INVITED REVIEW
Neurotransmitters and Electroconvulsive Therapy Pia Baldinger, MD,* Amit Lotan, MD,† Richard Frey, MD,* Siegfried Kasper, MD,* Bernard Lerer, MD,† and Rupert Lanzenberger, MD* Objectives: Electroconvulsive therapy (ECT) is a well-established effective treatment strategy in treatment-refractory depression. However, despite ECT’s widespread use, the exact neurobiological mechanisms underlying its efficacy are not fully understood. Over the past 3 decades, extensive work in rodents, primates, and humans has begun to delineate the impact of electroconvulsive seizures (ECS) and ECT on neurotransmission systems commonly implicated in depression. In the current review, we will focus on two major biogenic amine systems, namely serotonin and dopamine. Methods: The database of PubMed was searched for preclinical studies describing the effects of ECS on the serotonergic and dopaminergic system using behavioral sensitization paradigms, in vivo brain microdialysis, messenger RNA and protein expression, electrophysiology, and positron emission tomography. Additionally, human data describing ECT’s effects on neurotransmitter turnover, receptor binding, and functional imaging were reviewed together with relevant genetic association studies. Results: Literature research resulted in 40 published original studies related to ECS/ECT and the serotonergic system, whereby only three were studies in humans. Regarding dopamine, 15 preclinical and 12 human studies were found in PubMed database. Conclusions: Converging data obtained from genetic and imaging studies in humans have corroborated many of the earlier preclinical and clinical findings relating to enhancement of serotonergic neurotransmission and activation of the mesocorticolimbic dopamine system after ECS/ECT. Moreover, it seems that these effects are evident at various levels, including neurotransmitter release, receptor binding, and overall neurotransmission. Future studies combining convergent modalities could enhance our understanding of the mechanisms underlying ECT’s profound antidepressant effect and would support the development of better pharmacological and somatic treatment approaches for refractory depression. Key Words: electroconvulsive therapy, neurotransmitters, serotonin, dopamine, antidepressant From the *Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria and †Biological Psychiatry Laboratory at Hadassah, Hebrew University Medical Center, Jerusalem, Israel. Received for publication February 11, 2014; accepted March 17, 2014. Reprints: Rupert Lanzenberger, MD, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18–20, A-1090 Vienna, Austria (e‐mail: [email protected]). Pia Baldinger and Amit Lotan contributed equally to this work. Without any relevance to this work, S. Kasper declares that he has received grant/research support from Eli Lilly, Lundbeck A/S, Bristol-Myers Squibb, Servier, Sepracor, GlaxoSmithKline, Organon, Dr. Willmar Schwabe GmbH & Co. KG, and has served as a consultant or on advisory boards for AstraZeneca, Austrian Sick Found, Bristol-Myers Squibb, German Research Foundation (DFG), GlaxoSmithKline, Eli Lily, Lundbeck A/S, Pfizer, Organon, Sepracor, Janssen, and Novartis and has served on speakers’ bureaus for AstraZeneca, Eli Lilly, Lundbeck A/S, Servier, Sepracor, and Janssen. R. Lanzenberger received travel grants and conference speaker honoraria from AstraZeneca, Lundbeck A/S, and Roche Austria GmbH. R. Frey declares that he has received grants and research support from Bristol-Myers Squibb, AstraZeneca, Sandoz, Eli Lilly, and Janssen. P. Baldinger received travel grants from Roche Austria GmbH and AOP Orphan Pharmaceuticals AG. B. Lerer has received grants for studies unrelated to this work from the Israel Ministry of Science and Technology, the Israel Ministry of Economics, Trade and Industry, the Israel Science Foundation, Israel Academy of Sciences, the European Union, St Jude Medical, and Janssen Pharmaceuticals and has served as a paid consultant to St Jude Medical, Anima Scan Ltd, and Taliaz Diagnostics on unrelated projects. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/YCT.0000000000000138
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O
ver the years, research has attempted to define a relationship between different neurotransmitter systems and symptoms or manifestations of psychiatric syndromes. With regard to major depression, the significant involvement of at least 3 transmitter systems, specifically serotonin, noradrenaline, and dopamine, is largely uncontested. This understanding is based on a vast library of basic research, from animal studies to neuroimaging and genetic data, and is solidified by clinically validated pharmacological treatment options that specifically target key proteins of these transmitter networks in depressive patients, such as selective serotonin reuptake inhibitors (SSRIs). Electroconvulsive therapy (ECT) is a well-established effective treatment strategy in treatmentrefractory depression involving an electrical stimulus of the brain that provokes a therapeutic seizure.1–3 Aside from transient cognitive adverse effects after repeated treatments,4 ECT is a welltolerated therapy and was shown to be associated with response rates of 60% to 80%.1,5 Despite the frequent and widespread use of ECT for more than 70 years, the exact neurobiological mechanisms underlying its efficacy remain to be fully understood. As a result, the effect of ECT on cerebral blood flow and metabolism has been evaluated, and its impact on synaptic plasticity and neurogenesis has recently been investigated.6 Additionally, extensive work in rodents as well as in human subjects has been performed to characterize the impact of ECT on various neurotransmitter systems.6,7 Focus has been laid on the evaluation of ECT’s mechanism of action via modulation of neurotransmitters that are implicated in antidepressant actions, such as serotonin, as ECT was shown to lead to similar or even better effects than pharmacological agents currently in use.8,9 This review will focus on the relationship between major neurotransmitter systems underlying the pathogenesis of major depression and the mechanisms of action of ECT as well as provide a comprehensive overview over the current literature. This paper will specifically address serotonergic and dopaminergic (DA) neurotransmission focusing on both animal and human studies, as the availability of radioligands for the imaging of these neurotransmitter systems has led to a wealth of literature.
MATERIALS AND METHODS The database of PubMed was searched for both preclinical and clinical studies describing the effects of electroconvulsive seizures and ECT on the serotonergic and DA neurotransmitter systems, respectively. Various methodologies, such as behavioral sensitization paradigms, in vivo brain microdialysis, messenger RNA (mRNA) and protein expression, electrophysiology, and functional brain imaging, particularly positron emission tomography (PET), were applied in the reviewed investigations. Studies in rodents, primates, and humans were included in the review depending on their relevance to the subject. In total, 40 studies were reviewed related to electroconvulsive shocks (ECS)/ECT and the serotonergic system, including the serotonin transporter as well as the serotonin 1A and 2A receptors. Most of the original research articles were preclinical findings in rodents; one study included nonhuman primates, and 3 investigations were human studies. Regarding dopamine, 15 preclinical studies describing the effects Journal of ECT • Volume 30, Number 2, June 2014
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of ECS on dopamine concentration, transport, neurotransmission, and behavior were reviewed. These studies mainly used rats as a preclinical model, although a few recent studies have included primates as well. Additionally, 12 clinical studies assessing the effects of ECT on DA parameters in humans, using different approaches such as cerebrospinal fluid analysis, imaging, and genetics, were reviewed.
