Keith G. Rasmussen, MD

[[{"type":"media","view_mode":"media_crop","fid":"32074","attributes":{"alt":"ECT for depression","class":"media-image media-image-right","id":"media_crop_1210448114029","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4153","media_crop_rotate":"0","media_crop_scale_h":"147","media_crop_scale_w":"125","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]Electroconvulsive therapy (ECT) continues to be a vital treatment for severe depression and a few other psychiatric diagnoses. Its more widespread use has been limited primarily by the unwarranted stigma attached to the procedure. In addition, critics often cite a lack of knowledge about its mechanism of action as a reason to eschew its use. Here we review some of the knowledge base of ECT’s biological actions and discuss future directions for ECT research.

Decades of research in both animal models of ECT (referred to as electroconvulsive shock, or ECS) and clinical trials in humans have contributed to a vast evidence base of neurobiological changes associated with induced seizures. Undoubtedly, the biological events ultimately leading to relief from depression with ECT involve a cascade of effects related to molecules, cells, and circuits. While various researchers have focused primarily on one of these neurobiological domains, there is no currently articulated theory of the mechanism of action of ECT in depression that incorporates events at all 3 levels. It is likely that many of the myriad observed changes are epiphenomena not essential to the therapeutic effects of ECT.

Many technologies have been applied to the study of the neurobiological effects of ECT or ECS, including single photon emission CT, positron emission tomography, functional MRI (fMRI), magnetic resonance spectroscopy (MRS), EEG, body fluid chemical analysis (blood, urine, cerebrospinal fluid) and, in animals, histological examination and molecular genetic assays. The main theories of mechanism of action of ECT in depression can be classified as follows: neurotransmitter, neuroendocrine, anticonvulsant, neurotrophic, and neural connectivity hypotheses.

Contemporary ECT for Depression Part 1: Practice Update

The neurotransmitter theory of action of ECT arises from long-standing interest in the monoamines (serotonin, dopamine, norepinephrine) and other neurotransmitters, such as GABA and glutamate, in biological theories of the etiology of depression. Animal studies have shown consistent effects of ECS on monoamine neurotransmitter functioning, such as enhancement of serotoninergic transmission; results have been 

 MRS studies have reported increased cortical GABA concentrations after ECT in humans as well as increased glutamate/glutamine in the left dorsolateral prefrontal cortex and anterior cingulum.

of ECT is based on the findings of activation of the hypothalamic-pituitary axis during seizures, demonstrated by a surge in blood levels of adrenocorticotropic hormone, cortisol, and prolactin postictally.

 It is also based on the observation that abnormal overdrive of the hypothalamic-pituitary-adrenal axis in depression, as measured by the dexamethasone suppression test, can predict response to, and relapse after, ECT.

The anticonvulsant theory of ECT action arose from the observation that seizure threshold often rises and seizure duration shortens over a course of ECT, leading to the hypothesis that the inhibitory brain process associated with the progressive rise in seizure threshold is also responsible for depression relief. Support for this comes from EEG and cerebral blood flow studies that demonstrated suppression of neural activity (mostly in the frontal lobes) after a course of ECT, which 

The most recent conceptualizations of ECT mechanisms involve newer technologies for investigating cellular morphological changes, termed “neuroplasticity,” in animals, and “neural connectivity” in humans. The neuroplasticity (or neurotrophic) hypothesis of ECT mechanism holds that morphological changes, such as neurogenesis, gliogenesis, or alterations in dendritic or axonal arborization of existing neurons, are critical to the 

 Extensive animal studies of ECS document consistent evidence of neurogenesis in the hippocampus (mossy fiber sprouting), prefrontal cortex, and other limbic structures.

Remarkable brain structural detail can now be imaged with high–magnet-strength MRI. Such imaging has recently been applied to ECT patient populations at baseline (in the ill state, before ECT) and during and after a course of ECT. Findings indicate increased gray matter volume after ECT in the hippocampus, subgenual cortex, and amygdala.

It may be that baseline brain morphology is abnormal in severely depressed patients, and that ECT-induced neuroplasticity results in a return to normal size and morphology of structures such as the hippocampus and amygdala.

There have been several attempts to elucidate neurotrophic ECT mechanisms using MRS. 

 for neurogenesis in humans comes from MRS studies that show cell membrane turnover in areas felt to be critical to antidepressant mechanisms, which could reflect growth of new neurons.

 Other findings include increased N-acetylaspartate in the left amygdala and increased choline-containing compounds in the hippocampus with ECT.

 As these examples illustrate, MRS findings are diverse and do not allow a unifying conclusion. Undoubtedly, further refinement of MRS technology will enable assessment of other relevant brain molecules. It seems likely that neuroplastic and neurotrophic cellular events are the most critical of all in the causative chain of ECT antidepressant effect.

