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ORIGINAL ARTICLES |
From the Departments of Biological Psychiatry (S.R., J.C.B., J.A.B., J.K.), Pathology and Laboratory Medicine (I.P.K.), Gastroenterology and Hepatology (E.B.H.), and Medical Oncology (P.H.B.W., E.G.E.V.), University Hospital Groningen, the Netherlands.
Address correspondence and reprint requests to Sascha Russo, MD, Department of Psychiatry, Hanzeplein 1, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. E-mail: s.r.russo{at}acggn.azg.nl
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ABSTRACT |
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and ribavirin.
Patients and Methods: Eighteen patients with viral hepatitis C who received interferon were included. A psychiatrist screened patients before and while on interferon- treatment for 2 months, using a structured diagnostic interview. Fasting plasma tryptophan and platelet serotonin levels were measured at each visit.
Results: At baseline no evident psychopathology was observed. After 2 months of interferon treatment, 10 patients experienced increased irritability. No other structural psychopathology was observed. Decreased plasma tryptophan level correlated with the presence of irritability (p = .047). Platelet serotonin levels were found to be decreased during treatment (p = .002).
Conclusions: Aggressive impulse dysregulation is highly prevalent in patients receiving interferon treatment. This is associated with decreased plasma tryptophan levels which may lead to attenuated peripheral and central serotonergic neurotransmission.
Key Words: interferon • tryptophan • inflammation • serotonin • irritability
Abbreviations: 5-HT = serotonin; DSM = Diagnostic Statistical Manual.
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INTRODUCTION |
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-type, are powerful inducers of indoleamine dioxygenase in immune-activated cells such as macrophages and brain microglia. Indoleamine dioxygenase is an enzyme that can cause enhanced tryptophan degradation and thus low plasma levels of the amino acid (5). Decreased plasma levels of tryptophan have indeed been observed during interferon treatment (6). In 26 patients with malignant melanoma receiving high-dose interferon-, a relation between depressive symptoms and decreased availability of tryptophan was established (7). The patients underwent a semi-structured interview for the determination of DSM-IV depression. This implies that psychiatric symptoms other than depression have not been explored during the interview. Horikawa et al. (8) recommended further research to clarify the clinical features of interferon associated psychopathology other than depression. Here we report the effects of 2 months of interferon- treatment in hepatitis C patients on the development of psychopathological symptoms and on the levels of plasma tryptophan and platelet 5-HT. The patients were subjected to a standardized psychiatric interview to determine objectively and to detail possible psychopathology. We observed that increased irritability was present in about half of the patients. These symptoms correlated with indices of serotonin function. The possible therapeutic consequences in terms of diagnosis and treatment of the psychopathology will be discussed. |
PATIENTS AND METHODS |
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were asked to participate in the study. Diagnoses were based on positive serology and liver biopsy. Patients with mental illness including current substance abuse were excluded from the study. This was done to avoid difficulties in the discrimination between preexistent and interferon-induced psychopathology. Patients had to be free of substance abuse for at least 5 years. Some patients received interferon- 5 million U subcutaneously daily for 4 weeks. This was then followed by 8 weeks of 5 million U interferon- 3 times a week. Following this, a scheme of 3 million U three times a week was sustained. Other patients were treated with pegylated interferon- 100 or 125 µg/week subcutaneously. With either treatment equal plasma levels of interferon- are achieved, but the injections need only be administered weekly. All patients also received ribavirin 1000 or 1200 mg/day orally. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki and was a priori approved by the local medical ethical committee. After complete description of the study, all patients gave written consent.
Psychometric Measurements
One of us (J.C.B.) studied the patients making use of a structured interview (9) before and after 2 months of interferon treatment. Only symptoms present for at least half a month before the interview were taken into account. Additional diagnostic measurements were performed by making use of the Hamilton Rating Scale for Depression (Hamilton 1960), Hamilton Anxiety Scale (Hamilton 1959), and the Symptom-Checklist-90, a 90-item self-rating scale (Arrindell 1973). Diagnoses were based on DSM-IV (American Psychiatry Association, 1994) criteria. The interviewer was blind to the patients’ biochemical data.
