Tryptophan breakdown pathway in bipolar mania

Journal of Affective Disorders 102 (2007) 65 – 72 www.elsevier.com/locate/jad

Research report

Tryptophan breakdown pathway in bipolar mania Aye Mu Myint a,b, Yong-Ku Kim c,⁎, Robert Verkerk b, Sun Hwa Park d, Simon Scharpé b, Harry W.M. Steinbusch a, Brian E. Leonard a a

Department of Psychiatry and Neuropsychology, University of Maastricht, The Netherlands Department of Medical Biochemistry, Institute of Pharmaceutical Sciences, University of Antwerp, Belgium c Department of Psychiatry, Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Korea d Department of Anatomy, Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Korea b

Received 28 September 2006; received in revised form 6 December 2006; accepted 8 December 2006 Available online 30 January 2007

Abstract The upregulation of the initiating step of the kynurenine pathway was demonstrated in postmortem anterior cingulated cortex from individuals with schizophrenia and bipolar disorder. However, the tryptophan and kynurenine metabolism in bipolar mania patients especially in drug naïve state has not been clearly explored. This study explored the plasma tryptophan and its competing amino acids, kynurenine, kynurenic acid and 3-hydroxyanthranillic acid and their association with psychopathological scores in 39 drug naïve and drug-free bipolar manic patients in comparison with 80 healthy controls. When age and gender were controlled in multivariate analysis, bipolar manic patients have significantly lower tryptophan index than normal controls (f = 9.779, p = 0.004). The mean plasma tryptophan concentration and mean tryptophan index were reduced and mean tryptophan breakdown index was increased significantly after a 6-week treatment. The reduction in plasma tryptophan and reduction in tryptophan index showed significant negative correlation with reduction in YMRS score (r = −0.577, p = 0.019 and r = − 0.520, p = 0.039 respectively). The reduction in YMRS also showed positive correlation with both plasma tryptophan concentration and tryptophan index both at the time of admission (r = 0.464, p = 0.019 and r = 0.4, p = 0.047 respectively) and discharged (r = 0.529, p = 0.035 and r = 0.607, p = 0.013 respectively). The reduction in BPRS score also showed positive correlation with tryptophan index at the time of discharge (r = 0.406, p = 0.044). These findings indicated the involvement of bi-directional tryptophan metabolism and kynurenine pathway in pathophysiology and response to medication in bipolar mania. © 2006 Elsevier B.V. All rights reserved. Keywords: Bipolar mania; Tryptophan; Kynurenine

1. Introduction Bipolar disability Moreover, favourable

disorder is one of the leading causes of worldwide (Murray and Lopez, 1996). bipolar subjects on average showed less prognosis than those with major depression

⁎ Corresponding author. Department of Psychiatry, Korea University Mediccal Center Ansan Hospital, 425-020, Ansan, South Korea. E-mail address: [email protected] (Y.-K. Kim). 0165-0327/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2006.12.008

(Angst, 1986; Coryell et al., 1989; Cusin et al., 2000; Kessing, 1998; Kessing et al., 1998). In addition, the pathophysiology of bipolar disorder is less clear than other major psychiatric disorders. Current pathophysiologic hypotheses are categorized into three general categories 1) electrical signaling (especially presynaptic), 2) parasynaptic neurotransmitter–receptor signaling systems (first messenger), and 3) post-receptor neurochemical signaling systems (second and third messenger) (Askland and Parsons, 2006). In their biaxial

