Efficacy and safety assessment of different electrode placements during electroconvulsive therapy for the treatment of depression: a comparison of bitemporal, bifrontal and unilateral right-sided stimulation - a narrative review

Introduction: Consequences of depressive syndrome are changes in central nervous system, especially the reduction in volume and disturbances in neuronal metabolism. There are disturbances in cerebral blood flow, in areas responsible for concentration, memory and regulation of behaviour and emotions. ECT method has shown considerable effectiveness in treatment of depression. It has invariably remained effective as a form of treatment in psychiatry for many years. The way in which the method itself is applied and location of stimulation electrodes remains controversial. In clinical practice, bitemporal, bilateral or right unilateral applications are used, each of which activates slightly different regions in brain, resulting in different therapeutic effects. Methods: A review of available literature was performed by searching PubMed and Google Scholar databases, using the following keywords: bifrontal ECT, bitemporal ECT, right unilateral ECT, cognitive function for original papers, meta-analyses and review papers in Polish and English published from 1990 to 2022. The SANRA scale was used to maintain the high quality of the narrative review. Results: All three methods are effective in treating depressive disorders, but differ in impact on cognitive function. Bi-frontal stimulation is the most effective in emergencies, however related to a higher risk of cognitive impairment. Milder cognitive impairment, with similar therapeutic efficacy, is observed with bitemporal and unilateral placement. Conclusions: Individualised selection of ECT method is recommended, depending on patients' needs and clinical condition. The importance of individualising the dose, location of electrodes, and monitoring of cognitive function is emphasised in order to increase the effectiveness and minimise side effects.


Introduction
Electroconvulsive therapy (ECT) was first used in 1938 by two Italian physicians, Ugo Cerletti and Lucio Bini [1].Over the years, the method has been improved, minimising side effects.By changing the characteristics of the current, the type of location of the electrodes and the implementation of methods to select an individual dose of energy for the patient, the effectiveness and safety of ECT treatments increased [2].Currently, ECT is experiencing a new boom and remains the most effective method despite the introduction of new non-pharmacological biological therapies, such as transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS) and deep brain stimulation (DBS) [3].
As a result of the depressive syndrome, changes occur in different parts of the central nervous system.In particular, studies performed with magnetic resonance imaging or head computer tomography in people with major depressive disorder (MDD) have found reduced volume and abnormal neuronal metabolism, as well as altered cerebral blood flow in the hippocampus, amygdala, insula, basal ganglia, medial orbitofrontal cortex, anterior cingulate cortex, dorsolateral prefrontal cortex and thalamus.The above-mentioned regions are involved in, among other things, maintaining attention, consolidating memory and regulating emotions and behaviour [4][5][6].Some studies have also shown impaired functioning of the cerebellum and brainstem [7][8][9][10].The use of electroconvulsive therapy in patients suffering from depression improves cognitive function and accelerates remission of the disease [11].
The basic ECT series consists of 8-15 treatments performed 2-3 times a week [12].However, controversy still exists regarding the optimal methods of applying this treatment.In particular, the location of stimulation electrodes during ECT, is subject to debate [13,14].There is no standardised method of ECT stimulation worldwide.In clinical practice, bitemporal (BT), bifrontal (BF) or right unilateral (RUL) electrode placement is used.Data available in the literature confirm that seizures induced by BT application increased cerebral blood flow symmetrically in the bilateral temporal and frontal cortex, as well as in the parietal cortex and cerebellum, regions distant from the seizure induction site.RUL ECT activates similar regions to BT, but only in the right hemisphere [15,16].BF stimulation, on the other hand, mostly activates cerebellar regions around the prefrontal cortex and anterior cingulate cortex.It shows little effect on subcortical structures and temporal lobes [11].Thus, the placement of the electrodes may influence different therapeutic effects in patients.Therefore, in the treatment of depressive disorders, it is important to choose the best stimulation method during ECT treatments [11,14].
The aim of this study is to present the characteristics of the different types of stimulation in electroconvulsive therapy and to compare their efficacy and safety in the treatment of depressive disorders.

Methods
A review of the available literature was performed by searching PubMed and Google Scholar databases using the following keywords: bitemporal, bilateral, right unilateral ECT electrode placement.Original papers, meta-analyses and review papers in Polish and English published from 1990 to 2022 were included.The SANRA scale and the ANDJ narrative review checklist [17] were used to maintain the quality of the narrative review.

