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Treatment of Interferon-Induced Psychosis in Patients With Comorbid Hepatitis C and HIV

Received July 3, 2002; revision received Jan. 3, 2003; accepted Jan. 22, 2003. From the Mount Sinai Medical Center. Address reprint requests to Dr. Hoffman, AIDS Center, Box 1009, Mount Sinai Medical Center, One Gustave Levy Place, New York, NY 10029.

Four million people in the United States and over 100 million worldwide are estimated to have hepatitis C infection.¹ The modes of transmission of HIV and hepatitis C virus are similar, and coinfection is common, especially among intravenous drug users.² Among HIV-positive patients, approximately 30%–50% are coinfected with hepatitis C.^2,3 Approximately 70%–80% of those exposed to hepatitis C develop chronic infection.⁴ Although interferon has been the principal treatment for chronic hepatitis C for more than 10 years,⁵ treatment is complicated by its neurotoxic⁶ and psychiatric⁷ side effects. Several case reports have described depression and suicidal ideation in patients receiving interferon for hepatitis C.^8–10 Three reports have documented psychosis in HIV-negative patients receiving interferon ,^11–13 but to our knowledge no reports to date have described psychosis in HIV-positive patients receiving interferon treatment for comorbid hepatitis C.

All patients described in this study were enrolled at the Mount Sinai School of Medicine subsite of Hepatitis Resource Network 002, a multicenter trial of interferon -2b and ribavirin therapy in individuals coinfected with hepatitis C and HIV. Patients in this study were given ribavirin, 400 mg b.i.d., and were randomly assigned to receive interferon either daily or three times per week in a subcutaneous dose of 3 million units. At our subsite, all patients were screened for current depression and suicidality before enrollment and were followed throughout the study by a psychiatrist. The study was approved by the Mount Sinai School of Medicine Institutional Review Board. Table 1 describes the immunological parameters and antiretroviral therapy at study entry as well as treatment outcomes.

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TABLE 1. Immunological Parameters and Antiretroviral Treatment at Baseline and Treatment Outcome for Six Patients With Comorbid HIV and Hepatitis C Treated With Interferona

In our case series, four out of six patients with comorbid hepatitis C and HIV developed psychosis during interferon therapy. While all four of the patients who developed psychosis had prior histories of mood and substance use disorders, none had a previous history of psychosis. None of the patients engaged in substance abuse during interferon therapy. This is the first case series of new-onset psychosis in patients with comorbid HIV and hepatitis C during treatment with interferon .

Case 1

Ms. A was a 39-year-old woman who had been diagnosed with HIV and hepatitis C 6 years before study enrollment. At the time of her HIV diagnosis, she discontinued cocaine use and developed depression, anxiety, and suicidal ideation. She was treated with psychotherapy and a regimen of extended-release venlafaxine, 225 mg/day, and hydroxyzine, 50 mg at bedtime. She remained in psychiatric care and had not been suicidal for 6 years.

Ms. A's treatment with venlafaxine and hydroxyzine was continued as she entered the study. She began treatment with interferon daily and ribavirin. At 3 weeks, she began taking clonazepam, 1 mg at bedtime, for treatment of anxiety and insomnia.

During her 13th week of treatment, Ms. A became tearful and distressed. She was unable to sleep at night because she was hearing her deceased mother calling her name. She believed that there were strangers in her apartment at night and feared that she was losing her mind. She had no suicidal thoughts. She agreed to begin treatment with olanzapine, 2.5 mg/day, and her interferon regimen was decreased by half. Her auditory hallucinations resolved within a week, and she was able to sleep at night. Treatment with interferon and ribavirin was discontinued after 6 months because of insufficient hepatitis C viral load response. One year after inception of interferon treatment, she remained on a regimen of olanzapine because of recurrent mood swings and insomnia.

Case 2

Mr. B was a 49-year-old man who had been diagnosed with HIV and hepatitis C 7 years before study enrollment. He had been injecting heroin and using alcohol up until 10 years before this study. He had been treated for depression with psychotherapy and antidepressants since his diagnosis but was receiving only gabapentin for neuropathic pain and insomnia at the time of the study.

Within weeks of beginning treatment with interferon and ribavirin, he reported fever, chills, night sweats, diarrhea, and body pains. His wife reported that he had increased irritability. Mr. B missed several appointments over the ensuing months but returned to the clinic with his wife at the start of his sixth month of treatment. She reported that he had insomnia and that he had accused her of having extramarital affairs and of being part of a conspiracy against him. He reported no hallucinations but had paranoid delusions of infidelity. He agreed to initiate treatment with olanzapine, 2.5 mg/day. Interferon and ribavirin treatment was discontinued and was not restarted because of an inadequate hepatitis C viral load response. Mr. B continued receiving olanzapine, 2.5 mg/day, with complete resolution of his psychotic symptoms.

