Investigating the Impact of the ECT on Thiol-Disulphide Homeostasis in Depressive Disorders
Murat Ilhan Ataguna, Ozge Canbek Atayb, Ozlem Balabanb, Derya Ipekcioglub, Baris Alpuganb, Suat Yalcinb, Almila Senatc, Nesrin Karamustafalioglub, Mehmet Cem Ilnemb, Ozcan Erelc
a Department of Psychiatry, Ankara Yildirim Beyazit University Medical School
b Department of Psychiatry, Istanbul Bakirkoy Research and Treatment Hospital for Psychiatry
c Department of Medical Biochemistry, Ankara Yildirim Beyazit University Medical School
Background: Depressive disorders are characterized by oxidative stress and burden of oxidative stress may provoke cellular and biochemical challenges. Thiols are converted into non-reactive disulphides after reacting with oxygen radicals and converted back to thiols. N-terminus of the albumin can be modified by biochemical strain and modified albumin is called ischemia modified albumin (IMA). In this study, it was aimed to assess potential effects of electroconvulsive therapy (ECT) on thiol disulphide homeostasis and IMA levels in depression.
Methods: Twenty-three patients with depressive episodes (major depressive disorder n=16), and (bipolar disorder n=7) and 21 healthy controls were enrolled. Serum samples were collected at three time points: one day before ECT, one hour after the first ECT session and one hour after the last session (remission). Thiol disulphide homeostasis and IMA levels were measured.
Results: Total thiol levels were significantly (p=0.032), native thiol levels were trend level (p=0.056) depleted in patients with depression in comparison to that of the healthy control group. Disulphide levels did not differ between the groups. IMA levels were higher (p<0.001) in the patient group initially. Thiol disulphide or IMA levels did not significantly change in the depression group after the first and last ECT sessions.
Conclusion: Although previous studies have reported favorable effects of ECT on various oxidative stress markers, ECT did not influence thiol disulphide or IMA levels in the patient group. These findings provide biochemical support for the safety and efficacy of ECT at subcellular level.
KEYWORDS: Depressive disorders, thiol, disulphide, electroconvulsive therapy
Depressive disorders (DD) are extremely common mental disorders, with a lifetime prevalence of 18.4% . Although DD induce chemical and endocrine alterations [2, 3], their etiopathogenesis remains to be elucidated yet. Volumetric brain imaging studies have consistently shown volumetric loss in hippocampus and prefrontal cortex in depressed patients . Neuronal size and density as well as glial cell number and density have been shown to be reduced [5, 6]. Acute ischemia, physical trauma, infections, inflammation, oxidative stress, acidosis/alkalosis, electrolyte imbalances, metabolic syndrome, extreme temperature changes, high voltage electric currents may cause biochemical abnormalities that may result in cellular insult. Due to increased production of free radicals, oxidative stress is one of the most important causes of the neuronal alterations in DD [7-9]. Oxidative stress is defined as imbalance between free radicals and anti-oxidant defenses, which results in increased reactive oxygen species. The brain is under more severe risk for oxidative stress, because of its high metabolic rate and high density of fatty acids and metal ions which are notable electron donors . Increased oxidative stress may induce cellular dysfunction and apoptosis by causing lipid peroxidation, brakes in DNA strand, protein/enzyme inactivation, and disrupt cellular signaling cascades in the brain .
Sistine residues and sulfhydryl groups are functional groups of amino-acids which are also called thiols . Thiols are reductive organic compounds and turn into non-reactive disulphides such as sulphinic acid or thiol radicals if they react with reactive oxygen radicals. Disulphides are later converted to thiols by reductants such as thioredoxin, glutaredoxin and thiol-disulphide homeostasis is hereby maintained . Several proteins such as albumin, sistein, homo-sistein, glutathione, gamma-glutamyl sistein may contain thiol components and free thiols may also circulate in plasma . Several metabolic procedures are involved with thiol groups such as anti-oxidant defense, protein synthesis, cell proliferation and growth, signal transmission, apoptosis and immune regulation . Erel and Neşelioğlu have developed a new fully-automated assay to evaluate dynamic thiol-disulphide homeostasis . Thiol groups participate in the first line defense against oxidative stress, thus dynamic thiol-disulphide homeostasis has been investigated in several psychiatric disorders [14-17]. Thiol-disulphide homeostasis was also assessed in patients with major depressive disorder and the authors reported that serum level of thiols were depleted .
