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Interferon-alpha–induced changes in tryptophan metabolism
Interferon-Alpha–Induced Changes in Tryptophan Metabolism: Relationship to Depression and Paroxetine Treatment Lucile Capuron, Gabriele Neurauter, Dominique L. Musselman, David H. Lawson, Charles B. Nemeroff, Dietmar Fuchs, and Andrew H. Miller Background: Tryptophan (TRP) degradation into kynurenine (KYN) by the enzyme, indoleamine-2,3-dioxygenase, during immune activation may contribute to development of depressive symptoms during interferon (IFN)-␣ therapy. Methods: Twenty-six patients with malignant melanoma were randomly assigned in double-blind fashion to receive either placebo or paroxetine, beginning 2 weeks before IFN-␣ treatment and continuing for the first 12 weeks of IFN-␣ therapy. At treatment initiation and at 2, 4, and 12 weeks of IFN-␣ treatment, measurements of TRP, KYN, and neopterin (a marker of immune activation), were obtained, along with structured assessments of depression, anxiety, and neurotoxicity. Results: Regardless of antidepressant treatment status, all patients exhibited significant increases in KYN, neopterin, and the KYN/TRP ratio during IFN-␣ therapy. Among antidepressant-free patients, patients who developed major depression exhibited significantly greater increases in KYN and neopterin concentrations and more prolonged decreases in TRP concentrations than did nondepressed, antidepressant-free patients. Moreover, in antidepressantfree patients, decreases in TRP correlated with depressive, anxious, and cognitive symptoms, but not neurovegetative or somatic symptoms. No correlations were found between clinical and biological variables in antidepressant-treated patients. Conclusions: The results suggest that reduced TRP availability plays a role in IFN-␣–induced depressive symptoms, and paroxetine, although not altering the KYN or neopterin response to IFN-␣, attenuates the behavioral consequences of IFN-␣–mediated TRP depletion. Biol Psychiatry 2003;54:906 –914 © 2003 Society of Biological Psychiatry From the Department of Psychiatry and Behavioral Sciences (LC, DLM, CBN, AHM), Winship Cancer Institute (DLM, DHL, CBN, AHM), and Department of Hematology and Oncology (DHL), Emory University School of Medicine, Atlanta, Georgia; and the Institute of Medical Chemistry and Biochemistry (GN, DF), University of Innsbruck and Ludwig Boltzmann Institute of AIDS-Research, Innsbruck, Austria. Address reprint requests to Andrew H. Miller, M.D., Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, 1639 Pierce Drive, Suite 4000, Atlanta, GA 30322. Received October 16, 2002; revised January 17, 2003; accepted January 24, 2003.
© 2003 Society of Biological Psychiatry
Key Words: Interferon-alpha, tryptophan, kynurenine, neopterin, indoleamine-2,3-dioxygenase, depressive symptoms
Introduction
M
ajor depression frequently develops in medically ill patients who are administered cytokine therapies for infectious diseases or cancers. For example, it has been shown that the rate of major depression in patients with malignant melanoma receiving high-dose interferon (IFN)-␣ is almost 45% (Musselman et al 2001). Despite an increasing appreciation of cytokine-induced depressive syndromes, the mechanisms involved remain to be elucidated. In a recent study, cancer patients undergoing IFN-␣ and/or interleukin-2 therapy exhibited significant decreases in serum concentrations of tryptophan (TRP) and the ratio of TRP to large neutral amino acids (namely tyrosine, phenylalanine, leucine, isoleucine, valine) that correlated with increased depression scores (Capuron et al 2002b). These findings suggested that the development of depressive symptoms during cytokine therapy might be mediated, at least in part, by TRP depletion. Tryptophan is the precursor of serotonin (5HT), which is believed to play a prominent role in the neurobiology of mood disorders (see for review Malone and Mann 1993, Owens and Nemeroff 1994). Tryptophan availability is the rate-limiting step in the synthesis of 5HT. Reductions in blood TRP concentrations are associated with reduced 5HT availability within the central nervous system (CNS), and TRP depletion has been associated with the induction of depressive relapse in vulnerable patients (Delgado et al 1994; Moore et al 2000; Moreno et al 2000). Moreover, drug-free depressed patients have been reported to exhibit reduced plasma TRP concentrations compared with normal control subjects (Deakin 1990; Lucca et al 1992; Maes et al 1994; Ressler and Nemeroff 2000; Song et al 1998). Conversely, drugs that block the reuptake of 5HT, namely the selective serotonin reuptake inhibitors (SSRIs), and 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00173-2
Interferon-Alpha and Tryptophan Metabolism
Figure 1. Tryptophan metabolism and neopterin synthesis upon immune system activation. Cytokines (e.g., interferon [IFN]-␥) induce the enzyme indoleamine-2,3-dioxygenase (IDO) that catabolizes tryptophan into kynurenine and then quinolinic acid, thereby reducing the availability of tryptophan for serotonin synthesis via the enzyme tryptophan hydroxylase (TPH). The activation of the kynurenine pathway may also be due to the induction of the liver enzyme tryptophan dioxygenase (TDO) by cytokines. Cytokines induce neopterin synthesis from activated monocytes/macrophages by activating guanosine triphosphate cyclohydrolase 1 (GTP-CH1), an enzyme that catalyzes the formation of neopterin from guanosine triphosphate (GTP).
thereby increase 5HT availability within the CNS, are well known to be effective treatments for major depression (Tollefson and Rosenbaum 1998). The pathways by which IFN-␣ and/or interleukin-2 induce peripheral TRP depletion during cytokine therapy are unknown but may involve activation of the enzyme, indoleamine-2,3-dioxygenase (IDO). IDO catalyzes the rate-limiting step of TRP conversion into kynurenine (KYN) and then quinolinic acid (Byrne et al 1986), thereby reducing the availability of TRP for conversion into 5HT (Figure 1). In vivo, the activity of IDO is reflected by the relative plasma or serum concentrations of KYN and TRP. Indeed, the ratio of KYN/TRP is considered to be an estimate of IDO activity, independent of baseline TRP concentrations (Widner et al 2000). IDO can be induced in a variety of immune cells, such as monocyte-derived macrophages and microglia, by inflammatory cytokines, including, most notably, IFNs (Mellor and Munn 1999). Consistent with IDO induction by IFNs, decreased plasma TRP concentrations and a high KYN/ TRP ratio have been found to correlate with concentra-
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tions of neopterin in patients with infectious diseases (Fuchs et al 1990, 1991). Neopterin, a pteridine derived from guanosine triphosphate, is released from human monocytes and macrophages upon stimulation with IFNs, especially IFN-␥, and is therefore considered a marker of activated cell-mediated immunity (Murr et al 2002). Release of neopterin by IFN-stimulated immune cells is initiated at the expense of biopterin synthesis, a co-factor of several monooxygenase reactions, including tryptophan-5-hydroxylase (Widner et al 2000). Interestingly, increased concentrations of neopterin and IFN-␥, together with a lower availability of L-TRP, have been described in patients with major depression (Maes et al 1994). In a recent report, patients treated with IFN-␣ for chronic hepatitis C were found to exhibit evidence of increased IDO activity, including reduced TRP concentrations, increased KYN concentrations, and an increased KYN/TRP ratio. Although these patients also exhibited a corresponding increase in depressive symptoms (Bonaccorso et al 2002), the relationship between TRP metabolism and the development of specific depressive symptoms was not reported. Moreover, the impact of antidepressant treatment was not examined. Recent work by our group has shown that the antidepressant paroxetine, a 5HT and norepinephrine reuptake inhibitor (Gilmor et al 2002), was effective in preventing the development of major depression, especially its mood and cognitive features, in patients receiving high-dose IFN-␣ therapy for malignant melanoma (Capuron et al 2002a; Musselman et al 2001). The mechanisms by which paroxetine prevents depressive symptoms in IFN-␣– treated patients remain obscure. One possibility is that paroxetine may influence the effect of IFN-␣ on IDO activity and TRP metabolism, either directly or indirectly through an effect on the activation of relevant immune cells. Indeed, recent data indicate that antidepressants, most notably tricyclics, but also SSRIs, may inhibit inflammatory immunologic responses (Kubera et al 2001; Pellegrino and Bayer 2000). To further examine the relationships among TRP metabolism, immune cell activation, and the development and treatment of depressive symptoms during IFN-␣ therapy, we measured TRP, KYN, and neopterin in placebo- and paroxetine-treated patients undergoing highdose IFN-␣ therapy for malignant melanoma.
