Psychosomatics
Journal Home Search Current Issue Past Issues Subscribe All APPI Journals Help Contact Us
 
Psychosomatics 49:442-446, September-October 2008
doi: 10.1176/appi.psy.49.5.442
© 2008 Academy of Psychosomatic Medicine
Quicksearch
Advanced Search
Or Search All APPI Journals
This Article
* Abstract Freely available
* Full Text (PDF)
* Alert me when this article is cited
* Alert me if a correction is posted
Services
* Email this article to a Colleague
* Similar articles in this journal
* Similar articles in PubMed
* Alert me to new issues of the journal
* Add to My Articles & Searches
* Download to citation manager
* reprints & permissions
Citing Articles
* Citing Articles via Google Scholar
Google Scholar
* Articles by Schaefer, M.
* Articles by Friebe, A.
* Search for Related Content
PubMed
* PubMed Citation
* Articles by Schaefer, M.
* Articles by Friebe, A.
Related Collections
* Depression
* Syndromes Secondary to General Medical Disorders

Case Report

Three Cases of Successful Tryptophan Add-On or Monotherapy of Hepatitis C and IFN{alpha}-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., and Astrid Friebe, M.D.

Received March 26, 2007; revised July 13, 2007; accepted August 1, 2007. 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-45136 Essen, Germany. e-mail: martin.schaefer{at}charite.de
© 2008 The Academy of Psychosomatic Medicine


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 Case Reports
 Discussion
 REFERENCES
 
BACKGROUND: Interferon-alpha (IFN{alpha})-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{alpha} 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{alpha} treatment.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
Case Reports
 Discussion
 REFERENCES
 
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 serotonergic system, especially with decreased tryptophan concentrations and an increased kynurenin/tryptophan ratio.5 So far, interferon-alpha (IFN{alpha}) is the only effective immunotherapeutic agent for the treatment of viral hepatitis. However, clinical use of IFN{alpha} 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{alpha}. The most important psychiatric side effect of IFN{alpha} 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{alpha} treatment.7–15 IFN{alpha} activates the enzyme indoleamine-2,3-dioxygenase (IDO), which catalyzes the rate-limiting step of peripheral tryptophan conversion into kynurenine and 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 HCV-infected patients and 30% of IFN{alpha}-treated patients need antidepressant treatment.1 Regarding IFN{alpha}-associated mood changes, several case reports and case series demonstrated a positive effect of antidepressants, especially selective serotonin-reuptake inhibitors (SSRIs).16–22 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{alpha} treatment.23–25 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{alpha} 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{alpha} 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{alpha}-induced depression symptoms during and after IFN{alpha} treatment of chronic hepatitis C infection.


  Case Reports

 
TOP
 ABSTRACT
 INTRODUCTION
 Case Reports
Discussion
 REFERENCES
 
Case 1
A 42-year-old company employee ("Mr. A") was treated with pegylated IFN{alpha} 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{alpha} 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 µg/ml; normal range: 11.0 µg/ml–15.0 µg/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
View larger version (40K):
[in this window]
[in a new window]

 

FIGURE 1.  Ham–D Scores and Tryptophan Serum Levels for Patient #1 After Starting Tryptophan-Augmentation Treatment (1,000 mg/day)

Ham–D: Hamilton Rating Scale for Depression; normal tryptophan serum levels: 11 µg/ml–15 µg/ml.


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{alpha} and ribavirin in 1996. 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{alpha} 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{alpha}-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 µg/ml; normal range for women: 9.5 µg/ml–13.9 µg/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 µg/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{alpha}-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{alpha} 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 µg/ml; normal range: 9.5 µg/ml–13.9 µg/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

 
TOP
 ABSTRACT
 INTRODUCTION
 Case Reports
 Discussion
REFERENCES
 
Our cases reflect three different types of HCV- and IFN{alpha}-associated problems: depression during antiviral treatment, depression persisting over weeks or months after termination of IFN{alpha} treatment, and long-term psychiatric problems in patients with chronic HCV infection who had been treated with IFN{alpha} without success and who developed severe psychiatric side effects. None of the patients presented 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{alpha} treatment for chronic hepatitis C had been terminated.26–28