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hypothesis, they proposed that while all identified cellular signaling components may manifest detectable abnormalities, those in the second and third messenger systems are likely secondary to primary alterations in neuroelectrical and/or first messenger system (Askland and Parsons, 2006). Studies have been carried out on biogenic monoamines and amino acid systems (glutamate and GABA) but results are inconsistent (Anguelova et al., 2003a, b; Mahmood and Silverstone, 2001; Sanacora et al., 2003; Xie and Hagan, 1998). Also in genetic studies on tryptophan hydroxylase (TPH) gene and serotonin transporter gene 5-HTTLPR, the association between the polymorphism of those genes and bipolar disorders was still controversial (Bellivier et al., 1998; Collier et al., 1996; Cusin et al., 2001; Serretti et al., 2002). Recently, the NMDA receptor involvement in manic relapse of patients with bipolar 1 disorder was proposed by a study group (Hoekstra et al., 2006) and the upregulation of the initiating step of the kynurenine pathway was demonstrated in postmortem anterior cingulated cortex from individuals with schizophrenia and bipolar (Miller et al., 2006). When tryptophan is catabolised into kynurenine through IDO or tryptophan 2,3-dioxygenase (TDO), there is further catabolic pathway, the kynurenine pathway (Fig. 1), in which the metabolites contribute to the neuroprotective–neurodegenerative changes in the brain.

Kynurenine is further catabolised into 3-hydroxy kynurenine (3OHK), 3-hydroxyanthranallic acid (3HAA) and the NMDA receptor agonist quinolinic acid (Bender and McCreanor, 1985; Chiarugi et al., 2001). The quinolinic acid causes excitotoxic neurodegenerative changes (Schwarcz et al., 1983). However, kynurenine can also be catabolised into kynurenic acid which is NMDA receptor antagonist (Perkins and Stone, 1982) and is protective against the excitotoxic action of quinolinic acid (Kim and Choi, 1987; Stone and Darlington, 2002). In the brain, tryptophan catabolism occurs in the astrocytes and microglia (Grant and Kapoor, 1998; Grant et al., 2000; Heyes et al., 1996) though 60% of brain kynurenine was contributed from the periphery (Gal and Sherman, 1980). The role of NMDA receptor involvement related to cytokine–serotonin systems interaction through indoleamine 2,3-dioxygenase (IDO) enzyme that catabolises tryptophan into kynurenine was proposed to be involved in the pathophysiology of chronic treatment resistant major depression (Myint and Kim, 2003). The ratio between kynurenic acid and kynurenine which indicated how much portion of kynurenine goes to NMDA receptor antagonist metabolic pathway was showed to be lower in patients with major depression (Myint et al., 2007). Such impaired neuroprotection may also be involved in the pathophysiology of bipolar disorder which is also one of the mood disorders in which NMDA receptor involvement and manic relapse has been proposed. This study explored the alteration in tryptophan and kynurenine pathway metabolites in relation to psychopathology in patients with bipolar mania. 2. Methods 2.1. Subjects

Fig. 1. Kynurenine pathway. Above figure explains briefly on tryptophan catabolic pathway. It demonstrates that after tryptophan is catabolised into kynurenine, it is further catabolised into quinolinic acid and kynurenic acid. 5-HT = 5-hydroxy tryptamine (serotonin), IDO = indoleamine 2,3 dioxygenase, NAD = nicotinamide adenine dinucleotide.

The subjects were bipolar disorder manic patients admitted to the closed wards of Ansan Hospital of Korea University, during June 2003 to Feb 2005. The patients met the Diagnostic and Statistical Manual (DSM-IV) criteria for bipolar disorder (APA, 1994) and interviewed by Structured Clinical Interview for DSM-IV (First et al., 1998). All patients had manic or active symptoms at the time of study enrollment. All patients were either medication-naïve (first-onset) or medication-free for at least 4 months. Thirty of 39 bipolar manic disorder patients were recruited and 30 completed the six-week study. The high rate of drop-outs in our study was caused by the study protocol which only included patients who were still in the hospital on the 6 weeks of study. The reasons for the failure of follow-up included the change to out-patient

