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Suicidal Ideation With IFN- and Ribavirin in a Patient With Hepatitis C

Received September 12, 2000; revised January 23, 2001; accepted January 8, 2001. From the Department of Psychosomatics and Psychotherapy, Justus Liebig University Hospital, Paul-Meimbergstr.5, D-35392 Giessen, Germany; and the Department of Internal Medicine, Rodthohlstr.6, D-35392 Giessen, Germany. Address reprint requests to Dr. Ademmer, Friedrichstr. 33, D-35392 Giessen, Germany. E-mail: Karin.Ademmer{at}psycho.med.uni-giessen.de

Key Words: Suicide • Interferon • Ribavirin

Hepatitis C is a major health problem. The global prevalence of this disease is 3% with an estimated 4 million hepatitis C virus (HCV) carriers in Europe alone. The state-of-the art treatment for this infection is a combination therapy with interferon alpha (IFN-) and ribavirin.¹ This treatment results in a sustained clearance of HCV-RNA in 10%–20% of patients.² In view of the limited treatment options for this disease, early detection of side effects that restrict the use of this therapy are of paramount importance. One of the most serious side effects of IFN- treatment is the development of psychiatric symptoms, particularly depression and suicidal ideation.³ Attempts to screen for patients at risk for development of major depression and suicidal behavior have not been very successful.⁴ Furthermore, depression secondary to interferon therapy may not respond to antidepressant drugs in a predictable manner.^5,6

There are reports of major depression and suicide attempts in German patients treated with high-dose interferon for malignant melanoma.^7,8 Furthermore, a MEDLINE search of the current literature on depression and suicidal behavior developing during treatment with IFN- for hepatitis C infection showed case reports from the USA, Japan, and the Netherlands.^6,9–13

In contrast to previous case histories, we examined both the clinical course of the viral infection and the psychosocial context of the infection against the backdrop of the patients' life history and means of dealing with difficult life events. This approach may serve as an effective starting point for evaluating patients with hepatitis C who are selected for treatment with IFN- and ribavirin.

Case Report

Mr. A. was 55 years old when he was started on treatment with IFN- (3 million units of recombinant IFN- 3 times/week sc) and ribavirin (1,200 mg/day per os). The patient had no previous history of drug or alcohol dependence or usage. He had not received any blood transfusions, and there was no elicitable history of multiple sexual partners. The diagnosis of hepatitis C had been made 3 months prior to starting antiviral medication, when elevated levels of alanine transaminase (ALT) and bilirubin were found in preoperative laboratory investigations before a planned arthroscopy. Diagnostic procedures revealed a chronic active infection with HCV (genotype 1b, viral load=7.8 million copies/ml; which is considered to be a heavy load). A liver biopsy showed lymphocytic infiltration of the portal regions with destruction of liver parenchyma and partial effacement of the liver ducts. The Histology Activity Index score was 7; there was no evidence of fibrosis or cirrhosis. Hepatitis A and B infections were ruled out. HIV screening tests were negative.

Immediately after starting therapy according to the EASL guidelines,¹ Mr. A. suffered severe flu-like symptoms that were only partially alleviated by acetaminophen. Mr. A. was referred to our psychosomatic and psychotherapeutic service by his physician, who had noticed that the patient appeared to be "depressed." Mr. A. complained of extreme fatigue, insomnia, and upper abdominal pain, which improved spontaneously during the course of the day. He reported feelings of anxiety, tension, and guilt, and he was unable to relax. He became progressively socially isolated. He was unable to perform his job as an investment and insurance broker. He spent time brooding about his financial problems. Besides weekly psychoanalytically oriented psychotherapy, Mr. A. was started on trimipramine (75 mg/day), St. John's wort (900 mg), and zolpidem (10 mg at night), 2 months after starting the antiviral therapy. Therapeutic blood levels of the antidepressants were not monitored. This treatment did not improve Mr. A.'s symptoms, and he began having suicidal ideation ("it would be better for his family if he were not alive.") At this stage, 4 months after starting treatment for his hepatitis C infection, Mr. A. was admitted to our psychosomatic ward.

At the time of admission, Mr. A. met criteria for major depression, but he did not meet criteria for a personality disorder on the SCID-II interview for personality disorders. Two weeks prior to admission a RT-PCR test for HCV-RNA could detect no hepatitis C virus in his blood; furthermore, his ALT and bilirubin values were normal. The psychopharmaceutical drugs and IFN and ribavirin were continued. There are no established guidelines for when interferon therapy should be stopped when severe depression occurs. A further confounding factor is that the development of suicidal ideation is rare and unpredictable. At the time of admission, examination of the literature pertaining to this point revealed an Italian report¹⁴ on the continuation of interferon along with antidepressants and a report arguing strongly for the discontinuation of cytokine treatment.⁷

