PSY-07184; No of Pages 5

Psychiatry Research xxx (2012) xxxxxx

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Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Taurine and glutathione levels in plasma before and after ECT treatment
Martin Samuelsson a, d,, George Gerdin a, d, Karin llinger b, e, Magnus Vrethem c, f
a

Psychiatry, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkpings University, Linkping, Sweden Experimental Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkpings University, Linkping, Sweden c Neurology and Clinical Neurophysiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkpings University, Linkping, Sweden d Department of Psychiatry, County Council of stergtland, Linkping, Sweden e Department of Clinical Pathology and Clinical Genetics, County Council of stergtland, Linkping, Sweden f Department of Neurology and Clinical Neurophysiology, County Council of stergtland, Linkping, Sweden
b

a r t i c l e

i n f o

a b s t r a c t
Objectives: Taurine has been shown to be elevated in plasma and lymphocytes of depressed patients, but the level normalises after successful drug therapy. During depression, levels of glutathione (GSH) are decreased in the plasma and blood. This study was performed to examine taurine and GSH levels in depressed patients before and after electroconvulsive therapy (ECT). Methods: Fasting blood samples were collected from 23 patients before the rst and after the third ECT treatment. The severity of depression was estimated with the Montgomerysberg Depression Rating Scale (MADRS). We analysed GSH in blood and the levels of taurine and total GSH in plasma. Results: After three ECTs, a decrease in MADRS scores was found for the entire group (P = 0.0001). Simultaneously, the decrease in the plasma taurine levels was signicant for the responders (n = 7; P = 0.03) but not for the non-responders (n = 16; P = 0.09). We observed no differences in blood or plasma GSH levels after three ECT treatments when compared to values before the therapy. Conclusions: Plasma taurine levels decrease signicantly after three ECT treatments in patients who respond to treatment. GSH levels were not affected by ECT treatment. The results indicate that taurine may play a role in the pathophysiology of depression. 2012 Elsevier Ltd. All rights reserved.

Article history: Received 8 January 2012 Accepted 13 February 2012 Available online xxxx Keywords: ECT Taurine Glutathione Depression

1. Introduction Depression is a severe, life-threatening illness exposing the patient to direct risks, such as suicide and lower quality of life, and indirect risks, which include negative interactions with other concurrent diseases (Sadock et al., 2009). The monoamine hypothesis, which was formulated in the 1960s, stipulates that monoamines play an important role in the pathophysiology of depression (Schildkraut, 1965). Strong links between monoamine disturbances and depression have been established, but other factors are also important. These ndings are presumably related to the monoamine modulation of neurocircuits, which have a primary modulating effect on mood (Nestler and Carlezon, 2006; Ruh et al., 2007). Although the dominant theory of depression involves the lack of monoamine neurotransmitters, amino acid neurotransmitters are abundant in the brain (Bettler et al., 2004). Glutamate and gamma-aminobutyric acid (GABA) are the primary neurotransmitters in brain signalling and are implicated as possible therapeutic targets
The study was supported by grants from the stergtland County Council, Sweden. Corresponding author at: Division of Psychiatry, University Hospital, S-58185 Linkping, Sweden. Tel.: + 46 101030000; fax: + 46 101033393. E-mail address: martin.samuelsson@lio.se (M. Samuelsson). 0165-1781/$ see front matter 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.psychres.2012.02.016

in depression (Kendell et al., 2005). Moreover, aberrant levels of inammatory markers (Yanik et al., 2004) and pro-inammatory cytokines are associated with different psychiatric symptoms (Konsman et al., 2002; Kuloglu et al., 2002; Dinan, 2008). Plasma markers of oxidative stress are increased in subjects with major depression (Yanik et al., 2004), and the successful treatment of some psychiatric disorders is associated with a decrease in oxidants. Such ndings suggest that elevated oxidant levels may have a direct or indirect pathophysiological role in psychiatric disorders (Savas et al., 2006). Like glutathione (GSH), taurine is biosynthesised from cysteine. Both substances have antioxidant properties, and the literature emphasises their protective roles in the central nervous system (CNS) (Dringen, 2000; Atmaca, 2004; Albrecht and Wegrzynowicz, 2005). Taurine is one of the most abundant free amino acids in the body; it has documented functions as a neuroprotector and neuromodulator and has been found to be important for the development and regeneration of the CNS. In addition, the effects of glutamate and GABA are partially modulated by taurine (Wu et al., 2005). Elevated taurine plasma levels have been observed in depressed individuals when compared with healthy controls (Altamura et al., 1995; Mitani et al., 2006). Another study showed no difference between the serum taurine levels of healthy controls and patients with treatment-resistant depression (Maes et al., 1998). However, in the same study, the

