9. Mechanisms of ECT action

Electroconvulsive therapy increases hippocampal and amygdala volume in therapy refractory depression: a longitudinal pilot study. (2013) Tendolkar I, vanBeek M, vanOostrom I et al.
http://dx.doi.org/10.1016/j.pscychresns.2013.09.004
This was an MRI study of 15 anti-depressant free patients who were successfully treated with ECT. There was a significant volume increase in both hippocampus and amygdale but no obvious correlation in degree of volume change with outcome. The authors speculate that multiple mechanisms involving structure and function of different areas of the brain are involved and not just neurogenesis in the hippocampus as suggested by previous studies.

 

Electroconvulsive shock increases SIRT1 immunoreactivity in the mouse hippocampus and hypothalamus. (2013). Chung S, Kim H, Yoon I et al. J of ECT 29; 93-100.
This study demonstrated a change following one electroconvulsive shock in the enzyme ‘silent mating-type information regulation 2 homologue 1’ (SIRT1) which is present in the hippocampus and hypothalamus and is thought to be involved in regulatory processes including mood, neurogenesis, food intake and circadian rhythms. However it is not known if these changes are evident in successful ECT which takes several treatments to take effect and also whether SIRT1 is implicated in the beneficial or side effects of electrical stimulation.

 

Effects of electroconvulsive therapy on brain functional activation and connectivity in Depression. (2012). Beall E., Malone D., Dale R et al. J of ECT; 28:234-241.
The group used MRI scanning to study brain function of six patients undergoing ECT. They found that successful ECT for major depressive disorder was associated with decreased activation to an affective task in a region related to emotional regulation and also an increase in resting connectivity. Reference is made to the Mayberg depression model.

 

Electroconvulsive stimulations prevent chronic stress-induced increases in L-type calcium channel mRNAs in the hippocampus and basolateral amygdala.(2012). Maigaard K, Hageman I, Jorgensen A et al., Neuroscience Letters 516; 24-28.

Calcium ion dysfunction may be involved in the pathophysiology of major depression. In this study stress led to an up-regulation of certain calcium channels markers in the rat brain whilst electroconvulsive stimulation tended to normalise this effect.

Taurine and glutathione levels in plasma before and after ECT treatment. (2012). Samuelsson M, Gerdin G, Ollinger K et al., psychiatry Research. doi:10.1016/j.psychres.2012.02.016.

In this study of 23 patients plasma taurine levels decreased significantly after three ECT treatments in those patients who responded to ECT. Glutathione levels were not affected.

Effects of electroconvulsive stimulation on long-term potentiation and synaptophysin in the hippocampus of rats with depressive disorder. (2012). Li W, Liu L, Liu YY et al., J of ECT; 28:111-117.

This study adds to the growing body of evidence that electroconvulsive stimulation can reverse the damaging effects that chronic stress has on the hippocampus. The underlying mechanism may be related to neuroplasticity and synaptophysin levels modulated by cyclic adenosine monophosphate response element binding protein (CREB)

Electroconvulsive stimulations prevent chronic stress-induced increases in L-type calcium channel mRNAs in the hippocampus and basolateral amygdala (2012). Maigaard K, Hageman I, Jorgensen A et al., Neuroscience Letters 516; 24-28.

Calcium ion dysfunction may be involved in the pathophysiology of major depression. In this study stress led to an up-regulation of certain calcium channels markers in the rat brain whilst electroconvulsive stimulation tended to normalise this effect.

Taurine and glutathione levels in plasma before and after ECT treatment. (2012). Samuelsson M, Gerdin G, Ollinger K et al., psychiatry Research doi:10.1016/j.psychres.2012.02.016.

In this study of 23 patients plasma taurine levels decreased significantly after three ECT treatments in those patients who responded to ECT. Glutathione levels were not affected.

Effects of electroconvulsive stimulation on long-term potentiation and synaptophysin in the hippocampus of rats with depressive disorder. (2012). Li W, Liu L, Liu YY et al., J of ECT; 28:111-117.