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department treatment before the termination of the study (n = 7) and the switch to other drugs due to adverse effect or unresponsiveness (n = 2). Among 30 bipolar disorder patients, 18 patients were medicated with valproate sodium (mean, 988 mg/day; range, 750–1500 mg/day), 6 patients with lithium (mean, 900 mg/day; range, 600–1050 mg/day), and 6 patients with both lithium (mean, 791 mg/day; range, 500–1000) and valproate sodium (mean, 939 mg/day; range, 600–1200). Twenty-two of the 30 bipolar disorder patients also took an antipsychotic medication (14 patients with risperidone, 6 with quetiapine, 2 with olanzapine) for controlling the psychotic symptoms. Patients with a history of any concomitant illness, such as substance or alcohol abuse, infections or a known autoimmune disease were excluded. All the patients and normal controls recruited to the study had a normal blood and urine profile: SGOT, SGPT, haemoglobin, haematocrit, serum electrolytes, blood urea, and creatinine. Patients were given a standard set of tests by the Venereal Disease Research Laboratory (VDRL) and had normal electrocardiogram (EKG) and electroencephalogram (EEG). The laboratory tests were rechecked after 6 weeks and were not significantly different compare to those at the admission. The corresponding 80 normal controls were randomly selected healthy individuals who visited the University hospitals for regular health screenings during the same period. The healthy persons who had neither self-reported personal or familial psychiatric history nor medication history and had normal laboratory findings in blood chemistry, renal, thyroid and liver function, VDRL tests, chest X-ray, ECG, and EEG were included in this study. The study protocol was approved by the Ethics Committee of Korea University, and written informed consent was obtained from each patient and controls. 2.2. Psychopathological evaluation The psychopathological status of the patients was assessed by a trained physician using the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962) and the Young Mania Rating Scale (YMRS) (Young et al., 1978). Each patient's symptoms were assessed on admission and 6 weeks later by the same physician. In the acute state, the patients’ BPRS and YMRS total scores were 21.4 ± 8.1 and 34.5 ± 9.7 and after 6 weeks of treatment, the BPRS and YMRS scores were 4.7 ± 4.9 and 9.3 ± 9.7, respectively. According to the factor analysis as described by Gonzalez-Pinto et al. (2003), the YMRS was further categorized into 3 dimensions: ‘activation’ (items 2 [increased motor

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activation, energy], 6 [accelerated speech] and 7 [altered thinking and speech]), ‘hedonism’ (items 1 [euphoria], 3 [sexual interest], 4 [sleep] and 10 [appearance]), and ‘dysphoria’ (items 5 [irritability], 9 [aggressive behaviour], and 11 [lack of insight]). The detailed characteristics of the patients were shown in Table 1. 2.3. Biochemical analysis Fasting venous blood (10 ml) was withdrawn with a lithium heparin vacuum tube between 8:00–9:00 A.M. Plasma was separated immediately and stored at − 70 °C. For the bipolar manic patients, blood was sampled again at 6 weeks later. The high performance liquid chromatography was used to measure plasma tryptophan, competing amino acids (tyrosine, valine, phenylalanine, leucine, isoleucine) according to the method of Cooper et al. (1988), to measure plasma kynurenine, kynurenic acid and 3-hydroxyanthranilic acid (3HAA) (the metabolite from degenerative pathway, one step before quinolinic acid) according to the method of Herve et al. (1996). The tryptophan and competing amino acids were analysed in the plasma samples using reversed phase high performance liquid chromatography (HPLC) with Chromolith Performance PR-18e, 4.7 × 100 mm column (Merck, Darmstadt, Germany). Amino acids were detected fluorimetrically at an excitation wavelength

Table 1 Demographic data of the study subjects Bipolar mania Normal control (N = 39) (N = 80) Sex (male/female) Age (years) BMI (kg/m2) Age of onset(years) Duration of total illness (months) Duration of current episode (months) Numbers of previous admission (n) Family history (yes/no) Medication status on admission: Medication-naïve Medication-free Psychopathology scores: BPRS at admission BPRS at 6 weeks YMRS at admission YMRS at 6 weeks

15/24 37.6 ± 11.6 22.5 ± 3.5 30.7 ± 12.0 106.0 ± 173.5 1.5 ± 1.0

40/40 39.06 ± 8.75 21.93 ± 3.2

2.0 ± 1.8 9/30 22 17 21.4 ± 8.1 4.7 ± 4.9 34.5 ± 9.7 9.3 ± 9.7

No significant difference was detected between patients and controls. The psychopathological scores were based on the Brief Psychiatric Rating Scale (BPRS) and the Young Mania Rating Scale (YMRS).