Please cite this article as: Samuelsson, M., et al., Taurine and glutathione levels in plasma before and after ECT treatment, Psychiatry Res. (2012), doi:10.1016/j.psychres.2012.02.016

M. Samuelsson et al. / Psychiatry Research xxx (2012) xxxxxx Table 1 Demographic and clinical characteristics of patients before the rst and after the third ECT therapy. Number of Sex Agea patients (M/F) (years) MADRS scoreb before ECT1 after ECT3 19.5 9.6 8.1 4.2 24.5 6.7 pc 0.0001 0.02 0.002

serum taurine levels were decreased following depression remission. In patients with depression, elevated taurine levels in lymphocytes were normalised following treatment with the antidepressant mirtazapine (Lima et al., 2003). Because of its thiol group, GSH is a major intracellular redox regulator in the body and is important for protecting the brain from oxidative damage (Wang et al., 2004) and harmful xenobiotics (Atmaca, 2004). GSH has also been suggested to be involved in neurotransmission and neuromodulation (Dringen, 2000; Ristoff and Larsson, 2007). In addition, inborn errors that cause GSH deciency or depletion are associated with CNS damage (Ristoff and Larsson, 2007). Oxidative stress with disturbed GSH metabolism is described in schizophrenia, bipolar disorder and depression. N-Acetyl cysteine, which is an orally bioavailable precursor of GSH, has been shown to be an effective augmentation strategy for the treatment of depressive symptoms in bipolar disorder (Berk et al., 2008). It could be speculated that also taurine levels could be modied by N-acetyl cysteine addition. Electroconvulsive therapy (ECT) is an effective treatment for depression (Pandya et al., 2007). The mechanism by which ECT conveys its antidepressant effect in humans remains unclear, but some aspects of the mechanism have been elucidated, such as the modulation of monoamines, neuropeptides, hormones, neurotrophic factors and cytokines (Ishihara and Sasa, 1999; Wahlund and von Rosen, 2003; Dinan, 2008). However, alterations in taurine and GSH levels are less well studied. In a previous report, Palmio et al. (2005) found no immediate effect on plasma taurine levels during the rst 24 h after a single administration of ECT. Because several ECT treatments are required to induce an anti-depressive effect, we designed this study to examine the effect that followed a series of administrations. We aimed to determine the plasma taurine and total GSH (reduced and oxidised) levels and the blood levels of reduced GSH before and after a series of three ECT treatments in depressed patients.
2. Methods 2.1. Patients This study was conducted at the Department of Clinical and Experimental Medicine, Division of Psychiatry, Faculty of Health Sciences, Linkoping University, Sweden. Patients prescribed ECT by their psychiatrists were asked if they were willing to participate in the study. The study was approved by the Ethics Committee of Linkping University, ethical permission M187-88. All of the patients received verbal and written information and gave their written informed consent. The inclusion criterion was a diagnosis of depression, while the exclusion criteria were the following: younger than 18 years of age, involuntarily committed, subjected to ECT within 3 months prior to this study or inability to understand the information. The diagnoses (American Psychiatric Association, 1994) were established by a senior psychiatrist using the complete clinical presentation and a Mini-International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998) or a clinical diagnosis by two senior psychiatrists using the Montgomerysberg Depression Rating Scale (MADRS) scale (Montgomery and sberg, 1979). To estimate the severity of depression during the course of the ECT treatments, the psychiatrist performed a MADRS scoring before the rst and after the third ECT administration. In total, 30 patients were initially included in the study; three of them refused to participate, venipuncture failed in three patients and one patient received acute ECT before venipuncture. Thus, 23 patients were eligible for the study. Of those 23, 19 patients had been adequately treated with oral antidepressants but had not responded, and four were treatment nave. The patient characteristics and basic data are shown in Table 1. 2.2. ECT ECT was performed in the morning after at least 6 h of fasting. The patients were given atropine before anaesthesia was induced with thiopental and muscle relaxation with succinylcholine. The patients were ventilated with 100% oxygen. Right unilateral ECT treatments with ultrabrief or brief pulse waves were performed with a Mecta spECTrum 5000Q device (MECTA Corp, Tualatin, OR, USA), and the dosage was adjusted by age, sex and outcome. The seizure was monitored by electroencephalography and a stopwatch. 2.3. Analysis of taurine and GSH After overnight fasting, blood samples were collected in heparinised tubes before the rst and after the third ECT. After centrifugation (1438 g, 10 min), plasma was