This study adds to the growing body of evidence that electroconvulsive stimulation can reverse the damaging effects that chronic stress has on the hippocampus. The underlying mechanism may be related to neuroplasticity and synaptophysin levels modulated by cyclic adenosine monophosphate response element binding protein (CREB)

Electroconvulsive stimulations prevent chronic stress-induced increases in L-type calcium channel mRNAs in the hippocampus and basolateral amygdala(2012). Maigaard K, Hageman I, Jorgensen A et al., Neuroscience Letters 516; 24-28

Calcium ion dysfunction may be involved in the pathophysiology of major depression. In this study stress led to an up-regulation of certain calcium channels markers in the rat brain whilst electroconvulsive stimulation tended to normalise this effect.

Taurine and glutathione levels in plasma before and after ECT treatment. (2012). Samuelsson M, Gerdin G, Ollinger K et al., psychiatry Research doi:10.1016/j.psychres.2012.02.016.

In this study of 23 patients plasma taurine levels decreased significantly after three ECT treatments in those patients who responded to ECT. Glutathione levels were not affected.

Vascular endothelial growth factor (VEGF) serum concentration during electroconvulsive therapy (ECT) in treatment resistant depressed patients (2011). Minelli A, Zanardini R, Abate M et al. Prog Neuro-Psychopharmacol Biol Psychiatry, doi:10.1016/j.pnpbp.2011.04.013.

In this study of 19 patients there was a correlation between improvement following ECT, as measured by a fall in Montgomery Asberg Depression Score, and a rise in serum levels of VEGF at one month post treatment.

The molecular interaction between the glutamatergic, noradrenergic, dopaminergic and serotoninergic systems informs a detailed genetic perspective on depressive phenotypes. (2011). Drago A, Crisafulli C, Sidoti A et al. ScienceDirect Progress in Neurobiology, pii:s0301008211000876.

The authors summarise the various levels of interaction between glutamatergic and monoaminergic pathways in the brain and also list key proteins and coding genes.

Effect of electroconvulsive therapy on serotonin-1A receptor binding in major depressive disorder. (2011). Baldinger P, lanzenberger R, Hahn A et al. Basis and clinical neuroscience P.1.e.022.

Ten patients who responded to a combination of unilateral and bilateral ECT, according to clinical need, underwent PET scanning. There was a significant global decrease in 5-HT1A in depressed patients after ECT with considerable changes in the anterior cingulate cortex, orbitofrontal cortex and sybgenual part of the cingulate cortex.

Post-dexamethasone cortisol as a predictor for the efficacy of electroconvulsive therapy in depresses inpatients. (2011). Vukadin M, Birkenhager T, ,Wierdsma A et al. J of Psychiatric Research 45; 1165-1169.

This was a prospective study of 18 patients who met DSM-IV criteria for depressive disorder. Response to ECT was associated with increased response to dexamethasone leading the authors to suggest that this test might be a useful indicator of efficacy.

Asymmetric alteration of the hemodynamic response at the prefrontal cortex in patients with schizophrenia during electroconvulsive therapy: a near-infrared spectroscopy study. (2011). Fujita Y, Takebayashi M, Hisaoka K et al.Brain Research 1410; 132-140.

The group studied the spectroscopy scans of 11 patients with schizophrenia and 10 patients with mood disorder. Bilateral ECT caused haemodynamic changes in bilateral pre-frontal cortex and asymmetric alteration was found for schizophrenia, but not for mood disorders.

Analysis of target genes regulated by chronic electroconvulsive therapy reveasl role for Fzd6 in depression. (2012). Voleti B, Tanis K, Newton S et al. Biol Psychiatry; 71: 51-58.

 

Chronic electro-convulsive stimulations of rat brain resulted in enhanced cyclic adenosine monophosphate response element biding protein (CREB) binding and activity at selected genes in the hippocampus. Inhibition of the Fzd6 gene resulted in anxiety and depressive like effects.

Mode of action of electroconvulsive therapy: an update. (2011). Scott A. Advances in Psychiatric treatment, vol 17, 15-22.