Human albumin is a protein with 585 amino-acids, which contain 35 cysteine residues. The only free cysteine residue at position 34 (cys34) holds a free thiol group (-SH) accounting for 80 % of thiol groups in the plasma . One of the most important function of albumin is to bind molecules in the blood stream. Chemical configuration of the last 4 amino-acids forms a specialized structure for the N-terminal which enables albumin to bind transitional metals such as cobalt or iron [20, 21]. This function is disabled when the unique chemical structure of the N-terminus is altered. This phenomenon is called ischemia modified albumin (IMA), because the first observations were in cases of hypoxia and acidosis . Later, it became evident that N-terminus of the albumin can become modified by several medical cases causing biochemical stress such as extreme changes in temperature, disturbed acid-base balance, metabolic syndrome, inflammation or oxidative stress . In a recent study, it has been reported that IMA levels in remitted patients with recurrent depressive disorder were not significantly different from that of healthy controls . However, to our knowledge no studies have up to date evaluated the effects of ECT on IMA levels in patients with DD. Induction and seizure steps of the ECT may cause modification of the N-terminus of the albumin molecule.
Electroconvulsive therapy is an effective treatment modality for DD and in particular for treatment resistant depression . A number of studies have reported that the ECT has positive impact on neurotransmitters  as well as immune [25-28] and endocrine [27, 29, 30] systems. Only few studies assessed the effects of ECT on oxidative stress markers and consistently reported that ECT alleviated oxidative stress [31-34]. However, to our knowledge, up to date no studies assessed the effects of ECT on thiol disulphide homeostasis. Repetitive transcranial magnetic stimulation decreased serum levels of native and total thiols . In this study we aimed to investigate serum thiol disulphide homeostasis in patients with DD and potential effects of the ECT. Thiol pools are regulated by mechanisms linked to their intrinsic reactivity against antioxidants, thiol-disulphide exchange rates and their dynamic release/removal from plasma. The ECT may reorganize the thiol pool by altering chemical reactions. To our knowledge, this is the first study to assess the effects of ECT on thiol disulphide exchange in DD.
Local ethical committee approval was obtained for the study. All participants provided a written informed consent before study participation. Consecutive inpatients with depressive episodes (either Major Depressive Disorder or Bipolar Disorder) who were planned to be treated with ECT (decisions were made by independent senior physicians) were invited to participate in the study. Diagnoses were checked with structured clinical interview for DSM-IV (SCID-I) by a senior psychiatrist [36, 37]. Patients and healthy control subjects were evaluated according to the inclusion and exclusion criteria. Participation to the study was offered to the patients with an accompanying first-degree relative. Patients who accepted to participate were enrolled. Participants were between the age of 21-61. Medical and psychiatric history were checked in terms of exclusion criteria. The exclusion criteria were any medical comorbidities (systemic or neurological diseases), psychiatric comorbidities, history of major surgeries (brain, cardiac, thoracic or abdominal surgery), any infectious diseases in the preceding month, nutritional deficiencies and rapid reduction in weight. Totally 23 patients were enrolled into the depression group. A healthy control group (n=21) was also recruited. Healthy controls (HCs) were examined with the SCID nonpatient form. Exclusion criteria for HCs were history of substance and alcohol use disorder, cranial injury, major surgery, any infectious disease in the last month.
Hamilton Depression Rating Scale (HDRS): The HDRS has been the gold standard for the assessment of depression for almost 50 years. It is developed by Hamilton in 1960  and translated into Turkish by Akdemir and colleagues . 17, 21 and 24 item versions are available, the original 17 item version is the most frequently used version. Test retest reliability of the Turkish version was coefficient was 0.85, interrater reliability was ranging between 0.87-0.98 and the coefficients show that Turkish version of the scale has good reliability and validity measures . The scale is administered by clinicians.
Brief Psychiatric Rating Scale (BPRS): Developed by Overall and Gorham, using factor analysis . Interrater reliability ranges from 0.67 to 0.95; and reliability (p<0.01) and validity (p<0.01) measures were high in patients with schizophrenia . Five items are based on clinician’s observations (tension, emotional withdrawal, mannerism-posturing, motor retardation and uncooperativeness) and the other 13 items are assessed by patient’s verbal cooperation. Items are Likert type rated on a 7 points scale, 1 not present and 7 extremely severe. By summing the item scores, a total score is obtained which can vary between the range of 18-126 points.
