of depression seen in active drug use. Treating Depression from the Use of InterferonThe seriousness and frequency of the depression indicates the need for constant monitoring and vigorous treatment. Investigation into the treatment of interferon-associated depression has involved the use of opioid - receptor antagonists, stimulants and antidepressants (especially the SSRI group as previously noted). One study, reported in the New England Journal of Medicine, pretreated the patients before the initiation of interferon therapy, using paroxetine two weeks before the onset of treatment. Two of 18 (11%) of the paroxetine group developed depression, compared to 9 of 20 (45%) in those who did not use paroxetine. (It should be noted, however, that this study was in melanoma patients and the results may not be applicable to Hepatitis C. Also, the doses of interferon were larger than those used in Hepatitis C treatment regimens.) An approach for assessing and managing the patient with interferon-induced depression has been published by Zdilar et al. and suggested the following:
Transplantation and Psychiatric DisordersIn 1995, almost half of the liver transplants were performed on patients infected with HCV. The potential for adverse mental health consequences in the face of a physical illness is well recognized and the psychiatric distress of a chronic illness is frequently associated with a compromised quality of life. Psychiatric evaluation is suggested in all transplant patients prior to transplant, especially to help them deal with emotional and behavioral disorders that may reduce the chance of successful outcomes, as well as issues of anti - rejection regimens and death. In the work by Gayowski et al., the HCV patient undergoing transplantation showed more depression, mood disturbances and psychological stress than non - HCV transplant patients. This did not occur due to a greater severity of liver disease and, in fact, the HCV patients showed a greater level of fatigue, loss of appetite, weight loss, sleep problems and pain. Complicating the transplantation picture is the problem of recurrence of HCV hepatitis after transplant, as shown in the work by Singh et al. He reported that 41% of HCV patients had a recurrence of HCV infection after transplantation; 12 months after transplant, these patients showed a significantly poorer quality of life with worse depression and a lower physical function than other transplant patients. Medication Issues, Psychiatric Disorders and HCVWhen treating patients with hepatitis, one must be aware of the possibility of altered hepatic function leading to an altered metabolism of medications, especially antidepressants. The changes in metabolism could lead to toxicity. In a patient with liver disease and compromised liver function, encephalopathy can develop due to an inability to handle dietary protein. The use of antidepressants of the tricyclic class can cause impairment in the thinking processes due to their anticholinergic effects, adding to the encephalopathic impairment. A clinical picture of delirium can ensue. The use of benzodiazepines can worsen the delirium. RecommendationIt is critical for physicians and counselors to quickly recognize the pre-existing depression, or depression caused by Hepatitis C or the side effects of HCV pharmacologic therapy! They must be treated with supportive therapy, modification of doses of interferon and psychiatric medications. Failure to do so may result in limitation of therapy, noncompliance with therapy and serious personal, interpersonal and mental health consequences Click here Psych Impairment in Coinfected Women These data also demonstrate that HCV in combination with HIV results in substantially increased odds of NP impairment. For those women who were dually infected with HCV and HIV regardless of CD4 category, the odds of NP impairment were significantly elevated. The test for an interaction between HIV and HCV was not significant and the combined effect of HIV and HCV status on NP impairment appears to be additive. We also showed a significant increase in NP impairment for those who were co-infected and not on HIV antiretroviral therapy. These results are similar to those reported by others [22-24]. Due to our cross-sectional design, we must limit our conclusions to the observation of a strong statistical association between NP function and HCV, while suggesting that the combined effect of HCV and HIV is greater than either alone in terms of NP impairment. Psychiatric effects of hepatitis C infectionThe patient is a 61-year old Hispanic woman who has been attending the county outpatient hepatology clinic for laboratory monitoring since she was diagnosed with hepatitis C virus (HCV) infection 16 months ago. Case Study provided by Susie H. Park, Pharm D, Assistant Professor at the University of Southern California School of Pharmacy, USA. Presentation The patient is thought to been infected with HCV after having a tattoo on her arm 10 years ago in Mexico. She carries the HCV genotype 1b. She does not drink any alcohol, although she admits that she used to drink regularly a couple of years ago. She denies past or present intravenous drug use. During an initial consultation with the psychiatric pharmacist, the patient expresses having feelings of sadness, occurring at random times during the day, and having crying episodes around twice a week. She states that she has low energy levels, has a reduced ability to concentrate on certain tasks, no longer enjoys going to social gatherings to meet with friends, feels "slowed-down" and sluggish, and has a decreased appetite. The patient attributes these changes in her mood and behavior to the knowledge of being diagnosed with hepatitis. The fact she has been told that she can receive treatment for HCV infection gives her hope, but knowing that she has this virus makes her feel depressed. A Hamilton Rating Scale for Depression (HAM-D 17-Item) is completed and the patient's score is 21. The patient denies having any feelings of guilt, hopelessness, or worthlessness. There are currently no noticeable changes in her sleep pattern and she refutes having suicidal thoughts. The patient is informed that she is going to be treated with interferon (IFN) and ribavirin. Her most recent laboratory results indicate a consistently elevated viral load (HCV RNA >500 IU/mL). At first, she is slightly against accepting these treatments because she had heard that IFN may be associated with depressive symptoms and other possible psychiatric disturbances. She tells the pharmacist that she has been reading about IFN treatment and is concerned that her depressed feelings may worsen by taking this medication. She inquires about the use of milk thistle instead. The patient is informed that treatment with IFN is necessary at this time to decrease her elevated viral count. She has the option of refusing to take this medication, of course, but she is informed that she would then run the risk of developing liver cirrhosis or hepatocellular carcinoma. She is advised to start an antidepressant medication as soon as possible, and is discouraged from using milk thistle. The patient is asked to consider IFN therapy, and whether or not she wants to start this at her next visit. She is advised to discuss this with her family and return to the clinic when she has made a decision. She agrees to take an antidepressant.