Dr Scott reviews published studies dating back some 30 years and points out that our knowledge of the way in which ECT works is greater than we give credit for. Useful summary boxes include practical implications for the prescriber and practitioner and evidence for considering more than just the monoamine hypothesis in mode of action. The neuroanatomy of major depression and evolvinf teories onthe mode of action of antidepressant drugs are described.

Antidepressant electroconvulsive therapy: mechanism of action, recent advances and limitations. (2009). Merkl A, Heuser I, Bajbouj M. Experimental Neurology. 219, 20-26.

The authors acknowledge that ECT has stood the test of time even with the introduction of other physical therapies. The article contains sections on history and reviews of possible mechanism of action, efficacy data and adverse effects as well as anaesthetic concerns and possible interactions with prescribed medication.

Neurophysiological mechanisms of electroconvulsive therapy for depression. (2009). Nobuo Kato. Neuroscience Research. 64, 3-11.

A study of the Homer 1a scaffold protein present in neural circuits and induced by electroconvulsive stimulation (ECS). The resultant effect is a reduction in neuronal excitability and presumed modification of the synaptic plasticity. The author postulates that this may tie in with the GABAergic dysfunction hypothesis of depression which features increased excitability of the cerebral cortex in depressed patients.

Chronic treatment with electroconvulsive shock may modulate the immune function of macrophages. (December 2008) Roman A, Nawrat D, Nalepa I. J of ECT; 24;260-267.

The theory being postulated is that an increased number or increased activity of macrophages and their metabolites compared to normal response in the immune system results in depressive illness. Repeated electroconvulsive stimulation (ECS) was shown to change the biological properties of macrophages, reducing their tendency to cause inflammation without damaging their strucure.

Neurobiological correlates of the cognitive side effects of electroconvulsive therapy. March 2008. Nobler M & Sackeim H. J of ECT; 24:40-45.

This review highlights some of the biochemical, electrophysiological and neuroimaging correlates of amnesic effects of ECT. Brain regions associated with the therapeutic effects of ECT overlap with regions critical for cognitive side effects. The data suggest: [1] the neurophysiological alterations associated with retrograde and anterograde amnesia are distinct, [2] altered function in the prefrontal cortex may be associated with retrograde amnesia cf medial temporal lobe, [3] short term cerebral physiological changes as measured by PET scans may predict longer term retrograde amnesia.

Pharmacological attenuation of electroconvulsive therapy-induced cognitive deficits: theoretical background and clinical findings. March 2008. Pigot M, Andrade C, Loo C. J of ECT, 24:57-67.

Evidence now exists for the involvement of glutaminergic, cholinergic and glucocorticoid mechanisms in the genesis of cognitive side effects at ECT. Other systems have also been considered eg calcium channels, thyroid hormones, nitric oxide, opioid transmission and the hypertensive surge. As such there lies the potential for the development of neuroprotective strategies, as yet none emerge as superior.

Change in seizure threshold during electroconvulsive therapy. June 2008. Fink M et al. J of ECT; 24:114-116

This was a naturalistic study of 80 subjects entered for maintenance ECT after remission using bilateral treatment at 1.5 times seizure threshold. Retitration of the seizure threshold after remission showed no increase in 70% compared to that prior to treatment and a decrease in 9%. This study does not support the view that ECT exerts its benefit via anticonvulsant effects.

Electroconvulsive therapy, brain-derived neurotrophic factor, and possible neurorestorative benefit of the clinical application of electroconvulsive therapy. June 2008, Taylor S. J of ECT; 24:160-165.

This article describes the association of brain derived neurotrophic factor (BDNF) with hippocampal size and function, both low in treatment resistant depression. ECT results in an increase in BDNF and so may have a positive effect in restoring hippocampal grey matter.

The effects of electroconvulsive therapy on GABAergic function in major depressive patients. September 2008. Esel E et al. J of ECT; 24:224-228.

GABA levels were measured before and after ECT in 25 depressed patients compared to matched controls. Depressed patients had lower GABA at the outset and ECT caused a significant increase in levels post treatment although not to the level of healthy controls. ECT also appeared to potentiate growth hormone release to a baclofen challenge, a measure of GABAb receptor activity in the hypothalamus.

