A Primer for the Conceptualization of the Mechanism of Action of Electroconvulsive Therapy, 2: Organizing the Information

Clinical Problem

The previous article in this column1 presented an antidepressant-refractory, severely depressed patient for whom electroconvulsive therapy (ECT) had been suggested. The patient had asked why it was necessary for electricity to be passed through his brain. He wanted to know how ECT acts. The article1 explained why the question about the mechanism of action of ECT is a complex one and why it needs to be resolved into specific elements. The article also explained difficulties in the interpretation of research and academic concerns related to the generation of explanatory models. The present article deals with the problem of plenty; that is, how the large body of evidence on the subject may be organized so as to generate coherent explanations about the mechanism of action of ECT.

Much evidence is available on the electrophysiologic, neurochemical, neurotransmitter, neuroendocrine, histologic, and other changes that result with ECT, most or all of which have been offered as explanations for its mechanism of action. A considerable problem that one faces is to understand which of these changes are therapeutic and which are epiphenomena; which of the therapeutic changes are upstream and which are downstream; and how to fit electricity, seizure, premedication and comedication, and other elements into the model.

One possible way of organizing the information is to consider it under the headings of delivery components, therapeutic mediators, and therapeutic processes (Table 1).2

Delivery Components

Delivery components are the therapeutic elements of the ECT procedure that influence the rate and the extent to which a patient responds to ECT. Thus, the therapeutic elements determine the efficacy (response and remission rates) and the efficiency (speed of response to treatment) of ECT.

There are many clinically significant delivery components (Table 1). Bilateral ECT is generally associated with better chances of treatment response than unilateral ECT,3 possibly because of the use of higher electrical doses4 and because of better generalization of the central seizure.5 High-dose ECT is associated with higher response rates than low-dose ECT when electrode placement is unilateral,6-8 and when high-dose unilateral ECT is administered, response rates may equal those with bilateral ECT.7,9 High-dose ECT is also associated with faster clinical response, regardless of electrode placement.6 In this context, ECT dosage is generally reckoned in units of charge; that is, millicoulombs.4,10

The benefits of ECT cumulate across the ECT course, indicating that the number of ECT treatments administered is a necessary criterion for optimum improvement11; however, the rate at which these treatments are administered is also important because evidence suggests that more frequent ECT is associated with quicker antidepressant response when thrice- vs twice-weekly ECT are compared and with greater chances of response when thrice- vs once-weekly ECT are compared.12

Concurrent medication may improve treatment outcomes with ECT.13 Some14 but not all15 data suggest that ketamine anesthesia may improve ECT outcomes, perhaps through modulation of glutamatergic neurotransmission. Other delivery components may also have direct or indirect effects on clinical outcomes by influencing the ECT seizure or by direct effects on the brain; these range from aspects of premedication (eg, anticholinergic medication use) to aspects of the ECT procedure (eg, hyperventilation, to lower the seizure threshold). In fact, it is possible that even differences in the components (pulse amplitude, pulse width, pulse frequency, and stimulus duration) of the electrical stimulus may result in different neurobiological effects and hence in differences in clinical outcomes.16,17

Why are ECT delivery components important to an organization of research findings about the mechanism of action of ECT? The most important reason is that if variations in delivery components produce variations in treatment outcomes, then the neurobiological differences associated with these variations may be related to the neurobiological mechanisms responsible for the variations in outcomes. Some examples follow:

1. Bilateral ECT is associated with greater seizure generalization than unilateral ECT.5 Given that the occurrence of a seizure is essential for therapeusis, this suggests that seizure mechanisms mediate the greater efficacy of bilateral ECT in depression.
2. Relative to low-dose ECT, high-dose ECT is associated with greater suppression of neuroplasticity in the amygdala.18,19 This suggests that better suppression of negative affect related to noxious memories may explain why high-dose ECT is a more effective treatment.