All Responders Nonresponders

a b

23 7 16

12/11 44 37.1 7.8 (2070) 4/3 50 37.1 9.8 (2065) 8/8 42 37.1 7.1 (2270)

Mean age, range within brackets. Montgomery-Asberg Depression Rating Scale (MADRS) before the rst ECT1 and after third ECT3. c differences in MADRS was evaluated using Wilcoxon matched pair signed rank sum, signicant results are marked in bold letter.

collected and stored at 70 C until analysis. To determine the reduced GSH level, whole blood was deproteinised by the addition of 4 volumes of ice-cold 5% (wt/vol) metaphosphoric acid. After centrifugation (2000 g, 10 min), the supernatant was collected and stored at 20 C until the GSH analysis. Taurine was analysed using high-performance liquid chromatography (HPLC), by a Biochrom 30 Amino Acid Analyzer and spectrophotometrical detection. The EZChrom Elite program was used for the nal determination of concentrations (Jeppsson and Karlsson, 1972; Ekberg et al., 1974; Brattstrm et al., 1988). The total amount of GSH (reduced and oxidised) in plasma was analysed spectrophotometrically by the reduction of 5,5-dithiobis-2-nitrobenzoic acid (Akerboom and Sies, 1981), and GSH was determined in whole blood using HPLC and electrochemical detection (Honegger et al., 1989), as previously described (Samuelsson et al., 2011). 2.4. Statistics The statistical analysis was performed using the Statistica 8 software program (StatSoft, Tulsa, OK, USA, 2007). For the laboratory data, Student's t-test for dependent samples was used when comparing the data before and after the ECT, and Student's ttest for independent variables (by group) was used to compare the groups before the rst ECT. Pearson's correlation analysis was used for the correlation analysis. For the MADRS values, the Wilcoxon matched-pair signed-rank sum test was used to compare the data before and after three ECTs, and the MannWhitney U test was used to compare the groups before the rst ECT. A P-value b 0.05 was considered to be signicant. Each patient served as his or her own control.

3. Results The mean MADRS score for all patients was 37.1 7.8 before the therapy and 19.5 9.6 after three ECT administrations (P = 0.0001). Using the denitions for response (MADRS 15) and remission (MADRS 10) that were proposed by Keller (2003), we identied four patients in remission and three responders after three ECTs. The average decrease in the MADRS score were 28.4 points for the responders and 12.6 points for the 16 non-responders. The decreases in MADRS scores were signicant in both groups (Table 1 and Fig. 1). When stratifying the MADRS scores for the patients with or without antidepressant medication before the ECT treatment, the patients without medication (n = 4) had higher MADRS scores (44.5 5.3) than the patients with medication (n = 19) (35.4 7.4; P = 0.04). The plasma taurine level decreased from 59.5 16.0 mol l 1 before the therapy to 53.3 11.8 mol l 1 after three ECT administrations (P = 0.01) in the overall population (Table 2). When the data were subgrouped according to responders and non-responders, the plasma taurine was signicantly reduced in the responders; all but one of the responders showed a clear taurine decrease (Fig. 2(a)). Although the majority of the non-responders (10 out of 16) showed a decrease in taurine, the difference was not signicant (Fig. 2(b)). No difference in plasma taurine levels was found when comparing responders to non-responders to ECT in the groups before the rst ECT treatment. Before therapy, the blood GSH level was 0.7 0.3 mmol l 1, and the total plasma GSH level was 240 46 nmol l 1; and no signicant

