Three Cases of Successful Tryptophan Add-On or Monotherapy of Hepatitis C and IFN -Associated Mood Disorders

Transcription

1 Three Cases of Successful Tryptophan Add-On or Monotherapy of Hepatitis C and IFN -Associated Mood Disorders MARTIN SCHAEFER, M.D., JOCHEN WINTERER, M.D. RAHUL SARKAR, M.D, RALF UEBELHACK, M.D. LEONORA FRANKE, M.D., ANDREAS HEINZ, M.D. ASTRID FRIEBE, M.D. Background: Interferon-alpha (IFN )-associated mood disorder is a major complication of treatment for chronic hepatitis C. Method: The authors report on three patients infected with chronic hepatitis C showing severe depressive symptoms during or after IFN treatment. Because patients had lowered tryptophan blood levels and did not response to antidepressants, they received tryptophan up to a dosage of 1,000 mg/day as mono- or add-on treatment. Results: Tryptophan, used as augmentation or monotherapeutic treatment, led to a significant improvement of depressive symptoms in all three patients. Conclusion: A tryptophan deficit seems to be involved in the pathophysiology of persistent mood changes during and after IFN treatment. (Psychosomatics 2008; 49: ) Worldwide, 170 million people are estimated to be chronically infected with the hepatitis C virus (HCV). For patients with an HCV infection, an increased incidence of psychiatric symptoms have been described, especially symptoms of fatigue, mental tiredness, poor concentration, forgetfulness, depression, irritability, and sleeping problems. 1 Several pathophysiological mechanisms have been discussed, including changes in central dopamine and serotonin transporters, 2 as well as virus brain interactions. 3,4 Moreover, chronic infectious diseases have been shown to be associated with peripheral changes of the Received March 26, 2007; revised July 13, 2007; accepted August 1, From the Dept. of Psychiatry and Psychotherapy, Charité Universitätsmedizin, Berlin, Germany and the Dept. of Psychiatry, Psychotherapy and Addiction Medicine, Kliniken Essen-Mitte, Essen, Germany. Send correspondence and reprint requests to Martin Schaefer, M.D., Dept. of Psychiatry, Psychotherapy, and Addiction Medicine, Kliniken Essen-Mitte, Henricistr, 92, D Essen, Germany. martin. schaefer@charite.de 2008 The Academy of Psychosomatic Medicine serotonergic system, especially with decreased tryptophan concentrations and an increased kynurenin/tryptophan ratio. 5 So far, interferon-alpha (IFN ) is the only effective immunotherapeutic agent for the treatment of viral hepatitis. However, clinical use of IFN is often complicated by psychiatric side effects. 6 Sleep disturbance, fatigue, irritability, mania, anhedonia, depression, cognitive disturbances, and even suicidal thoughts or suicide attempts have been observed during treatment with IFN. The most important psychiatric side effect of IFN is the induction of episodes of major depression, which has been reported to occur in 30% 50% of patients. Depression and fatigue are thought to be associated with changes in serotonergic neurotransmission and metabolism. 6 Besides an increase of serotonin transporters and a decrease of postsynaptic serotonin receptors, reduced tryptophan availability has been reported during hepatitis C infection and IFN treatment IFN activates the enzyme indoleamine-2,3-dioxygenase (IDO), which catalyzes the rate-limiting step of peripheral tryptophan conversion into kynurenine and Psychosomatics 49:5, September-October 2008

