Invited Review

Alpha Psychiatry 2021;23(2):47-56

DOI: 10.5152/alphapsychiatry.2021.21584

A Systematic Review of the Literature Regarding the Relationship Between Oxidative Stress and Electroconvulsive Therapy

Murat İlhan Atagün¹

Özge Atay Canbek²

¹ Department of Psychiatry, Çanakkale Onsekiz Mart University School of Medicine, Terzioglu Campus, Çanakkale, Turkey

² Department of Psychiatry, Electroconvulsive Therapy Unit, İstanbul Bakırköy Research and Training Hospital for Psychiatry, Istanbul, Turkey

Corresponding author: Murat İlhan Atagün ✉ ilhan.atagun@gmail.com

Cite this article as: Ilhan Atagun M, Atay Canbek O. A systematic review of the literature regarding the relationship between oxidative stress and electroconvulsive therapy. Alpha Psychiatry. 2022;23(2):47-56.

ABSTRACT:

Objective: Brain’s aerobic energy metabolism, abundance of the fatty acids and unsaturated lipids, generation of Reactive Oxygen Species (ROS) by hormones, physiological roles of transition metals (i.e., iron and copper), and free radicals in the nervous system may cause inclination to oxidative stress in psychiatric disorders. Electroconvulsive therapy (ECT) may cause oxidative stress by the electrical field or by the induced seizure. It was aimed to review the literature in terms of the influence of ECT on levels of oxidant and antioxidant compounds.

Methods: The literature search was performed with the keywords that were oxidative stress or "DNA damage" or "RNA damage" or "lipid peroxidase" or "superoxide dismutase" or "catalase" or "glutathione" or "nitrite" or "nitric oxide" and "electroconvulsive therapy" or "electroconvulsive shock" or "electroconvulsive seizure". Twenty of 1480 records were included.

Results: Eleven studies were performed in human subjects, whereas 9 studies were performed in rats. Human studies are conducted with serum, plasma, or urine samples; rat studies include brain tissues from various sites. In rats, four independent studies showed increased levels of lipid oxidation markers, and four independent studies reported increased levels of oxidative stress markers in brain samples. In human studies, studies were performed with circulating blood samples and the results were more inconsistent.

Conclusion: Although some markers like superoxide dismutase or thioredoxin imply that ECT may increase the balance for oxidative stress, this notion is not supported by other markers of ECT. The current literature does not clearly suggest that the ECT is associated with oxidative stress in psychiatric disorders. Further studies with similar methods should be performed in big samples.

Keywords: Electroconvulsive therapy; oxidative stress; glutathione peroxidase; superoxide dismutase

Introduction

Psychiatric disorders are leading causes of disability,¹ with high rates of morbidity and premature death.²,³ For example, the risk of oncologic diseases⁴ or cardiovascular diseases⁵ increase significantly, even the metabolic risk factors were controlled for. The medical comorbidities may emerge both directly, through biological pathways, and indirectly, through risky health behaviors. Furthermore, alteration in brain volumes, disruption of neuroplasticity, and cell survival may highlight potential abnormalities in cellular longevity and resilience in mood disorders⁶ and schizophrenia.⁷ Inflammatory activation and oxidative stress are the leading common chemical risk factors of underlying metabolic abnormalities of the abovementioned clinical outcomes in psychiatric disorders.

Active oxygen species and available antioxidant buffering efficiency are on a balance in physiological conditions. Increased levels of the oxidant compound excess the capacity of the antioxidant systems, and the redox disequilibrium on behalf of reactive oxygen species (ROS) may damage all cellular components including lipids, proteins, nucleic acid, or carbohydrates by altering their chemical structure and function.⁸ Several antioxidant defense systems include non-enzymatic molecules (vitamins A, C, and E, glutathione, and dietary supplied antioxidants) as well as enzymatic scavengers of ROS, with superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) are the most common defense systems.⁹ Major proportion of the superoxide radical (O₂ •−) is generated at the level of the mitochondrial electron transport chain and can be easily converted to hydrogen peroxide (H₂O₂) spontaneously or using SOD. On the other hand, transition metal ions (e.g., iron and copper), H₂O₂ can generate via Fenton reaction the highly reactive hydroxyl radical (HO•). Reactive species may also be enzymatically produced by xanthine oxidase, uncoupled nitric oxide synthases, and NADPH oxidase.