Efficacy and effects on cognitive function of ECT therapy in bitemporal electrode placement (BT).
Bai et al. performed magnetic resonance imaging of brain activity after ECT, comparing the effects of three types of stimulation -BT, BF, RUL.They showed that BT ECT gives a different brain stimulation profile from the other electrode placements, which may result in a slightly different clinical outcome.BT, compared to RUL and BF stimulation, produces greater stimulation of deep midline structures (nucleus accumbens, ventral striatum, anterior cingulate cortex, thalamus), temporal structures (including bilateral hippocampus), as well as posterior orbitofrontal cortex, brainstem and cerebellum [18].Most of these structures have been implicated in the pathophysiology of depression, and some of them (in particular the cortex of the cingulate gyrus) are particularly associated with the response to antidepressants [18][19][20][21][22]. Keller et al. emphasised that the differences in the efficacy of ECT therapy in the BT, BF and RUL placements are small, but may be crucial in terms of individualising treatment [14].A 2019 randomised trial with 40 patients showed that the efficacy of treating MDD with ECT in the RUL and BF position was similar to that of BT, and side effects were comparable in all three groups.However, BT electrode placement in ECT did not have a statistically significant effect on cognitive function, whereas the other two types of electrode placement were associated with improvements [23].Bakewell et al. described, based on data collected between 1994 and 2000, that the use of BT stimulation contributes to faster clinical improvement in the patient's condition and reduces the number of hospitalisations, while it is more likely to result in cognitive impairment compared to the BF method [24].BT ECT was found to produce greater deficits in global cognitive functions, delayed verbal memory and retrospective autobiographical memory compared to RUL ECT [25].The choice of type of ECT stimulation with regard to the effect on cognitive function remains controversial [26].Some experts argue that cognitive impairment at the location of BT leads is temporary and of minor importance [27], while other researchers describe that they are a major obstacle to the wider use of ECT [28,29].A randomised clinical trial conducted between 2001 and 2006 with 230 patients showed that efficacy was not related to the location of the electrodes, but was dependent on the dose applied.ECT leads to a faster reduction of symptoms and should be considered as a reference in clinical emergencies, such as high suicide risk, severe comorbidities and catatonia.The remission rate with BT was 64%, while in RUL it was 55%.However, the use of BT was associated with a higher risk of cognitive impairment [30].Multiple randomised trials and a meta-analysis have shown that BT ECT is moderately more effective than RUL ECT [31][32][33][34].

Efficacy and impact on cognitive function of ECT therapy in the right unilateral (RUL) placement.
A study by Jelovac et al. involving 61 patients suffering from MDD showed that the therapeutic effects after highdose RUL ECT did not differ from those obtained after BF ECT stimulation.The prognosis is particularly beneficial in elderly patients, those with psychotic depression and patients treated with lithium [35].Abbot et al. state that the heterogeneity of studies makes it difficult to compare different types of stimulation, but nevertheless the common point for RUL and BF positioning are the lower side effects compared to BT [36].However, RUL ECT must be delivered at multiples of the convulsant threshold (8-12 times according to McCall et al. [37]) to be the most effective [37,38].A randomised trial from 2021 compared the time to clinical improvement in patients with MDD.It showed no significant differences between RUL and BT in terms of rapidity of clinical improvement, response to treatment or disease remission [39].In contrast, in 2002, Heikman et al. showed that the use of high-dose RUL stimulation contributed to a faster reduction in depressive symptoms, and patients required fewer treatments compared to low-dose BF stimulation [14].
In a 2023 systematic review the authors conclude that RUL ECT is associated with a higher risk of developing bradycardia and asystole than in BT and BF [40].Although BT ECT remains the most common form of ECT worldwide, high-dose RUL may be a better alternative for patients with cognitive impairment.According to a meta-analysis by Kolshus et al., electroconvulsive therapy in RUL stimulation is as effective as BT ECT in treating depression, but has a better effect on cognitive functions [41].Also, a randomised clinical trial involving 750 patients showed that the use of high-dose unilateral stimulation resulted in less amnesia than bilateral stimulation [42].While it's important to acknowledge that high-dose RUL ECT can potentially lead to declines in verbal memory, visual recognition, and semantic memory recovery [25], it's worth noting that this treatment option also tends to result in fewer cognitive side effects compared to alternatives.However, it's essential to consider that achieving comparable antidepressant efficacy may necessitate higher doses, which could potentially alleviate these benefits [43].

