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Interferon Treatment of Hepatitis C Associated With Symptoms of PTSD

Received June 17, 1997; revised October 2, 1997; accepted October 23, 1997. From the Department of Psychiatry, University of Toronto; the Psychosomatic Program, Mount Sinai Hospital; the Department of Medicine, University of Toronto; and the Liver Study Unit, Mount Sinai Hospital, Toronto, Ontario, Canada. Address reprint requests to Dr. Maunder, Department of Psychiatry, 9th Floor, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada, M5G 1X5.

Key Words: Inteferon • Hepatitis • Posttraumatic Stress Disorder

The interferons are a family of related proteins produced by many cells in the periphery and in the brain, including fibroblasts and macrophages.¹ Physiologically, interferon (IFN) mediates the immune and endocrine response to viral invasion. Interferon-2b is used in the treatment of cancer and hepatitis C and is considered to carry a risk of depression of 8%–10% (Intron A product monograph, Schering-Plough [Brinny] Co., Innishannon, Ireland). There has, however, been no reported association of IFN and posttraumatic stress disorder (PTSD). We report here three cases in which symptoms related to PTSD were precipitated by treatment of hepatitis C with IFN-2b.

In the first case, a man with a past history of PTSD in long remission experiences a recurrence. In the second case, a man with a past history of trauma and depression experiences PTSD symptoms for the first time while being treated with IFN. In the third case, a man with no history of trauma or PTSD experiences an exaggerated startle response while being treated with IFN.

The IFN response and PTSD have physiological properties in common, particularly in systems involving catecholamines, endogenous opioids, and serotonin.^1,2 Following the presentation of the cases, we present hypotheses regarding the possible mechanism by which IFN could trigger a relapse of PTSD.

Case Histories

Case 1: Mr. A was 42 when he was referred for psychiatric consultation by a gastroenterologist treating him with IFN-2b. Hepatitis C had been diagnosed 4 years previously, and abnormal liver-function tests had been noted for years. A liver biopsy confirmed chronic hepatitis. Risk factors for hepatitis infection included a past history of intravenous drug use, promiscuity, and one blood transfusion. The drug had been discontinued after 21 injections of 3 million units (MU) intramuscular (im) IFN-2b (3/week) because of the emergence of nightmares with vivid, grotesque content—some of it fantastic and some of it portraying with little distortion events of his previous experience as a political prisoner. He reported a rapid heartbeat occurring on the day following his injections. Mr. A was also experiencing episodes of severe anxiety associated with chest tightness. The week before consultation he had, while awake, vividly reexperienced being pursued by police. He believed that he was becoming paranoid. He found that these experiences were triggered by watching TV and by talking to a friend about innocuous things, which in retrospect he associated indirectly to his past trauma. He met DSM-IV criteria for PTSD and major depression.

In the early 1970s, Mr. A had worked for 5 years in the organized resistance to a totalitarian regime in Chile. In 1973 he was imprisoned there. Friends close to him "disappeared," and he lived in fear for his own life. His trauma derived from his imprisonment and his close relationship to friends who were tortured and his awareness that he could be next. He himself was not tortured. He left Chile and came to Canada in 1974.

After coming to Canada, Mr. A became a heavy drinker and user of cocaine and intravenous drugs. He reported that after leaving Chile, he had symptoms of depression and difficulties with nightmares but usually attributed these to the effects of intoxication or withdrawal. He attributed the substance abuse to his isolation, low self-worth, and survivor guilt. He experienced "paranoia" (by which he referred to vigilance and fear) and frequent suicidal ideas. The nightmares diminished in frequency over 2–3 years, and he was virtually free of them by the late 1970s. Although he was a talented artist, and his wife and two teenage children from whom he was separated lived in the same city, he described himself as living in the streets.