Methods and Materials Patients Twenty-six patients (mean [SD] age 53 [10] years, range 32–74; 14 male, 12 female) with malignant melanoma eligible to receive IFN-␣ (IntronA, Schering-Plough, Kenilworth, NJ) were recruited from the Winship Cancer Institute of Emory University
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of Medicine. These patients constituted a subpopulation of the 40 patients described by Musselman et al (2001), in which blood samples were available for at least the first month of IFN-␣ therapy. Patients with unresectable metastases, brain metastases, a score ⬍ 24 in the Mini-Mental State Examination or a diagnosis of schizophrenia or bipolar disorder as determined by the Structured Clinical Interview for the DSM-IV were excluded from the study. Medications for pain, nausea, and fever were allowed during the study. All patients provided written, informed consent before enrollment. The study was approved by the Human Investigations Committee of the Emory University School of Medicine.
Treatments Interferon-␣ was administered at the dose of 20 million international units (MIU) per square meter of body surface area 5 days per week for the first 4 weeks of therapy, followed by 10 MIU/m2 subcutaneously 3 days per week for the remaining 8 weeks of the study. Two weeks before the initiation of IFN-␣ therapy, patients were randomly assigned in double-blind fashion to receive either placebo or paroxetine (Paxil, GlaxoSmithKline, Research Triangle Park, NC). The dosage of study medication was 10 mg paroxetine or placebo per day for the first week, followed by 20 mg paroxetine or placebo per day for the second week. The dosage could be increased up to 40 mg per day 2 weeks after the initiation of IFN-␣. Among the 26 patients considered in the study, 15 patients (age 53 [13] years; 9 male, 6 female) received placebo and 11 patients (age 52 [7] years; 5 male, 6 female) received paroxetine.
Psychiatric and Biological Measurements Psychiatric and biological assessments occurred at regularly scheduled intervals during the first 12 weeks of IFN-␣ treatment. Scheduled visits included the first day of IFN-␣ therapy (day 1, i.e., treatment initiation), and weeks 2, 4, and 12 of IFN-␣ treatment. Psychiatric evaluations at each scheduled visit included a semi-structured interview with a psychiatrist to determine DSM-IV symptom criteria for major depression, as well as the administration of the Hamilton Depression Rating Scale (HAM-D; Hamilton 1960), the Hamilton Anxiety Scale (HAM-A; Maier et al 1988), and the self-report Neurotoxicity Rating Scale (NRS; Valentine et al 1995). On the basis of data from these scales, individual scores were calculated for each subject on specific symptom dimensions, including depressive (depressed mood, anhedonia, guilt, suicidal thoughts), anxious (anxious mood, fear, tension/irritability), cognitive (e.g., memory disturbances, distractibility, indecisiveness), neurovegetative (e.g., fatigue, anorexia), and somatic symptoms (e.g., pain, gastrointestinal distress) as described elsewhere (Capuron et al 2002a). It should be noted that according to DSM-IV classification, a depressive syndrome that develops during IFN-␣ therapy is referred to as a substance (IFN-␣)-induced mood disorder (American Psychiatric Association 1994). Blood samples were collected in ethylenediaminetetraacetic acid– containing vacutainer tubes on day 1 and at the beginning
of weeks 2, 4, and 12 of IFN-␣ therapy, at hourly intervals from the first to third hour after the injection of IFN-␣. Blood was immediately chilled on ice and subsequently centrifuged at 1000 g for 10 min at 4°C. Plasma was then separated and stored at ⫺80°C until assayed. Free TRP and KYN plasma concentrations were determined by high-performance liquid chromatography, as described elsewhere (Widner et al 1997). Neopterin plasma concentrations were measured by enzyme-linked immunosorbent assay (BRAHMS Diagnostics, Berlin, Germany).
Data Analyses and Statistics Time points corresponding to treatment initiation (day 1), and weeks 2, 4, and 12 of IFN-␣ treatment were used for data analysis to assess both the acute and chronic effects of IFN-␣ on biological and clinical variables. When a patient exited the study before week 12, data were analyzed using the last observation carried forward (LOCF) method. This method was used for nine patients in the antidepressant-free group and three patients in the paroxetine-treated group. Where indicated, complementary statistical analyses were conducted without the use of the LOCF method. In all cases, results were similar with and without the LOCF method. At each time point, the mean serum TRP, KYN, and neopterin concentrations, as well as the mean KYN/TRP ratio (corresponding to the mean value of the measurements collected respectively at 1 hour, 2 hours, and 3 hours post–IFN-␣ administration) were computed for data analysis. Changes in the concentrations of biological markers during IFN-␣ therapy were analyzed using a two-way repeated-measures analysis of variance (ANOVA), with group as the independent factor and time as the repeated-measure factor. When appropriate, simple main effects and post hoc comparisons using the corrected Bonferroni test were performed. For repeated measures, sphericity was checked using the Mauchly test, and a correction for sphericity was applied when necessary (Greenhouse-Greiser adjustment). For each subject, the overall mean changes in TRP, KYN, and neopterin concentrations and in the ratio KYN/TRP during IFN-␣ therapy (as determined by the average of the changes measured in biological parameters at each time point of IFN-␣ therapy relative to day 1 [i.e., treatment initiation]) were also calculated for correlational analyses. Relationships between the overall mean changes in biological measures and the maximum intensity of depressive symptoms exhibited by patients during IFN-␣ therapy were estimated using the Bravais-Pearson (R) correlation coefficient for continuous variables and the Spearman rank order correlation (Rs) for discrete variables. All probabilities were two-tailed, with the level of significance set at p ⬍ .05.
Results Changes in TRP, KYN, Neopterin Concentrations, and in the KYN/TRP Ratio During IFN-Alpha Therapy in Antidepressant-Free Patients and Paroxetine-Treated Patients Separate ANOVAs performed on TRP, KYN, KYN/TRP ratio, and neopterin indicated in all cases a significant
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Table 1. Changes in TRP, KYN, KYN/TRP Ratio, and Neopterin Concentrations during IFNAlpha Therapy in Antidepressant-Free Patients and Paroxetine-Treated Patients
Antidepressant-free Patients TRP (mol/L) KYN (mol/L) KYN/TRP ⫻ 1000 (mmol/mol) Neopterin (nmol/l) Paroxetine-treated Patients TRP (mol/L) KYN (mol/L) KYN/TRP ⫻ 1000 (mmol/mol) Neopterin (nmol/l)
Treatment Initiation
Week 2
Week 4
Week 12
35.9 (8.4) 1.6 (.5) 45.8 (12.1) 7.9 (5.1)
30.4 (10.5)a 3.7 (1.4)b 130.6 (48.1)b 20.3 (9.6)b
30.7 (11.1)a 2.8 (1.1)b 100.3 (40.4)b 17.9 (9.9)b
38.0 (6.7) 2.8 (.8)b 75.4 (19.6)a 25.9 (13.1)b
33.5 (9.2) 1.3 (.5) 38.2 (9.8) 6.2 (1.3)
30.8 (10.8) 3.5 (1.3)b 123.2 (48.2)b 22.4 (7.7)b
31.4 (7.3) 2.8 (.9)b 91.7 (29.5)b 21.3 (6.2)b
32.7 (8.0) 2.9 (.9)b 91.6 (27.2)b 27.0 (10.0)b
Data are presented as mean (SD). There was no significant difference between groups at any time point. IFN, interferon; TRP, tryptophan; KYN, kynurenine. a p ⬍ .05 compared with treatment initiation (within group). b p ⬍ .01 compared with treatment initiation (within group).
effect of time [TRP: F(3,72) ⫽ 6.02, p ⬍ .001; KYN: F(3,72) ⫽ 47.62, p ⬍ .001; KYN/TRP: F(3,72) ⫽ 46.74, p ⬍ .001; Neopterin: F(3,72) ⫽ 33.58, p ⬍ .001] but no significant group effect or interaction. Relative to treatment initiation, TRP concentrations decreased at weeks 2 and 4 in all patients during IFN-␣ treatment. Nevertheless, these TRP decreases only reached statistical significance in the antidepressant-free patients (p ⬍ .05). Plasma TRP concentrations returned to their initial values in both groups at week 12 (Table 1). Compared with treatment initiation, KYN and neopterin concentrations, as well as the ratio of KYN/TRP, were significantly increased during IFN-␣ therapy in both antidepressant-free patients and paroxetine-treated patients. In the two groups of patients, these increases were apparent as early as the second week of IFN-␣ therapy and remained significant at later stages of IFN-␣ treatment (all p ⬍ .01). In the study population as a whole, Bravais-Pearson correlations showed that overall mean changes in plasma neopterin concentrations during IFN-␣ therapy relative to treatment initiation (day 1) were associated with the overall mean changes in plasma KYN concentrations, plasma TRP concentrations, and in the KYN/TRP ratio (R ⫽ .701, p ⬍ .001; R ⫽ ⫺.439, p ⬍ .05; R ⫽ .769, p ⬍ .001, respectively). There was also a trend for a correlation between the overall mean changes in TRP and KYN concentrations during IFN-␣ therapy (R ⫽ ⫺.358, p ⫽ .07).