Oxidative stress is pronounced in psychiatric disorders due to a combination of various characteristics of the nervous system. The dense aerobic energy metabolism, abundancy of the fatty acids and unsaturated lipids, generation of ROS by hormones, physiological roles of transition metals (i.e., iron and copper), and free radicals may cause inclination to damage by oxidative stress in the central nervous system.⁷ On the other hand, pathophysiological mechanisms, disorganized lifestyle, nutritional deficiencies, metabolic and endocrine alterations, and long-term consequences of the medications may enhance the risk for oxidative stress in psychiatric disorders.¹⁰ Consistently, previous studies consistently detected severe oxidative stress in psychiatric disorders and further showed that oxidative stress causes damage to proteins, lipids, and nucleic acid material in the brain, induces telomere shortening, apoptosis, and cell death in the chronic terms of schizophrenia⁷, bipolar disorder¹¹, and major depressive disorder.¹² Clinical (i.e., episodes, disease severity), metabolic and pharmacological factors that may influence the oxidative status.¹³,¹⁴

Intermediate metabolites of the catecholaminergic and dopaminergic catabolic cascades are prone to produce oxidative compounds and irregularities or excess levels of the neurotransmitters may cause oxidative stress in the brain.¹⁵ Based on this information, intriguing questions about the effects modulators of the neurotransmitters arise. The literature regarding the effects of antipsychotics on the levels of oxidative compounds is not conclusive.¹⁶ However, it was reported that lithium decreased levels of oxidant compounds and oxidized lipid levels in patients with bipolar disorder and the levels of oxidized lipids were associated with clinical response to lithium.¹⁷,¹⁸ On the other hand, antidepressants use is clearly associated with depleted levels of oxidative markers in patients with major depressive disorder¹⁹,²⁰. However, it is still not clear yet, whether the changes in oxidative stress markers are related to remission in patients or the chemical effects of the medications on neurotransmitter metabolism.

MAIN POINTS

Inflammatory activation and oxidative stress are the leading common chemical risk factors of underlying metabolic abnormalities of the abovementioned clinical outcomes in psychiatric disorders.

The dense aerobic energy metabolism, abundancy of the fatty acids and unsaturated lipids, generation of ROS by hormones, physiological roles of transition metals (i.e., iron and copper), and free radicals may cause inclination to damage by oxidative stress in the central nervous system.

Electrical currents, epileptic seizures and other procedures of the electroconvulsive therapy may interfere with the electrical balance between oxidant and antioxidant molecules.

It has been consistently shown in experimental models that following electroconvulsive seizures, oxidative stress markers increase in the rat brain.

In the circulating blood, oxidative stress markers do not change following electroconvulsive therapy in human studies.

Although more studies are needed, it can be speculated that acute and transient changes in oxidative balance do not cause any harm to the brain.

The electroconvulsive therapy (ECT) has been used in the treatment of major psychiatric disorders for more than 80 years. The ECT is considered to be a safe treatment modality, even in risky populations.²¹-23 In the last decades modified version of the ECT application which is under anesthesia conditions is being practiced. The ECT is based on electrical current stimulation (induction phase) which leads to a short seizure activity (seizure phase) ideally lasting between 20 and 50 seconds. The third and last phase is the recovery phase. The induction and seizure phases have the potential to induce chemical effects in the nervous system tissues.²² Electrical currents are based on the flow of electrons and theoretically, electrons may interact with molecules and produce oxidant compounds. Likewise, epilepsy models triggered by chemical agents (i.e., pilocarpine) or electrical stimulus showed similar trends in oxidative stress.²⁴ Electrical stimuli triggered mitochondrial autophagy by inducing oxidative stress in cell cultures.²⁵ It is not clear yet whether levels of oxidative compounds elevate in the patients treated with ECT. Furthermore, anesthetic agents may also influence the chemical balance between oxidant and antioxidant systems. Seizures may provoke oxidative stress that leads to disruption in neurotransmission, ion channel physiology, and DNA break in the hippocampus²⁴ in rat models. Disruption of the neuronal physiology in the hippocampus may cause memory dysfunction. This notion suggests a possible relationship between ECT-related memory dysfunction and oxidative stress. It was aimed to perform a systematic literature review regarding the potential effects of the ECT on oxidative stress markers in patients treated with ECT.