Two years before treatment, Mr. A. had sought psychotherapeutic help to deal with marital problems; however, he discontinued therapy after three sessions, and a further attempt at psychotherapy also ended after initial sessions. At the time of admission, Mr. A. had been having psychotherapeutic therapy for his depressive mood for 2 months. Although it was difficult to establish an initial rapport with the patient, Mr. A. readily entered into a written agreement that in case of increasing suicidal ideation or tension, he would actively seek the help from staff. Further motivation for living included Mr. A.'s obligations to his daughter and to his girlfriend. During exploration, Mr. A. was emotionally distant, especially in his manner of speech, which was archaic. He referred to himself in the third person. He was distrustful and resentful of his attending doctors. Retrospective evidence showed that he had HCV infection since 1992, and because of the low specificity of the then prevailing diagnostic test he had not been informed of the infection at that time. Three years later, Mr. A. participated in a study in which samples of his blood were drawn for other investigations. He was convinced that at that time his HCV infection must have been discovered and that the study coordinator had omitted to inform him. He was contemplating suing the previous two institutions for malpractice when the RT-PCR evidence of HCV was shown to be negative. Mr. A. felt cheated by the medical world. He felt that he had not been sufficiently informed about the side effects of the interferon therapy and the curtailments it would impose on his functioning. These feelings could be related to other similar situations in his life, where he felt that he was not being taken seriously and was a helpless victim of circumstances. These situations angered Mr. A., which he turned against himself in a depressive modus.

The psychodynamic relevance of Mr. A.'s symptoms and situation can be more clearly interpreted in the light of his life history. In his first year of life, Mr. A.'s mother died of an unknown illness. She had been rumored to have had syphilis. He had apparently been severely neglected and probably experienced psychosocial deprivation. He was brought up by his paternal grandparents until he rejoined his family at age 6. His father had remarried, and besides his three older siblings, Mr. A. had a younger half-sister. He was often physically punished by his strict, domineering, and authoritative father. He felt torn between feelings of loyalty to his father and to his older siblings who openly rejected their father. Furthermore, he harbored feelings of jealousy toward his younger step-sister who was favored by both parents. Later, Mr. A. found support in the family of his wife, whom he met at the age of 20 and married shortly thereafter. After 30 years of marriage, during which he described feelings of guilt for not being able to live up to the financial and social expectations of his wife, his wife separated from him. He had a distanced and strained relationship with his son but was much closer to his daughter, who had a history of cannabis dependence. After his daughter was admitted to a psychiatric ward because of psychotic symptoms, there was a dramatic increase in tension in his relationship with his wife. There followed a period of repeated separations, with feelings of guilt and guarded aggression toward his wife. However, Mr. A. found a new and satisfying relationship outside his marriage. The diagnosis of hepatitis C and its management made him insecure and doubtful of the medical interventions and his own self efficacy.

Eight days after admission, Mr. A. attempted suicide with trimipramine (3,000 mg) and zolpidem (2,000 mg) on the ward, after which he was discovered unconscious in his room. His vital signs were stable. It was difficult to understand his abrupt suicide attempt at this stage because there had been no clinical evidence of deterioration of depressive symptoms. After the necessary treatment in the internal medicine department, Mr. A.'s condition stabilized and he was transferred back to our inpatient psychosomatic unit after 5 days. The IFN- and ribavirin medications were stopped. Other reports on suicidal ideation and interferon therapy have shown that stopping the cytokine medication results in immediate amelioration of suicidal tendencies.^7,13 Mr. A. still complained of insomnia and was started on a benzodiazepine. He had clearly distanced himself from suicidal ideation and appeared more authentic in contact with his therapist. He expressed relief that his suicide attempt had been unsuccessful, and he no longer felt helpless or forlorn. He began communicating his wishes more clearly and reported having more energy. Laboratory values, including ALT, showed no abnormalities. Mr. A. was discharged in a stable physical and mental state. He started psychodynamically-oriented psychotherapy and returned to work. Six months after discharge, Mr. A. is leading a successful social and professional life.

Discussion

In this case history we examined psychosocial factors in the context of the life history of a patient with hepatitis C infection who was treated with IFN- and ribavirin. During inpatient care, Mr. A. attempted suicide. We were able to explore this situation in detail with Mr. A. and tried to find reasons for his suicidal behavior. Initially, he appeared cooperative, so that his abrupt suicide attempt by toxic doses of medicines, which he had surreptitiously brought along with him to the hospital, appeared to be an act of revenge on the medical world, to which he attributed his sufferings.

An important aspect in the consideration of Mr. A.'s case history is the course of the infection per se. In keeping with the observation of Lerner et al.⁵ and Renault and Hoofnagle,¹⁵ we found that Mr. A.'s deterioration in psychosocial functioning and the increase in the severity of his depressive symptoms corresponded with negative evidence of HCV-RNA in serum. However, there are no empirical studies that examine the relationship between viral load and patient-related depression scores. Ribavirin does not appear to have a significant impact on mood, although adverse side effects occur more frequently in combination therapy. The most common adverse effects are anemia, fatigue, and depression.¹⁶ In view of Mr. A.'s childhood experiences and his use of a depressive modus for reacting to stress, Mr. A.'s psychological predisposition could have played an important role in the development of depression.