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of 340 nm and an emission wavelength of 440 nm after derivatisation with o-phtalicdialdehyde and on-line microdialysis by an ASTED autosampler (Gilson, Viliers le Bel, France). The mobile phase was set in gradient by mixing Solvent A (57.2 g Na2HPO4·12H2O and 160 ml of Acetonitrile in Milli Q water which is made to total 2 l, pH 6.5) and Solvent B (420 water/280 ACN/320 MeOH). The different amino acid standards (tyrosine, valine, tryptophan, phenylalanine, isoleusine and leusine) are prepared as stock by weighing off 100 mg of each compound and dissolving in Milli Q water in 100 ml measuring flasks. For Working Standard solution, 5 ml of those amino acid stock standards are diluted with Milli Q water. Norvaline 0.5 mg/ml was used as internal standard. Borate buffer (pH 9.5) was used for dialysis of the sample. The kynurenine, kynurenic acid and 3HAA were analysed in the deproteinised plasma samples using reversed phase high performance liquid chromatography (HPLC) with Chromolith performance PR-18e, 4.7 × 100 mm column (Merck, Darmstadt, Germany). Kynurenine was detected spectrophotometrically at 365 nm, kynurenic acid was detected fluorimetrically at an excitation wavelength of 334 nm and an emission wavelength of 388 nm and 3HAA was detected fluorimetrically at an excitation wavelength of 316 nm and an emission wavelength of 420 nm. The mobile phase was prepared with 250 mM zinc-acetate in distilled water (27.4 g in 500 ml) and pH was brought to 5.8 with acetic acid and made up to a volume of 455 ml with water. A total of 45 ml acetonitrile was added into this mixture. The intra- and inter-assay coefficient of variations ranged from 5% to 7% for all the metabolites. To avoid the effect of inter-assay variation, the samples from both patients and normal controls were mixed alternately in each set of analyses. To avoid the operator bias the samples’ order was arranged by the investigator and the laboratory technician was blind to the information of the sample whether depressed or normal. For each 20 samples 3 standards and one quality control sample (pooled drug-free EDTA plasma) were used as quality control.

The tryptophan index that indicated the tryptophan availability in the brain was taken as the ratio between plasma tryptophan and the competing amino acids (CAA).

2.4. Calculations

3. Results

The tyrosine index that indicated the tyrosine availability in the brain was calculated as the ratio between plasma tyrosine and sum of other amino acids in plasma (typtophan, valine, phenylalanine, leucine, isoleucine).