Clinical Global Impression (CGI): The CGI is designed to assess global severity of illness and change in the clinical condition over time. The scale provides an overall summary measure that evaluates all available information, including a knowledge of the patient’s history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient’s ability to function. It consists of 3 global subscales: Severity of Illness; Global Improvement; Efficacy Index. Item 1 is rated on a seven-point scale (1=normal to 7=extremely ill); item 2 on a seven-point scale (1=very much improved to 7=very much worse); and item 3 on a four-point scale (from none to outweighs therapeutic effect).
The decision of ECT was made by the patients’ attending psychiatrists. A written informed consent was obtained from the patient or a first-degree relative before the administration. Electroconvulsive therapy (ECT) sessions were performed in the ECT unit of the hospital, between 08.00 – 11:00 in the morning. ECT applications of the hospital are all performed in an equipped unit for anesthesia procedures of the hospital [42-44]. The ECT unit was fully equipped with the devices needed for ECT applications under anesthesia and life supporting systems such as ventilators, respirators, defibrillator, electrocardiogram (ECG). According to the routine ECT procedures, all patients were controlled with laboratory tests including hemogram, liver, kidney and thyroid function tests. Patients were on fasting for 12 hours prior to ECT sessions. Blood pressure, ECG and oxygen saturation were monitored. A pulse oximeter (Nonin 2500A pulse oximeter) placed on the index finger monitored the vital signs. Succinylcholine (0.5 mg/kg) and Propofol (0.75-1 mg/kg) were administered as anesthetic medications. Before electrical stimulation patients had ventilation support with an airway, ambu mask and bag. During the electrical stimulation and convulsive phase, dental arches were protected with a sponge. A brief-pulse square-wave ECT device (Thymatron System IV ECT; Somatics, Inc., Lake Bluff, IL, USA) was used. ECT applications were bilateral fronto-temporal. Initial electrical stimulus charge energy was set by the doctor according to the half-age criteria and other influential factors such as concomitant pharmacotherapy, age, gender, prior to the ECT treatment. Seizures were considered as effective if they lasted more than 25 seconds. All patients were under intense medical care until complete recovery (30-60 minutes).
Blood samples were obtained from antecubital veins, at 08:00-12:00 am. All participants were controlled to be on 12 hours of fasting. Three samples were collected from each patient at different time points: prior to the first ECT session [first], after the first session [second] and after the last session [third]. Blood samples were obtained 30 minutes after the ECT sessions. The blood samples were left for 30 minutes at room temperature (22 °C) to activate clotting process followed by centrifuges at 1500 g x15 minutes. Serum samples were aliquoted and kept at -80 °C freezer. Samples were transferred to the biochemistry laboratory for analyses.
Serum thiol/disulphide homeostasis parameters were measured according to Erel and Neselioglu method . Briefly, disulphide bonds in serum were reduced with sodium borohydride to form free thiol groups and unused sodium borohydride was removed with formaldehyde. After that, native (-SH) and reduced thiol (-SH and -SS) groups were determined by using reaction with 5,5’-dithiobis-(2-nitrobenzoic acid). Serum disulphide levels (-SS) were calculated via half of the difference between the total thiols and native thiols. Native thiol, total thiol and disulphide amounts (SS), disulphide/total thiol percent ratios (SS/SH+SS), disulfide/native thiol percent ratios (SS/SH) and native thiol/ total thiol percent ratios (SH/SH+SS) were calculated. These results are presented as micromole/liter (μmol/L), ratio and percentage.
Serum albumin levels were evaluated with bromocresol green (BCG) method and IMA levels were detected by the method described by Bar-Or and colleagues . This manual colorimetric assay measures exogenous cobalt (Co+2) binding facility of the serum albumin. 50 μL water with % 0.1 cobalt chloride (CoCl2.6H2O) solution was mixed with serum (200 μL) and leaved in a dark room for ten minutes. Moreover, 50 μL dithiothreitol solution with 1.5 mg/mL H2O was added to the serum and placed for two minutes. In order to trim the reaction, % 0.9 NaCl was also added to the solution. The blank was laid just as the exclusion of dithiothreitol. Absorbencies of the specimens were evaluated with spectrophotometer at 470 nm. IMA concentrations were obtained by measuring the difference between the samples with and without dithiothreitol. IMA levels are measured as absorbance units (ABSU).