Serotonin and ECT Preclinical Data Those aiming to elucidate a modulatory effect of ECT on neurotransmission have focused on the effects of ECS on the serotonergic system as the amount of studies conducted in this field, including those using electrophysiological methods, microdialysis, and preclinical experiments in rodents, is extensive.7,10
Serotonin-1A Receptor Originally, Goodwin et al11 suggested a role for the serotonin1A (5-HT1A) receptor in the effects of ECS by determining that repeated ECS leads to an attenuation of 5-HT1A–mediated effects, namely, the hypothermic response in rodents to 8-hydroxy-2-(din-propylamino)tetralin (8-OH-DPAT), which is thought to be regulated via presynaptic 5-HT1A receptors. Subsequently, particular attention has been paid to the hippocampus, as hippocampal functions are primarily regulated by the serotonergic system, which is highly involved in both the pathobiological diagnosis and treatment of depression.12 In this context, de Montigny13 showed that the responsiveness of hippocampal pyramidal neurons to microiontophoretic applications of serotonin and the postsynaptic agonist 5-methoxydimethyltryptamine was markedly increased after repeated ECS in rats, indicating a postsynaptic serotonin receptor sensitization, which is similar to observations after the administration of tricyclic antidepressants14 and might substantially mediate antidepressants effects.15 This finding was confirmed by a study conducted by Chaput et al,16 which additionally showed that ECS, in contrast to the SSRI paroxetine, did not attenuate the negative feedback exerted by serotonin-1A autoreceptors on serotonin release, suggesting that the effect of ECS is solely mediated by postsynaptic serotonin-1A receptors. Moreover, ECS were shown to exert receptor subtype specific, temporally and anatomically selective effects on 5-HT receptor expression17: 5-HT1A receptor mRNA was increased after repeated ECS in the dentate gyrus, whereas it was decreased in the CA4 hippocampal region after single and repeated ECS, with parallel alterations in [3H]8-OHDPAT binding, respectively.17 Additionally, repeated ECS were accompanied by an increase of serotonin-2A (5-HT2A) receptor mRNA and [3H]ketanserine binding.17
Serotonin-2A Receptor Most studies investigating the effects of ECS on 5-HT2A receptors, which are mainly located postsynaptically in cortical brain areas, postulate an increased 5-HT2A receptor number in the cerebral cortex. This is paralleled by enhancement of 5-HT2A gene expression after chronic ECS, as has been shown in a rodent model.7 Burnet et al18 found repeated ECS to increase 5-HT2A mRNA in the neocortex in rats and that increased responsiveness of the serotonergic system after chronic ECS was shown to be mediated by an increase of 5-HT2A receptor density.19,20 However, in a study applying [18F]setoperone to nonhuman primates, ECS led to a decreased 5-HT2A–binding potential in cortical regions,21 which is in accordance with findings retrieved from pharmacological studies showing that various antidepressants cause a downregulation of cerebral 5-HT2A receptors.22–25 These discrepancies implicate species differences in cortical circuits and the mediation of antidepressant treatment response. © 2014 Lippincott Williams & Wilkins
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Serotonin Transporter Another key molecule of the serotonergic neurotransmission is the serotonin transporter (5-HTT), which is the primary target of the most commonly used antidepressants, particularly SSRIs. Findings regarding the effects of ECS on the number of 5-HTT in rodents are inconsistent and scarce. Interestingly, 5-HTT binding was shown to be unaltered in rats using [3H]paroxetine,26 and 5-HTT mRNA in the dorsal raphe was unchanged after repeated ECS.17 However, Hayakawa et al27 determined an increased number of serotonin uptake sites in the frontal cortex after single and repeated ECS, and this finding was confirmed by Shen et al28 who showed that repetitive ECS stably increased 5-HTT in rats’ frontal cortex but not hippocampus and dorsal raphe. A possible explanation might be that the increased protein expression in the frontal cortex represents a compensatory mechanism to the enhanced serotonergic neurotransmission by ECS.
Human Data Compared to the abundance of data describing the effects of ECS on serotonergic neurotransmission in animals, research in humans in this field remains scarce.
Serotonin-1A Receptor To the best of our knowledge, there are two recent studies using PET investigating the effects of ECT on 5-HT1A receptor binding in patients with major depression. In 2010, Saijo et al29 published a study including 9 depressed patients undergoing 6 to 7 bilateral ECT sessions and showed unaltered 5-HT1A receptor binding using the radioligand [carbonyl 11C]WAY-100635 even after recovery from depressive episode. This finding is in line with preclinical studies reporting no changes of 5-HT1A receptor binding after chronic ECS30,31 and indicates the involvement of neurotransmitter mechanisms other than 5-HT1A receptor alterations in the mode of action of ECT. However, our research group conducted a very similar study including 12 severely depressed patients undergoing a mean of 10 ECT sessions and a global reduction of 5-HT1A receptor binding in the anterior cingulate cortex including its subgenual part, the orbitofrontal cortex, the amygdala, the insula, and the hippocampus was detected (Fig. 1).32 This finding is in accordance with the previously described preclinical study conducted by Burnet et al17 that shows a decreased 5-HT1A receptor mRNA in the CA4 hippocampal region, as well as with the reported reduced 5-HT1A receptor binding in the hippocampus and the anterior cingulate cortex after a 12-week treatment with escitalopram in patients with anxiety disorders.33 However, they stand in contrast to extensive studies reporting enhanced serotonergic neurotransmission after chronic ECS.13,16 This contradiction may be ascribed to species differences as seen with regard to the 5-HT2A receptor. The discrepancies between the study published by Saijo et al29 and our paper32 might be explained by methodological differences but also the number of administered ECT, the sex distribution (predominance of men in the study by Saijo et al), and population differences (Asian vs white patients).32 In our study, changes in Hamilton Depression Rating Scale after ECT, reflecting treatment-response, were unaffected by variations of 5-HT1A receptor binding which indicates that the effect of ECT on 5-HT1A receptor binding is dose-independent.32
Serotonin-2A Receptor More than 20 years ago, before functional brain imaging techniques were available, Shapira et al34 determined an enhanced serotonergic responsivity to ECT in patients with major depression using a neuroendocrine measurement, namely, the prolactin response to fenfluramine challenge, which reflects serotonin www.ectjournal.com
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FIGURE 1. Average serotonin-1A (5-HT1A) receptor binding potential (BPND) of patients with major depression (n = 12), superimposed on a T1-weighted magnetic resonance imaging template in Montreal Neurologic Institute space, before (A) and after (B) ECT using PET and the radioligand [carbonyl 11C]WAY-100635. Note that 5-HT1A BPND is reduced across almost the entire cortex after ECT. Color table indicates 5-HT1A BPND. Adapted from Lanzenberger et al.32 (All permission requests for this image should be made to the copyright holder).