Metabolic correlates of antidepressant and antipsychotic response in patients with psychotic depression undergoing electroconvulsive therapy. McCormick L. et al. December 2007. J of ECT;23:265-273.

Positron emission tomography was used to assess cerebral glucose metabolism in ten subjects before and after a course of ECT. Antidepressant efficacy was associated with increased metabolism in the left subgenual anterior cingulated cortex and the hippocampus. Reduction in antipsychotic symptoms was associated with increased metabolism in the left hippocampal region.

CREB binding and activity in brain: regional specificity and induction by electroconvulsive seizure. Tanis K, Duman R, Newton S. 2008, Biological Psychiatry (in press)

The group looked at cyclic AMP response element binding (CREB) receptor sites in the rat brain and conclude that CREB is an important mediator of the biological responses to electroconvulsive therapy seizure. Also that such studies play an important role in understanding psychiatric and cognitive function.

Long-term follow up in depressed patients treated with electroconvulsive therapy. Johanson et al. J of ECT 2005;21(4):214-220.

This was a study of ten patients who underwent neurophysiological measurements with regional cerebral blood flow and EEG before the first ECT, 6 months later and after approximately 1 year. The authors found a lower, but not significant, bilateral cerebral frontal flow compared to controls at one year follow up. Eight patients had a normal EEG.

Electroconvulsive seizures induce angiogenesis in adult rat hippocampus. Hellsten et al. Biological Psychiatry 2005;58:871-878.

This paper describes animal model experiments using convulsive stimulations. The authors postulate that the beneficial effects of ECT result from increased vascularisation of the hippocampus.

Non convulsive seizures in electroconvulsive therapy: further evidence of differential neurophysiological aspects of bitemporal versus bifrontal electrode placement. Teman P et al. J of ECT 2006; 22(1):46-48.

This article discusses the possible reasons for the different rates of non-convulsive seizures seen with different types of ECT and postulates that bifrontal ECT is more likely to generate non-convulsive seizures localised to the frontal lobes.

Effects of right unilateral electroconvulsive therapy on motor cortical excitability in depressive patients. Bajbouj M et al. J of Psychiatric Research 2005 (in press).

The reduction in seizure duration in the course of ECT was associated with clinical improvement and an increase in intracortical inhibition. The authors postulate GABA-ergic neurotransmission involvement and refer to similar studies.

Metabolic Changes within the Left Dorsolateral Prefrontal Cortex occurring with Electroconvulsive Therapy in patients with Treatment Resistant Unipolar Depression. Michael N et al; Psychological Medicine. October 2003. 33(7):11277-1284.

Proton STEAM Spectroscopy was used to study metabolic changes in the dorsolateral prefrontal cortex (DLPFC) pre and post ECT in 12 severely depressed patients. The DLPFC glutamate/glutamine levels correlated negatively with severity of depression. Successful ECT resulted in an increase in the level of glutamate/glutamine to that of the control group.

Raised Plasma levels of Tumour Necrosis Factor (alpha) in Patients with Depression. Hestad K et al; Journal of ECT. December 2003. 19:183-188.

Tumour Necrosis Factor (TNF) is an indication of inflammation and was found to be high in the fifteen patients studied, returning to normal after successful ECT. Factors such as concomitant medication were controlled for and patients excluded if other sources on inflammation detected. The TNF of those depressed patients not receiving ECT remained high.

Increased Cortical GABA Concentrations in depressed Patients Receiving ECT. Sancora G et al. Am J of Psychiatry March 2003, 160: 577-579.

Occipital cortex GABA concentrations in eight depressed patients were measured before and after a course of ECT. A significant increase in GABA was seen following treatment. Treatment was terminated solely on the basis of clinical judgement and outcome was measured by a fall in the Hamilton Rating Scale for Depression.

Relationship between Prolactin Responses to ECT and Dopaminergic and Serotonergic Responsivity in Depressed Patients. Markianos et al. European Archives of Psychiatry & Clinical Neuroscience, 2002, Vol 252 Issue 4, p166-172.

This study on 15 male depressed patients matched with 15 male controls concludes that the rise in prolactin levels seen at ECT is a reflection of a decrease in the dopamine mediated inhibitory hypothalamo-pituitary system.