Efficacy and impact on cognitive function in ECT therapy in bifrontal electrode placement (BF).
BF ECT is being used particularly frequently in Canada and Australia.Researchers are increasingly describing the efficacy of this method in the treatment of depressive disorders [44,45].
It is theorised that moving the electrodes further from the temporal lobes and hippocampus should result in a reduced risk of cognitive impairment after ECT treatments [30].Single photon emission computer tomography (SPECT) indicates increased blood flow in activated brain areas during ECT stimulation.SPECT imaging during BF stimulation shows increased blood flow in the prefrontal cortex and anterior cingulate nerve with little activation of the temporal lobes and subcortical structures [11].However, there has been concern that inducing seizures in the frontal lobes may contribute to impairments in executive function, problem solving, planning and self-control, for which the prefrontal region of the brain is responsible.However, this concern has not been confirmed in randomised trials [11,30].Lawson et al. in a study involving 45 patients suffering from MDD, showed that after six sessions of ECT with the BF method, patients performed better on verbal memory functioning compared to BT stimulation and scored higher on nonverbal memory and planning skills compared to BT and RUL [46].Bailine et al. in a clinical trial involving 48 patients with an episode of major depression, described significantly better scores on the MMSE Test (Mini-Mental Status Examination) in a group of patients following BF stimulation compared to the BT treatment group [47].In 2005, Ranjkesh et al. in a randomised clinical trial involving a group of 45 patients diagnosed with depressive disorders, confirmed that the best MMSE scores were achieved by patients using a moderate dose with BF stimulation compared to high doses in RUL and low doses in BT.And, at the same time, they showed no significant differences in assessing the reduction of depressive symptom severity using all three methods [48].In a randomised clinical trial conducted between 2001 and 2006, the remission rate of depressive disorders after all series of ECT treatments was: 61% in the BF stimulation and 55% in the RUL method.Thus, the BF method was shown to be more effective compared to RUL stimulation [30].Sienaert et al. in a randomised clinical trial, involving 81 patients, showed comparable efficacy of BF and RUL stimulation.Treatment response occurred in 78.1% of the subjects with BF and RUL stimulation.However, long-term remission was reported in 34.38% of the patients in the study group with BF placement and in 43.75% of the patients with RUL stimulation.Therefore, the group of patients treated with BF stimulation required more treatments.No significant difference in cognitive function was shown in the two groups [49].In contrast, Letemendia et al. in a randomised trial showed that BF stimulation stabilised the clinical status of patients with a major depressive episode significantly faster compared to the use of RUL and BT stimulation [31].The authors of the 2011 meta-analysis conclude that BF stimulation is not more effective in treating depression than BT or RUL.The meta-analysis reports that BF stimulation may have short-term benefits in terms of affecting specific memory domains [50].

Results
Multiple studies confirm the effectiveness of all the types of stimulation discussed -BT, RUL and BF in the treatment of depressive disorders [14,23].The opinions of researchers are divided in the selection of a particular technique as the best in clinical practice.There are reports indicating that BT stimulation should be the preferred method of stimulation in urgent cases requiring a rapid treatment response, particularly when MDD coexists with catatonia or other severe comorbidities [24,30].However, BF and RUL may have less of an impact on cognitive functions, such as verbal memory, non-verbal memory or action planning skills [14,46,49].However, it should be emphasised that the cognitive functions described are measured by neuropsychological tests, which are complex in structure and difficult to administer in severely ill individuals, and the assessment of respondents' responses may be subjective.MDD often disturbs memory functioning, so in order to reliably assess clinical improvement in individual patients, neuropsychological tests should also be performed prior to ECT treatment [14].The selection of appropriate stimulus doses of BF, BT and RUL stimulation appears to be important.Indeed, comparable efficacy in reducing depressive symptoms over a given period of time has been shown with high doses of RUL, moderate doses of BF and low-dose BT stimulation [48].Some researchers emphasise the need for a multiple of the convulsant threshold during RUL stimulation to be comparably effective to BT.Despite this, RUL and BF appear to have a milder cognitive side effect profile than BT [47].For this reason, patients with cognitive deficits, multiple comorbidities or when minimising retrograde amnesia is a priority, RUL or BF appears to be the preferred treatment [46,47].No significant differences in treatment efficacy and remission prevention have been demonstrated with RUL or BF.However, BF treatment uses lower doses than RUL and single studies have shown a better profile of effects on cognitive function after BF stimulation [46,48].However, the use of BF is more likely Curr Probl Psychiatry, Vol. 25 (2024) to require more ECT series [14,49].Current international guidelines provide widely different recommendations for the use and dose level of RUL, BT and BF stimulation and in monitoring cognitive function after ECT treatment.Unification of the guidelines would improve the outcomes of ECT treatment, which is, among other things, a form of breaking drug resistance, being a serious clinical problem in daily medical practice [14,[51][52][53][54]. Based on the available literature, according to the researchers, the choice of treatment technique should be based on the individual needs and clinical condition of each patient.Indeed, the way the electrodes are placed during ECT implies different therapeutic effects depending on the individual patient's needs and medical condition [14].