Neurobiological variations associated with delivery components also provide other clues about ECT mechanisms. For example, at constant electrical dose, variations in the electrical components of the ECT stimulus result in variations in ictal, postictal, and interictal electroencephalographic (EEG) markers of ECT efficacy.16 As another example, ultrabrief-pulse ECT, which may be less effective than brief-pulse ECT,20 is associated with poorer induction of hippocampal neuroplasticity,17 strengthening the suggestion that neuroplasticity changes are at least in part responsible for antidepressant action.21-23

Therapeutic Mediators

Therapeutic mediators (Table 1) are physiologic or psychological effects of ECT that in themselves are not therapeutic but that may result in beneficial changes. Historically, a number of psychological hypotheses were proposed (but now discarded), including that ECT causes regression, fear, or a sense of punishment and that these effects psychodynamically result in absolution from guilt and, thereby, in attenuation of depression. Another discarded hypothesis is that ECT-induced amnesia attenuates the memory of the stressor and hence lessens depression.24,25

For over half a century, the occurrence of a generalized seizure has been recognized as the sine qua non for ECT-induced therapeutic benefits,26 and measures of seizure efficacy that have been proposed include seizure duration (presently discredited; see Andrade26), changes in seizure threshold,27 and patterns of EEG activity during, immediately after, and between ECT seizures.16,28,29 Neurobiological changes that the seizure induces have been well described, and these include neurohormonal and neurotransmitter changes,24,30-33 gene transcription,34 and neuroplasticity.35-37

Other treatment mediators include increases in cerebral blood flow and blood-brain barrier breach; there is, however, no convincing evidence in support of these as treatment mediators.38

Therapeutic Processes

Therapeutic processes are neurohormonal, neurotransmitter, neuroreceptor, second messenger system, genetic transcription, protein synthesis, neuroplasticity, and other specific changes that occur with ECT and that correct or compensate for the disease state. Therapeutic processes (with special reference to neuroplasticity) will be dealt with in greater detail in the next article in this series. To be strictly correct, strengthening or weakening of neuronal pathways, or increased or decreased structural neuroplasticity changes, are probably the only final common pathway therapeutic processes; however, given how little we understand about the brain in health and disease, it is reasonable to subsume all the mechanisms that lead to these ends as therapeutic processes.

Synthesis

Far too much information is available on the mechanism of action of ECT to be covered in a single article; readers may prefer to consult other reviews for additional information.23-25,30-33,39 For reasons explained in the previous article in this series,1 one cannot offer even a single hypothesis with certainty. Therefore, the present article does not seek to be either comprehensive or reductionistic. Rather, it seeks to provide a framework for putting evidence together and for understanding and communicating information about ECT. By way of example, a clinician may explain ECT as follows:

Delivery of a small but adequate dose of electricity to the brain results in the elicitation of seizure activity in the brain; higher electrical doses elicit a better quality of seizure. The seizure releases a large number of signaling chemicals that, in turn, produce changes on the surface and then within nerve and glial cells in target areas of the brain such as the hippocampus, amygdala, and prefrontal cortex. Genes in these cells are activated or suppressed, which in turn leads to increase or decrease in the number, activity, and connectivity of these cells. Increased number and connectivity of cells in the hippocampus and prefrontal cortex probably improve thinking and coping abilities, whereas decreased number and connectivity of cells in the amygdala reduce negative emotions attached to unpleasant memories; both effects can be expected to be therapeutic in depressed patients. The time course of recovery from depression seems to parallel the time course of occurrence of these cellular changes.

Detailed though such an explanation is, it is nevertheless a simplification and might need to be further simplified when educating laypersons about the mechanism of action of ECT. There is certainly a lot more to the mechanism of action of ECT, and certainly other explanations as well, as an earlier article indicated.1 However, the explanation provided is a reasonable hypothesis, at least for the beneficial action of ECT in depression3 and posttraumatic stress disorder.40

Parting Note

Adverse effects of ECT can also be explained in terms of delivery components, mediators, and processes (Table 1). A discussion

Each month in his online column, Dr Andrade considers theoretical and practical ideas in clinical psychopharmacology with a view to update the knowledge and skills of medical practitioners who treat patients with psychiatric conditions.

Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences, Bangalore, India (candrade@psychiatrist.com).
Financial disclosure and more about Dr Andrade.on the subject, however, is out of the scope of the present article.

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