release. Yatham et al35 investigated the effects of ECT on 5-HT2A receptors in major depression and demonstrated a widespread reduction of 5-HT2A receptor binding in the bilateral occipital cortex, the medial parietal cortex, the limbic cortex, and the bilateral prefrontal cortex using [18F]setoperone in 15 depressed patients (Fig. 2). This is in complete agreement with a high number of studies showing a 5-HT2A receptor down-regulation by various antidepressants and suggests that this mechanism might substantially mediate antidepressant effects.23,24 As already mentioned, this is in accordance with the observations made in nonhuman primates but not in rodents (Fig. 2).21,36 Changes of [18F]setoperone binding were not significantly related to clinical improvement as assessed using Hamilton Depression Rating Scale.35
Dopamine and ECT Preclinical Data Dopamine Levels In rodents, repeated electroconvulsive stimulation has consistently been found to enhance brain dopamine function. A 10-fold increase of interstitial dopamine concentrations in the striatum after acute ECS was demonstrated using in vivo brain microdialysis in rats, and this dopamine is of neuronal origin.37,38 Interestingly, this effect was not seen with chemically (flurothyl) induced seizures.38 Moreover, a higher voltage applied longer resulted in greater dopamine release without a concomitant increase
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in seizure duration.39 These data suggest that the passage of current may be directly responsible for ECS-induced dopamine release. Notably, dopamine release after ECS is not limited to the striatum; after 6 ECS treatments over 2 weeks, Stenfors et al40 found a 30% increase in dopamine concentrations in the frontal and occipital cortices.
Dopamine Receptors The aforementioned impact on the DA system is corroborated by findings of changes in dopamine receptor subtypes within the mesocorticolimbic system. For instance, repeated ECS was shown to increase dopamine D1 and D3 receptor mRNA and binding in dorsal and ventral striatum41 and even more specifically within the shell of the nucleus accumbens.42
Dopaminergic Neurotransmission Increasing attention has recently focused on reduced DA neurotransmission in the forebrain as contributing to depression. However, several recent studies in rats assessing whether ECS might compensate for such a change by altering the neuronal activity of DA neurons in the ventral tegmental area have yielded conflicting results. For instance, whereas West and Weiss43 reported that both spontaneous firing rate and burst firing of DA neurons in the ventral tegmental area increased after repeated ECS, Tsen et al44 observed no change in the overall firing activity of these neurons. However, the authors found that there were more spontaneously active neurons after ECS in the substantia nigra © 2014 Lippincott Williams & Wilkins
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FIGURE 2. Distribution of the serotonin-2A (5-HT2A) receptor binding in healthy subjects superimposed on a T1-weighted magnetic resonance imaging template in Montreal Neurologic Institute space using PET and the radioligand [18F]altanserin (adapted from Savli et al62). Color table indicates receptor binding potential. Black numbers represent brain regions where 5-HT2A receptor binding was shown to be reduced after ECT in humans (based on the study performed by Yatham et al35) using PET and [18F]setoperone. White numbers stand for homologous areas in nonhuman primates where a reduction of 5-HT2A receptor binding was observed after ECT (based on Strome et al21). 1, left cuneus; 2, left lateral occipital gyrus; 3, right lingual gyrus; 4, right medial frontal gyrus; 5, right parahippocampal gyrus; 6, occipital cortex; 7, parietal cortex; 8, central cortex; 9, temporal cortex; 10, frontal cortex; 11, orbital cortex; 12, posterior cingulate cortex; and 13, anterior cingulate cortex.
pars compacta.44 In parallel to the rodent data, a recent PET study in the rhesus monkey nigrostriatal system revealed that repeated ECS leads to increased DA neurotransmission, most prominent at the presynaptic level.45
Dopamine-Mediated Behavior Administration of ECS has been consistently shown to affect dopamine-mediated behavior (eg, locomotion) in rodents.46 Moreover, after ECS, behavioral sensitization, characterized by an increased behavioral response to dopamine receptor agonists, has been reported.46,47 Importantly, ECS was shown to alleviate motor retardation in 6-hydroxidopamine–lesioned rats, a rodent model of parkinsonism, possibly through exerting greater DA tone in the nigrostriatal pathway.41
Human Data Dopamine Levels Human studies indicate that ECT leads to significant changes in the levels of dopamine and its metabolites. For instance, Nikisch and Mathé48 reported a significant increase of homovanillic acid, a measure of dopamine turnover, in the cerebrospinal fluid after a completed ECT series. On the other hand, another recent study revealed that in plasma, ECT significantly reduced homovanillic acid levels in parallel with the improvement of depressive symptoms.49
Dopaminergic Neurotransmission The beneficial effect of ECT in Parkinson disease (PD) was discovered serendipitously; in depressed patients with PD receiving ECT for their depressive symptoms, a rapid amelioration of motor symptoms was observed independently and well before the antidepressant effects.50 This observation prompted the inception of better-designed studies that established ECT’s positive effects across a wide range of movement disorders such as PD, drug-induced parkinsonism, dystonia, and tardive dyskinesia, with or without psychiatric comorbidity.51 Evidence that ECT enhances DA neurotransmission in the living human brain has been obtained from imaging studies over the past decade. For instance, Henry et al52 measured regional © 2014 Lippincott Williams & Wilkins
brain activity before and after ECT using [18F]fluorodeoxyglucose PET among 6 medication-free depressed patients. Whereas a decrease in absolute metabolic rate throughout the brain was noted after ECT after normalization of [18F]fluorodeoxyglucose uptake to the global metabolic rate, significant increases in regions with known DA innervations, including the basal ganglia and upper brainstem, were demonstrated.52 Another line of evidence suggesting that ECT enhances DA neurotransmission was obtained from studies that reported significant increases in dopamine-mediated responses, such as growth hormone release, when dopamine agonists were administered after a course of ECT.53
Dopamine Receptors Using PET scans with the radioligand [11C]FLB 457, Saijo et al54 reported recently that ECT decreased dopamine D2 receptor (DRD2) binding in the rostral anterior cingulate in patients with major depressive disorder. Further supporting the role of DRD2 in mediating response to ECT, Huuhka et al55 demonstrated that the combination of DRD2 C957T and catechol-O methyltransferase Val158Met polymorphisms was associated with a less favorable response to ECT. Relating to the preclinical data showing enhanced striatal dopamine D3 receptor (DRD3) binding after ECT, the potential impact of DRD3 gene variation on ECT outcome in treatment-resistant major depression was recently evaluated by applying a combined molecular and imaging genetic approach.56 The authors reported associations of several DRD3 variants with response and remission after ECT. Possibly mediating the impact of DRD3 gene variation on ECT response, the authors reported that when assessed in independent samples of depressed patients by means of functional magnetic resonance imaging, the allele conferring a more favorable treatment response was found to be associated with stronger striatal responsiveness to happy facial expressions.