Methods

A quantitative literature review was performed in PubMed database on July 30, 2021 according to the PRISM guidelines.²⁶ The literature search was performed according to The keywords were oxidative stress or "DNA damage" or "RNA damage" or "lipid peroxidase" or "superoxide dismutase" or "catalase" or "glutathione" or "nitrite" or "nitric oxide" and "electroconvulsive therapy" or "electroconvulsive shock" or "electroconvulsive seizure". The English language was the only filter and no date limitation was applied. The literature search retrieved 1480 records. Total 1423 records were eliminated by title and abstract in the first assessment. Fifty-seven records remained in the second phase. Thirty-seven studies were eliminated in the second phase full-text review. Twenty studies remained after the process. Nine studies were preclinical laboratory studies and 11 studies were clinical studies in humans. For details of the review process, please see the flowchart in Figure 1.

Figure 1. Flowchart of the algorithm of literature research and study inclusion/exclusion cascades.

Results

Human Studies

Glutathione peroxidase (GSH), SOD, and CAT are antioxidant enzymes that catalyze oxygen radicals and defend the tissues against oxidative compounds. Glutathione peroxidase and CAT levels were measured in 3 studies by independent groups²⁷,²⁸ and the ECT did not alter the levels of these enzymes in schizophrenia²⁷ or BD²⁸ (see Table 1). Superoxide dismutase levels were assessed by 3 different studies by 3 independent groups.²⁸-30 Two studies consistently reported that SOD levels were decreased after ECT treatment in the patient groups. NO is a compound with an unpaired electron and XO generates reactive oxygen compounds. Virit et al³⁰ examined NO and XO levels in patients with MDD before and after ECT. The authors reported that the level of NO and XO did not change after ECT. Kartalci et al²⁷ examined NO levels in schizophrenia patients before and after ECT. Similarly, the authors did not observe any change in NO levels. Atagun et al³¹ examined NO and its nitrite and nitrate components in depressed patients (n = 23) treated with ECT. The authors reported that NO levels decrease after the 7th ECT session. The authors claim was that the decrease of the NO may contribute to the increased systemic systolic tension.