Statistical analyses were performed with SPSS 21 (IBM incorporation, New York, USA) software. Continuous variables are reported with means and standard deviations or medians and percentiles. Categorical variables are reported with frequencies and percentages. Continuous variables were checked with Shapiro Wilk Test for their distribution characteristics. Parametric tests were picked for normally distributed variables and non-parametric tests were chosen for skewed variables. The groups were compared to determine whether there is any statistical difference between the groups in any variables. In the first step, patients with DD were compared with the HC group and for two group comparison t test or Mann Whitney U Test were selected. In the second step, levels of biochemical variables were compared within the DD at the beginning, after the first session and after the third session. Three time points were compared with Analysis of Variance (ANOVA) or Kruskal Wallis Test . Categorical variables such as gender or marital status were analyzed with Chi-Square Test. Correlations between the variables were performed with Spearman’s Rank Correlation Test. Analysis of covariance (ANCOVA) is a test to examine the differences in the mean values of the dependent variables that are related to the effect of the controlled independent variables while taking into account the influence of the uncontrolled independent variables. Potential covariance effects were assessed with univariate ANCOVA test. Logarithmic transformation was applied to the deviated variables (Native Thiol and Total Thiol) to meet the assumptions of the univariate ANCOVA. Level of statistical significance was set as p<0.05. All tests results were two-tailed.
Sociodemographic and clinical variables of the participants are presented in Table 1. The study enrolled 23 patients with DD (7 bipolar disorder, depressive episode; 16 major depressive disorder episode) and 21 healthy control subjects. Genders were matched between the groups, however there were difference between age (p=0.022) and education (p<0.001). 12 of the patients were treated with ECT because of medical emergency (severe suicide risk, catatonia, refusing to eat, refusal of treatment) and 11 patients had ECT because of treatment resistance. Mean number of ECT sessions were 7.14±2.03 (minimum 5, maximum 10). All patients were on psychotropic medications. All patients were taking two (n=10) or more (n=13) medications. Medications included antidepressants, antipsychotics, benzodiazepines, mood stabilizers and biperiden. During the study enrollment, mean score of the HDRS was 35.70±12.10 and BPRS was 30.96±10.68 and after the treatment mean HRDS score was 11.32±8.59 and mean BPRS score was 8.91±7.11 in the patient group.
Comparison of thiol and disulphide levels between DD and HCs are presented in Table 2. According to the Shapiro Wilks Test results, total (p=0.264) and native (p=0.186) thiol levels rejected the null hypothesis that the compounds were normally distributed. Disulphide (p=0.039) and IMA (p=0.034) levels were normally distributed. Serum total thiol levels were significantly lower in DD patients in comparison with HCs (p=0.032). Difference between the groups in native thiol levels were at trend level (p=0.056). Disulphide levels and disulphide to thiol levels or native to total thiol levels did not differ between the groups.
Comparisons within the DD patients’ samples before ECT, after first session and after last session are presented in Table 3. No significant difference was observed between the time points.
Correlation analysis was performed with Spearman’s Rank Correlation Test. Age, education, duration of the disease, duration of the episode, number of previous episodes, number of hospitalizations, hemogram and routine biochemistry measures, total thiol, native thiol, disulphide and IMA levels were the biochemical parameters entered to the correlation analysis. Fasting glucose levels correlated with native (r=-0.43, p=0.044) and total (r=-0.46, p=0.030) thiol levels in the DD group. No other significant correlation was observed (Table 4).
In this study, total thiol levels were significantly lower in patients with DD in comparison to the healthy control group. Moreover, native thiol levels were lower in the DD group compared to the healthy control group at trend level. Disulphide levels did not differ between the groups. Lower total thiol levels without decrease of disulphide levels may be due to decrease of native thiol levels. After the ECT sessions, thiol disulphide levels did not change in the DD group. NO levels were higher in the patient group in comparison to the healthy control group. However, NO level did not differ after ECT in patients with DD.