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{alpha} 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{alpha}. 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{alpha} 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{alpha}-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{alpha} treatment. IFN{alpha} activates the enzyme IDO; therefore, tryptophan augmentation during IFN{alpha} 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{alpha}-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{alpha} treatment in patients with chronic hepatitis C in order to develop effective therapeutic strategies.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 Case Reports
 Discussion
 REFERENCES
 

  1. Dieperink E, Willenbring M, Ho SB: Neuropsychiatric symptoms associated with hepatitis C and interferon{alpha}: a review. Am J Psychiatry 2000; 157:867–876[Abstract/Free Full Text]
  2. Weissenborn K, Berding G, Kostler H: Altered striatal dopamine D2 receptor density and dopamine transport in a patient with hepatic encephalopathy. Metab Brain Dis 2000; 15:173–178[Medline]
  3. Forton DM, Taylor-Robinson SD, Thomas HC: Cerebral dysfunction in chronic hepatitis C infection. J Viral Hepat 2003; 10:81–86[CrossRef][Medline]
  4. Weissenborn K, Krause J, Bokemeyer M, et al: Hepatitis C virus infection affects the brain: evidence from psychometric studies and magnetic resonance spectroscopy. J Hepatol 2004; 41:845–851[CrossRef][Medline]
  5. Fuchs D, Moller AA, Reibnegger G, et al: Increased endogenous interferon-gamma and neopterin correlate with increased degradation of tryptophan in HIV type 1 infection. Immunol Lett 1991; 28:207–211[CrossRef][Medline]
  6. Schaefer M, Engelbrecht MA, Gut O, et al: Interferon alpha (IFN{alpha}) and psychiatric syndromes: a review. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26:731–746[CrossRef][Medline]
  7. Abe S, Hori T, Suzuki T, et al: Effects of chronic administration of interferon alpha A/D on serotonergic receptors in rat brain. Neurochem Res 1999; 24:359–363[CrossRef][Medline]
  8. Asnis GM, De La Garza R II: Interferon-induced depression in chronic hepatitis C: a review of its prevalence, risk factors, biology, and treatment approaches. J Clin Gastroenterol 2006; 40:322–335[CrossRef][Medline]
  9. Bonaccorso S, Marino V, Puzella A, et al: Increased depressive ratings in patients with hepatitis C receiving interferon{alpha}–based immunotherapy are related to interferon{alpha}–induced changes in the serotonergic system. J Clin Psychopharmacol 2002; 22:86–90[CrossRef][Medline]
  10. Cai W, Khaoustov VI, Xie Q, et al: Interferon{alpha}–induced modulation of glucocorticoid and serotonin receptors as a mechanism of depression. J Hepatol 2005; 42:880–887[CrossRef][Medline]
  11. Capuron L, Neurauter G, Musselman DL, et al: Interferon{alpha}–induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol Psychiatry 2003; 54:906–914[CrossRef][Medline]
  12. Licinio J, Kling MA, Hauser P: Cytokines and brain function: relevance to interferon{alpha}–induced mood and cognitive changes. Semin Oncol 1998; 25:30–38[Medline]
  13. Maes M, Meltzer HY, Scharpe S, et al: Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression. Psychiatry Res 1993; 49:151–165[CrossRef][Medline]
  14. Schaefer M, Schwaiger M, Pich M, et al: Neurotransmitter changes by interferon{alpha} and therapeutic implications. Pharmacopsychiatry 2003; 36(Suppl 3):S203-S206
  15. Tsao CW, Lin YS, Cheng JT, et al: Serotonin transporter mRNA expression is decreased by lamivudine and ribavirin and increased by interferon in immune cells. Scand J Immunol 2006; 63:106–115[CrossRef][Medline]
  16. Hauser P, Khosla J, Aurora H, et al: A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 2002; 7:942–947[CrossRef][Medline]
  17. Kraus MR, Schafer A, Faller H, et al: Paroxetine for the treatment of interferon{alpha}–induced depression in chronic hepatitis C. Aliment Pharmacol Ther 2002; 16:1091–1099[CrossRef][Medline]