Biochemical and Hematological Measurements
Venous blood samples were collected at baseline and after 2 months of treatment in vacutainer tubes containing 0.12 ml (0.34 mmol/L) EDTA solution. Participants fasted for at least 4 hours before venipuncture. Plasma samples were centrifuged and stored at –20°C until analysis. Total plasma tryptophan (in µmol/L) and platelet 5-HT (in nmol 5-HT/109 platelets) were quantified using high performance liquid chromatography with fluorometric detection (10). We particularly focused on changes in plasma tryptophan and platelet 5-HT during interferon treatment in relation to psychopathology. Therefore, patients served as their own controls on these parameters. For platelet 5-HT levels, reference ranges of 2.8 to 5.4 nmol/109 platelets, and for plasma tryptophan levels reference values between 40 and 70 µmol/L were sustained (11). To estimate the whole blood content of 5-HT, the platelet count was multiplied with platelet 5-HT content. This was multiplied with an estimated factor 0.5, for the hematocrit, to yield the content of 5-HT per liter blood. As bone marrow depression is a known side effect of interferon, total platelet count was determined before and during therapy. Serum levels of thyroid stimulating hormone were routinely monitored because of previous reports of hypothyroidism during interferon treatment (12).
To investigate whether interferon- directly influences platelet 5-HT uptake, this was measured in vitro in EDTA anticoagulated blood of 3 healthy volunteers containing various concentrations of interferon-. To measure platelet 5-HT uptake, 1 ml plasma was incubated with 500 ng of 5-HT dissolved in 50 µL 0.9% NaCl for 60 minutes at 37°C, and 500 µL plasma was used for 5-HT determination (13).
Statistical Analysis
Plasma levels of tryptophan and platelet 5-HT levels were compared before and during 2 months of interferon treatment using the paired two-tailed Student t test. A crosstab was composed by dividing patients into those with and those without increased irritability in relation with attenuation of plasma tryptophan levels during therapy. The two-tailed 
2 test was applied. The same procedure was followed by dividing patients into those who experienced sustained viral clearance after treatment and those who did not versus decreased plasma tryptophan level. The Spearman rank test was used to assess possible relationships between baseline plasma tryptophan levels, levels observed during interferon treatment, and the presence of psychopathology during the treatment. The same procedure was applied to platelet 5-HT concentration. Outcomes of psychometric scales were analyzed before and during interferon treatment using the paired Student t test.
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RESULTS |
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. The other 13 patients were treated with pegylated interferon (Table 1).
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Psychiatric Examination
At baseline, no evident psychopathology was observed in any of the 18 patients. After 2 months of interferon treatment, 10 patients (two women) experienced increased irritability and expression of aggressive impulses (Figure 1). The symptomatology reached DSM-IV criteria in seven patients because of impaired social functioning. They were diagnosed as having a substance-induced mood disorder, DSM-IV code 292.8. Three patients reported increased irritability without impairments in social or occupational functioning. Irritable patients were characterized particularly by a high expression of verbal aggression. The aggressiveness is marked by impulsivity, because patients feel regret shortly after an offense is made. This led to relational problems in married patients (n = 6). Employed patients suffering from increased irritability experienced vocational problems (n = 5). The presence of increased irritability was not especially present in former intravenous drug users. The type of interferon medication did not appear to be associated with psychiatric disturbances. Major depression was diagnosed in three patients, one of whom also experienced increased irritability. One woman showed an increase of serum thyroid stimulating hormone up to 37 mU/L without exhibiting clinical signs of hypothyroidism. This patient also displayed increased aggression. No significant changes were measured on the Hamilton Rating Scale for Depression (before treatment mean 5.56, range 1–12, SD 3.03; during treatment mean 5.94, range 1–10, SD 2.80), the Hamilton Anxiety Scale (before treatment mean 6, range 3–10, SD 2.28; during treatment mean 6.56, range 2–9, SD 2.01) and the Symptom-Cecklist-90 (before treatment mean 129, range 101–156, SD 15.10; during treatment mean 127, range 103–171, SD 22.51). However, on the six items of the SCL-90 measuring hostility, a slight increase was measured during treatment (before treatment mean 7.40, range 6–11, SD 1.40; during treatment mean 10.40, range 6–15, SD 2.80, t = –5.196, df = 17, p = .044).
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Biochemical Data
No significant changes in mean plasma tryptophan levels were detected before (mean 49.4 mmol/L, range 34.6–59.6) or during treatment (mean 47.4, range 34.6–58.2) (df = 17, p = .21 see Figure 1). No influence of interferon- on platelet 5-HT uptake was observed as tested in vitro. Platelets obtained from patients treated with interferon- also did not show altered 5-HT uptake in vitro. A relationship between treatment success, defined as sustained viral clearance after treatment, and attenuated tryptophan levels was also not established (df = 1, p = .618).