Table 1. A Brief Presentation of the Human Studies

Study ID | Study Population | Samples | Markers | Assays | Study Design | Results
Ozcan et al²⁹ 2004 | BD manic (n = 16), BD depressed (n = 2), recurrent MDD (n = 6) and schizoaffective disorder manic (n = 6) | Eritrocyte sediments | SOD, GSH, CAT, MDA, NO | Automated Spectrophotometer | Samples were collected before and 3 months after the treatment | No significant difference was observed between pre and post ECT comparison
Virit et al³⁰ 2010 | Depressed (n = 16) | Plasma | MDA, NO, SOD, XO | Automated spectrophotometry | Samples were collected from the participants before the first session and after the 7th session | The level of SOD was significantly lower after the seventh session in comparison to the initial assessment
Kartalci et al²⁷ 2011 | Schizophrenia (n = 30), HCs (n = 20) | Plasma | NO, MDA, GSH, CAT | Automated spectrophotometry | Samples were collected from each group, 2 more samples were obtained from the ECT group after the first and last sessions | Serum MDA levels decreased significantly after the 9th session. No other changes were observed between the samples of the patients
Jorgensen et al³⁸ 2013 | Depressed (ECT, n = 29, non-medicated, n = 26), HC (n = 28) | Urine | DNA/RNA oxidation markers* | Liquid chromatography/ tandem mass spectrometry | Samples were collected from each group, one more sample was obtained from the ECT group 1 week after the last session | 8-oxoGuo was increased in the depressed groups, after the ECT 8-oxoGuo levels further increased. 8-oxodG did not show any difference between the groups
Kalelioglu et al³² 2014 | BD-mania (AP, n = 46 vs AP + ECT, n = 22), HCs (n = 30) | Serum | TAS, TOS, OSI | Erel method, Automated spectrophotometry | Samples of the patients before and after the treatment were compared | TAS and TOS levels did not show any difference before and after treatment. OSI increased after the treatment. The ECT group had typical antipsychotics whereas the other group had atypical antipsychotics
Genc et al³⁵ 2014 | BD-mania (n = 68), HCs (n = 30) | Plasma | Thioredoxin | ELISA | 22 of the patients were treated with ECT and antipsychotics; 44 patients were treated with antipsychotics. Pre- and post-treatment samples were compared | Thioredoxin levels decreased after treatment in all patients (n = 68), ECT + antipsychotics group did not differ from the antipsychotics group
Sahin et al³³ 2017 | MDD (n = 23), HCs (n = 22) | Serum | TAS, TOS | Erel method, Automated spectrophotometry | Seven sessions of ECT cure were administered, pre and post ECT samples were compared | In the initial assessment, TAS levels were significantly lower in the patient group in comparison to the HCs. After the ECT treatment, TAS levels significantly increased in the patient group and no difference was observed between the HC group
Senyurt et al³⁴ 2017 | MDD (n = 14), schizophrenia (n = 11), BD (n = 8), HCs (n = 37) | Serum | TAS, TOS, OSI | Erel method, Automated spectrophotometry | Initial samples from both patients and HCs, 2 more samples from the patients (after the first and last sessions) | TOS levels were higher, TAS levels were lower in the patient group initially. After the ECT administration, TOS levels decreased, TAS levels increased in the patient groups
Atagun et al³⁶ 2020 | Depressed (MDD = 16, BD = 7) and HCs (n = 21) | Serum | Thiol-Disulphit, IMA | Erel and Neselioglu method, automated spectrophotometry | Twenty-three patients with depressive episodes were treated with ECT, samples were collected before ECT, after 1st and 7th sessions. Three samples of each participant were compared | Thiol-disulphit levels did not change between the time points. IMA levels did not change before and after the ECT cure
Lv et al²⁸ 2020 | BD (n = 28), HCs (n = 49) | Plasma | SOD, GSH, CAT, MDA | ELISA | Initial samples were collected from the patients and HCs, one more sample was obtained from the patients after 6 weeks of ECT treatment | SOD, levels were lower, GSH and MDA levels were higher in the patient group compared to the HCs. After the ECT, MDA levels decreased significantly in the ECT responder patients
Atagun et al³¹ 2021 | Depressed (MDD = 16, BD = 7) and HCs (n = 21) | Serum | Nitrite, Nitrate, NO | Automated spectrophotometry | NO levels of the patients with treatment-resistant depression and healthy controls were compared, patients also evaluated after the first and seventh ECT sessions | No differences were observed between the patient and control group in terms of nitrite and NO levels. Nitrate levels were lower in the patient group. Nitrite and NO levels decreased after the seventh ECT session

Studies are listed according to their chronological order. *DNA oxidation markers: 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG), RNA oxidation marker: 8-oxo-7,8-dihydroguanosine (8-oxoGuo); IMA, ischemia modified albumin; TAS, total antioxidant status; TOS, total oxidant status; OSI, oxidative stress index (TOS/TAS ratio); XO, xanthine oxidase; MDA, malonaldehyde; SOD, superoxide dismutase; GSH, glutathione peroxidase; MDD, major depressive disorder; BD, bipolar disorder; HCs, healthy controls; AP, antipsychotics; ELISA, enzyme linked immune assay; NO, nitric oxide; ECT, electroconvulsive therapy.

Total oxidant status (TOS) is an index measure that contains all oxidant molecules and total antioxidant status (TAS) is an index measure that contains all antioxidant measures cumulatively. Total antioxidant status and TOS are in balance normally using the antioxidant defense systems. Total antioxidant status and TOS levels were measured by 3 studies by independent groups.³²-34 Kalelioglu et al³² have enrolled 68 patients with acute mania. Twenty-two of the patients had antipsychotic and ECT treatment, while 46 of the patients had only antipsychotic treatment. The groups did not show any difference in TAS and TOS levels. Sahin et al³³ enrolled 23 patients with major depressive disorder and 22 healthy controls. Total antioxidant status levels were significantly lower before the treatment in the patient group increased significantly after the ECT treatment. Senyurt et al³⁴ had a mixed sample consisting of major depressive disorder (n = 14), schizophrenia (n = 11), BD (n = 8), and HCs (n = 37). In the first assessment, TOS levels were higher, and TAS levels were lower in the patient group. After ECT treatment, TOS levels decreased and TAS levels increased in the patient group.