Diagnosis The patient meets the criteria of clinical major depressive disorder (MDD) [Figure 1].
Symptoms of MDD with the patient's symptoms shown in bold
 Fig 1. © 2004 Current Medicine Group Ltd.
Treatment and outcome The patient is started on the antidepressant citalopram, administered orally at a dose of 10 mg on the day of the initial consultation. She is found to be able to tolerate the medication without any increase in liver enzymes or experiencing adverse drug reactions. One week later, after discussing the situation with her family, the patient decides that she will start treatment for HCV. She is started on pegylated interferon alfa-2a at a dose of 180 µg once a week and ribavirin at a daily dose of 800 mg. The patient is followed up over the telephone 1 week later. She continues to tolerate citalopram 10 mg and does not report experiencing any side effects such as nausea, dry mouth, sleep pattern changes, increased tendency to sweat, diarrhea, or changes in sexual function. The patient admits to occasional crying spells. She is instructed to increase her antidepressant dose and to begin taking 20 mg of citalopram a day. She complains that after she first injected the IFN it caused her to feel muscle pain and extremely tired. The patient returns to the clinic for a follow-up appointment, at which time she is encouraged to continue with the IFN and ribavirin therapy. She is re-evaluated for major depression by mental status examination. The patient scores 20 on the HAM-D-17 scale. The patient is continuously monitored for a period of 6 months, at the end of which her viral load has decreased, but not substantially. She reports that her depression has improved at the current dose of citalopram. Her HAM-D score improved to 9. The patient continues to adhere to the IFN therapy and citalopram at the maintenance dose.
Case discussion Hepatitis, depression, and IFN treatment are interconnected in the course of diagnosis, treatment, and side effects. HCV infection is associated with fatigue, anhedonia, loss of appetite, and depressed mood. Depression is common in patients with chronic HCV and this may be caused by the stress and anxiety associated with confronting a potentially fatal medical illness. People diagnosed with hepatitis C are more likely to have psychiatric problems, including major depression [1], which may necessitate treatment with psychotropic agents. When treated with IFN therapy for HCV infection, a patient may develop symptoms that can mimic or worsen depression: fatigue, poor appetite, apathy, irritability, insomnia, and cognitive changes [2], as well as hypersomnia, lethargy, emotional lability, social withdrawal, and psychomotor slowness [3]. This can complicate the treatment of the medical illness, hepatitis C, as well as the psychiatric disturbance, major depression. There is clearly a causal relationship between the use of this biologic agent and the emergence of depression due to the fact that the psychiatric side effects due to IFN remit once its use is discontinued. Nonetheless, neuropsychiatric symptoms are associated with both HCV and IFN therapy [4], therefore careful monitoring of symptoms before, during, and after treatment is necessary. Major depression is a relative contraindication to the use of IFN [5]. However, in most cases, the use of IFN in affected individuals may be required to prevent the progression of hepatitis. The use of IFN can improve the quality of life in patients with chronic HCV infection [6] by treating the illness that may have lead to the depressive symptoms. Nevertheless, careful monitoring is required in patients starting this therapy who are already depressed. More extensive monitoring may be required in these patients, as IFN use has been associated with suicide [7]. When suicidal ideation manifests in a patient being treated with IFN, the medication should be discontinued. The antidepressants that have been used most often in patients who develop depression in association with IFN therapy are the class called selective serotonin reuptake inhibitors (SSRIs). This particular class of antidepressants is generally considered the first-line of agents to treat depression. The SSRIs that have been used in IFN-induced depression in HCV patients are listed in Table 1. Few studies have used tricyclic antidepressants (TCAs), a class of second/third-line agents, in HCV patients. Treating pre-existing depression before IFN treatment causes it to worsen may prevent patients from discontinuing their treatment. This can facilitate successful HCV therapy by improving adherence to antiviral treatment. The patient was started on citalopram 10 mg once day, which was titrated after 14 days to 20 mg per day, resulting in good improvement in her depressive symptoms. It is feasible to titrate the dose within a matter of a few days to a week in most patients started on an antidepressant. However, greater caution was taken in this HCV patient due to the fact that she had also begun IFN treatment. Side effect tolerance of both