Increased irritability proved to be the predominant symptom. Therefore, we divided the cohort into patients who reported this symptom spontaneously and those who did not, regardless of the symptoms reached DSM-IV criteria. A relationship between decreased plasma tryptophan during interferon treatment and increased irritability and aggression was present as measured with the 2 test (p = .047). No relation between baseline plasma tryptophan levels and increased aggression during treatment was observed in the Spearman rank test (p = .865). At baseline one patient and during interferon treatment four patients exhibited a plasma tryptophan level below the reference value. Platelet 5-HT levels were higher before (mean 3.7 nmol/109 platelets, range 2.5–5.4) than during treatment (mean 3.0 nmol/109 platelets, range 1.1–4.8, df = 17, p = .002, see Figure 2). Before treatment one patient exhibited platelet 5-HT level under the reference value whereas six displayed this during interferon treatment. Whole blood platelet count was attenuated in all patients after 2 months of interferon treatment. The mean number of platelets was 206 x 109/L (range 116–330) before and 160 x 109/L (range 104–247) during interferon treatment. The mean content of 5-HT in whole blood decreased from 382 to 242 nmol/L blood. There was a trend both for baseline and during treatment platelet 5-HT levels to be lower in patients suffering from increased irritability during treatment (df = 1, p = .065, df = 1, p = .073, respectively).
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DISCUSSION |
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These clinical symptoms are in line with the findings of increased hostility following acute tryptophan depletion seen in healthy volunteers (14). We observed more pronounced symptoms than Young and Leyton possibly because of the chronic character of the changes in 5-HT transmission in our patients. Our findings support a role for cerebral 5-HT in the modulation of aggressive behavior, as has been reported in both animal experiments and in other patients (15). In the study of Capuron et al. (7), the psychiatric interview focused on depressive symptoms. In another study in which 50 patients were treated with interferon for viral hepatitis, 2 patients developed severe dysphoria. In one of those patients this resulted in discontinuation of the therapy (16). Maddock et al. (17) observed severe irritability in 2 of 60 patients receiving interferon. Treatment with thioridazide was successful in only one patient.
Increased incidence of psychopathology according to DSM-IV criteria could barely be measured by the psychometric scales used by us. This was in part because of the observation that depression was not the predominant pathology; therefore, psychometric scales could not be used, except for a few sub-items on these scales. Another issue to be discussed here is subjectivity in the assessment of the symptoms. The interviewing clinician was, however, blind to the chemistry; in fact, his conclusions were supported by the tryptophan data. An advantage of the present approach is that the clinical interview’s open structure allowed us to explore beyond the boundaries of DSM-IV syndromes such as depression. Therefore a too strict application of DSM-IV criteria may allow only a limited assessment of the psychiatric complaints in our patients.
Whole blood 5-HT levels decreased in all patients, suggesting that the availability of peripheral tryptophan for the conversion to 5-HT was indeed decreased during interferon treatment. This suggests that platelet 5-HT level is indicative for peripheral availability of tryptophan whereas plasma tryptophan level is indicative of cerebral availability of the amino acid. Total platelet counts were diminished as expected during interferon therapy because of the depression of bone marrow. No relationship between any biochemical or clinical parameter and sustained viral clearance after the treatment could be established. Our patient group did not lend itself to draw conclusions on this subject because various viral subtypes were included that vary strongly in treatment success chances. The size of our patient sample was too small for stratification of this parameter. A larger study has to be performed in the future. All patients were co-medicated with ribavirin. Ribavirin is believed to interfere with viral RNA and DNA replication. Theoretically, ribavirin may have contributed to psychiatric side effects; however, Maddrey observed no additional effect of comedication with ribavirin on psychiatric symptoms in 2089 patients treated for hepatitis C (18). Thirteen patients were treated with pegylated interferon whereas five patients received nonpegylated interferon. However, the pharmacodynamics, including plasma levels have been shown to be comparable between these groups (19).
The results of this study could have direct clinical implications. We advise providing information about the nature of the symptoms to the patient and his or her relatives, which may help to improve social functioning. Pharmacological treatment options include selective serotonin reuptake inhibitors.
Our results emphasize that peripheral and central 5-HT levels can be modulated by immune-activating therapeutic interventions. In general, the present results illustrate how biological factors such as cytokines may contribute to the development of psychiatric comorbidity in somatic conditions.
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NOTES |
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Received for publication May 31, 2004; revision received March 20, 2005; date accepted March 24, 2005.
DOI:10.1097/01.psy.0000171193.28044.d8
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONNOTESREFERENCES |
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in patients with chronic hepatitis and mood or anxiety disorders. Lancet 1999;354:131–2.[CrossRef][Medline]
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