Relationship with Major Depression in Antidepressant-Free Patients Among the 15 antidepressant-free patients, 7 patients (age 59.2 [10.8] years; 5 male, 2 female) fulfilled DSM-IV criteria for major depression during the course of IFN-␣ therapy (mean onset 6.7 weeks) and 8 patients (age 48.4 [12.8] years; 4 male, 4 female) remained free of major
depression. Of note, none of the patients included in the paroxetine-treated group met symptom criteria for major depression during the study. Table 2 presents the clinical characteristics of patients in the antidepressant-free group who developed major depression during IFN-␣ compared with those who did not. Biological variables in these two groups are presented in Figure 2. To compare changes in biological measures during IFN-␣ therapy between depressed and nondepressed patients, a two-way repeated-measures ANOVA was performed using the differences (␦) in TRP, KYN, neopterin concentrations, and in the KYN/TRP ratio between treatment initiation and each subsequent time point as a repeated-measure factor. Analysis of variance performed on TRP data indicated a significant group effect [F(1,13) ⫽ 4.74, p ⬍ .05], a significant time effect [F(2,26) ⫽ 9.69, p ⬍ .001], as well as a significant interaction [F(2,26) ⫽ 3.37, p ⬍ .05] [Figure 2a]. During the first month of IFN-␣ therapy, changes in TRP concentrations relative to treatment initiation were comparable in patients who developed major depression and patients who remained free of major depression; however, a significant difference between the two subgroups was observed at week 12 of IFN-␣ therapy (p ⬍ .01). At this time point, depressed patients continued to exhibit significant decreases in TRP concentrations, whereas TRP decreases resolved in patients free of major depression. This result was also apparent when not using the LOCF method (p ⬍ .05). Of note, differences in plasma TRP concentrations between groups at week 12 corresponded with increases in several symptom dimensions in the depressed group relative to nondepressed patients at this time point (Table 2). There was a significant group effect [F(1,13) ⫽ 4.99, p ⬍ .05], a significant time effect [F(2,26) ⫽ 12.92, p ⬍ .001], and a significant interaction [F(2,26) ⫽ 6.67, p ⬍
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Table 2. Changes in Symptom Dimensions during IFN-Alpha Therapy in Antidepressant-Free Patients Who Developed Major Depression (n ⫽ 7) and Those Who Remained Free of Depression (n ⫽ 8) during IFN-Alpha Therapy
Patients with Major Depression Total HAM-D score Depressive symptoms Anxious symptoms Cognitive symptoms Neurovegetative symptoms Somatic symptoms Nondepressed Patients Total HAM-D score Depressive symptoms Anxious symptoms Cognitive symptoms Neurovegetative symptoms Somatic symptoms
Treatment Initiation
Week 2
Week 4
Week 12
6.3 (7.4) 1.4 (1.8) 1.3 (1.7) 1.1 (2.0) 2.3 (2.7) 1.6 (2.4)
9.0 (3.6) .7 (.9) .7 (.7) 1.1 (1.6) 4.0 (3.3) 4.3 (3.4)
16.1 (6.5)a 2.9 (2.4) 1.4 (.7) 1.4 (1.8) 6.1 (4.9) 4.7 (2.6)a
24.3 (7.6)c 6.9 (4.9)c 3.7 (2.2)a 5.4 (5.3)a 8.0 (4.1)c 4.4 (1.7)a
1.8 (1.9) 0 (0) .1 (.3) .5 (1.4) 1.9 (3.3) .8 (1.1)
5.6 (3.6) .3 (.7) .4 (.5) .1 (.3) 2.8 (3.0) 2.4 (2.2)
6.1 (4.5)d .4 (.7)b .9 (.6) .1 (.3) 3.0 (3.1) 1.9 (2.1)
6.4 (4.2)d .6 (1.1)d .6 (.7)d .9 (1.2)d 4.0 (3.6) 3.4 (3.2)a
Data are presented as mean (SD). IFN, interferon; HAM-D, Hamilton Depression Rating Scale. a p ⬍ .05 compared with treatment initiation (within group). b p ⬍ .05 compared with patients with major depression (between-group difference). c p ⬍ .01 compared with treatment initiation (within group). d p ⬍ .01 compared with patients with major depression (between-group difference).
.01] on KYN data (Figure 2b). In patients who remained free of major depression, KYN increases remained constant during IFN-␣ treatment. In contrast, increases in KYN concentrations were more marked at week 2 than at the subsequent time points in patients who met DSM-IV criteria for major depression during IFN-␣ therapy (p ⬍ .001). At week 2, patients who developed major depression exhibited higher increases in KYN concentrations relative to treatment initiation compared with patients who remained free of major depression (p ⬍ .01). At the subsequent time points, changes in KYN concentrations were comparable in the two subgroups of patients. No significant difference was observed in the KYN/TRP ratio between patients who met DSM-IV criteria for major depression during IFN-␣ therapy and patients who remained free of major depression. In both groups, increases in the KYN/TRP ratio relative to treatment initiation were more pronounced at week 2 than at subsequent time points (Figure 2c). There was an overall significant effect of time [F(2,26) ⫽ 4.05, p ⬍ .05] and a trend for a group effect [F(1,13) ⫽ 3.18, p ⫽ .09] on neopterin changes during IFN-␣ therapy. Post hoc comparisons revealed that at week 2, increases in neopterin concentrations relative to treatment initiation were more pronounced in patients who developed major depression compared with patients who remained free of major depression (p ⬍ .05) (Figure 2d). Of note, similar results were obtained for each biological variable when ANOVAs were performed controlling for age and gender.
Correlations with Symptom Dimensions In antidepressant-free patients, the average change in TRP concentrations during IFN-␣ therapy relative to day 1 (as determined by the average of the changes measured in TRP concentrations between treatment day 1 [i.e., treatment initiation] and each subsequent time point during IFN-␣ therapy) was correlated with the maximum depression score exhibited by the patients in the HAM-D during the first 12 weeks of IFN-␣ therapy (R ⫽ ⫺.545, p ⬍ .05). Furthermore, consistent with the extended decrease in TRP in antidepressant-free patients and the later development of depression during IFN-␣ (that we have previously reported), decreases in TRP concentrations between day 1 and week 12 of IFN-␣ correlated with the increases in HAM-D scores over the same time period (R ⫽ ⫺.844, p ⬍ .001). No significant association was noted between changes in HAM-D scores and the other biological variables at these time points. Correlations with symptom dimensions, at the time of the maximal HAM-D scores, indicated that the average decreases in plasma TRP concentrations during IFN-␣ therapy were associated with depressive symptoms (Rs ⫽ ⫺.627, p ⬍ .05) (especially depressed mood, anhedonia, and suicidal thoughts), anxious symptoms (Rs ⫽ ⫺.674, p ⬍ .01) (especially anxious mood and tension/irritability), and cognitive symptoms (Rs ⫽ ⫺.636, p ⬍ .05) (especially memory disturbances, word-finding problems, and confusion) but not with neurovegetative and somatic symptoms (Rs ⫽ ⫺.381, p ⫽ .16 and Rs ⫽ ⫺.22, p ⫽ .43, respectively).