In 1993 he found a new relationship, attended church and Alcoholics Anonymous, and became abstinent from alcohol and nonprescription drugs. He found an apartment and a studio and began painting and selling his art again. Before the treatment with IFN, he had been free of nightmares and intrusive memories for about 15 years and did not have significant depression. He was abstinent from alcohol, opiates, and other street drugs for 2 years. This period of remission from posttraumatic and depressive symptoms was interrupted shortly after the IFN treatment began. Mr. A has continued to have nightmares, severe anxiety, and depressive symptoms, which are not well controlled with pharmacological treatment over 2 years since the brief trial of IFN. There is no clear temporal relationship between symptoms of hepatitis and PTSD symptoms, nor any known anniversary related to the onset of PTSD symptoms. Trials of pharmacological treatment have included fluoxetine, paroxetine, sertraline, amitriptyline, nortriptyline, and benzodiazepines. In this context, 1.5 years after the initial consultation he experienced a relapse of substance abuse.

Case 2: Mr. B was a 43-year-old youth counselor who acquired hepatitis C through an intravenous drug habit that ended in 1978. He reported a past history of depressive symptoms that had never led to psychiatric assessment or treatment. Mr. B was diagnosed with hepatitis C in 1995 and was treated with IFN-2b in 1996 for 8 weeks. He was referred for psychiatric consultation in 1997 in anticipation of a second trial of IFN-2b. During the first trial of IFN-2b, he experienced mood swings, headaches, and muscle aches throughout his body. The mood symptoms included frequent crying, low tolerance of frustration, difficulty making decisions, lack of confidence in his work, and self-blame for getting the illness. Of much more concern to him was the emergence during IFN-2b treatment of nightmares and intrusive memories in which the content was the experience of taking intravenous drugs and the life circumstances surrounding that habit.

He also reported a general increase in arousal and anxiety. Of special note, Mr. B described the act of self-injecting his IFN intramuscularly as being a potent cue that reminded him of his experiences with heroin. He had developed anticipatory anxiety leading up to the self-injection, especially fear of reexperiencing his memories of substance abuse. The nightmares, intrusive memories, and generalized anxiety associated with the first trial had subsided after the IFN treatment ended.

Mr. B was followed through the second trial in which he received 36 injections of 3 MU im IFN-2b (3/week) and ribaviron (1,200 mg/day). Again he experienced nightmares, anxiety, and, associated with his IFN treatment, suicidal thoughts. He reported feeling like he was going crazy because of the recurrence of several traumatic memories, which "I thought I had dealt with and put behind me," including being raped by his cousin and his father beating his sister with a skipping rope. He did not meet DSM-IV criteria for major depression. He met the DSM-IV PTSD criteria A (exposure to trauma), B (reexperience of trauma), and D (increased arousal)—but not C (avoidance). Mr. B chose against pharmacological treatment of his psychiatric symptoms, which improved spontaneously after discontinuation of IFN-2b.

Case 3: Mr. C was a 43-year-old man with a past history of 3 possible untreated episodes of depression over 8 years, each characterized by fatigue and profound amotivation, and each possibly related to abuse of marijuana and cocaine. His hepatitis C was discovered during a workup for diminished sex drive. The only reported risk factor was intravenous drug use 2 years previously. He received 72 three-times weekly im injections of 10 MU IFN-2b. During this treatment, he again had fatigue and amotivation, and met DSM-IV criteria for major depression. His depression responded adequately to treatment with moclobemide (300 mg bid) during the 6-month course of IFN treatment. He reported his concern at the third month of IFN treatment that he was experiencing an easily triggered and severe startle response. There were no other symptoms of PTSD present and no past history of significant trauma.

Discussion

These cases are presented, in the first place, to alert clinicians to a previously unreported complication of interferon treatment. While it has been noted that IFN treatment is associated with increased vulnerability to emotion, including scenes of violence on television,³ ours is the first report of PTSD symptoms emerging in IFN patients with a past history of trauma. Accentuation of previous symptoms such as phobias, obsessional thoughts, and rituals has also been noted as a late psychiatric side effect of alpha interferon.⁴

Interpretation of the events in these cases is difficult for several reasons. Comorbidity, especially with major depression and substance abuse, complicates all aspects of living with and treating PTSD. Any causal interpretation of the possible association of PTSD and IFN-2b is also complicated by this comorbidity. In addition, hepatitis C is an illness with predisposing factors (particularly intravenous drug use) that are probably more common in people with a past history of PTSD; thus, the treatment population may contain a disproportionate number of people who are vulnerable to PTSD. Furthermore, medical illness in itself has been implicated as a provocative factor for exacerbation of PTSD.⁵ In discussing these case presentations, therefore, we are limited in making inferences about causal links between IFN-2b and PTSD by the complicated series of events and the limitations of the retrospective history-gathering method. As much as possible, we have acquired collateral history to confirm the accuracy of these case reports.