IFN and citalopram was documented before the citalopram dose was increased. SSRIs are metabolized extensively by the liver cytochrome P450 isoenzyme system (i.e., citalopram via CYP3A4 and CYP2C19) and caution must be taken when using higher doses of SSRIs in hepatically-compromised patients. The oral clearance of citalopram may be reduced up to 35% in patients with reduced hepatic function. Citalopram is metabolized to demethylcitalopram, didemethylcitalopram, and other metabolites, all of which do not contribute significantly to the antidepressant effect of the drug. Due to the fact that biotransformation of citalopram is mainly hepatic, it is recommended that the lowest possible dose of the SSRI be started while monitoring for changes in liver function tests in HCV patients. The manufacturer states that 20 mg per day of citalopram is the recommended maximum dose for most hepatically-impaired patients and that the dose may be increased to 40 mg per day only in nonresponders [8]. The maximum dose of citalopram is 60mg per day.
SSRIs that have been used in the treatment of IFN-associated
depression in patients with HCV infection
 Fig 2. © 2004 Current Medicine Group Ltd. There are additional studies and reports on the use of SSRIs in INF-induced depression in patients with other diseases. The results of one study suggest that pretreatment with paroxetine in malignant melanoma patients using IFN alfa-2b is an effective strategy for minimizing IFN-induced depression [14]. It has been argued that pre-treatment may not be necessary in HCV-infected patients because the rate of depression may not be as high compared to other diseases for which much higher doses of IFN are indicated. Patients are often open to alternative considerations for treating their medical illnesses. Medical providers should be familiar with the various non-labeled uses of agents that patients may inquire about. In the case of hepatic conditions, patients might consider using a bioflavinoid called milk thistle (silybum marianum). Milk thistle is an herbal product and the most studied herb for hepatobiliary disease [15]. The active bioconstituent is the lipophilic substance called silymarin. Limited studies show mixed results that this herbal compound is effective for treating HCV. A meta-analysis on the use of milk thistle reported no reduction in mortality (frequency of death as an outcome), no improvements in histology (tissue studies) observed through liver biopsy, or in biochemical markers of liver function. The authors of the analysis concluded that they were unable to support the recommendation to use milk thistle for liver disease treatment [16]. Silymarin does have anti-inflammatory, hepatoprotective, and regenerative properties that may give it some usefulness in treating some of the symptoms associated with viral infection. It is unknown whether or not this herbal remedy has any effect on INF and ribavirin co-treatment, should a patient decide to start milk thistle once conventional treatment has begun. In order to obtain more extensive and reliable data, the National Center for Complementary and Alternative Medicine (NCCAM) is sponsoring a large clinical trial on the use of milk thistle for hepatitis C [17]. Finally, this case illustrates the importance of educating patients about side effects of IFN therapy, including depression. This psychiatric complication occurs in about a third of patients who are started on interferon therapy for the treatment of hepatitis C [18]. The authors of a study who treated chronic hepatitis C patients with interferon-alfa concluded that psychiatric symptoms may be the most common reason for stopping therapy [19]. Medication intolerability, including psychiatric side effects associated with IFN, should be communicated to the patient as well as to his/her family members. Family members should be asked to inform the patient's treating physician about changes in the patient's behavior. In doing so, medication doses can be adjusted and side effects can be managed. Ongoing communication between the clinician and the patient is encouraged so that he/she can adhere to the medication regimen and successfully complete the treatment for HCV.
Key case points
 Fig 3. © 2004 Current Medicine Group Ltd.
Author biography
Susie Park is a clinical pharmacist practicing at the University of Southern California-Los Angeles County Hospital and Psychiatric Clinic. She is assistant professor at the USC School of Pharmacy and teaches in the area of psychiatric pharmacy practice. She is a member of the College of Psychiatric and Neurologic Pharmacists, American Association of Colleges of Pharmacy, American Society of Health-System Pharmacists, and the American Pharmaceutical Association. Her research interests include pharmacogenetics of mood and psychotic disorders and psychoneuroimmunology. She is currently performing research in the area of genetic polymorphism of the serotonin transporter in patients infected with HCV.
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