Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression

Michael, Nikolaus; Erfurth, Andreas; Ohrmann, Patricia; Arolt, Volker; Heindel, Walter; Pfleiderer, Bettina

doi:10.1017/s0033291703007931

Cited by 229 publications

(139 citation statements)

References 36 publications

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“…13 We did not observe changes in Glx levels, either in the whole group or in TMS-responder or nonresponder subgroups. Glx levels have been found to be reduced in the MPFC at baseline in patients with depression, 22 and these levels have normalized in the lateral prefrontal cortex, 31 …”

Section: Discussionmentioning

confidence: 99%

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

Dubin

Mao

Banerjee

et al. 2016

jpn

113

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IntroductionTranscranial magnetic stimulation (TMS) is an effective treatment for major depressive disorder (MDD), particularly in individuals resistant to first-line antidepressants.1-3 Effect sizes of TMS from recent meta-analyses range from 0.39 to 0.55. 4,5 Less is known about the neurobiological mechanisms of antidepressant response to TMS. Emerging evidence suggests that in addition to its effects on the dorsolateral prefrontal cortex (DLPFC), TMS also affects structures to which the DLPFC projects, including the medial prefrontal cortex (MPFC). 6 The MPFC is overactive in individuals with MDD,7 and functional connectivity between the DLPFC and MPFC predicts response to TMS. [8][9][10] Little is known about how connectivity between the DLPFC and MPFC gives rise to the antidepressant effect of TMS.Other antidepressants appear to act in part by modulating the excitability of cortical circuits. Levels of γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, which are generally decreased in depressed individuals, 11 have been reported to increase after treatment with selective serotonin reuptake inhibitors (SSRIs) 12 and electroconvulsive therapy (ECT).13 Although TMS affects the balance of excitation and inhibition in cortical circuits, 14 it is unknown whether changes in excitation-inhibition balance mediate antidepressant response.In this naturalistic study, we tested whether TMS alters the levels of GABA and those of the combined resonance of glutamate and glutamine (Glx) in patients with MDD. Specifically, the standard J-edited spin echo difference proton magnetic resonance spectroscopy ( 1 H MRS) technique was implemented at 3 T to measure levels of MPFC GABA and Background: GABAergic and glutamatergic neurotransmitter systems are central to the pathophysiology of depression and are potential targets of repetitive transcranial magnetic stimulation (rTMS). We assessed the effect of 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) of patients with major depressive disorder on the levels of medial prefrontal cortex (MPFC) γ-aminobutyric acid (GABA) and the combined resonance of glutamate and glutamine (Glx) as assessed in vivo with proton magnetic resonance spectroscopy ( 1 H MRS). Methods: Currently depressed individuals between the ages of 23 and 68 years participated in a 5-week naturalistic, open-label treatment study of rTMS, with 1 H MRS measurements of MPFC GABA and Glx levels at baseline and following 5 weeks of the rTMS intervention. We applied rTMS pulses over the left DLPFC at 10 Hz and 80%-120% of motor threshold for 25 daily sessions, with each session consisting of 3000 pulses. We assessed therapeutic response using the 24-item Hamilton Rating Scale for Depression (HAMD24). The GABA and Glx levels are expressed as ratios of peak areas relative to the area of the synchronously acquired and similarly fitted unsuppressed voxel water signal (W). Results: Twenty-three currently depressed individuals (7 men) participated in the study. GABA/W in the MPFC i...

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Section: Discussionmentioning

confidence: 99%

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

Dubin

Mao

Banerjee

et al. 2016

jpn

113

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“…33 Studies in depressed patients have found decreased frontal cortical measures of glutamate measured in vivo by magnetic resonance spectroscopy (MRS), which normalise with effective treatment. 32 In studies involving ECT, reduced pretreatment glutamate and glutamate-related concentrations have been found in the dorsolateral prefrontal cortex 34 and ACC 35,36 and these either normalised after ECT 34,36 or predicted treatment response. 35 Glutamate also has a central role in cognition, especially learning and memory, through its role in synaptic plasticity and the signalling pathway involved in long-term potentiation in the hippocampus.…”

Section: Clinical Use Of Electroconvulsive Therapymentioning

confidence: 99%

Randomised controlled trial of ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT study)