Case 3

Ms. C was a 37-year-old woman diagnosed with HIV 11 years before study enrollment, and she had been diagnosed with hepatitis C 2 years before enrollment. She had a history of depression and intravenous cocaine and heroin use that was in full sustained remission. She was not depressed or suicidal and was receiving no antidepressants when she enrolled in the study.

At week 20, Ms. C discontinued interferon and ribavirin treatment because of depression, weakness, and fatigue. When Ms. C was seen by a psychiatrist 2 weeks later, she was depressed but denied suicidal ideation. She admitted to hearing the voices of babies crying and calling her. She had paranoid ideation and reported seeing shadows of people as well. She was started on a regimen of olanzapine, 2.5 mg/day, and gabapentin, 300 mg at bedtime, for treatment of auditory and visual hallucinations. Three weeks later, the depression and auditory hallucinations continued, but her paranoid ideation and visual hallucinations had resolved. She was then started on a regimen of citalopram that was gradually increased to 40 mg at bedtime over a 4-week period. Two months later she was treated for interferon-induced thyroiditis with levothyroxine, 75 µg/day.

Ms. C was seen 6 months later and reported feeling less depressed with fewer episodes of auditory hallucinations. She had discontinued all of the psychotropic medications because she had been feeling better.

Case 4

Mr. D was a 43-year-old man who had been diagnosed with HIV and hepatitis C 12 years before study enrollment. He had a history of mood disorder and alcohol and cocaine dependence that had been in full sustained remission for 11 years before the study. He was receiving psychotherapy and a regimen of olanzapine, 2.5 mg/day, and bupropion, 150 mg b.i.d., for treatment of depression at the time of enrollment. Two months after starting interferon, he reported irritability and a worsening of the depression. He did not report any psychotic symptoms during the year of interferon therapy and was able to complete the treatment course. Three months after completing the study, he revealed that while receiving interferon he was not only depressed but also had auditory and visual hallucinations and paranoid ideation. He also reported that he was suspicious at times. Psychotic symptoms diminished only after interferon therapy ended. He remained on a regimen of bupropion, 150 mg b.i.d., and olanzapine, 5 mg/day, and continued in psychotherapy.

Discussion

All four of the patients with comorbid HIV and hepatitis C reported here who were treated with interferon therapy developed psychosis. We did not observe any signs or symptoms of delirium in our patients during the course of their treatment with interferon . Although psychosis may also be induced by antiretroviral therapy, delirium, HIV, or hepatitis C, our patients developed psychosis shortly after beginning interferon treatment.

Treatment with interferon may adversely affect mood, cognition, and perception. The neurotoxic effects of interferon may be a result of the production of cytokines causing an alteration in the normal release of signaling molecules in the brain.¹⁴ Patients with comorbid HIV and hepatitis C may be at greater risk for psychosis during interferon treatment because of additional neurotoxic effects of HIV.¹⁵

Our patients had a history of intravenous drug use as well as use of alcohol or benzodiazepines. This may have predisposed them to interferon-induced psychosis. Although depression is a well-documented consequence of treatment with high-dose interferon in patients with malignant melanoma^16,17 and hepatitis B,¹⁸ patients with hepatitis C may have other concomitant psychiatric disorders¹⁹ and may be especially vulnerable not only to depression but also to psychosis. Since antidepressants may precipitate mania and worsen psychosis,^20–22 we do not recommend the use of prophylactic antidepressants in patients with comorbid HIV and hepatitis C who also have substance-related disorders. Furthermore, the subpopulation of HIV intravenous drug users with hepatitis C is extremely vulnerable to delirium, dementia, and psychosis in addition to major depressive disorder and other mood disorders. Careful screening for psychosis, mania, substance use, and cognitive disorders is imperative in persons with both HIV and hepatitis C before beginning psychotropic medications. Since antidepressants have a 2–6-week period from the beginning of treatment to therapeutic effect, they are unlikely to be helpful in the short-term management of the patient. Antipsychotic and mood stabilizing medications are often more helpful in the management of interferon-induced psychosis and mood disorders. The only patient in our series who was able to tolerate interferon for a full year was receiving both an antidepressant and an antipsychotic and was in psychotherapy throughout the course of treatment. Although he developed psychotic symptoms, they did not interfere with his treatment. If symptoms of major depressive disorder develop, we recommend the addition of an antidepressant.²³

A history of drug or alcohol abuse may increase the risk of psychiatric morbidity in addition to the risk of a more rapid progression of disease. The co-occurrence of substance-related disorders, HIV, and hepatitis C may contraindicate pretreatment with antidepressants. Since the prevalence of depression and suicide are high in patients with HIV alone,^24,25 the added risk for psychosis in patients with HIV, hepatitis C, and intravenous drug use warrants grave concern. Before interferon treatment, we recommend screening for psychiatric disorders. Pretreatment with antidepressants is not recommended in this subpopulation. Treatment with mood stabilizing and antipsychotic medication can alleviate psychosis and suffering in these vulnerable patients.

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