Thioredoxin is a protective protein against oxidative stress by neutralizing oxidative compounds. Patients with bipolar disorder in the manic episode (n = 68) were compared with healthy controls (n = 30) in terms of plasma thioredoxin levels, and thioredoxin levels were significantly lower in the patient group. After ECT treatment, thioredoxin levels in the mania group further reduced significantly in this study.³⁵ Albumin is the most abundant protein and its last 5 amino acids of the chain might be modified by chemical stress including oxidative stress. Atagun et al³⁶ evaluated the levels of ischemia modified albumin (IMA) in patients with depression (n = 23) and healthy individuals (n = 21). Ischemia modified albumin levels were significantly higher in the patient group in the first assessment. However, IMA levels did not differ in the patient group before and after ECT. Furthermore, the authors also evaluated thiol/disulfide balance in the same group. Sistine residues and sulfur groups are functional units of amino acids which are also called thiols. Thiols can be reduced into non-reactive disulfides after reacting with reactive oxygen compounds and disulfides can be converted to thiols and thiol-disulfide homeostasis is maintained. Thiol/disulfide levels did not differ between the groups in the first assessment and in the patient group before and after ECT treatment. Another recent study that examined the effects of rTMS on maintenance of the thiol/disulfide homeostasis in patients with treatment-resistant depression reported that thiol levels depleted significantly in the patient group.³⁷ However, there was no relationship between the thiol levels and clinical improvement. Polyunsaturated fatty acids and lipid peroxidation result in malonaldehyde (MDA). Malonaldehyde levels were evaluated in 2 studies.²⁷,³⁰ Malonaldehyde levels were decreased after 9th session of ECT in patients with schizophrenia.²⁷ However, no difference was observed in patients with depression.³⁰

Nucleic acid materials are also prone to oxidative damage and DNA [8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG)] and RNA [8-oxo-7,8-dihydroguanosine (8-oxoGuo)] oxidation markers can be identified in urine. Oxidative stress cause oxidation of the DNA and RNA in psychiatric disorders. A study evaluated the effects of ECT on oxidation markers of DNA and RNA.³⁸ The study included 2 patient groups and a healthy control group (n = 28). One depression group was moderately depressed and medication-free (n = 26) and the other group was severely depressed and treated with ECT (n = 29). RNA oxidation marker (8-oxoGuo) was significantly higher in the severely depressed group and further increased after ECT treatment. However, there was no difference between the groups in terms of DNA oxidation marker (8-oxodG) level and no change was observed after ECT. Telomere length (TL) is believed to be a measure of biological aging, which progressively shortens with the increase of global neurochemical risk.³⁹ Oxidative stress is frequently observed in depressive disorders and cumulative exposure to oxidative stress causes functional and structural brain abnormalities⁴⁰ as well as telomere erosion and somatic morbidity⁴¹ in depressed individuals. A recent study has investigated a potential relationship between TL and cognitive side effects of ECT, by comparing severely depressed patients (n = 100) with healthy controls (n = 80).⁴² No difference was observed between the groups in terms of TL and TL was not associated with cognitive measures.

Experimental Studies

Human studies are performed in serum or plasma samples. However, experimental studies are performed in brain tissue directly. This is an important advantage for oxidative stress studies since systemic circulation can poorly reflect the changes that occur in the brain (see Table 2). Superoxide dismutase was assessed in 6 studies.⁴³-48 Samples were collected from various tissues such as the frontal cortex, hippocampus, striatum, and cerebellum in these studies. One study found decreased⁴³ and three studies found increased⁴⁴,46,47 or no alteration⁴⁵,⁴⁸ levels of SOD. Catalase levels were evaluated in 3 studies⁴⁴,45,48 and CAT levels were increased in a study.⁴⁴ Whereas 2 studies did not report any change in CAT levels after treatment with ECS. Glutathione peroxidase levels were evaluated by 2 studies.⁴³,⁴⁷ Erakovic et al⁴³ found increased levels of GSH, whereas Zahedi et al⁴⁷ found decreased levels of GSH. NO was assessed in 3 studies and the studies reported increased levels of nitrite⁴⁷ and nitrate levels⁴⁸ and decreased levels of nitrite.³¹