We wish to extract for the sake of hypothesis generation the following plausible but unproven claims: 1) in the first case, that a person with a clear past history of PTSD, but in a remission of several years' duration, experiences a relapse of PTSD as a result of treatment with IFN; 2) in the second case, that a person with a past history of trauma but not PTSD experiences some symptoms of PTSD as a result of treatment with IFN; and 3) in the third case, that a person with no history of trauma experiences an exaggerated startle response (one symptom of PTSD) as a result of treatment with IFN. We introduce three causal hypotheses that would explain an association of PTSD symptoms and IFN.

As a first approach, it is known that images and feeling states associated with PTSD can be elicited in people with prior PTSD via the infusion of medications that stimulate autonomic nervous-system arousal, such as lactate⁶ or yohimbine.⁷ It is conceivable that IFN may also work this way. IFN-2b has been shown to increase plasma catecholamine levels in healthy volunteers.⁸ IFN also increases cortisol in vitro⁹ and in vivo⁸ in healthy volunteers and in hepatitis C patients.¹⁰ Thus, the injection of IFN may increase autonomic arousal or adrenergic activity generally, much like lactate or yohimbine, thereby exacerbating PTSD symptoms.

The second hypothesis is similar but more involved. The neurological and immune systems may be thought of as the two major mechanisms of human adaptation to an environmental threat. It is to be expected that there would be links between these systems. In fact, the burgeoning field of psychoneuroimmunology has demonstrated many bidirectional connections between these systems at several levels.¹¹ Given a high level of interconnection, it is reasonable to conjecture that a substantial perturbation in one system would have an effect on the other. There is no doubt that PTSD creates a very substantial perturbation of the central nervous system, including predictable changes in the activity of catecholamines, glucocorticoids, endogenous opioids, and serotonin at the time of acute trauma and in the chronic state.² The involvement of the immune system in PTSD has been much less thoroughly studied. It is known that low-grade acute stressors such as medical student examinations decrease measured IFN,^12,13 but the role of IFN, if any, in major trauma is not known. We hypothesize that part of the immune perturbation in the acute response to major trauma may be an increase in IFN activity and, furthermore, that the use of IFN therapeutically recreates an immune state similar to that which occurs with acute psychological trauma. The "reexperience" of a high level of IFN or its physiological consequences may then trigger a relapse of PTSD in a manner analogous to the precipitation of relapse through the reexperience of psychologically relevant triggers.

The third hypothesis is not exclusive of the previous two. It is likely that in people with a past history of intravenous drug abuse, the experience of self-administering a drug with a needle acts as a psychological trigger of memories associated with past drug abuse, as seems to have occurred in Mr. B during his first course of IFN treatment. This association would be explained as a conditioned (learned) response, consistent with our understanding of other psychologically relevant triggers of PTSD.

These hypotheses are speculative until tested empirically. First, the apparent association of PTSD and IFN would require substantiation, controlling for the effects of major illness such as hepatitis C. Substantiation of a biological hypothesis would require control for the psychological effects of self-administering parenteral medication. Beyond this, research to investigate a biological association of IFN and PTSD might be directed at 1) testing the hypothesis that increases in endogenous IFN are associated with acute major trauma, 2) identifying increases in endogenous IFN associated with situations known to trigger PTSD symptoms, and 3) identifying PTSD-type symptoms such as exaggerated startle response in patients treated with therapeutic IFN in the absence of a previous diagnosis of PTSD.

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