DISCUSSION In summary, there is strong evidence supporting a major role of the serotonergic system in the mechanism of action and the therapeutic efficacy of ECT. Most of the preclinical findings suggest an enhancement of serotonergic neurotransmission, which is mirrored by an up-regulation of both postsynaptic 5-HT1A and www.ectjournal.com
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5-HT2A receptors in the hippocampus and prefrontal cortical regions, respectively. In humans, ECT was shown to globally decrease 5-HT1A and 5-HT2A receptor binding, which is in line with observations after the intake of antidepressants. The 5-HTT does not seem to play a major role in these mechanisms. However, regarding pharmacological treatments such as SSRI, targeting of the 5-HTT represents the initial step in their mode of action, subsequently leading to alterations of serotonergic receptor densities as seen for ECT. At this stage, for ECT, this primary target remains unexplored. The literature we have reviewed indicates that the effects of ECT on the DA system are evident at various levels, including dopamine release, DA neurotransmission, and receptor binding. Moreover, data from rodent and primate models are mostly consistent with human data. Recently, converging data obtained from genetic and imaging studies in humans have corroborated many of the earlier findings relating to activation of the mesocorticolimbic dopamine system after ECT. Based on the strong activation of the hypothalamic-pituitary-adrenal axis after ECT, Fosse and Read57 have recently suggested that ECT can be conceptualized as severe stress. The activation of the DA system by ECT is consistent with this notion, since increase in DA tone often accompanies stress-induced hypothalamic-pituitary-adrenal activation.58 Dopamine signaling is thought to affect consciousness by modulating corticobasal ganglia-thalamic loops, with a central end mechanism being the impact on glutamate–γaminobutyric acid processes in frontal cortical and temporal lobe regions.59 Hence, in line with the general effects of dopamine,60 it is highly conceivable that dopamine system activation by ECT contributes to the reduction of depressive and anxious symptoms, whereas motivation, concentration, and attention tend to improve. This hypothesis has recently gained further support by the ability to relieve symptoms of anhedonia in severely depressed patients by direct stimulation of the nucleus accumbens, a key structure in the mesocorticolimbic dopamine system.61 In summary, it is uncontested that recent advances in molecular brain imaging have allowed for an increased understanding of the mechanisms of action of ECT. Long-term electroconvulsive stimulation leads to alterations of various neurotransmitter systems on multiple levels, as we show for serotonin and dopamine in this review. This mechanism seems to be crucially involved in the antidepressant efficacy of ECT. However, the link between the observed changes of neurotransmitter levels and thereby also postsynaptic signal transduction and the electrical stimulus itself remains to be discovered. Additionally, besides serotonin and dopamine, other neurotransmitters, such as noradrenaline,7 might equally play a role, and the complex interrelations between these major neurotransmitters systems, which might potentiate the effect of ECT, must not remain unmentioned. Future studies combining convergent modalities could enhance our understanding of the mechanisms underlying ECT’s profound antidepressant effect, thus supporting the development of better pharmacological and somatic treatment approaches for refractory depression. ACKNOWLEDGMENTS The authors thank Marie Spies for linguistic revision of the manuscript and Andreas Hahn and Markus Savli for preparation of the figures. REFERENCES 1. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders; Part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013;14:334–385.
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43. West CHK, Weiss JM. Effects of chronic antidepressant drug administration and electroconvulsive shock on activity of dopaminergic neurons in the ventral tegmentum. Int J Neuropsychopharmacol. 2011;14:201–210. 44. Tsen P, El Mansari M, Blier P. Effects of repeated electroconvulsive shocks on catecholamine systems: electrophysiological studies in the rat brain. Synapse. 2013;67:716–727. 45. Landau AM, Chakravarty MM, Clark CM, et al. Electroconvulsive therapy alters dopamine signaling in the striatum of non-human primates. Neuropsychopharmacology. 2011;36:511–518. 46. Nomikos GG, Mathe AA, Mathe JM, et al. MK-801 prevents the enhanced behavioural response to apomorphine elicited by repeated electroconvulsive treatment in mice. Psychopharmacology (Berl). 1992;108:367–370. 47. Smith SE, Sharp T. Evidence that the enhancement of dopamine function by repeated electroconvulsive shock requires concomitant activation of D1-like and D2-like dopamine receptors. Psychopharmacology. 1997;133:77–84. 48. Nikisch G, Mathé AA. CSF monoamine metabolites and neuropeptides in depressed patients before and after electroconvulsive therapy. Eur Psychiatry. 2008;23:356–359. 49. Okamoto T, Yoshimura R, Ikenouchi-Sugita A, et al. Efficacy of electroconvulsive therapy is associated with changing blood levels of homovanillic acid and brain-derived neurotrophic factor (BDNF) in refractory depressed patients: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1185–1190. 50. Andersen K, Balldin J, Gottfries CG, et al. A double-blind evaluation of electroconvulsive therapy in Parkinson’s disease with “on-off ” phenomena. Acta Neurol Scand. 1987;76:191–199. 51. Faber R, Trimble MR. Electroconvulsive therapy in Parkinson’s disease and other movement disorders. Mov Disord. 1991;6:293–303. 52. Henry ME, Schmidt ME, Matochik JA, et al. The effects of ECT on brain glucose: a pilot FDG PET study. J ECT. 2001;17:33–40.
33. Spindelegger C, Lanzenberger R, Wadsak W, et al. Influence of escitalopram treatment on 5-HT1A receptor binding in limbic regions in patients with anxiety disorders. Mol Psychiatry. 2008;14:1040–1050.
53. Costain DW, Cowen PJ, Gelder MG, et al. Electroconvulsive therapy and the brain: evidence for increased dopamine-mediated responses. Lancet. 1982;2:400–404.
34. Shapira B, Lerer B, Kindler S, et al. Enhanced serotonergic responsivity following electroconvulsive therapy in patients with major depression. Br J Psychiatry. 1992;160:223–229.
54. Saijo T, Takano A, Suhara T, et al. Electroconvulsive therapy decreases dopamine D2receptor binding in the anterior cingulate in patients with depression: a controlled study using positron emission tomography with radioligand [11C]FLB 457. J Clin Psychiatry. 2010;71:793–799.