Table 2. A Brief Presentation of the Experimental Studies

Study ID | Study Population | Samples | Markers | Assay | Study Design | Results
Erakovic et al⁴³ 2000 | Wistar rats (n = 30) | Frontal cortex, hippocampus, cerebellum samples | SOD, GSH | Automated spectrophotometry | Five groups each including 5 rats. A control group, a single session group with 2 h rest, a single session group with 24 h rest, a group had 5 ECS sessions with 24 h rest and a group had 10 ECS sessions with 48 h rest | SOD and GSH levels were significantly decreased
Barichello et al⁴⁴ 2004 | Adult male Wistar rats (n = 40) | Hippocampus | TBARS, SOD, CAT, Protein carbonyl | Automated spectrophotometry | Acute (single session ECS) and chronic [sacrificed at 48 h, 7 days, and 30 days after treatment (n = 5 animals per group)] | Catalase (CAT) and superoxide dismutase (SOD) increased, lipid peroxidation decreased in acute and chronic terms (30 days)
Feier et al⁴⁵ 2006 | Adult male Wistar rats (n = 30) | Cortex, striatum, hippocampus | TBARS, SOD, CAT, protein carbonyls | Automated spectrophotometry | Acute: Single session ECS administration; Chronic: 8 sessions of ECS administration and scarification 45, 60, 90, and 120 days after the ECS (n= 5 animals per group) | Lipid and protein peroxidation markers showed increased levels of oxidation
Jornada et al⁴⁹ 2007 | Adult male Wistar rats (n = 35) | Hippocampus, cortex, striatum, cerebellum samples | TBARS, MDA, protein carbonyls | Automated spectrophotometry | Seven groups each including 5 rats, after 8 sessions of ECS, changes of the metabolites were assessed. The first group was sacrificed right after the 8th session, each other group had one more week before obtaining their samples | No effects were observed on the assessed parameters in any of the groups
Župan et al⁴⁶ 2008 | Female Wistar rats | Hippocampus, cerebellum, frontal cortex and the pons–medulla | TBARS, SOD, GSH-Px | Automated spectrophotometry | Sham and single ECS groups (scarification groups: 0.5 h, 1 h, 3 h, 5 h, 8 h, 12 h, 24 h after the ECS) | Oxidative lipid damage was observed only in the frontal cortex. SOD and GSH-Px activities were significantly increased in the hippocampus and cerebellum
Zahedi et al⁴⁷ 2018 | Adult male Wistar rats (n = 42) | Frontal cortex | NO, MDA, SOD, GSH | Automated spectrophotometry | Three groups were formed: Control, depression, and ECS groups. The ECS group had 7 sessions daily ECS on consecutive days. | Nitrite, GSH, and SOD levels were increased in the ECS group
Jorgensen et al⁵⁰ 2019 | Sprague Dawley rats (n = 48) | Frontal cortex, hippocampus, CSF, urine | 8-oxodG and 8-oxoGuo, corticosterone, glucocorticoid receptor mRNA | Mass spectrometry, ELISA, in situ hybridization | Young and middle-aged rats went through a 3-week ECS treatment period (ECS and Sham groups). After 24 hours rest of the samples were collected on day 34. | RNA/DNA oxidation markers remained not altered, corticosterone levels increased, cerebral glucocorticoid receptor mRNA expression decreased
Nielsen et al⁵¹ 2019 | Male Sprang-Dawley rats (n = 20) | Piriform cortex sample | 8-oxoGuo, guanosine levels, mitochondrial respiration markers, citrate synthase activity | Mass spectrometry, high-resolution respirometry | 10 rats ECS and 10 sham ECS. 9 treatments were performed in 3 weeks. Brain tissues were obtained 3 days after the last sessions. | Mitochondrial respiration was reduced, RNA oxidation markers were increased significantly, hydrogen peroxide production was not increased
Gonçalves et al⁴⁸ 2021 | Male Wistar rats (n = 40) | Prefrontal cortex, hippocampus and serum | TBARS, MDA, nitrite, nitrate, SOD, CAT, cytokines | ELISA, Spectrophotometry | Saline, ketamine, fluoxetine, bupropion groups had sham and ECS subgroups. Five rats were enrolled in each group. 5 days of ECS treatment were administered to each group. | ECS increased lipid peroxidation markers, nitrite, and nitrate levels significantly, except for the ketamine group. Similarly, IL1B was increased in the ECS groups, except ketamine groups