et al. 2017

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BackgroundElectroconvulsive therapy (ECT) is the most effective acute treatment for severe depression, but there are concerns about its adverse cognitive effects. ECT may impair cognition through stimulation of glutamate receptors, and preliminary evidence has suggested that ketamine, a glutamate antagonist, may alleviate these effects. Ketamine has been shown to have a rapid, but temporary, antidepressant effect after a single infusion.ObjectiveTo determine the efficacy and safety of adjunctive low-dose ketamine to reduce cognitive impairments caused by ECT and, secondarily, to improve symptomatic outcome.DesignMulticentre, two-arm, parallel-group, patient-randomised, placebo-controlled superiority trial.SettingEleven ECT suites based in seven NHS trusts in the north of England.ParticipantsSeverely depressed hospitalised patients or outpatients who received ECT as part of their usual clinical care.InterventionsPatients were randomised to ketamine (0.5 mg/kg) or saline as an adjunct to their anaesthetic for their ECT course in a 1 : 1 ratio.Main outcome measuresThe primary outcome was delayed verbal recall on the Hopkins Verbal Learning Task – Revised (HVLT-R) after four ECT treatments (mid-ECT), analysed using a Gaussian repeated measures model. Secondary outcomes included autobiographical, working and visual memory and verbal fluency, symptoms and quality of life; assessments occurred at mid-ECT, end of treatment and 1 and 4 months after the last ECT. Neuropsychological function was compared with that of healthy control subjects and a functional near-infrared spectroscopy (fNIRS) substudy investigated prefrontal cortex function. A patient survey of study participation was carried out.ResultsSeventy-nine severely depressed patients were randomised to ketamine (0.5 mg/kg) or saline as an adjunct to their anaesthetic for their ECT course; the modified intention-to-treat sample included 70 patients. Compared with saline, adjunctive ketamine had no significant effect on HVLT-R delayed recall [treatment effect difference –0.43, 95% confidence interval (CI) –1.73 to 0.87], other neuropsychological outcomes, improvement in depression [difference in Montgomery–Åsberg Depression Rating Scale (MADRS) score of 0.44, 95% CI –1.03 to 1.91], the number of ECT treatments to remission (MADRS score of ≤ 10: 0.83, 95% CI –3.2 to 4.9), anxiety symptoms or quality of life. By the end of ECT treatment, 37% (saline 35%, ketamine 39%) of patients had remitted. Tolerability was similar in the two treatment arms; two patients had isolated transient psychological effects attributable to ketamine. Preliminary fNIRS analysis found that patients had blunted prefrontal cortical haemodynamic responses compared with control subjects during a verbal fluency task at baseline; this was further diminished at mid-ECT without modulation by ketamine. Greater haemodynamic responsivity to ECT appeared to be associated with a better clinical response. The majority of patients surveyed reported a positive experience of study participation.ConclusionsThe results of the study do not support the use of adjunctive ketamine in routine ECT treatment in the NHS. Although no evidence of benefit was found for ketamine, moderate benefits or harms cannot be excluded, as recruitment was < 50% of that planned, limiting the power of the clinical trial. Low numbers also meant that in the fNIRS substudy the effect of ketamine could not be assessed and the other findings must be viewed as preliminary. Included patients were younger than those not included and had only limited cognitive impairment with ECT, limiting generalisation to more cognitively compromised patients. fNIRS appeared to be a potentially feasible portable brain imaging technology in severely ill patients and further research is warranted to investigate its clinical utility.Trial registrationCurrent Controlled Trials ISRCTN14689382.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

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“…It can be speculated that the functional difference between the left and right HPCs affected our results, as shown by the laterality of NMDA receptor distribution in the HPCs in a previous study (Goto et al, 2010). Since ECT is suggested to alter NMDA receptor (Park et al, 2014) and glutamate/glutamine expression levels (Michael et al, 2003), the asymmetric effects of ECT on neuronal HPC circuits associated with NMDA might occur after ECT. Further studies to reveal the pathophysiological mechanisms underlying the long-term effects of ECT on brain function are neces- There were several limitations in this study.…”

Section: Discussionmentioning

confidence: 72%

Can We Find Any Sustained Neurofunctional Alteration in Remitted Depressive Patients with a History of Modified Electroconvulsive Therapy?

Saito¹,

Fujihara²,

Kasagi³

et al. 2017

OJD

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Background and Aim: Recent magnetic resonance imaging (MRI) studies have revealed structural and functional differences in the human brain before and after an electroconvulsive therapy (ECT) series in patients with depression. The hippocampus is one of the well-documented subcortical areas that show an increase in cortical volume following an ECT series. Moreover, some resting-state functional MRI studies have shown that an ECT series alters the connectivities of the hippocampus with several brain areas. However, it remains unknown whether ECT can induce some sustained neurofunctional alterations in the human brain. Methods: In this study of the depressive patients with and without a history of modified ECT (N = 5 and 9, respectively) using a cross-sectional design, we investigated the functional connectivity between the left and right hippocampi in terms of blood-oxygenation-level dependent signal changes with time by resting-state functional MRI. Results: Voxel-based morphometry showed no significant structural differences in hippocampal volume between the ECT and non-ECT groups. The ECT group showed a significantly lower functional connectivity between the same brain areas than the non-ECT group (p < 0.01). Conclusions: Although their clinical significance remains unclear, our results suggest that an ECT series induces a sustained neurofunctional alteration in the human brain.

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Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression

Abstract: Our results indicate that major depressive disorder is accompanied by state-dependent metabolic alterations, especially in glutamate/glutamine metabolism, which can be reversed by successful ECT.

Cited by 229 publications

References 36 publications

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

Randomised controlled trial of ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT study)

Can We Find Any Sustained Neurofunctional Alteration in Remitted Depressive Patients with a History of Modified Electroconvulsive Therapy?

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