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Figure 2. Changes (relative to interferon [IFN]-␣ therapy initiation) in tryptophan (TRP), kynurenine (KYN), neopterin concentrations, and in the KYN/TRP ratio in antidepressant-free patients who developed major depression compared with antidepressant-free patients who remained free of depression during IFN-␣ therapy. The figure depicts the changes (⌬) in TRP (A), KYN (B), KYN/TRP ⫻ 1000 (C), and neopterin (D) between treatment initiation and each time point in patients who developed major depression (open circles, n ⫽ 7) and patients who remained free of depression (filled circles, n ⫽ 8). Data are given as mean (⫾ SEM). † p ⬍ .05; ‡ p ⬍ .01 (between group difference).
In contrast to antidepressant-free patients, no significant correlations were measured between TRP changes and behavioral scores in paroxetine-treated patients. Finally, there were no significant correlations between behavioral scores and changes in KYN and neopterin concentrations and in the KYN/TRP ratio in antidepressant-free or paroxetine-treated patients during the study.
Discussion Interferon-␣ administration to patients with malignant melanoma induced significant increases in plasma KYN and neopterin concentrations, as well as in the KYN/TRP ratio. Increases in these biological parameters have been previously described in patients with chronic hepatitis C undergoing
IFN-␣ therapy (Bonaccorso et al 2002; Fuchs et al 1992). In the present study, changes in KYN, neopterin, and the KYN/TRP ratio developed early during IFN-␣ therapy and persisted at later stages of treatment. These changes were observed in all patients, whether or not they met criteria for major depression during IFN-␣ therapy and whether or not they were concomitantly treated with the antidepressant paroxetine. Together with decreased TRP concentrations, these findings support the hypothesis of IDOmediated activation of KYN pathway and cell-mediated (Th1-type) immunity during IFN-␣ treatment. Increases in KYN and neopterin concentrations were more marked in antidepressant-free (placebo-treated) patients who developed major depression during the course of IFN-␣ therapy, especially at the early stages of IFN-␣
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therapy. Consistent with this finding, those patients also exhibited more pronounced and long-lasting decreases in TRP concentrations relative to treatment initiation during the study. These results, which are in accordance with our previous data showing a relationship between TRP depletion and depressive symptoms in cancer patients undergoing interleukin-2 and/or IFN-␣ therapy (Capuron et al 2002b), support the hypothesis of the involvement of increased TRP metabolism (via the KYN pathway) in the development of symptoms of major depression in patients undergoing IFN-␣ therapy. Consistent with the finding that IFN-␣–induced TRP depletion was more pronounced in patients who met symptom criteria for major depression, our data indicated significant correlations between decreases in TRP concentrations and the development/intensity of mood and cognitive symptoms during IFN-␣ therapy. In contrast, TRP decreases were not associated with neurovegetative (e.g., fatigue, anorexia) and somatic symptoms (e.g., pain, gastrointestinal distress) during IFN-␣ treatment. As noted earlier, TRP is the major precursor of 5HT, and reduced CNS 5HT availability has been associated in many studies with the pathophysiology of major depression. IDOmediated TRP metabolism into KYN is associated with reduced availability of TRP for conversion into 5HT (Byrne et al 1986; Mellor and Munn 1999; Murr et al 2000). In the present study, the concomitant inverse changes in KYN and TRP concentrations (suggesting reduced 5HT synthesis), as well as the specific relationship between TRP decreases and mood and cognitive symptoms, support the role for 5HT in the mediation of these symptoms during IFN-␣ administration. In the dimension of mood, TRP decreases correlated particularly with the symptoms of depressed mood, anhedonia/loss of interest, suicidal thoughts, anxious mood, and tension/ irritability. These findings are in accordance with previous data supporting a role for serotonergic systems in mood regulation and aggressive/impulsive behavior (Oquendo and Mann 2000; Owens and Nemeroff 1994; Ravidran et al 1999; Young and Leyton 2002). Similarly and consistent with our findings, various studies have demonstrated a relationship between TRP depletion and cognitive alterations, especially in the form of memory and learning disturbances and executive dysfunction (Murphy et al 2002; Riedel et al 1999). Interestingly, correlations between decreased TRP concentrations and neurocognitive symptoms have also been reported in patients infected with human immunodeficiency virus (Fuchs et al 1990). The hypothesis of a role for 5HT in the mediation of mood and cognitive symptoms during IFN-␣ therapy is also supported by data that the antidepressant paroxetine, which increases 5HT availability within the CNS, prevented the development of mood and cognitive symptoms
associated with IFN-␣ administration while having a minimal effect on neurovegetative and somatic symptoms (Capuron et al 2002a). In the present study, patients pretreated with paroxetine exhibited significant increases in KYN and neopterin concentrations during IFN-␣ therapy, similar to antidepressant-free patients, suggesting that paroxetine does not inhibit the activation of cell-mediated immunity nor the activation of the KYN pathway during IFN-␣ therapy. Tryptophan concentrations also decreased during IFN-␣ therapy in both groups, but this effect was only statistically significant in antidepressant-free patients. Because of the limited number of patients treated with paroxetine, it remains unclear whether the absence of significant change in TRP concentrations during IFN-␣ therapy in this group reflects an effect of paroxetine on TRP metabolism or is the consequence of reduced statistical power. Mechanisms by which paroxetine might counterbalance the effects of IFN-␣ on TRP metabolism are unknown but could involve both peripheral and central effects. In the periphery, paroxetine has been shown to inhibit TRP pyrrolase (also referred to as TRP dioxygenase), a liver enzyme that, like IDO, metabolizes TRP to KYN in the liver (see Figure 1) (Badawy and Morgan 1991). Nevertheless, the absence of marked differences in plasma TRP and KYN between patients treated with paroxetine compared with antidepressant-free patients argues against the notion that the behavioral effects of paroxetine are secondary to inhibition of this enzyme. Based on our data, it may be more likely that paroxetine obviates IFN-␣– induced changes in tryptophan metabolism in the periphery by enhancing central 5HT availability through inhibition of synaptic reuptake. Finally, the question arises whether TRP supplementation might be useful in clinical conditions in which IDO pathways are activated, such as during IFN-␣ therapy. Although this treatment might address several relevant symptoms, activation of degradative pathways may overwhelm the effects of supplementation. Nevertheless, further consideration of this treatment is warranted.
This research was supported with grants from the National Institute of Mental Health (MH00680 and MH60723), the Centers for Disease Control and Prevention, Schering-Plough Pharmaceuticals, Glaxo-SmithKline, and the Austrian Federal Ministry of Social Affairs and Generations.
References American Psychiatric Association (1994): Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Press.
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Badawy AA, Morgan CJ (1991): Effects of acute paroxetine administration on tryptophan metabolism and disposition in the rat. Br J Pharmacol 102:429 –433. Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M, et al (2002): 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 22:86 –90. Byrne GI, Lehmann LK, Kirschbaum JG, Borden EC, Lee CM, Brown RR (1986): Induction of tryptophan degradation in vitro and in vivo: A gamma-interferon-stimulated activity. J Interferon Res 6:389 –396. Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB, Miller AH (2002a): Neurobehavioral effects of interferon-alpha in cancer patients: Phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 26:643–652. Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R (2002b): Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 7:468 –473. Deakin JF, Pennell I, Upadhyaya AJ, Lofthouse R (1990): A neuroendocrine study of 5HT function in depression: Evidence for biological mechanisms of endogenous and psychosocial causation. Psychopharmacology (Berl) 101:85–92. Delgado PL, Price LH, Miller HL, Salomon RM, Aghajanian GK, Heninger GR, Charney DS (1994): Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients. Arch Gen Psychiatry 51:865– 874. Fuchs D, Moller AA, Reibnegger G, Stockle E, Werner ER, Wachter H (1990): Decreased serum tryptophan in patients with HIV-1 infection correlates with increased serum neopterin and with neurologic/psychiatric symptoms. J Acquir Immune Defic Syndr 3:873–876. Fuchs D, Moller AA, Reibnegger G, Werner ER, WernerFelmayer G, Dierich MP, Wachter H (1991): Increased endogenous interferon-gamma and neopterin correlate with increased degradation of tryptophan in human immunodeficiency virus type 1 infection. Immunol Lett 28:207–211. Fuchs D, Norkrans G, Wejstal R, Reibnegger G, Weiss G, Weiland O, et al (1992): Changes of serum neopterin, beta 2-microglobulin and interferon-gamma in patients with chronic hepatitis C treated with interferon-alpha 2b. Eur J Med 1:196 –200. Gilmor ML, Owens MJ, Nemeroff (2002): Inhibition of norepinephrine uptake in patients with major depression treated with paroxetine. Am J Psychiatry 159:1702–1710. Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:52–62. Kubera M, Maes M, Holan V, Basta-Kaim A, Roman A, Shani J (2001): Prolonged desipramine treatment increases the production of interleukin-10, an anti-inflammatory cytokine, in C57BL/6 mice subjected to the chronic mild stress model of depression. J Affect Disord 63:171–178. Lucca A, Lucini V, Piatti E, Ronchi P, Smeraldi E (1992): Plasma tryptophan levels and plasma tryptophan/neutral amino acids ratio in patients with mood disorder, patients with obsessive-compulsive disorder, and normal subjects. Psychiatry Res 44:85–91.