Please cite this article as: Samuelsson, M., et al., Taurine and glutathione levels in plasma before and after ECT treatment, Psychiatry Res. (2012), doi:10.1016/j.psychres.2012.02.016

M. Samuelsson et al. / Psychiatry Research xxx (2012) xxxxxx

A
45

80 70

Responders

Taurine (moles/L)

60 50 40 30 20 10 0

MADRS

30

15

Nonresponder Responder

0 Before ECT After ECT

Before ECT

After ECT

B
Taurine (moles/L)

Fig. 1. MADRS scores that were determined before the rst ECT administration and after the third ECT administration. The patients were grouped depending on the treatment outcome into responders (MADRS score 15; n = 7) and non-responders (MADRS score >15; n = 16). The values are presented as the means SD.

120 100 80 60 40 20 0

Non-responders

differences were found after three ECT administrations. When the values were subgrouped into responders and non-responders, no signicant differences in plasma or blood GSH levels were observed in either group (Table 3). No signicant differences were found in plasma or blood GSH levels in the responders versus the non-responders before the ECT therapy was initiated. We found no statistically signicant correlation between the plasma taurine levels and the severity of depression (MADRS score before or after ECT) or the degree of remission (reduction in MADRS score). The MADRS scores did not show a correlation with either plasma or blood GSH levels. All of the correlations were tested on the entire group of patients and by subgrouping the patients into responders and non-responders or into patients with and without antidepressant medication.

Before ECT

After ECT

Fig. 2. Plasma taurine levels that were obtained before the rst and after the third ECT treatment. A. Patients who responded to the treatment, which was estimated by a reduction of the MADRS score 15 (n = 7). B. Patients who did not respond to the treatment, which was estimated by a reduction of the MADRS score >15 (n = 16).

4. Discussion The present study is, to our knowledge, the rst to analyse the effect of a series of ECT treatments on plasma taurine and GSH levels. The primary nding is an overall decrease in plasma taurine levels following a series of three administrations of ECT. When the patients were subgrouped, there was a signicant decrease in taurine for the responders but not for the non-responders. No alteration in the blood or plasma GSH levels was detected. We also showed that ECT is an effective treatment for depression. For both the responders and non-responders, the decrease in the MADRS score is consistent with or even better than previous results that were obtained following pharmacological treatment for 12 weeks (Januel et al., 2003). It is noteworthy that, with the exception of four patients, all of our patients had received previous antidepressant medication in adequate doses and for an adequate time without responding.

Several studies have shown elevations of plasma taurine levels in depressed patients (Altamura et al., 1995; Mitani et al., 2006). Our ndings corroborate previous ndings of a reduction in serum taurine during antidepressant treatment (Maes et al., 1998). It is still unclear whether taurine acts by itself or by interacting with other neurotransmitters during depression. In our study, 19 of the 23 patients had been treated with antidepressants for an adequate time and at an adequate dosage before ECT, but they had not responded to the medication. This could be a confounding factor because it has been shown that plasma taurine levels decrease in depressed patients upon antidepressant drug treatment (Maes et al., 1998). The taurine levels among the depressed
Table 3 Total glutathione in plasma and reduced glutathione in blood of patients before the rst and after the third ECT therapy. Number of patients Total GSH, plasma (nmoles/L) before ECT1 All (23) Responders (7) Non-responders (16) 240 46 236 53 242 45 after ECT3 227 40 223 53 229 37 pa 0.07 0.42 0.12

Table 2 Plasma taurine in patients before the rst and after the third ECT therapy. Number of patients Taurine (mol/L) before ECT1 All (23) Responders (7) Non-responders (16) 59.5 16.0 57.4 8.3 60.5 18.6 after ECT3 53.3 11.8 49.6 13.5 54.9 11.0 pa 0.01 0.03 0.09

GSH, blood (mmoles/L) before ECT1 All (21) Responders (7) Non-responders (14) 0.72 0.30 0.63 0.21 0.73 0.33 after ECT3 0.75 0.36 0.66 0.11 0.79 0.43 pa 0.94 0.67 0.88

a Taurine was compared using student's t test, signicant results are marked in bold letter.

a Glutathione was compared using student's t test, signicant results are marked in bold letter.