35. Yatham LN, Liddle PF, Lam RW, et al. Effect of electroconvulsive therapy on brain 5-HT(2) receptors in major depression. Br J Psychiatry. 2010;196:474–479. 36. Kellar KJ, Cascio CS, Butler JA, et al. Differential effects of electroconvulsive shock and antidepressant drugs on serotonin-2 receptors in rat brain. Eur J Pharmacol. 1981;69:515–518. 37. Nomikos GG, Zis AP, Damsma G, et al. Electroconvulsive shock produces large increases in interstitial concentrations of dopamine in the rat striatum: an in vivo microdialysis study. Neuropsychopharmacology. 1991;4:65–69. 38. Zis AP, Nomikos GG, Damsma G, et al. In vivo neurochemical effects of electroconvulsive shock studied by microdialysis in the rat striatum. Psychopharmacology (Berl). 1991;103:343–350. 39. McGarvey KA, Zis AP, Brown EE, et al. ECS-induced dopamine release: Effects of electrode placement, anticonvulsant treatment, and stimulus intensity. Biol Psychiatry. 1993;34:152–157. 40. Stenfors C, Bjellerup P, Mathé AA, et al. Concurrent analysis of neuropeptides and biogenic amines in brain tissue of rats treated with electroconvulsive stimuli. Brain Res. 1995;698:39–45. 41. Strome EM, Zis AP, Doudet DJ. Electroconvulsive shock enhances striatal dopamine D1 and D3 receptor binding and improves motor performance in 6-OHDA–lesioned rats. J Psychiatry Neurosci. 2007;32:193–202. 42. Lammers CH, Diaz J, Schwartz JC, et al. Selective increase of dopamine D3 receptor gene expression as a common effect of chronic antidepressant treatments. Mol Psychiatry. 2000;5:378–388.
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55. Huuhka K, Anttila S, Huuhka M, et al. Dopamine 2 receptor C957T and catechol-o-methyltransferase Val158Met polymorphisms are associated with treatment response in electroconvulsive therapy. Neurosci Lett. 2008;448:79–83. 56. Dannlowski U, Domschke K, Birosova E, et al. Dopamine D3 receptor gene variation: impact on electroconvulsive therapy response and ventral striatum responsiveness in depression. Int J Neuropsychopharmacol. 2013;16:1443–1459. 57. Fosse R, Read J. Electroconvulsive treatment: hypotheses about mechanisms of action. Front Psychiatry. 2013;4. 58. Pruessner JC, Champagne F, Meaney MJ, et al. Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C] raclopride. J Neurosci. 2004;24:2825–2831. 59. Tononi G, Koch C. The neural correlates of consciousness: an update. Ann N Y Acad Sci. 2008;1124:239–261. 60. Palmiter RD. Dopamine signaling as a neural correlate of consciousness. Neuroscience. 2011;198:213–220. 61. Schlaepfer TE, Cohen MX, Frick C, et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology. 2008;33:368–377. 62. Savli M, Bauer A, Mitterhauser M, et al. Normative database of the serotonergic system in healthy subjects using multi-tracer PET. Neuroimage. 2012;63:447–459.
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Neurotransmitters and Electroconvulsive Therapy Pia Baldinger, MD,* Amit Lotan, MD,† Richard Frey, MD,* Siegfried Kasper, MD,* Bernard Lerer, MD,† and Rupert Lanzenberger, MD* Objectives: Electroconvulsive therapy (ECT) is a well-established effective treatment strategy in treatment-refractory depression. However, despite ECT’s widespread use, the exact neurobiological mechanisms underlying its efficacy are not fully understood. Over the past 3 decades, extensive work in rodents, primates, and humans has begun to delineate the impact of electroconvulsive seizures (ECS) and ECT on neurotransmission systems commonly implicated in depression. In the current review, we will focus on two major biogenic amine systems, namely serotonin and dopamine. Methods: The database of PubMed was searched for preclinical studies describing the effects of ECS on the serotonergic and dopaminergic system using behavioral sensitization paradigms, in vivo brain microdialysis, messenger RNA and protein expression, electrophysiology, and positron emission tomography. Additionally, human data describing ECT’s effects on neurotransmitter turnover, receptor binding, and functional imaging were reviewed together with relevant genetic association studies. Results: Literature research resulted in 40 published original studies related to ECS/ECT and the serotonergic system, whereby only three were studies in humans. Regarding dopamine, 15 preclinical and 12 human studies were found in PubMed database. Conclusions: Converging data obtained from genetic and imaging studies in humans have corroborated many of the earlier preclinical and clinical findings relating to enhancement of serotonergic neurotransmission and activation of the mesocorticolimbic dopamine system after ECS/ECT. Moreover, it seems that these effects are evident at various levels, including neurotransmitter release, receptor binding, and overall neurotransmission. Future studies combining convergent modalities could enhance our understanding of the mechanisms underlying ECT’s profound antidepressant effect and would support the development of better pharmacological and somatic treatment approaches for refractory depression. Key Words: electroconvulsive therapy, neurotransmitters, serotonin, dopamine, antidepressant From the *Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria and †Biological Psychiatry Laboratory at Hadassah, Hebrew University Medical Center, Jerusalem, Israel. Received for publication February 11, 2014; accepted March 17, 2014. Reprints: Rupert Lanzenberger, MD, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18–20, A-1090 Vienna, Austria (e‐mail: [email protected]). Pia Baldinger and Amit Lotan contributed equally to this work. Without any relevance to this work, S. Kasper declares that he has received grant/research support from Eli Lilly, Lundbeck A/S, Bristol-Myers Squibb, Servier, Sepracor, GlaxoSmithKline, Organon, Dr. Willmar Schwabe GmbH & Co. KG, and has served as a consultant or on advisory boards for AstraZeneca, Austrian Sick Found, Bristol-Myers Squibb, German Research Foundation (DFG), GlaxoSmithKline, Eli Lily, Lundbeck A/S, Pfizer, Organon, Sepracor, Janssen, and Novartis and has served on speakers’ bureaus for AstraZeneca, Eli Lilly, Lundbeck A/S, Servier, Sepracor, and Janssen. R. Lanzenberger received travel grants and conference speaker honoraria from AstraZeneca, Lundbeck A/S, and Roche Austria GmbH. R. Frey declares that he has received grants and research support from Bristol-Myers Squibb, AstraZeneca, Sandoz, Eli Lilly, and Janssen. P. Baldinger received travel grants from Roche Austria GmbH and AOP Orphan Pharmaceuticals AG. B. Lerer has received grants for studies unrelated to this work from the Israel Ministry of Science and Technology, the Israel Ministry of Economics, Trade and Industry, the Israel Science Foundation, Israel Academy of Sciences, the European Union, St Jude Medical, and Janssen Pharmaceuticals and has served as a paid consultant to St Jude Medical, Anima Scan Ltd, and Taliaz Diagnostics on unrelated projects. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/YCT.0000000000000138
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O