3.1. General characteristics

Tyrosine index ¼

100  plasma tyrosine ðlmol=lÞ Sum of other amino acids ðlmol=lÞ

Tryptophan index ¼

100  plasma tryptophanðlmol=lÞ Sum of plasma CAAðlmol=lÞ

The plasma CAAvalue was the sum of plasma tyrosine, valine, phenylalanine, leucine, isoleucine values. The tryptophan breakdown index, that indirectly indicated the sum of the activities of TDO and IDO, was calculated as shown; Tryptophan breakdown index plasma kynurenineðlmol=lÞ ¼ : plasma tryptophanðlmol=lÞ The ratio between plasma kynurenic acid and plasma kynurenine, from which kynurenic acid and quinolinic acid are formed, enabled the neuroprotective ratio to be determined; Neuroprotective ratio 100  plasma kynurenic acidðnmol=lÞ : ¼ plasma kynurenineðnmol=lÞ 2.5. Data analysis The data was checked using K-S D test to confirm whether they are under normal distribution. The data was analysed in by controlling age and gender in multivariate and univariate analyses. The comparison of the mean values of the parameters, that showed normal distributions between depressed patients and controls, were analysed using Student's ‘t’ test. The comparison of the parameters with normal distribution in the patients on admission and at the time of discharge, were analysed using paired ‘t’ test. Multivariate analysis was used to determine the differences between depressed patients and controls when age and gender were controlled. The SPSS 11.05 version was used for the statistical analyses and the ‘p’ value of 0.05 and below was considered significant.

Table 1 shows the general characteristics of the patients and the control subjects. There was no significant difference in mean age, mean body mass index on admission and gender ratio between patients and normal controls.

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3.2. Biochemical data between patients and control The statistics on the plasma tryptophan and competing amino acids, kynurenine, kynurenic acid, 3-hydroxyanthranillic acid, tryptophan index, tryptophan breakdown index and neuroprotective ratio were shown in Table 2. The mean plasma tryptophan concentration, mean kynurenic acid concentration and mean tryptophan index in the bipolar manic patients were significantly lower than those of normal controls whereas mean plasma competing amino acids concentration was higher in the patients (Table 2). When age and gender were controlled in multivariate analysis, either being a bipolar manic patient or normal control has significant influence only on mean tryptophan index ( f = 9.779, p = 0.004) (Fig. 2). 3.3. Biochemical data on admission versus at the time of discharge The statistics on the plasma tryptophan and competing amino acids, kynurenine, kynurenic acid, 3-hydroxyanthranillic acid, tryptophan index, tryptophan breakdown index and neuroprotective ratio were shown in Table 3. The mean plasma tryptophan concentration and mean tryptophan index were reduced and mean tryptophan breakdown index was increased significantly after a 6-week treatment.

Table 2 Biochemical data on admission of bipolar patients and normal controls Parameters

Plasma tyrosine (μmol/l) (mean ± SD) Plasma tryptophan (μmol/l) (mean ± SD) Plasmacompeting amino acids (μmol/l) (mean ± SD) Plasmakynurenine (μmol/l) (mean ± SD) Plasmakynurenic acid (nmol/l) (mean ± SD) Plasma 3-hydroxyanthranillic acid (nmol/l) (mean ± SD) Tyrosine index (mean ± SD) Tryptophan index (mean ± SD) Tryptophan breakdown index (mean ± SD) Neuroprotective ratio (mean ± SD)

Bipolar manic

Controls

N = 39

N = 80

74.44 ± 25.37

68.15 ± 14.68

61.03 ± 15.88*

70.55 ± 12.69

775.33 ± 183.65*

713.65 ± 139.43

1.72 ± 0.65

1.88 ± 0.46

27.67 ± 11.66*

34.58 ± 13.03

24.41 ± 16.54

23.26 ± 8.77

9.71 ± 2.28 8.15 ± 2.25* 0.028 ± 0.011

9.61 ± 1.4 10.02 ± 1.47 0.027 ± 0.007

17.18 ± 6.97

18.69 ± 5.75

*Indicated the significant difference from controls at p b 0.01 by Student's ‘t’ test.

Fig. 2. Comparison of tryptophan index between bipolar mania and controls.

3.4. Correlations between biochemical and clinical parameters The above biochemical data in patients on admission showed no correlation with BPRS and YMRS scores of the patients on admission. Similar finding was observed between biochemical parameters at the time of discharge and clinical parameters at the time of discharge. Only with the YMRS dimensions, the ‘activation’ score on admission and ‘hedonism’ score on admission showed significant negative correlations with plasma 3HAA (r = − 0.356, p = 0.033 and r = −0.344, p = 0.04 respectively). However, significant negative correlation was found between plasma tryptophan index on admission and both BPRS score (r = − 0.424, p = 0.01) and YMRS score (r = − 0.415, p = 0.05) at the time of discharge. Table 3 Biochemical parameters of patients on admission and at discharge Parameters