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Maes M, Scharpe S, Meltzer HY, Okayli G, Bosmans E, D’Hondt P, et al (1994): Increased neopterin and interferongamma secretion and lower availability of L-tryptophan in major depression: Further evidence for an immune response. Psychiatry Res 54:143–160. Maier W, Buller R, Philipp M, Heuser I (1988): The Hamilton Anxiety Scale: Reliability, validity and sensitivity to change in anxiety and depressive disorders. J Affect Disord 14:61–68. Malone KM, Mann JJ (1993): Serotonin and major depression. In: Mann JJ, Kupfe DJ, editors. Biology of Depressive Disorders, vol 3, part A: A System Perspective. New York: Plenum Press, 29 –49. Mellor AL, Munn DH (1999): Tryptophan catabolism and T-cell tolerance: Immunosuppression by starvation? Immunol Today 20:469 –473. Moore P, Landolt HP, Seifritz E, Clark C, Bhatti T, Kelsoe J, et al (2000): Clinical and physiological consequences of rapid tryptophan depletion. Neuropsychopharmacology 23:601– 622. Moreno FA, Heninger GR, McGahuey CA, Delgado PL (2000): Tryptophan depletion and risk of depression relapse: A prospective study of tryptophan depletion as a potential predictor of depressive episodes. Biol Psychiatry 48:327–329. Murphy FC, Smith KA, Cowen PJ, Robbins TW, Sahakian BJ (2002): The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers. Psychopharmacol (Berl) 163:42–53. Murr C, Widner B, Sperner-Unterweger B, Ledochowski M, Schubert C, Fuchs D (2000): Immune reaction links disease progression in cancer patients with depression. Med Hypotheses 55:137–140. Murr C, Widner B, Wirleitner B, Fuchs D (2002): Neopterin as a marker for immune system activation. Curr Drug Metab 3:175–187. Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, et al (2001): Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 344:961–966. Oquendo MA, Mann JJ (2000): The biology of impulsivity and suicidality. Psychiatr Clin North Am 23:11–25. Owens MJ, Nemeroff CB (1994): Role of serotonin in the pathophysiology of depression: Focus on the serotonin transporter. Clin Chem 40:288 –295. Pellegrino TC, Bayer BM (2000): Specific serotonin reuptake inhibitor-induced decreases in lymphocyte activity require endogenous serotonin release. Neuroimmunomodulation 8:179 –187. Ravindran AV, Griffiths J, Merali Z, Knott VJ, Anisman H (1999): Influence of acute tryptophan depletion on mood and immune measures in healthy males. Psychoneuroendocrinology 24:99 –113. Ressler KJ, Nemeroff CB (2000): Role of serotoninergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12(suppl 1):2–19. Riedel WJ, Klaassen T, Deutz NE, van Someren A, van Praag HM (1999): Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation. Psychopharmacology (Berl) 141:362–369.
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Song C, Lin A, Bonaccorso S, Heide C, Verkerk R, Kenis G, et al (1998): The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression. J Affect Disord 49:211–219. Tollefson GD, Rosenbaum JF (1998): Selective serotonin reuptake inhibitors. In: Schatzberg AF, Nemeroff CB, editors. Textbook of Psychopharmacology, 2nd ed. Washington, DC: American Psychiatric Press, 219 –237. Valentine AD, Meyers CA, Talpaz M (1995): Treatment of neurotoxic side effects of interferon-alpha with naltrexone. Cancer Invest 13:561–566.
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Widner B, Ledochowski M, Fuchs D (2000): Interferongamma-induced tryptophan degradation: Neuropsychiatric and immunological consequences. Curr Drug Metab 1:193–204. Widner B, Werner ER, Schennach H, Wachter H, Fuchs D (1997): Simultaneous measurement of serum tryptophan and kynurenine by HPLC. Clin Chem 43:2424 –2426. Young SN, Leyton M (2002): The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels. Pharmacol Biochem Behav 71:857–865.
© 2003 Society of Biological Psychiatry
Key Words: Interferon-alpha, tryptophan, kynurenine, neopterin, indoleamine-2,3-dioxygenase, depressive symptoms
Introduction
M
ajor depression frequently develops in medically ill patients who are administered cytokine therapies for infectious diseases or cancers. For example, it has been shown that the rate of major depression in patients with malignant melanoma receiving high-dose interferon (IFN)-␣ is almost 45% (Musselman et al 2001). Despite an increasing appreciation of cytokine-induced depressive syndromes, the mechanisms involved remain to be elucidated. In a recent study, cancer patients undergoing IFN-␣ and/or interleukin-2 therapy exhibited significant decreases in serum concentrations of tryptophan (TRP) and the ratio of TRP to large neutral amino acids (namely tyrosine, phenylalanine, leucine, isoleucine, valine) that correlated with increased depression scores (Capuron et al 2002b). These findings suggested that the development of depressive symptoms during cytokine therapy might be mediated, at least in part, by TRP depletion. Tryptophan is the precursor of serotonin (5HT), which is believed to play a prominent role in the neurobiology of mood disorders (see for review Malone and Mann 1993, Owens and Nemeroff 1994). Tryptophan availability is the rate-limiting step in the synthesis of 5HT. Reductions in blood TRP concentrations are associated with reduced 5HT availability within the central nervous system (CNS), and TRP depletion has been associated with the induction of depressive relapse in vulnerable patients (Delgado et al 1994; Moore et al 2000; Moreno et al 2000). Moreover, drug-free depressed patients have been reported to exhibit reduced plasma TRP concentrations compared with normal control subjects (Deakin 1990; Lucca et al 1992; Maes et al 1994; Ressler and Nemeroff 2000; Song et al 1998). Conversely, drugs that block the reuptake of 5HT, namely the selective serotonin reuptake inhibitors (SSRIs), and 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00173-2
Interferon-Alpha and Tryptophan Metabolism
Figure 1. Tryptophan metabolism and neopterin synthesis upon immune system activation. Cytokines (e.g., interferon [IFN]-␥) induce the enzyme indoleamine-2,3-dioxygenase (IDO) that catabolizes tryptophan into kynurenine and then quinolinic acid, thereby reducing the availability of tryptophan for serotonin synthesis via the enzyme tryptophan hydroxylase (TPH). The activation of the kynurenine pathway may also be due to the induction of the liver enzyme tryptophan dioxygenase (TDO) by cytokines. Cytokines induce neopterin synthesis from activated monocytes/macrophages by activating guanosine triphosphate cyclohydrolase 1 (GTP-CH1), an enzyme that catalyzes the formation of neopterin from guanosine triphosphate (GTP).