ver the years, research has attempted to define a relationship between different neurotransmitter systems and symptoms or manifestations of psychiatric syndromes. With regard to major depression, the significant involvement of at least 3 transmitter systems, specifically serotonin, noradrenaline, and dopamine, is largely uncontested. This understanding is based on a vast library of basic research, from animal studies to neuroimaging and genetic data, and is solidified by clinically validated pharmacological treatment options that specifically target key proteins of these transmitter networks in depressive patients, such as selective serotonin reuptake inhibitors (SSRIs). Electroconvulsive therapy (ECT) is a well-established effective treatment strategy in treatmentrefractory depression involving an electrical stimulus of the brain that provokes a therapeutic seizure.1–3 Aside from transient cognitive adverse effects after repeated treatments,4 ECT is a welltolerated therapy and was shown to be associated with response rates of 60% to 80%.1,5 Despite the frequent and widespread use of ECT for more than 70 years, the exact neurobiological mechanisms underlying its efficacy remain to be fully understood. As a result, the effect of ECT on cerebral blood flow and metabolism has been evaluated, and its impact on synaptic plasticity and neurogenesis has recently been investigated.6 Additionally, extensive work in rodents as well as in human subjects has been performed to characterize the impact of ECT on various neurotransmitter systems.6,7 Focus has been laid on the evaluation of ECT’s mechanism of action via modulation of neurotransmitters that are implicated in antidepressant actions, such as serotonin, as ECT was shown to lead to similar or even better effects than pharmacological agents currently in use.8,9 This review will focus on the relationship between major neurotransmitter systems underlying the pathogenesis of major depression and the mechanisms of action of ECT as well as provide a comprehensive overview over the current literature. This paper will specifically address serotonergic and dopaminergic (DA) neurotransmission focusing on both animal and human studies, as the availability of radioligands for the imaging of these neurotransmitter systems has led to a wealth of literature.
MATERIALS AND METHODS The database of PubMed was searched for both preclinical and clinical studies describing the effects of electroconvulsive seizures and ECT on the serotonergic and DA neurotransmitter systems, respectively. Various methodologies, such as behavioral sensitization paradigms, in vivo brain microdialysis, messenger RNA (mRNA) and protein expression, electrophysiology, and functional brain imaging, particularly positron emission tomography (PET), were applied in the reviewed investigations. Studies in rodents, primates, and humans were included in the review depending on their relevance to the subject. In total, 40 studies were reviewed related to electroconvulsive shocks (ECS)/ECT and the serotonergic system, including the serotonin transporter as well as the serotonin 1A and 2A receptors. Most of the original research articles were preclinical findings in rodents; one study included nonhuman primates, and 3 investigations were human studies. Regarding dopamine, 15 preclinical studies describing the effects Journal of ECT • Volume 30, Number 2, June 2014
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of ECS on dopamine concentration, transport, neurotransmission, and behavior were reviewed. These studies mainly used rats as a preclinical model, although a few recent studies have included primates as well. Additionally, 12 clinical studies assessing the effects of ECT on DA parameters in humans, using different approaches such as cerebrospinal fluid analysis, imaging, and genetics, were reviewed.
Serotonin and ECT Preclinical Data Those aiming to elucidate a modulatory effect of ECT on neurotransmission have focused on the effects of ECS on the serotonergic system as the amount of studies conducted in this field, including those using electrophysiological methods, microdialysis, and preclinical experiments in rodents, is extensive.7,10
Serotonin-1A Receptor Originally, Goodwin et al11 suggested a role for the serotonin1A (5-HT1A) receptor in the effects of ECS by determining that repeated ECS leads to an attenuation of 5-HT1A–mediated effects, namely, the hypothermic response in rodents to 8-hydroxy-2-(din-propylamino)tetralin (8-OH-DPAT), which is thought to be regulated via presynaptic 5-HT1A receptors. Subsequently, particular attention has been paid to the hippocampus, as hippocampal functions are primarily regulated by the serotonergic system, which is highly involved in both the pathobiological diagnosis and treatment of depression.12 In this context, de Montigny13 showed that the responsiveness of hippocampal pyramidal neurons to microiontophoretic applications of serotonin and the postsynaptic agonist 5-methoxydimethyltryptamine was markedly increased after repeated ECS in rats, indicating a postsynaptic serotonin receptor sensitization, which is similar to observations after the administration of tricyclic antidepressants14 and might substantially mediate antidepressants effects.15 This finding was confirmed by a study conducted by Chaput et al,16 which additionally showed that ECS, in contrast to the SSRI paroxetine, did not attenuate the negative feedback exerted by serotonin-1A autoreceptors on serotonin release, suggesting that the effect of ECS is solely mediated by postsynaptic serotonin-1A receptors. Moreover, ECS were shown to exert receptor subtype specific, temporally and anatomically selective effects on 5-HT receptor expression17: 5-HT1A receptor mRNA was increased after repeated ECS in the dentate gyrus, whereas it was decreased in the CA4 hippocampal region after single and repeated ECS, with parallel alterations in [3H]8-OHDPAT binding, respectively.17 Additionally, repeated ECS were accompanied by an increase of serotonin-2A (5-HT2A) receptor mRNA and [3H]ketanserine binding.17
Serotonin-2A Receptor Most studies investigating the effects of ECS on 5-HT2A receptors, which are mainly located postsynaptically in cortical brain areas, postulate an increased 5-HT2A receptor number in the cerebral cortex. This is paralleled by enhancement of 5-HT2A gene expression after chronic ECS, as has been shown in a rodent model.7 Burnet et al18 found repeated ECS to increase 5-HT2A mRNA in the neocortex in rats and that increased responsiveness of the serotonergic system after chronic ECS was shown to be mediated by an increase of 5-HT2A receptor density.19,20 However, in a study applying [18F]setoperone to nonhuman primates, ECS led to a decreased 5-HT2A–binding potential in cortical regions,21 which is in accordance with findings retrieved from pharmacological studies showing that various antidepressants cause a downregulation of cerebral 5-HT2A receptors.22–25 These discrepancies implicate species differences in cortical circuits and the mediation of antidepressant treatment response. © 2014 Lippincott Williams & Wilkins
Neurotransmitters and ECT
Serotonin Transporter Another key molecule of the serotonergic neurotransmission is the serotonin transporter (5-HTT), which is the primary target of the most commonly used antidepressants, particularly SSRIs. Findings regarding the effects of ECS on the number of 5-HTT in rodents are inconsistent and scarce. Interestingly, 5-HTT binding was shown to be unaltered in rats using [3H]paroxetine,26 and 5-HTT mRNA in the dorsal raphe was unchanged after repeated ECS.17 However, Hayakawa et al27 determined an increased number of serotonin uptake sites in the frontal cortex after single and repeated ECS, and this finding was confirmed by Shen et al28 who showed that repetitive ECS stably increased 5-HTT in rats’ frontal cortex but not hippocampus and dorsal raphe. A possible explanation might be that the increased protein expression in the frontal cortex represents a compensatory mechanism to the enhanced serotonergic neurotransmission by ECS.