Studies are listed according to their chronological order. *DNA oxidation markers, 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG); RNA oxidation marker, 8-oxo-7,8-dihydroguanosine (8-oxoGuo); IMA, ischemia modified albumin; TAS, total antioxidant status; TOS, total oxidant status; OSI, oxidative stress index (TOS/TAS ratio); XO, xanthine oxidase; MDA, malonaldehyde; SOD, superoxide dismutase; GSH, glutathione peroxidase; MDD, major depressive disorder; BD, bipolar disorder; HCs, healthy controls; AP, antipsychotics; ELISA, enzyme-linked immune absorbent assay; ECS, electroconvulsive seizures; IL, interleucine, TBARS, thiobarbituric acid reactive substances; CSF, cerebrospinal fluid; NO, nitric oxide.

Thiobarbituric acid reactive substances (TBARS) and MDA are markers of lipid peroxidation. Five studies evaluated TBARS levels⁴⁴-46,48,49, whereas MDA levels were assessed in 2 studies.⁴⁸,⁴⁹ Increased⁴⁵,46,48, decreased⁴⁴, or unaltered⁴⁹ levels of lipid peroxidation markers have been detected in various studies. Protein carbonyls are protein peroxidation markers and were assessed in 3 studies⁴⁴,⁴⁵,⁴⁹ and neither of the studies found any change in protein carbonyl levels before and after ECT treatment. DNA (8-oxodG) and RNA (8-oxoGuo) oxidation markers did not differ before and after ECS.⁵⁰ The authors also detected that glucocorticoid receptor mRNA expression decreased. However, another study found that RNA oxidation marker significantly increased in another study.⁵¹

Discussion

An electroconvulsive therapy session has induction of the seizure, seizure, and post-ictal phases. In addition, anesthetic agents may also have the potential to influence oxidative metabolism. However, Propofol is the most preferred agent and is known to reduce oxidative stress.⁵²,⁵³ Prolonged epileptic seizures disturb the balance between oxidative metabolites and antioxidant systems by increasing cellular energy demand and hindering mitochondrial functions.⁵⁴ The electrical stimulation that induces the seizure may also cause oxidative stress by biophysical effects (flow of the current through the tissue).²⁵ The ECT is capable of inducing electrical dose-dependent neuroplasticity.⁵⁵,⁵⁶ Neurogenesis, angiogenesis, synaptogenesis, and gliogenesis might be stimulated by the electrical current.⁵⁷,⁵⁸ Different aspects of the application may complicate the picture and the global effect might be influenced by several factors. Electroconvulsive therapy-mediated changes in the brain could be related to the combined effects of seizure activity, cerebral blood flow, and electrical field strength. Cerebral blood flow increases following ECT administration probably due to increased demand.⁵⁹,⁶⁰ Therefore, the cumulative effect should be measured to determine the global outcomes of the ECT and the balance between oxidant and antioxidant compounds. The electrical field determines the initial region of the seizure, propagation, and termination processes may determine the outcomes of the ECT-related effects. The discussion regarding the components of the ECT has progressed and lately, the seizure component is claimed to be the unnecessary component of the ECT.⁶¹

The included studies measured oxidative stress with SOD, CAT, GSH, NO, XO, TAS, TOS, malonaldehyde, thioredoxine, IMA, and thiol/disulfide balance, 8-oxodG, 8-oxoGuo, and telomere length in patients treated with ECT. Human studies are conducted with serum, plasma, or urine samples. These samples can only reflect a major fluctuation, which cannot be counterbalanced by the systemic antioxidant resources. In human studies, significant differences were found in SOD levels in 2 different studies and a study reported a further decline of thioredoxin levels in manic patients after treatment with ECT. Moreover, the RNA oxidation marker was increased after the successful treatment of severely depressed individuals with ECT. However, telomere length did not differ before and after ECT treatment. Experimental studies are conducted in brain tissues. However, the results are inconsistent between studies.