thereby increase 5HT availability within the CNS, are well known to be effective treatments for major depression (Tollefson and Rosenbaum 1998). The pathways by which IFN-␣ and/or interleukin-2 induce peripheral TRP depletion during cytokine therapy are unknown but may involve activation of the enzyme, indoleamine-2,3-dioxygenase (IDO). IDO catalyzes the rate-limiting step of TRP conversion into kynurenine (KYN) and then quinolinic acid (Byrne et al 1986), thereby reducing the availability of TRP for conversion into 5HT (Figure 1). In vivo, the activity of IDO is reflected by the relative plasma or serum concentrations of KYN and TRP. Indeed, the ratio of KYN/TRP is considered to be an estimate of IDO activity, independent of baseline TRP concentrations (Widner et al 2000). IDO can be induced in a variety of immune cells, such as monocyte-derived macrophages and microglia, by inflammatory cytokines, including, most notably, IFNs (Mellor and Munn 1999). Consistent with IDO induction by IFNs, decreased plasma TRP concentrations and a high KYN/ TRP ratio have been found to correlate with concentra-
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tions of neopterin in patients with infectious diseases (Fuchs et al 1990, 1991). Neopterin, a pteridine derived from guanosine triphosphate, is released from human monocytes and macrophages upon stimulation with IFNs, especially IFN-␥, and is therefore considered a marker of activated cell-mediated immunity (Murr et al 2002). Release of neopterin by IFN-stimulated immune cells is initiated at the expense of biopterin synthesis, a co-factor of several monooxygenase reactions, including tryptophan-5-hydroxylase (Widner et al 2000). Interestingly, increased concentrations of neopterin and IFN-␥, together with a lower availability of L-TRP, have been described in patients with major depression (Maes et al 1994). In a recent report, patients treated with IFN-␣ for chronic hepatitis C were found to exhibit evidence of increased IDO activity, including reduced TRP concentrations, increased KYN concentrations, and an increased KYN/TRP ratio. Although these patients also exhibited a corresponding increase in depressive symptoms (Bonaccorso et al 2002), the relationship between TRP metabolism and the development of specific depressive symptoms was not reported. Moreover, the impact of antidepressant treatment was not examined. Recent work by our group has shown that the antidepressant paroxetine, a 5HT and norepinephrine reuptake inhibitor (Gilmor et al 2002), was effective in preventing the development of major depression, especially its mood and cognitive features, in patients receiving high-dose IFN-␣ therapy for malignant melanoma (Capuron et al 2002a; Musselman et al 2001). The mechanisms by which paroxetine prevents depressive symptoms in IFN-␣– treated patients remain obscure. One possibility is that paroxetine may influence the effect of IFN-␣ on IDO activity and TRP metabolism, either directly or indirectly through an effect on the activation of relevant immune cells. Indeed, recent data indicate that antidepressants, most notably tricyclics, but also SSRIs, may inhibit inflammatory immunologic responses (Kubera et al 2001; Pellegrino and Bayer 2000). To further examine the relationships among TRP metabolism, immune cell activation, and the development and treatment of depressive symptoms during IFN-␣ therapy, we measured TRP, KYN, and neopterin in placebo- and paroxetine-treated patients undergoing highdose IFN-␣ therapy for malignant melanoma.
Methods and Materials Patients Twenty-six patients (mean [SD] age 53 [10] years, range 32–74; 14 male, 12 female) with malignant melanoma eligible to receive IFN-␣ (IntronA, Schering-Plough, Kenilworth, NJ) were recruited from the Winship Cancer Institute of Emory University
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of Medicine. These patients constituted a subpopulation of the 40 patients described by Musselman et al (2001), in which blood samples were available for at least the first month of IFN-␣ therapy. Patients with unresectable metastases, brain metastases, a score ⬍ 24 in the Mini-Mental State Examination or a diagnosis of schizophrenia or bipolar disorder as determined by the Structured Clinical Interview for the DSM-IV were excluded from the study. Medications for pain, nausea, and fever were allowed during the study. All patients provided written, informed consent before enrollment. The study was approved by the Human Investigations Committee of the Emory University School of Medicine.
Treatments Interferon-␣ was administered at the dose of 20 million international units (MIU) per square meter of body surface area 5 days per week for the first 4 weeks of therapy, followed by 10 MIU/m2 subcutaneously 3 days per week for the remaining 8 weeks of the study. Two weeks before the initiation of IFN-␣ therapy, patients were randomly assigned in double-blind fashion to receive either placebo or paroxetine (Paxil, GlaxoSmithKline, Research Triangle Park, NC). The dosage of study medication was 10 mg paroxetine or placebo per day for the first week, followed by 20 mg paroxetine or placebo per day for the second week. The dosage could be increased up to 40 mg per day 2 weeks after the initiation of IFN-␣. Among the 26 patients considered in the study, 15 patients (age 53 [13] years; 9 male, 6 female) received placebo and 11 patients (age 52 [7] years; 5 male, 6 female) received paroxetine.
Psychiatric and Biological Measurements Psychiatric and biological assessments occurred at regularly scheduled intervals during the first 12 weeks of IFN-␣ treatment. Scheduled visits included the first day of IFN-␣ therapy (day 1, i.e., treatment initiation), and weeks 2, 4, and 12 of IFN-␣ treatment. Psychiatric evaluations at each scheduled visit included a semi-structured interview with a psychiatrist to determine DSM-IV symptom criteria for major depression, as well as the administration of the Hamilton Depression Rating Scale (HAM-D; Hamilton 1960), the Hamilton Anxiety Scale (HAM-A; Maier et al 1988), and the self-report Neurotoxicity Rating Scale (NRS; Valentine et al 1995). On the basis of data from these scales, individual scores were calculated for each subject on specific symptom dimensions, including depressive (depressed mood, anhedonia, guilt, suicidal thoughts), anxious (anxious mood, fear, tension/irritability), cognitive (e.g., memory disturbances, distractibility, indecisiveness), neurovegetative (e.g., fatigue, anorexia), and somatic symptoms (e.g., pain, gastrointestinal distress) as described elsewhere (Capuron et al 2002a). It should be noted that according to DSM-IV classification, a depressive syndrome that develops during IFN-␣ therapy is referred to as a substance (IFN-␣)-induced mood disorder (American Psychiatric Association 1994). Blood samples were collected in ethylenediaminetetraacetic acid– containing vacutainer tubes on day 1 and at the beginning
of weeks 2, 4, and 12 of IFN-␣ therapy, at hourly intervals from the first to third hour after the injection of IFN-␣. Blood was immediately chilled on ice and subsequently centrifuged at 1000 g for 10 min at 4°C. Plasma was then separated and stored at ⫺80°C until assayed. Free TRP and KYN plasma concentrations were determined by high-performance liquid chromatography, as described elsewhere (Widner et al 1997). Neopterin plasma concentrations were measured by enzyme-linked immunosorbent assay (BRAHMS Diagnostics, Berlin, Germany).
Data Analyses and Statistics Time points corresponding to treatment initiation (day 1), and weeks 2, 4, and 12 of IFN-␣ treatment were used for data analysis to assess both the acute and chronic effects of IFN-␣ on biological and clinical variables. When a patient exited the study before week 12, data were analyzed using the last observation carried forward (LOCF) method. This method was used for nine patients in the antidepressant-free group and three patients in the paroxetine-treated group. Where indicated, complementary statistical analyses were conducted without the use of the LOCF method. In all cases, results were similar with and without the LOCF method. At each time point, the mean serum TRP, KYN, and neopterin concentrations, as well as the mean KYN/TRP ratio (corresponding to the mean value of the measurements collected respectively at 1 hour, 2 hours, and 3 hours post–IFN-␣ administration) were computed for data analysis. Changes in the concentrations of biological markers during IFN-␣ therapy were analyzed using a two-way repeated-measures analysis of variance (ANOVA), with group as the independent factor and time as the repeated-measure factor. When appropriate, simple main effects and post hoc comparisons using the corrected Bonferroni test were performed. For repeated measures, sphericity was checked using the Mauchly test, and a correction for sphericity was applied when necessary (Greenhouse-Greiser adjustment). For each subject, the overall mean changes in TRP, KYN, and neopterin concentrations and in the ratio KYN/TRP during IFN-␣ therapy (as determined by the average of the changes measured in biological parameters at each time point of IFN-␣ therapy relative to day 1 [i.e., treatment initiation]) were also calculated for correlational analyses. Relationships between the overall mean changes in biological measures and the maximum intensity of depressive symptoms exhibited by patients during IFN-␣ therapy were estimated using the Bravais-Pearson (R) correlation coefficient for continuous variables and the Spearman rank order correlation (Rs) for discrete variables. All probabilities were two-tailed, with the level of significance set at p ⬍ .05.