Please cite this article as: Samuelsson, M., et al., Taurine and glutathione levels in plasma before and after ECT treatment, Psychiatry Res. (2012), doi:10.1016/j.psychres.2012.02.016

M. Samuelsson et al. / Psychiatry Research xxx (2012) xxxxxx

patients that were found in this study were lower than the levels that were found in healthy volunteers in a previous study (Samuelsson et al., 2009). However, in the present study, each patient served as his/her own control and consequently decrease in taurine could be detected after ECT treatment. It is also possible that antidepressant medication masks a greater impact of ECT than the impact that was found in our study by causing a decrease in plasma taurine already before the ECT treatment. Depression is accompanied by the production of pro-inammatory cytokines and the activation of the inammatory response system (Dinan, 2008). Many antidepressants have anti-inammatory effects, either by increasing anti-inammatory cytokines or by decreasing pro-inammatory cytokines. The impact of ECT on immune regulation has not been extensively studied, and the results are currently inconclusive; both reduced and increased inammatory responses have been documented, which is illustrated by a decrease in tumour necrosis factor (TNF)- (Hestad et al., 2003) and an increase in interleukin (IL)-6 (Lehtimki et al., 2008). Taurine has anti-inammatory action, and the change in plasma taurine of the responders in this study prompts the speculation that taurine participates in the modulation of ILs in an antidepressant manner, which is consistent with the cytokine hypothesis of depression (Maes et al., 2009). The cytokine hypothesis postulates that internal or external stressors trigger depression via inammatory processes. Oxidative stress has previously been shown to occur during depression and was measured as the reduced activity of glutathione peroxidase and the reduction of blood GSH (Kodydkov et al., 2009). In blood, GSH is predominantly found in red blood cells (approximately 99%), whereas less than 1% of GSH is present in the plasma (Mills and Lang, 1996). However, the pool of plasma GSH is considered to be the pool that is the most sensitive to oxidation and is also easily available for exchange with other compartments, such as the cerebrospinal uid. A reduction in GSH measured in red blood cells was documented in depressed patients when compared with a healthy control group (Kodydkov et al., 2009). However, in our study group, we did not identify signicant alterations in blood GSH or total GSH in plasma when we compared the levels before and after ECT. In a previous study, in which we determined the blood and plasma GSH levels of healthy males, the GSH concentrations showed similar levels in our depressed patients when compared to the healthy males (Samuelsson et al., 2011). Because the majority of the patients had taken antidepressant medication in the present study, their GSH levels may have normalised before ECT was initiated. According to the MADRS scores, all of the patients maintained or increased their appetite (data not shown). Thus, the decreased plasma taurine is not caused by decreased taurine and cysteine intake due to loss of appetite. When the data were stratied, we found that the diagnosis (depression with or without melancholia) did not have an impact on the results. Neither did we observe any relationship between the plasma taurine levels and the severity of depression or the degree of remission. On group level, the drop in taurine levels correlates to lower MADRS scores, however. This observation is consistent with the results of previous studies (Altamura et al., 1995; Mitani et al., 2006). Additional factors that may affect the levels of taurine and GSH are the use of muscle relaxants or anaesthetic agents; both of these compounds may have neuroprotective functions, which possibly occurs due to their reduction of extracellular glutamate concentrations (Miao et al., 1998). A study design using a sham group would have eliminated these confounding factors, but it could not be used due to ethical considerations. In conclusion, we found that plasma taurine levels decreased during successful ECT treatment. The decrease was signicant for the responders as estimated by MADRS scores 15. This nding indicates that taurine may have a role in the pathophysiology of depression, but the clinical signicance of taurine remains to be elucidated.

Moreover, ECT was shown to reliably induce remission among depressed subjects. Acknowledgements In memory of Professor Conny Nordin, who initiated the study but died before its completion. We also thank our research team at the Division of Psychiatry and the Division of Experimental Pathology at Linkping University and the ECT unit at the University Hospital for their excellent assistance. The study was supported by grants from the stergtland County Council. References
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