Consistent evidence indicate that DD are characterized by oxidative stress  and burden of oxidants might be a possible reason of the loss of cellular and subcellular components [46, 47]. Cellular components with sulfhydryl groups (-SH), also called thiols, can easily be reduced by unengaged electrons and covert into disulphide forms (-SS). Low levels of thiols might also be due to insufficient intake, or metabolic utilization (i.e. synthesis of neuromelanin or pheomelanin) as well as increased consumption by oxidation into disulphides . Depletion of thiols without any change in disulphide level may indicate dietary insufficiency or enhanced consumption by metabolic utilization, rather than transformation to disulphides. Although none of the participants had nutritional insufficiency prior to study enrollment, patients with DD typically lose their appetite and thus lose weight. However, there were no significant correlation between thiol and disulphide levels and biochemical markers in this study and none of the patients reported nutritional deficiency.
Effects of ECT on oxidative stress have been investigated by few studies. In a study with schizophrenia patients, effects of ECT on serum levels of nitric oxide, malondialdehyde, glutathione, catalase were investigated . Serum samples of patients with schizophrenia were collected before ECT, after first session and after the last session. At baseline, patients had significantly higher levels of malondialdehyde and catalase levels compared to healthy controls and malondialdehyde levels decreased significantly after the last session and level of the other compounds did not differ. It is also reported that ECT normalizes total oxidant status in major depressive disorder  and total oxidant status / total antioxidant status ratio (oxidative stress index) in schizophrenia  and mania . On the other hand, successful treatment with antidepressants also decrease the levels of oxidant compounds in patients with major depressive disorder  and antipsychotic treatment in schizophrenia . It should be identified whether the reduction of oxidants is because of the ECT or remission itself. Therefore, we have made an assessment after the first session to control the effect of a single session. Thiol-disulphide levels did not differ within the DD group during the ECT course. Similarly, it has been reported that plasma thioredoxin levels in patients with mania who were treated with ECT did not change during the ECT course . Thioredoxin is one of the several thiol proteins that has active sulfhydryl sites which are capable of scavenging reactive oxygen species and thus serum thioredoxin levels are vulnerable to oxidative stress . Several small compounds (amino acids, peptides, thiol proteins such as thioredoxin) contribute to the thiol pool, however they are not in equilibrium and each compound may present specific oxidized/reduced ratio. Thioredoxin is a class of redox proteins facilitating the reduction of other proteins by cysteine thiol-disulphide exchange.
Levels of IMA were higher in patients with DD in comparison with the healthy control group in this study. IMA levels were not significantly enhanced in remitted patients with recurrent depressive disorder in a previous study . Participants of this study were severely depressed and chemical burden might be greater during episodes in DD. Furthermore, the authors also reported that IMA levels were associated with total oxidant status in depressed patients in the study. Oxidative stress  neuroendocrine  and inflammatory changes [2, 25] are robust in DD, particularly during episodes. Moreover, IMA levels did not significantly change during the ECT course and did not show any association with disease severity in this study. The results suggest that ECT does not modify albumin molecules, which means that ECT does not produce a chemical or physical stress. Furthermore, decrease of IMA levels may require longer period for synthesis of new albumin molecules.
This study has several limitations. First, age, gender, nicotine, dietary factors, personal life style, metabolic factors may also influence the results as well as disease states in psychiatric disorders [45, 48, 50]. Furthermore, diagnoses, medications and disease stages may also have altered the results . However, due to small sample size, we could not be able to analyze potential effects of the abovementioned confounders. Second, serum assessments of venous blood samples may not be fully associated with the brain. Third, depressed patients with both major depressive disorder and bipolar disorder were enrolled into this study. Fourth, ECT parameters of the patients were personalized and thus were not standard. Fifth, albumin has several sites for drug binding and measurement of the IMA levels could be interfered in by the patients’ medications. Finally, small study groups may have inflated the risk for type II statistical error. These limitations interfere with generalizability of the results and further studies are needed to confirm the results.
In summary, thiol disulphide homeostasis is assessed in patients with DD in this study. Thiols were significantly lower in the DD group, however ECT did not seem to influence thiol-disulphide levels in this study. ECT is a safe treatment modality [52-54] and these findings may provide biochemical support for the safety of ECT at subcellular level. Further controlled longitudinal studies with larger sample sizes may investigate the thiol-disulphide homeostasis in patients with DD. The effects of electrical stimulation and convulsion on redox status, chemical reactions, balance between oxidant compounds and antioxidant systems might be investigated with preclinical laboratory methods in future studies.
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