Results Changes in TRP, KYN, Neopterin Concentrations, and in the KYN/TRP Ratio During IFN-Alpha Therapy in Antidepressant-Free Patients and Paroxetine-Treated Patients Separate ANOVAs performed on TRP, KYN, KYN/TRP ratio, and neopterin indicated in all cases a significant
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Table 1. Changes in TRP, KYN, KYN/TRP Ratio, and Neopterin Concentrations during IFNAlpha Therapy in Antidepressant-Free Patients and Paroxetine-Treated Patients
Antidepressant-free Patients TRP (mol/L) KYN (mol/L) KYN/TRP ⫻ 1000 (mmol/mol) Neopterin (nmol/l) Paroxetine-treated Patients TRP (mol/L) KYN (mol/L) KYN/TRP ⫻ 1000 (mmol/mol) Neopterin (nmol/l)
Treatment Initiation
Week 2
Week 4
Week 12
35.9 (8.4) 1.6 (.5) 45.8 (12.1) 7.9 (5.1)
30.4 (10.5)a 3.7 (1.4)b 130.6 (48.1)b 20.3 (9.6)b
30.7 (11.1)a 2.8 (1.1)b 100.3 (40.4)b 17.9 (9.9)b
38.0 (6.7) 2.8 (.8)b 75.4 (19.6)a 25.9 (13.1)b
33.5 (9.2) 1.3 (.5) 38.2 (9.8) 6.2 (1.3)
30.8 (10.8) 3.5 (1.3)b 123.2 (48.2)b 22.4 (7.7)b
31.4 (7.3) 2.8 (.9)b 91.7 (29.5)b 21.3 (6.2)b
32.7 (8.0) 2.9 (.9)b 91.6 (27.2)b 27.0 (10.0)b
Data are presented as mean (SD). There was no significant difference between groups at any time point. IFN, interferon; TRP, tryptophan; KYN, kynurenine. a p ⬍ .05 compared with treatment initiation (within group). b p ⬍ .01 compared with treatment initiation (within group).
effect of time [TRP: F(3,72) ⫽ 6.02, p ⬍ .001; KYN: F(3,72) ⫽ 47.62, p ⬍ .001; KYN/TRP: F(3,72) ⫽ 46.74, p ⬍ .001; Neopterin: F(3,72) ⫽ 33.58, p ⬍ .001] but no significant group effect or interaction. Relative to treatment initiation, TRP concentrations decreased at weeks 2 and 4 in all patients during IFN-␣ treatment. Nevertheless, these TRP decreases only reached statistical significance in the antidepressant-free patients (p ⬍ .05). Plasma TRP concentrations returned to their initial values in both groups at week 12 (Table 1). Compared with treatment initiation, KYN and neopterin concentrations, as well as the ratio of KYN/TRP, were significantly increased during IFN-␣ therapy in both antidepressant-free patients and paroxetine-treated patients. In the two groups of patients, these increases were apparent as early as the second week of IFN-␣ therapy and remained significant at later stages of IFN-␣ treatment (all p ⬍ .01). In the study population as a whole, Bravais-Pearson correlations showed that overall mean changes in plasma neopterin concentrations during IFN-␣ therapy relative to treatment initiation (day 1) were associated with the overall mean changes in plasma KYN concentrations, plasma TRP concentrations, and in the KYN/TRP ratio (R ⫽ .701, p ⬍ .001; R ⫽ ⫺.439, p ⬍ .05; R ⫽ .769, p ⬍ .001, respectively). There was also a trend for a correlation between the overall mean changes in TRP and KYN concentrations during IFN-␣ therapy (R ⫽ ⫺.358, p ⫽ .07).
Relationship with Major Depression in Antidepressant-Free Patients Among the 15 antidepressant-free patients, 7 patients (age 59.2 [10.8] years; 5 male, 2 female) fulfilled DSM-IV criteria for major depression during the course of IFN-␣ therapy (mean onset 6.7 weeks) and 8 patients (age 48.4 [12.8] years; 4 male, 4 female) remained free of major
depression. Of note, none of the patients included in the paroxetine-treated group met symptom criteria for major depression during the study. Table 2 presents the clinical characteristics of patients in the antidepressant-free group who developed major depression during IFN-␣ compared with those who did not. Biological variables in these two groups are presented in Figure 2. To compare changes in biological measures during IFN-␣ therapy between depressed and nondepressed patients, a two-way repeated-measures ANOVA was performed using the differences (␦) in TRP, KYN, neopterin concentrations, and in the KYN/TRP ratio between treatment initiation and each subsequent time point as a repeated-measure factor. Analysis of variance performed on TRP data indicated a significant group effect [F(1,13) ⫽ 4.74, p ⬍ .05], a significant time effect [F(2,26) ⫽ 9.69, p ⬍ .001], as well as a significant interaction [F(2,26) ⫽ 3.37, p ⬍ .05] [Figure 2a]. During the first month of IFN-␣ therapy, changes in TRP concentrations relative to treatment initiation were comparable in patients who developed major depression and patients who remained free of major depression; however, a significant difference between the two subgroups was observed at week 12 of IFN-␣ therapy (p ⬍ .01). At this time point, depressed patients continued to exhibit significant decreases in TRP concentrations, whereas TRP decreases resolved in patients free of major depression. This result was also apparent when not using the LOCF method (p ⬍ .05). Of note, differences in plasma TRP concentrations between groups at week 12 corresponded with increases in several symptom dimensions in the depressed group relative to nondepressed patients at this time point (Table 2). There was a significant group effect [F(1,13) ⫽ 4.99, p ⬍ .05], a significant time effect [F(2,26) ⫽ 12.92, p ⬍ .001], and a significant interaction [F(2,26) ⫽ 6.67, p ⬍
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Table 2. Changes in Symptom Dimensions during IFN-Alpha Therapy in Antidepressant-Free Patients Who Developed Major Depression (n ⫽ 7) and Those Who Remained Free of Depression (n ⫽ 8) during IFN-Alpha Therapy
Patients with Major Depression Total HAM-D score Depressive symptoms Anxious symptoms Cognitive symptoms Neurovegetative symptoms Somatic symptoms Nondepressed Patients Total HAM-D score Depressive symptoms Anxious symptoms Cognitive symptoms Neurovegetative symptoms Somatic symptoms
Treatment Initiation
Week 2
Week 4
Week 12
6.3 (7.4) 1.4 (1.8) 1.3 (1.7) 1.1 (2.0) 2.3 (2.7) 1.6 (2.4)
9.0 (3.6) .7 (.9) .7 (.7) 1.1 (1.6) 4.0 (3.3) 4.3 (3.4)
16.1 (6.5)a 2.9 (2.4) 1.4 (.7) 1.4 (1.8) 6.1 (4.9) 4.7 (2.6)a
24.3 (7.6)c 6.9 (4.9)c 3.7 (2.2)a 5.4 (5.3)a 8.0 (4.1)c 4.4 (1.7)a
1.8 (1.9) 0 (0) .1 (.3) .5 (1.4) 1.9 (3.3) .8 (1.1)
5.6 (3.6) .3 (.7) .4 (.5) .1 (.3) 2.8 (3.0) 2.4 (2.2)
6.1 (4.5)d .4 (.7)b .9 (.6) .1 (.3) 3.0 (3.1) 1.9 (2.1)
6.4 (4.2)d .6 (1.1)d .6 (.7)d .9 (1.2)d 4.0 (3.6) 3.4 (3.2)a
Data are presented as mean (SD). IFN, interferon; HAM-D, Hamilton Depression Rating Scale. a p ⬍ .05 compared with treatment initiation (within group). b p ⬍ .05 compared with patients with major depression (between-group difference). c p ⬍ .01 compared with treatment initiation (within group). d p ⬍ .01 compared with patients with major depression (between-group difference).
.01] on KYN data (Figure 2b). In patients who remained free of major depression, KYN increases remained constant during IFN-␣ treatment. In contrast, increases in KYN concentrations were more marked at week 2 than at the subsequent time points in patients who met DSM-IV criteria for major depression during IFN-␣ therapy (p ⬍ .001). At week 2, patients who developed major depression exhibited higher increases in KYN concentrations relative to treatment initiation compared with patients who remained free of major depression (p ⬍ .01). At the subsequent time points, changes in KYN concentrations were comparable in the two subgroups of patients. No significant difference was observed in the KYN/TRP ratio between patients who met DSM-IV criteria for major depression during IFN-␣ therapy and patients who remained free of major depression. In both groups, increases in the KYN/TRP ratio relative to treatment initiation were more pronounced at week 2 than at subsequent time points (Figure 2c). There was an overall significant effect of time [F(2,26) ⫽ 4.05, p ⬍ .05] and a trend for a group effect [F(1,13) ⫽ 3.18, p ⫽ .09] on neopterin changes during IFN-␣ therapy. Post hoc comparisons revealed that at week 2, increases in neopterin concentrations relative to treatment initiation were more pronounced in patients who developed major depression compared with patients who remained free of major depression (p ⬍ .05) (Figure 2d). Of note, similar results were obtained for each biological variable when ANOVAs were performed controlling for age and gender.