2 Schaefer et al. quinolinic acid. Because tryptophan is the essential precursor of central serotonin (5-HT) production, this effect might contribute to a central serotonin deficit. Low tryptophan levels have been shown to be associated with symptoms of depression. 11 It has been postulated that about 25% of chronic HCVinfected patients and 30% of IFN -treated patients need antidepressant treatment. 1 Regarding IFN -associated mood changes, several case reports and case series demonstrated a positive effect of antidepressants, especially selective serotonin-reuptake inhibitors (SSRIs) So far, three prospective trials have provided evidence that preemptive antidepressant therapy with SSRIs can significantly reduce the incidence and severity of depression during IFN treatment However, although the response rate of HCV- and IFN-associated depression to antidepressant treatment seems to be very high, most of the patients do not show a complete remission of depression symptoms, sleeping disturbances, anxiety, or fatigue. This might be due to the fact that reuptake-inhibition of serotonin does not fully compensate for the hypothesized serotonergic deficit during chronic HCV-infection and IFN treatment. Thus, reduced tryptophan availability might be an additional important factor explaining HCV- or IFN-associated mental changes. We therefore hypothesized that tryptophan as augmentation strategy or as monotherapy may have its own specific antidepressant effect in patients with depression during chronic hepatitis C infection or during/after antiviral treatment with IFN by increasing the availability of tryptophan for conversion into 5-HT. In the following article, we report on three cases in which tryptophan treatment resulted in a significant improvement of IFN -induced depression symptoms during and after IFN treatment of chronic hepatitis C infection. Case Reports Case 1 A 42-year-old company employee ( Mr. A ) was treated with pegylated IFN and ribavirin because of a chronic hepatitis C infection (genotype 1). After 4 months, he developed depressive mood changes accompanied by anxiety, diminished activity and self-confidence, social withdrawal, and suicidal thoughts. Treatment efforts with mirtazapine (up to 60 mg/day), lithium (1,150 mg/day), and valproic acid (1,000 mg/day) led to only a slight improvement, but not a remission of symptoms. Because depressive symptoms worsened (suicidal thoughts, sleeping disturbances, and agitation occurred), IFN treatment had to be stopped. Nevertheless, psychiatric symptoms did not improve spontaneously during the next 6 weeks, and the patient was admitted to our psychiatric ward with a Hamilton Rating Scale for Depression (Ham D) score of 23. During the next 4 weeks, we changed antidepressant treatment to a dosage of up to 40 mg/day of citalopram. The patient complained about an increase in agitation and sleeplessness, without a significant improvement in depressive symptoms. At this time, he even attempted suicide. Because of the strong agitation, citalopram was reduced to 20 mg/day, and amisulpirid was administered to the patient over the course of 2 weeks (200 mg 400 mg/day). This resulted in only a slight improvement in anxiety and agitation symptoms. Measurement of plasma tryptophan at this time showed a significant lowering (8.8 lg/ml; normal range: 11.0 lg/ml 15.0 lg/ ml). We therefore started augmentation treatment with L- tryptophan up to 1,000 mg in the evening. During the next 3 weeks, Mr. A showed rapid and significant improvement, with a decrease in depression symptoms and also a normalization of sleep, followed by a reduction of his agitation (Figure 1). With only 20 mg citalopram/day and L-tryptophan 1,000 mg/day, his Ham D score significantly dropped to normal range (a score of 6), reflecting a significant stabilization of his affective status. FIGURE 1. Serum Tryptophan (µg/ml) Ham D Scores and Tryptophan Serum Levels for Patient #1 After Starting Tryptophan-Augmentation Treatment (1,000 mg/day) Ham D Day 0 Day 7 Day 14 Day 21 Days of Treatment Tryptophan (11 15µg/ml) Ham D: Hamilton Rating Scale for Depression; normal tryptophan serum levels: 11 lg/ml 15 lg/ml. Psychosomatics 49:5, September-October

3 Case Reports Case 2 A 50-year-old woman ( Ms. B ), who had been infected with HCV (genotype 1) for 25 years, was initially treated with standard IFN and ribavirin in She developed psychiatric side effects including fatigue, severe depression, and difficulties in concentration and memory. After 3 months, she had to discontinue treatment because of suicidal thoughts. During the following years, the patient complained about recurrent or even persistent psychiatric symptoms such as fatigue and depression. Because of the increased fibrosis diagnosed by liver histology in 2003, a hepatologist and the patient decided to start a new antiviral combination treatment with peg- IFN and ribavirin. Before the treatment, the patient was seen in our psychiatric outpatient clinic and received antidepressant treatment with citalopram 20 mg/day for the first time. While being treated, most of her depression symptoms disappeared. Three months later, the patient was able to start antiviral treatment with peg-ifn -2a and ribavirin. During the first 4 weeks, she developed flu-like symptoms, sleeping disturbance, and fatigue, but no depressive symptoms. Zopiclon was added to the antidepressant treatment to improve sleep. In the second treatment month, depression scores significantly increased, and citalopram was increased to 40 mg/day. Nevertheless, the patient complained about a worsening of fatigue and depressive symptoms such as anhedonia, spontaneous crying, ruminative thinking, feelings of desperation, and hopelessness, combined with difficulties in concentration and memory. Add-on treatment with mirtazapine (30 mg/day) was started, but depression scores and symptoms did not improve during the next 3 weeks. Because her HCV PCR was negative, suggesting that she was a responder, the patient and the hepatologist decided to continue the antiviral treatment without any reduction in dosage. We measured tryptophan plasma concentration, which was low (7.5 lg/ml; normal range for women: 9.5 lg/ml 13.9 lg/ml). With the patient s informed consent, mirtazapine was stopped, and tryptophan was started, with 1,000 mg in the evening as add-on medication to the continuous treatment with citalopram 40 mg/ day. In the next days, the patient complained about hyperactivity, agitation, and sleeplessness, although other symptoms, such as fatigue, depressive mood changes, lack of motivation, and reduced psychomotor activity improved. At this time, tryptophan plasma concentration was significantly increased (to 21 lg/ml). Citalopram was reduced to 20 mg per day, and tryptophan to 500 mg for several days, and than again increased to 1,000 mg/day. During the next 3 weeks, depression scores decreased significantly. Ms. B also reported a significant improvement in fatigue and a slight improvement in concentration and memory, respectively. With a combined treatment of 20 mg citalopram/day and 500 mg tryptophan/day, the patient was able to continue antiviral treatment without the need to reduce the dosage of antiviral treatment with peg-ifn -2a and ribavirin. Case 3 A 61-year-old woman ( Ms. C ) had a chronic HCV (genotype 1) infection after having worked in a medical laboratory in the 1980s. Antiviral treatment with IFN was started in 2000, but had to be stopped after 3 months without clearance of HCV because of severe depressive symptoms, including suicidal ideation, inactivity, psychomotor slowing, and severe fatigue. However, even after antiviral treatment was discontinued, she complained about a persistent lack of motivation, inactivity, chronic fatigue, and repeated episodes of depressed mood over the next 2 years, significantly affecting her quality of life and ability to work. In 2003, she came to our psychiatric outpatient department. Her Montgomery-Asberg Depression Rating Scale (MADRS) score was 19, and serum levels of tryptophan were significantly reduced (at 6.6 lg/ml; normal range: 9.5 lg/ml 13.9 lg/ml). Ms. C refused treatment with antidepressants because of her lack of response to paroxetine treatment, with persistent side effects, 2 years earlier. With her informed consent, we started tryptophan 1,000 mg/day as monotherapy. Serum tryptophan levels continually increased over the next 6 weeks, while MADRS scores decreased over the same period of time, to a total score of 9. Over the next 6 months, the patient reported an ongoing and significant improvement of mood, a reduction of fatigue, and an increase in daily activities. Discussion Our cases reflect three different types of HCV- and IFN - associated problems: depression during antiviral treatment, depression persisting over weeks or months after termination of IFN treatment, and long-term psychiatric problems in patients with chronic HCV infection who had been treated with IFN without success and who developed severe psychiatric side effects. None of the patients presented Psychosomatics 49:5, September-October 2008