Oxidative stress and inflammatory activation usually develop together with a self-sustaining loop, particularly in certain disease states and the co-existing entities worsen the disease progress.⁶² Under normal physiologic conditions, oxidative stress, and activation of the immune system are generally short-lived due to intrinsic negative feedback mechanisms, such as increased production of antioxidant compounds or of anti-inflammatory cytokines. Psychiatric disorders are characterized by oxidative stress and abnormal inflammatory states, which may disrupt feedback mechanisms. Likewise, both systems remain activated and may, indeed, form a positive self-sustaining feedback loop, or a “co-activation” state.⁶³ Over time, such co-activation may lead to a higher risk of disease and to more serious disease.⁶⁴ Electroconvulsive therapy causes alteration in the immune system⁶⁵ and the variations in the immune system are associated with cognitive side effects of ECT.⁶⁶ Oxidative stress may also be triggered by inflammatory activation in the brain.⁶⁷,⁶⁸

Electroconvulsive therapy may cause memory disturbances⁶⁹,⁷⁰ and it is proposed that neurotoxic materials in the hippocampus are associated with memory problems.⁶⁶ The literature fails to approve this claim and more studies are needed for clarification. However, the transient dysfunction of the hippocampus might be explained by neurogenerative and neurochemical load. Unilateral ECT administration seems to be advantageous for memory side effects, compared to bilateral ECT application.⁷¹ This finding supports the notion that the hippocampus is vulnerable to the effects of ECT. Likewise, unilateral administration of the ECT causes volumetric changes in the stimulated hemisphere.⁵⁵ These findings suggest that rather than the convulsive seizure, neuroplasticity effects of the ECT depend on electrical fields.

Conclusion

The current literature has several shortcomings and limitations. First, the variable nature of the oxidant and antioxidant compounds might be reflected differentially in psychiatric disorders, and therefore evaluating the effects of ECT might be confusing. Second, although markers of oxidant and antioxidant systems are similar, different designs of the studies may have caused confusing results. Third, the evaluation of serum or plasma does not necessarily reflect the state of brain tissue. This is particularly important since the main event occurs in the brain. Fourth, different components of the ECT may trigger different effects. Fifth, animal models of ECS might be poorly associated with the human ECT. Sixth, our literature review was limited to the PubMed database which may have lower the sensitivity of our scan.

The effects of ECT on oxidant and antioxidant molecules are evaluated in this review. Electroconvulsive therapy has anesthesia, electrical field, and seizure components which may all trigger oxidative stress. Methodological obstacles limit the studies to determine the changes. Studies reported an increase of oxidant compounds following electroconvulsive seizures in rats. Although some markers like SOD or thioredoxin imply that ECT may increase the balance for oxidative stress, this notion is not supported by other markers of ECT. It can be concluded that current literature does not clearly suggest that the ECT is associated with oxidative stress in psychiatric disorders. It is possible to speculate that the ECT may cause an increase of oxidant compounds, however, the buffering capacity of the tissue can neutralize the oxidant compounds. Further studies with similar methods are needed to clarify the effects of ECT on oxidative stress. Mechanism of the effect of neuromodulation therapies may enlighten our understanding of the pathogenesis of psychiatric disorders and developing novel treatments.

Ethics Committee Approval: N/A.

Informed Consent: N/A.

Peer Review: Externally peer-reviewed.

Author Contributions: Concept – M.I.A., Ö.A.C.; Design – M.I.A., Ö.A.C.; Data Collection and Processing – M.İ.A., Ö.A.C.; Literature Review – M.İ.A., Ö.A.C.; Writing – M.İ.A.; Critical Review – Ö.A.C.

Conflict of Interest: The authors declare no conflict of interest.

Financial Disclosure: The authors declare no financial support for this review article.

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Received: July 26, 2021
Accepted: August 16, 2021

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