Correlations with Symptom Dimensions In antidepressant-free patients, the average change in TRP concentrations during IFN-␣ therapy relative to day 1 (as determined by the average of the changes measured in TRP concentrations between treatment day 1 [i.e., treatment initiation] and each subsequent time point during IFN-␣ therapy) was correlated with the maximum depression score exhibited by the patients in the HAM-D during the first 12 weeks of IFN-␣ therapy (R ⫽ ⫺.545, p ⬍ .05). Furthermore, consistent with the extended decrease in TRP in antidepressant-free patients and the later development of depression during IFN-␣ (that we have previously reported), decreases in TRP concentrations between day 1 and week 12 of IFN-␣ correlated with the increases in HAM-D scores over the same time period (R ⫽ ⫺.844, p ⬍ .001). No significant association was noted between changes in HAM-D scores and the other biological variables at these time points. Correlations with symptom dimensions, at the time of the maximal HAM-D scores, indicated that the average decreases in plasma TRP concentrations during IFN-␣ therapy were associated with depressive symptoms (Rs ⫽ ⫺.627, p ⬍ .05) (especially depressed mood, anhedonia, and suicidal thoughts), anxious symptoms (Rs ⫽ ⫺.674, p ⬍ .01) (especially anxious mood and tension/irritability), and cognitive symptoms (Rs ⫽ ⫺.636, p ⬍ .05) (especially memory disturbances, word-finding problems, and confusion) but not with neurovegetative and somatic symptoms (Rs ⫽ ⫺.381, p ⫽ .16 and Rs ⫽ ⫺.22, p ⫽ .43, respectively).
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Figure 2. Changes (relative to interferon [IFN]-␣ therapy initiation) in tryptophan (TRP), kynurenine (KYN), neopterin concentrations, and in the KYN/TRP ratio in antidepressant-free patients who developed major depression compared with antidepressant-free patients who remained free of depression during IFN-␣ therapy. The figure depicts the changes (⌬) in TRP (A), KYN (B), KYN/TRP ⫻ 1000 (C), and neopterin (D) between treatment initiation and each time point in patients who developed major depression (open circles, n ⫽ 7) and patients who remained free of depression (filled circles, n ⫽ 8). Data are given as mean (⫾ SEM). † p ⬍ .05; ‡ p ⬍ .01 (between group difference).
In contrast to antidepressant-free patients, no significant correlations were measured between TRP changes and behavioral scores in paroxetine-treated patients. Finally, there were no significant correlations between behavioral scores and changes in KYN and neopterin concentrations and in the KYN/TRP ratio in antidepressant-free or paroxetine-treated patients during the study.
Discussion Interferon-␣ administration to patients with malignant melanoma induced significant increases in plasma KYN and neopterin concentrations, as well as in the KYN/TRP ratio. Increases in these biological parameters have been previously described in patients with chronic hepatitis C undergoing
IFN-␣ therapy (Bonaccorso et al 2002; Fuchs et al 1992). In the present study, changes in KYN, neopterin, and the KYN/TRP ratio developed early during IFN-␣ therapy and persisted at later stages of treatment. These changes were observed in all patients, whether or not they met criteria for major depression during IFN-␣ therapy and whether or not they were concomitantly treated with the antidepressant paroxetine. Together with decreased TRP concentrations, these findings support the hypothesis of IDOmediated activation of KYN pathway and cell-mediated (Th1-type) immunity during IFN-␣ treatment. Increases in KYN and neopterin concentrations were more marked in antidepressant-free (placebo-treated) patients who developed major depression during the course of IFN-␣ therapy, especially at the early stages of IFN-␣
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therapy. Consistent with this finding, those patients also exhibited more pronounced and long-lasting decreases in TRP concentrations relative to treatment initiation during the study. These results, which are in accordance with our previous data showing a relationship between TRP depletion and depressive symptoms in cancer patients undergoing interleukin-2 and/or IFN-␣ therapy (Capuron et al 2002b), support the hypothesis of the involvement of increased TRP metabolism (via the KYN pathway) in the development of symptoms of major depression in patients undergoing IFN-␣ therapy. Consistent with the finding that IFN-␣–induced TRP depletion was more pronounced in patients who met symptom criteria for major depression, our data indicated significant correlations between decreases in TRP concentrations and the development/intensity of mood and cognitive symptoms during IFN-␣ therapy. In contrast, TRP decreases were not associated with neurovegetative (e.g., fatigue, anorexia) and somatic symptoms (e.g., pain, gastrointestinal distress) during IFN-␣ treatment. As noted earlier, TRP is the major precursor of 5HT, and reduced CNS 5HT availability has been associated in many studies with the pathophysiology of major depression. IDOmediated TRP metabolism into KYN is associated with reduced availability of TRP for conversion into 5HT (Byrne et al 1986; Mellor and Munn 1999; Murr et al 2000). In the present study, the concomitant inverse changes in KYN and TRP concentrations (suggesting reduced 5HT synthesis), as well as the specific relationship between TRP decreases and mood and cognitive symptoms, support the role for 5HT in the mediation of these symptoms during IFN-␣ administration. In the dimension of mood, TRP decreases correlated particularly with the symptoms of depressed mood, anhedonia/loss of interest, suicidal thoughts, anxious mood, and tension/ irritability. These findings are in accordance with previous data supporting a role for serotonergic systems in mood regulation and aggressive/impulsive behavior (Oquendo and Mann 2000; Owens and Nemeroff 1994; Ravidran et al 1999; Young and Leyton 2002). Similarly and consistent with our findings, various studies have demonstrated a relationship between TRP depletion and cognitive alterations, especially in the form of memory and learning disturbances and executive dysfunction (Murphy et al 2002; Riedel et al 1999). Interestingly, correlations between decreased TRP concentrations and neurocognitive symptoms have also been reported in patients infected with human immunodeficiency virus (Fuchs et al 1990). The hypothesis of a role for 5HT in the mediation of mood and cognitive symptoms during IFN-␣ therapy is also supported by data that the antidepressant paroxetine, which increases 5HT availability within the CNS, prevented the development of mood and cognitive symptoms
associated with IFN-␣ administration while having a minimal effect on neurovegetative and somatic symptoms (Capuron et al 2002a). In the present study, patients pretreated with paroxetine exhibited significant increases in KYN and neopterin concentrations during IFN-␣ therapy, similar to antidepressant-free patients, suggesting that paroxetine does not inhibit the activation of cell-mediated immunity nor the activation of the KYN pathway during IFN-␣ therapy. Tryptophan concentrations also decreased during IFN-␣ therapy in both groups, but this effect was only statistically significant in antidepressant-free patients. Because of the limited number of patients treated with paroxetine, it remains unclear whether the absence of significant change in TRP concentrations during IFN-␣ therapy in this group reflects an effect of paroxetine on TRP metabolism or is the consequence of reduced statistical power. Mechanisms by which paroxetine might counterbalance the effects of IFN-␣ on TRP metabolism are unknown but could involve both peripheral and central effects. In the periphery, paroxetine has been shown to inhibit TRP pyrrolase (also referred to as TRP dioxygenase), a liver enzyme that, like IDO, metabolizes TRP to KYN in the liver (see Figure 1) (Badawy and Morgan 1991). Nevertheless, the absence of marked differences in plasma TRP and KYN between patients treated with paroxetine compared with antidepressant-free patients argues against the notion that the behavioral effects of paroxetine are secondary to inhibition of this enzyme. Based on our data, it may be more likely that paroxetine obviates IFN-␣– induced changes in tryptophan metabolism in the periphery by enhancing central 5HT availability through inhibition of synaptic reuptake. Finally, the question arises whether TRP supplementation might be useful in clinical conditions in which IDO pathways are activated, such as during IFN-␣ therapy. Although this treatment might address several relevant symptoms, activation of degradative pathways may overwhelm the effects of supplementation. Nevertheless, further consideration of this treatment is warranted.
This research was supported with grants from the National Institute of Mental Health (MH00680 and MH60723), the Centers for Disease Control and Prevention, Schering-Plough Pharmaceuticals, Glaxo-SmithKline, and the Austrian Federal Ministry of Social Affairs and Generations.
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