4 Schaefer et al. here had a preexisting psychiatric disorder, especially depression, independent from chronic hepatitis C infection or cytokine treatment. Psychiatric symptoms developed during the treatment with standard or pegylated interferons and, interestingly, did not disappear after discontinuation of antiviral therapy for all three of these patients. Although, so far, no long-term data from large, prospective, controlled trials are available, several case reports have recently been presented reporting on ongoing psychiatric problems lasting several months after IFN treatment for chronic hepatitis C had been terminated Proinflammatory cytokines and an increased consumption of tryptophan via activation of IDO are currently discussed as an important part of the pathophysiological model of depressive states during inflammatory somatic disorders. 29 In our patients with persistent mood changes, significantly lowered tryptophan blood levels were measured several weeks or even months after IFN treatment had been terminated. Normalization of serum levels during tryptophan treatment was associated with an improvement of depressive symptoms in these patients. Our cases support the view that psychiatric or psychosomatic symptoms during or after IFN treatment in HCV-infected patients might also be associated with a tryptophan deficit. In all three patients, tryptophan augmentation or monotherapy was a useful and effective pharmacotherapeutic strategy to reduce psychiatric symptoms after only partial response to antidepressants. Moreover, patients also reported a significant improvement in fatigue, psychomotor slowing, lack of motivation, and inactivity. A lowered availability of plasma tryptophan has been shown in patients with chronic infectious diseases, sleeping disturbances, and depression. 5,30 As a consequence, reduced tryptophan levels in our patients might be associated with both chronic HCV infection and the cytokine treatment with IFN. Preexisting changes in tryptophan or serotonergic homeostasis cannot be excluded because of the lack of pretreatment blood samples. However, the observation that mood changes in all patients occurred only during or after interferon treatment rather indicates a direct involvement of cytokine treatment with IFN in metabolic changes of the tryptophan pathway. In one patient, tryptophan treatment was followed by agitation, irritability, and insomnia. This was probably part of a beginning serotonergic syndrome, which disappeared after citalopram and tryptophan were reduced. Although our patient did not develop a full serotonergic syndrome including clonus, diarrhea, diaphoresis, or rigidity, the risk of a serotonergic syndrome due to increased central 5-HT concentrations has to be considered, and patients should be carefully monitored. Also, a mixed mood state could be possible, but these patients had no history of bipolar symptoms and did not demonstrate bipolar mood changes in the following months. However, in addition to the acute positive effects on IFN -induced mood changes demonstrated in our cases, tryptophan and its metabolism are also believed to be involved in long-term changes such as depression or cognitive disturbances in patients with chronic hepatitis C during or after IFN treatment. IFN activates the enzyme IDO; therefore, tryptophan augmentation during IFN treatment may lead to an increased production of quinolinic acid. 11,31 Quinolinic acid is a potent neurotoxin with an additional and marked free-radical producing property. There are a number of inflammatory and neurodegenerative disorders whose pathogenesis has been demonstrated to involve multiple imbalances of kynurenine-pathway metabolism (multiple sclerosis, Parkinson s, Alzheimer s, and Huntington s diseases). 32 All in all, our case reports are the first to indicate a significant therapeutic benefit of tryptophan augmentation in patients with IFN -associated depression. This seems to be especially successful in patients with non-response or only partial response to antidepressants. However, more clinical data are needed to understand the long-term mood and cognitive changes during or after IFN treatment in patients with chronic hepatitis C in order to develop effective therapeutic strategies. 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