Bipolar manic (admission)

Bipolar manic (discharge)

N = 30

N = 30

Plasma tyrosine (μmol/l) 75.33 ± 26.99 74.84 ± 22.98 (mean ± SD) Plasma tryptophan (μmol/l) 62.51 ± 14.85 49.97 ± 17.68* (mean ± SD) Plasmacompeting amino acids 787.69 ± 183.65 798.43 ± 166.31 (μmol/l) (mean ± SD) Plasmakynurenine (μmol/l) 1.81 ± 0.69 1.70 ± 0.73 (mean ± SD) Plasmakynurenic acid (nmol/l) 31.76 ± 12.47 31.25 ± 15.21 (mean ± SD) Plasma 3-hydroxyanthranillic acid 25.57 ± 20.07 26.89 ± 14.93 (nmol/l) (mean ± SD) Tyrosine index (mean ± SD) 9.66 ± 2.49 9.11 ± 1.76 Tryptophan index (mean ± SD) 8.19 ± 2.05 6.35 ± 1.99* Tryptophan breakdown index 0.029 ± 0.011 0.035 ± 0.013* (mean ± SD) *Indicates the significant difference from admission at p b 0.01 by Student's ‘t’ test.

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The reduction in plasma tryptophan and reduction in tryptophan index showed significant negative correlation with reduction in YMRS score (r = − 0.577, p = 0.019 and r = − 0.520, p = 0.039 respectively). The reduction in YMRS also showed positive correlation with both plasma tryptophan concentration and tryptophan index both at the time of admission (r = 0.464, p = 0.019 and r = 0.4, p = 0.047 respectively) and discharged (r = 0.529, p = 0.035 and r = 0.607, p = 0.013 respectively). The reduction in BPRS score also showed positive correlation with tryptophan index at the time of discharge (r = 0.406, p = 0.044). 4. Discussions The patients recovered well after the six-week treatment at the hospital. On admission, compared to their normal controls, manic patients showed lower plasma tryptophan, tryptophan index and kynurenic acid concentration. However, when age and gender were controlled in multivariate analysis, only tryptophan index showed significant difference from normal controls. Moreover, the plasma CAA concentration is higher in the patients. These above findings are different from our previous findings regarding tryptophan and kynurenine pathway metabolites in major depression where significant differences were observed not only in tryptophan index but also in tryptophan breakdown, plasma kynurenic acid and neuroprotective ratio but no difference in CAA (Myint et al., 2007). This may be due to the fact that the change in kynurenine metabolism which indicates the neuroprotecion–neurodegeneration balance or NMDA receptor agonist–antagonist balance in the brain may not play an important role in pathophysiology of bipolar mania. Unfortunately, we could not measure the quinolinic acid, the NMDA agonist and it is difficult to conclude that there is no role of NMDA receptor activity through this metabolism in pathophysiology of bipolar mania. However, the plasma 3HAA, which the metabolite in the kynurenine metabolism a step before quinolinic acid showed negative correlation with YMRS dimension ‘activation’ and ‘hedonism’ scores at the time of admission. This may indicate that the lesser NMDA receptor activation might related to severer active symptoms. In addition, Miller et al. (2006) demonstrated the increased TDO2 activity and kynurenine level in anterior cingulated area of postmortem brain tissues of bipolar patients. Lack of obvious change in peripheral metabolism might be due to the fact that the extent of change in kynurenine metabolic pathway in bipolar patients may not be great enough to be reflected by the detectable peripheral change.