IFN--induced depression may differ from major depression in response to antidepressants. Lerner et al.⁵ found that patients receiving IFN- were less likely to respond to antidepressants, a finding that has been supported by another report from the United Kingdom¹⁷ about antidepressant response being reversed by interferon. There has also been a report of a patient with a known schizoaffective disorder who had suicidal ideation under interferon therapy but responded favorably to treatment with nefazodone and flupentixol.¹⁸ Further research is required to show whether interferon-induced depression represents a subtype of depression with characteristic features.

In addition to pretreatment screening for psychiatric comorbidity, patients being started on IFN- treatment for hepatitis C should be monitored for symptoms of depression and for suicidal ideation. If depression or suicidal ideation are suspected, therapy should be immediately stopped because impulsive suicide attempt is known with treatment with interferon,^7,13 as was the case with our patient. Another important aspect of psychiatric screening includes a careful history of adverse life events and patient reaction to stressful life events, as those who are unable to cope with such events may develop severe depression. This hypothesis is supported by the findings of Maunder et al.,¹⁰ who reported on the emergence of posttraumatic stress disorder during IFN- treatment for hepatitis C in three patients.

Mr. A.'s case emphasizes the question of when to stop interferon therapy for chronic hepatitis C in patients who develop severe depression. The literature pertaining to this point offers contradicting answers,^6,9,13,17,18 and there is an acute need for empirical research that examines the use of antidepressants in controlled studies with larger numbers of patients.

REFERENCES

1. Consensus Statement: EASL International Consensus Conference on Hepatitis C. J Hepatol 1999; 30:956-961[CrossRef][Medline]
2. National Institutes of Health Consensus Development Conference Panel Statement: Management of Hepatitis C. Hepatology 1997; 26 (suppl 1):2S-10S
3. Renault PF, Hoofnagle JH, Park Y, et al: Psychiatric complications of long-term interferon alpha therapy. Arch Intern Med 1987; 147:1577-1580[Abstract/Free Full Text]
4. Capuron L: Prediction of the depressive effects of interferon alfa therapy by the patients initial affective state. N Engl J Med 1999; 340:1370[Free Full Text]
5. Lerner DM, Stoudemire A, Rosenstein DL: Neuropsychiatric toxicity associated with cytokine therapies. Psychosomatics 1999; 40:428-435[Abstract/Free Full Text]
6. Gleason OC, Yates WR: Five cases of interferon-alpha-induced depression treated with antidepressant therapy. Psychosomatics 1999; 40:510-512[Free Full Text]
7. Schäfer M, Messer T, Wegner U, et al: Psychiatric side effects during adjuvant therapy with interferon-alpha in patients with malignant melanoma: clinical evaluation as well as diagnostic and therapeutic possibilities. Hautarzt 1999; 50:654-658[Medline]
8. Windemuth D, Bacharach-Buhles M, Hoffmann K, et al: Depression and suicidal intentions as a side effect of high dosage interferon therapy—two cases. Hautarzt 1999; 50:266-269[Medline]
9. Levenson JL, Fallon HJ: Fluoxetine treatment of depression caused by interferon-. Am J Gastroenterol 1993; 88:760-761[Medline]
10. Maunder RG, Hunter JJ, Feinman SV: Interferon treatment of hepatitis C associated with symptoms of PTSD. Psychosomatics 1998; 39:461-464[Free Full Text]
11. Fukunishi K, Tanaka H, Maruyama et al: Burns in a suicide attempt related to psychiatric side effects of interferon. Burns 1998; 24:581-583[CrossRef][Medline]
12. Heeringa M, Honkoop P, de-Man RA, et al: Major psychiatric side effects of interferon alfa 2b. Ned Tijdschr Geneeskd 1998; 142:1618-1621[Medline]
13. Janssen H, Brouwer J, van der Mast, et al: Suicide associated with alfa-interferon therapy for chronic viral hepatitis. J Hepatol 1994; 21:241-243[CrossRef][Medline]
14. Pariante AM, Orrù MG, Baita A, et al: Treatment with interferon- in patients with chronic hepatitis and mood or anxiety disorders. Lancet 1999; 354:131-132[CrossRef][Medline]
15. Renault PF, Hoofnagle JH: Side effects of alpha interferon. Semin Liver Dis 1989; 9:273-277[Medline]
16. Reichard O, Schwarcz R, Weiland O: Therapy of hepatitis C: alpha interferon and ribavirin. Hepatology 1997; 26(suppl 1):108S-111S
17. Mc-Allister-Williams RH, Young AH: Antidepressant response reversed by interferon. Br J Psychiatry 2000; 176:93-94[Free Full Text]
18. Schaefer M, Schmidt F, Amann B, Schlösser S, et al: Adding low-dose antidepressants to interferon alpha treatment for chronic hepatitis C improved psychiatric tolerability in a patient with schizoaffective psychosis. Neuropsychobiolology 2000; 42(suppl):43-45

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