  18. Kraus MR, Schafer A, Scheurlen M: Paroxetine for the prevention of depression induced by interferon{alpha}. N Engl J Med 2001; 345:375–376[Free Full Text]
  19. Levenson JL, Fallon HJ: Fluoxetine treatment of depression caused by interferon{alpha}. Am J Gastroenterol 1993; 88:760–761[Medline]
  20. Schafer M, Schmidt F, Amann B, et al: Adding low-dose antidepressants to interferon{alpha} treatment for chronic hepatitis C improved psychiatric tolerability in a patient with schizoaffective psychosis. Neuropsychobiology 2000; 42(Suppl 1):43-45
  21. Schramm TM, Lawford BR, Macdonald GA, et al: Sertraline treatment of interferon{alpha}–induced depressive disorder. Med J Aust 2000; 173:359–361[Medline]
  22. Valentine AD, Meyers CA: Successful treatment of interferon{alpha}–induced mood disorder with nortriptyline. Psychosomatics 1995; 36:418–419[Free Full Text]
  23. Kraus MR, Schafer A, Al Taie O, et al: Prophylactic SSRI during interferon{alpha} re-therapy in patients with chronic hepatitis C and a history of interferon-induced depression. J Viral Hepat 2005; 12:96–100[CrossRef][Medline]
  24. Musselman DL, Lawson DH, Gumnick JF, et al: Paroxetine for the prevention of depression induced by high-dose interferon{alpha}. N Engl J Med 2001; 344:961–966[Abstract/Free Full Text]
  25. Schaefer M, Schwaiger M, Garkisch AS, et al: Prevention of interferon{alpha}–associated depression in psychiatric risk patients with chronic hepatitis C. J Hepatol 2005; 42:793–798[CrossRef][Medline]
  26. Gohier B, Goeb JL, Rannou-Dubas K, et al: Hepatitis C, alpha interferon, anxiety, and depression disorders: a prospective study of 71 patients. World J Biol Psychiatry 2003; 4:115–118[CrossRef][Medline]
  27. Nickel T, Sonntag A, Backmund M, et al: Depression during therapy with interferon{alpha}: how long should an antidepressant treatment last? Pharmacopsychiatry 2005; 38:102–104[CrossRef][Medline]
  28. Rifflet H, Vuillemin E, Oberti F, et al: [Suicidal impulses in patients with chronic viral hepatitis C during or after therapy with interferon{alpha}]. Gastroenterol Clin Biol 1998; 22:353–357[Medline]
  29. Muller N, Schwarz MJ: The immune-mediated alteration of serotonin and glutamate: toward an integrated view of depression. Mol Psychiatry 2007; 12:988–1000[CrossRef][Medline]
  30. Song C, Lin A, Bonaccorso S, et al: The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression. J Affect Disord 1998; 49:211–219[CrossRef][Medline]
  31. Turner EH, Blackwell AD: 5-Hydroxytryptophan plus SSRIs for interferon-induced depression: synergistic mechanisms for normalizing synaptic serotonin. Med Hypotheses 2005; 65:138–144[CrossRef][Medline]
  32. Sas K, Robotka H, Toldi J, et al: Mitochondria, metabolic disturbances, oxidative stress, and the kynurenine system, with focus on neurodegenerative disorders. J Neurol Sci 2007; 257:221–239[CrossRef][Medline]




This Article
* Abstract Freely available
* Full Text (PDF)
* Alert me when this article is cited
* Alert me if a correction is posted
Services
* Email this article to a Colleague
* Similar articles in this journal
* Similar articles in PubMed
* Alert me to new issues of the journal
* Add to My Articles & Searches
* Download to citation manager
* reprints & permissions
Citing Articles
* Citing Articles via Google Scholar
Google Scholar
* Articles by Schaefer, M.
* Articles by Friebe, A.
* Search for Related Content
PubMed
* PubMed Citation
* Articles by Schaefer, M.
* Articles by Friebe, A.
Related Collections
* Depression
* Syndromes Secondary to General Medical Disorders

Get information about faster international access.

Privacy Policy

Copyright © 2008 Academy of Psychosomatic Medicine. All rights reserved.

Home | Search | Current Issue | Past Issues | Subscribe | All APPI Journals | Help | Contact Us

American Psychiatric Publishing, Inc. Academy of Psychosomatic Medicine
1000 Wilson Boulevard, Suite 1825, Arlington, VA 22209-3901 * 800-368-5777 * appi at psych.org