Human Data Compared to the abundance of data describing the effects of ECS on serotonergic neurotransmission in animals, research in humans in this field remains scarce.
Serotonin-1A Receptor To the best of our knowledge, there are two recent studies using PET investigating the effects of ECT on 5-HT1A receptor binding in patients with major depression. In 2010, Saijo et al29 published a study including 9 depressed patients undergoing 6 to 7 bilateral ECT sessions and showed unaltered 5-HT1A receptor binding using the radioligand [carbonyl 11C]WAY-100635 even after recovery from depressive episode. This finding is in line with preclinical studies reporting no changes of 5-HT1A receptor binding after chronic ECS30,31 and indicates the involvement of neurotransmitter mechanisms other than 5-HT1A receptor alterations in the mode of action of ECT. However, our research group conducted a very similar study including 12 severely depressed patients undergoing a mean of 10 ECT sessions and a global reduction of 5-HT1A receptor binding in the anterior cingulate cortex including its subgenual part, the orbitofrontal cortex, the amygdala, the insula, and the hippocampus was detected (Fig. 1).32 This finding is in accordance with the previously described preclinical study conducted by Burnet et al17 that shows a decreased 5-HT1A receptor mRNA in the CA4 hippocampal region, as well as with the reported reduced 5-HT1A receptor binding in the hippocampus and the anterior cingulate cortex after a 12-week treatment with escitalopram in patients with anxiety disorders.33 However, they stand in contrast to extensive studies reporting enhanced serotonergic neurotransmission after chronic ECS.13,16 This contradiction may be ascribed to species differences as seen with regard to the 5-HT2A receptor. The discrepancies between the study published by Saijo et al29 and our paper32 might be explained by methodological differences but also the number of administered ECT, the sex distribution (predominance of men in the study by Saijo et al), and population differences (Asian vs white patients).32 In our study, changes in Hamilton Depression Rating Scale after ECT, reflecting treatment-response, were unaffected by variations of 5-HT1A receptor binding which indicates that the effect of ECT on 5-HT1A receptor binding is dose-independent.32
Serotonin-2A Receptor More than 20 years ago, before functional brain imaging techniques were available, Shapira et al34 determined an enhanced serotonergic responsivity to ECT in patients with major depression using a neuroendocrine measurement, namely, the prolactin response to fenfluramine challenge, which reflects serotonin www.ectjournal.com
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FIGURE 1. Average serotonin-1A (5-HT1A) receptor binding potential (BPND) of patients with major depression (n = 12), superimposed on a T1-weighted magnetic resonance imaging template in Montreal Neurologic Institute space, before (A) and after (B) ECT using PET and the radioligand [carbonyl 11C]WAY-100635. Note that 5-HT1A BPND is reduced across almost the entire cortex after ECT. Color table indicates 5-HT1A BPND. Adapted from Lanzenberger et al.32 (All permission requests for this image should be made to the copyright holder).
release. Yatham et al35 investigated the effects of ECT on 5-HT2A receptors in major depression and demonstrated a widespread reduction of 5-HT2A receptor binding in the bilateral occipital cortex, the medial parietal cortex, the limbic cortex, and the bilateral prefrontal cortex using [18F]setoperone in 15 depressed patients (Fig. 2). This is in complete agreement with a high number of studies showing a 5-HT2A receptor down-regulation by various antidepressants and suggests that this mechanism might substantially mediate antidepressant effects.23,24 As already mentioned, this is in accordance with the observations made in nonhuman primates but not in rodents (Fig. 2).21,36 Changes of [18F]setoperone binding were not significantly related to clinical improvement as assessed using Hamilton Depression Rating Scale.35
Dopamine and ECT Preclinical Data Dopamine Levels In rodents, repeated electroconvulsive stimulation has consistently been found to enhance brain dopamine function. A 10-fold increase of interstitial dopamine concentrations in the striatum after acute ECS was demonstrated using in vivo brain microdialysis in rats, and this dopamine is of neuronal origin.37,38 Interestingly, this effect was not seen with chemically (flurothyl) induced seizures.38 Moreover, a higher voltage applied longer resulted in greater dopamine release without a concomitant increase
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in seizure duration.39 These data suggest that the passage of current may be directly responsible for ECS-induced dopamine release. Notably, dopamine release after ECS is not limited to the striatum; after 6 ECS treatments over 2 weeks, Stenfors et al40 found a 30% increase in dopamine concentrations in the frontal and occipital cortices.
Dopamine Receptors The aforementioned impact on the DA system is corroborated by findings of changes in dopamine receptor subtypes within the mesocorticolimbic system. For instance, repeated ECS was shown to increase dopamine D1 and D3 receptor mRNA and binding in dorsal and ventral striatum41 and even more specifically within the shell of the nucleus accumbens.42
Dopaminergic Neurotransmission Increasing attention has recently focused on reduced DA neurotransmission in the forebrain as contributing to depression. However, several recent studies in rats assessing whether ECS might compensate for such a change by altering the neuronal activity of DA neurons in the ventral tegmental area have yielded conflicting results. For instance, whereas West and Weiss43 reported that both spontaneous firing rate and burst firing of DA neurons in the ventral tegmental area increased after repeated ECS, Tsen et al44 observed no change in the overall firing activity of these neurons. However, the authors found that there were more spontaneously active neurons after ECS in the substantia nigra © 2014 Lippincott Williams & Wilkins
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FIGURE 2. Distribution of the serotonin-2A (5-HT2A) receptor binding in healthy subjects superimposed on a T1-weighted magnetic resonance imaging template in Montreal Neurologic Institute space using PET and the radioligand [18F]altanserin (adapted from Savli et al62). Color table indicates receptor binding potential. Black numbers represent brain regions where 5-HT2A receptor binding was shown to be reduced after ECT in humans (based on the study performed by Yatham et al35) using PET and [18F]setoperone. White numbers stand for homologous areas in nonhuman primates where a reduction of 5-HT2A receptor binding was observed after ECT (based on Strome et al21). 1, left cuneus; 2, left lateral occipital gyrus; 3, right lingual gyrus; 4, right medial frontal gyrus; 5, right parahippocampal gyrus; 6, occipital cortex; 7, parietal cortex; 8, central cortex; 9, temporal cortex; 10, frontal cortex; 11, orbital cortex; 12, posterior cingulate cortex; and 13, anterior cingulate cortex.