Electroconvulsive Stimuli Alter the Regional Concentrations of Nerve Growth Factor, Brain-Derived Neurotrophic Factor in Adult Rat Brain. Angelucci F et al. Journal of ECT. 18(3):138-143.

This research on rat brains indicate that neurotrophic factors play a role in the mechanism of action of ECS and, by extrapolation, may play a role in the mechanism of ECT.

Magnetic and seizure thresholds before and after six electroconvulsive therapy treatments. Amiaz R et al. Journal of ECT. September 2001, 17(3): 195-197.

This study was designed to determine if there was a common mechanism for the effectiveness of ECT and TMS in terms of their effect on seizure and magnetic threshold. It concluded that there was not but of interest is the fact that the seizure threshold rose on average by a factor of x5.

The effects of electroconvulsive therapy on melatonin. Krahn et al. December 2000, J of ECT, 16(4):391-398.

Results from a study of 14 patients suggesting an association between therapeutic response and a decrease in endogenous melatonin production post ECT.

Electrophysiological correlates of the adverse cognitive effects of electroconvulsive therapy. Sakeim H et al. June 2000, J of ECT 16(2):110-120.

Further evidence to support the observation that post-ictal disorientation is related to post-ECT retrograde amnesia. These may share a common mechanism detectable by EEG.

Quantitative EEG during seizures induced by electroconvulsive therapy: relations to treatment modality and clinical features; I global analyses. Nobler MS et al, September 2000, Journal of ECT, Vol 16, no3, 211-228.

The authors conclude that manipulations of ECT technique strongly determine the magnitude of seizure expression, but relations with clinical outcome are weak thereby casting doubt on the analysis of EEG features to determine machine settings.

Quantitative EEG during seizures induced by electroconvulsive therapy: relations to treatment modality and clinical features; II topographical analyses. Luber et al. September 2000, Journal of ECT, Vol 16, no3, 229-243.

The companion study looking for EEG supports for the mechanisms of ECT. The authors report evidence for
i) transcortical EEG changes and superior clinical outcome (small effect size)
ii) superior clinical outcome associated with more intense seizure expression in the prefrontal regions.
but no evidence for efficacy in relation to stimulation of the deep brain structures.

Electroconvulsive therapy and the alpha-2 noradrenergic receptor: implications of treatment schedule effects. Andrade C & Sudha S. September 2000, J of ECT, 16(3):268-278.

Six animal studies designed to look at the noradrenergic system concluded that ECS produces time dependent downregulation of the alpha-2 receptor. Maintenance ECS produced sustained downregulation.

Bolwig T, Woldbye D, Mikkelsen J, (1999), Electroconvulsive therapy as an anticonvulsant: a possible role of neuropeptide Y. Journal of ECT, 15(1):93-101.

Duman R. & Vaidya V., (1998), Molecular and cellular actions of chronic electroconvulsive seizures. Journal of ECT, 14(3):181-193

Hiroi N., Marek G., Brown J. et al., (1998), Essential role of the fosB gene in molecular, cellular and behavioural actions of chronic electroconvulsive therapy seizures. Journal of neuroscience, 18(17):6952-6962.

Krystal A.D., Weiner R.D., (1999),EEG correlates of the response to ECT: A possible antidepressant role of brain-derived neurotrophic factor. Journal of ECT. 15(1):27-38.

Mann J, (1998), Neurobiological correlates of the antidepressant action of electroconvulsive therapy. , Journal of ECT, 14(3):172-180

Mathe A. (1999), Neuropeptides and electroconvulsive treatment. Journal of ECT, 15(1):60-75.

Newman M., Gur E. et. al. (1998),Neurochemical mechanisms of the action of ECS: evidence from in vivo studies. Journal of ECT, 14(3):153-171.

Sackeim H., (1999), The anticonvulsant hypothesis of the mechanisms of action of ECT: current status. Journal of ECT, 15(1):5-26

Sattin A., (1990), The role of TRH and related peptides in the mechanism of action of ECT. Journal of ECT, 15(1):76-92.