In our study, we found that the plasma tryptophan and tryptophan index were decreased after the treatment and the tryptophan breakdown was increased. Since there is no significant increase in CAA but a significant decrease in plasma tryptophan itself and significant increase in tryptophan breakdown, the reduction in tryptophan index might be due to increased tryptophan breakdown. This is in agreement with the finding of Miller et al. (2006). In their study, since the materials were from postmortem brain, their findings might be influenced by the medication given to those individuals. It was also reported that in the bipolar patients with manic relapse and treated with different psychotropics showed lower tryptophan, tryptophan ratio (100 × tryptophan / large amino acids) and higher glycine compared to lithium alone treated euthymic controls (Hoekstra et al., 2006). They proposed that the decreased in tryptophan and tryptophan might be due to the use of anticonvulsant like valproate. This might also be the reason in our study since major portion of the patients were treated with valporate alone or mixture of lithium and valproate or also with other psychotropics. It was reported that in the brain of seizure-prone Balb/c mice, valproate treatment increased serotonin and its metabolites and enhanced the activity of tryptophan hydroxylase (TPH) enzyme that involves in synthesis of serotonin from tryptophan (Vriend and Alexiuk, 1996). Moreover, the increased mRNA expression of TPH2 was greater in the postmortem dorsolateral prefrontal cortex tissue of bipolar patients than in that of unaffected controls (De Luca et al., 2005). Though they did not discuss the effect of medication, most of the patients might get medication before death and there might be influence of medication in postmortem tissue. This TPH activity after medication may also be another reason why we observed lower plasma tryptophan and tryptophan index. However, since we could not measure serum serotonin concentration, it is difficult to conclude that there was increased synthesis of serotonin. In our finding, however, though there was increased tryptophan breakdown, there was no increased in absolute value of kynurenine nor kynurenic acid nor 3HAA nor CAA and only decreased in absolute tryptophan value and tryptophan index. This indicates indirectly that the lower tryptophan and tryptophan index after treatment was not only due to higher breakdown of tryptophan, and tryptophan metabolism went to both directions towards synthesis of serotonin and breakdown into kynurenine pathway. Our results also demonstrated that the clinical improvement which is indicated by reduction in YMRS and BPRS scores was positively related to plasma trytophan

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and tryptophan index on admission and at the time of discharge and negatively related to reduction in tryptophan index. This finding indicated that though the medication brought the patients to clinical improvement and biochemical reduction in plasma tryptophan and tryptophan index, this biochemical change might not be a favourable situation for the clinical outcome. This biochemical change may be a point to consider regarding the rapid cycling though both valproate and lithium were reported to be effective in long-term management of rapid-cycling bipolar disorder with similar relapse rates about 50% (Calabrese et al., 2005). In conclusion, this study has some limitations such as patients were treated with different medications and lack of data on serum serotonin and plasma quinolinic acid. Since lithium and valproate are shown to have neuroprotective capacity against NMDA receptor mediated apoptosis (Chuang, 2005), a study on the effect of medication with lithium and valproate on detailed kynurenine pathway metabolite changes in bipolar manic patients is recommended. A follow-up may also be necessary to find out the effect of change in tryptophan and cyclicality. Nevertheless, the results indicated the involvement of bi-directional tryptophan metabolism and kynurenine pathway in pathophysiology and response to medication in bipolar mania. Acknowledgement This study was mainly funded by Institute of Brain and Behaviour, University of Maastricht and partly supported by Institute of Pharmaceutical Sciences, University of Antwerp and Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (HMP-00-GN-01-0002). References Angst, J., 1986. The course of affective disorders. Psychopathology 19 (Suppl 2), 47–52. Anguelova, M., Benkelfat, C., Turecki, G., 2003a. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders. Mol. Psychiatry 8, 574–591. Anguelova, M., Benkelfat, C., Turecki, G., 2003b. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior. Mol. Psychiatry 8, 646–653. APA, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Press, Washington, DC. Askland, K., Parsons, M., 2006. Toward a biaxial model of “bipolar” affective disorders: Spectrum phenotypes as the products of neuroelectrical and neurochemical alterations. J. Affect. Disord. 94, 15–33.

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