pars compacta.44 In parallel to the rodent data, a recent PET study in the rhesus monkey nigrostriatal system revealed that repeated ECS leads to increased DA neurotransmission, most prominent at the presynaptic level.45
Dopamine-Mediated Behavior Administration of ECS has been consistently shown to affect dopamine-mediated behavior (eg, locomotion) in rodents.46 Moreover, after ECS, behavioral sensitization, characterized by an increased behavioral response to dopamine receptor agonists, has been reported.46,47 Importantly, ECS was shown to alleviate motor retardation in 6-hydroxidopamine–lesioned rats, a rodent model of parkinsonism, possibly through exerting greater DA tone in the nigrostriatal pathway.41
Human Data Dopamine Levels Human studies indicate that ECT leads to significant changes in the levels of dopamine and its metabolites. For instance, Nikisch and Mathé48 reported a significant increase of homovanillic acid, a measure of dopamine turnover, in the cerebrospinal fluid after a completed ECT series. On the other hand, another recent study revealed that in plasma, ECT significantly reduced homovanillic acid levels in parallel with the improvement of depressive symptoms.49
Dopaminergic Neurotransmission The beneficial effect of ECT in Parkinson disease (PD) was discovered serendipitously; in depressed patients with PD receiving ECT for their depressive symptoms, a rapid amelioration of motor symptoms was observed independently and well before the antidepressant effects.50 This observation prompted the inception of better-designed studies that established ECT’s positive effects across a wide range of movement disorders such as PD, drug-induced parkinsonism, dystonia, and tardive dyskinesia, with or without psychiatric comorbidity.51 Evidence that ECT enhances DA neurotransmission in the living human brain has been obtained from imaging studies over the past decade. For instance, Henry et al52 measured regional © 2014 Lippincott Williams & Wilkins
brain activity before and after ECT using [18F]fluorodeoxyglucose PET among 6 medication-free depressed patients. Whereas a decrease in absolute metabolic rate throughout the brain was noted after ECT after normalization of [18F]fluorodeoxyglucose uptake to the global metabolic rate, significant increases in regions with known DA innervations, including the basal ganglia and upper brainstem, were demonstrated.52 Another line of evidence suggesting that ECT enhances DA neurotransmission was obtained from studies that reported significant increases in dopamine-mediated responses, such as growth hormone release, when dopamine agonists were administered after a course of ECT.53
Dopamine Receptors Using PET scans with the radioligand [11C]FLB 457, Saijo et al54 reported recently that ECT decreased dopamine D2 receptor (DRD2) binding in the rostral anterior cingulate in patients with major depressive disorder. Further supporting the role of DRD2 in mediating response to ECT, Huuhka et al55 demonstrated that the combination of DRD2 C957T and catechol-O methyltransferase Val158Met polymorphisms was associated with a less favorable response to ECT. Relating to the preclinical data showing enhanced striatal dopamine D3 receptor (DRD3) binding after ECT, the potential impact of DRD3 gene variation on ECT outcome in treatment-resistant major depression was recently evaluated by applying a combined molecular and imaging genetic approach.56 The authors reported associations of several DRD3 variants with response and remission after ECT. Possibly mediating the impact of DRD3 gene variation on ECT response, the authors reported that when assessed in independent samples of depressed patients by means of functional magnetic resonance imaging, the allele conferring a more favorable treatment response was found to be associated with stronger striatal responsiveness to happy facial expressions.
DISCUSSION In summary, there is strong evidence supporting a major role of the serotonergic system in the mechanism of action and the therapeutic efficacy of ECT. Most of the preclinical findings suggest an enhancement of serotonergic neurotransmission, which is mirrored by an up-regulation of both postsynaptic 5-HT1A and www.ectjournal.com
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5-HT2A receptors in the hippocampus and prefrontal cortical regions, respectively. In humans, ECT was shown to globally decrease 5-HT1A and 5-HT2A receptor binding, which is in line with observations after the intake of antidepressants. The 5-HTT does not seem to play a major role in these mechanisms. However, regarding pharmacological treatments such as SSRI, targeting of the 5-HTT represents the initial step in their mode of action, subsequently leading to alterations of serotonergic receptor densities as seen for ECT. At this stage, for ECT, this primary target remains unexplored. The literature we have reviewed indicates that the effects of ECT on the DA system are evident at various levels, including dopamine release, DA neurotransmission, and receptor binding. Moreover, data from rodent and primate models are mostly consistent with human data. Recently, converging data obtained from genetic and imaging studies in humans have corroborated many of the earlier findings relating to activation of the mesocorticolimbic dopamine system after ECT. Based on the strong activation of the hypothalamic-pituitary-adrenal axis after ECT, Fosse and Read57 have recently suggested that ECT can be conceptualized as severe stress. The activation of the DA system by ECT is consistent with this notion, since increase in DA tone often accompanies stress-induced hypothalamic-pituitary-adrenal activation.58 Dopamine signaling is thought to affect consciousness by modulating corticobasal ganglia-thalamic loops, with a central end mechanism being the impact on glutamate–γaminobutyric acid processes in frontal cortical and temporal lobe regions.59 Hence, in line with the general effects of dopamine,60 it is highly conceivable that dopamine system activation by ECT contributes to the reduction of depressive and anxious symptoms, whereas motivation, concentration, and attention tend to improve. This hypothesis has recently gained further support by the ability to relieve symptoms of anhedonia in severely depressed patients by direct stimulation of the nucleus accumbens, a key structure in the mesocorticolimbic dopamine system.61 In summary, it is uncontested that recent advances in molecular brain imaging have allowed for an increased understanding of the mechanisms of action of ECT. Long-term electroconvulsive stimulation leads to alterations of various neurotransmitter systems on multiple levels, as we show for serotonin and dopamine in this review. This mechanism seems to be crucially involved in the antidepressant efficacy of ECT. However, the link between the observed changes of neurotransmitter levels and thereby also postsynaptic signal transduction and the electrical stimulus itself remains to be discovered. Additionally, besides serotonin and dopamine, other neurotransmitters, such as noradrenaline,7 might equally play a role, and the complex interrelations between these major neurotransmitters systems, which might potentiate the effect of ECT, must not remain unmentioned. Future studies combining convergent modalities could enhance our understanding of the mechanisms underlying ECT’s profound antidepressant effect, thus supporting the development of better pharmacological and somatic treatment approaches for refractory depression. ACKNOWLEDGMENTS The authors thank Marie Spies for linguistic revision of the manuscript and Andreas Hahn and Markus Savli for preparation of the figures. REFERENCES 1. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders; Part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013;14:334–385.
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