Quantitative EEG and fMRI have only recently been applied to ECT populations. 

 utilizing a new EEG analytic method-low-resolution electromagnetic tomography-found that increases after ECT in theta frequency (4 to 7 Hz) in the subgenual cingulate, an area of interest in the pathophysiology of depression, correlated robustly with reductions in psychotic depression.

 found evidence that reduction of baseline frontal cortical hyperconnectivity correlated with resolution of depression with ECT. However, 

 demonstrated that improvement in depression correlated with increased frontal cortical connectivity. The researchers ascribed the differential findings to different fMRI techniques.

In an fMRI study of 6 patients treated with ECT, 

 found that orbitofrontal activation in response to an affect-laden task decreased with successful ECT, but the sample size was too small for definitive conclusions. Finally, 

 studied 11 ECT patients with fMRI using an auditory task-related activation of multiple cortical areas. They found that patients had more task-related activation after ECT, but the implications of this finding are unclear. Methodologically sound, adequately powered fMRI studies in ECT populations are needed to advance our knowledge of neural network alterations in severe depression and subsequent recovery.

While we await a definitive understanding of the biological changes underpinning the mechanism of action of ECT, there is no need to be defeatist. Simply telling patients “we don’t know how ECT works” neglects our abundant knowledge of what this powerful treatment does. As 

 suggests, it is more helpful to patients to explain and categorize several of the biological effects of ECT; it is a “glass half full” approach, which is both truthful and positive.

ECT research will continue to focus on refining aspects of technique and personalizing ECT type and schedule, as well as further elucidating its mechanisms of action. Technical refinements are aimed at preserving antidepressant efficacy while increasing cognitive tolerability. Techniques to more precisely target particular brain structures or areas for seizure initiation and/or to limit the spread of the seizure are under development.

 undertook a feasibility study of a modified type of ECT using a unidirectional electrical stimulus, 2 different sized electrodes, and novel electrode placement. Modifications of the stimulus package (ie, further reductions in pulse width and varying frequency, amplitude, or duration) are also being studied. Further research, including biomarker discovery for response/relapse prediction, should help inform practitioners about how to determine the optimal type and number of acute treatments for a given patient and how to individualize continuation/maintenance ECT schedules.

Dr Kellner is Professor in the department of psychiatry at the Icahn School of Medicine at Mount Sinai, Chief of Geriatric Psychiatry for the Mount Sinai Health System, and Director of the ECT Service at the Mount Sinai Hospital in New York. Dr Rasmussen is Professor in the department of psychiatry and psychology at the Mayo Clinic in Rochester, Minn. The authors report no conflicts of interest concerning the subject matter of this article.

 Baldinger P, Lotan A, Frey R, et al. Neurotransmitters and electroconvulsive therapy. 

 Sanacora G, Mason GF, Rothman DL, et al. Increased cortical GABA concentrations in depressed patients receiving ECT. 

 Michael N, Erfurth A, Ohrmann P, et al. Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression. 

 Merkl A, Schubert F, Quante A, et al. Abnormal cingulate and prefrontal cortical neurochemistry in major depression after electroconvulsive therapy. 

 Pfleiderer B, Michael N, Erfurth A, et al. Effective electroconvulsive therapy reverses glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed patients. 

 Haskett RF. Electroconvulsive therapy’s mechanism of action: neuroendocrine hypotheses. 

 Farzan F, Boutros NN, Blumberger DM, Daskalakis ZJ. What does the electroencephalogram tell us about the mechanisms of action of ECT in major depressive disorders? 

 Bouckaert F, Sienaert P, Obbels J, et al. ECT: its brain-enabling effects: a review of electroconvulsive therapy–induced structural brain plasticity. 

 Dukart, Regen F, Kherif F, et al. Electroconvulsive therapy-induced brain plasticity determines therapeutic outcome in mood disorders. 

 Nordanskog P, Dahlstrand U, Larsson MR, et al. Increase in hippocampal volume after electroconvulsive therapy in patients with depression: a volumetric magnetic resonance imaging study. 

 Tendolkar I, van Beek M, van Oostrom I, et al. Electroconvulsive therapy increases hippocampal and amygdala volume in therapy refractory depression: a longitudinal pilot study. 

 Joshi SH, Espinoza RT, Pirnia R, et al. Structural plasticity of the hippocampus and amygdala induced by electroconvulsive therapy in major depression. 2015 Mar 5; [Epub ahead of print].

 Abbott CC, Gallegos P, Rediske N, et al. A review of longitudinal electroconvulsive therapy: neuroimaging investigations. 

 Michael N, Erfurth A, Ohrmann P, et al. Neurotrophic effects of electroconvulsive therapy: a proton magnetic resonance study of the left amygdalar region in patients with treatment-resistant depression. 

 Ende G, Braus DF, Walter S, et al. The hippocampus in patients treated with electroconvulsive therapy: a proton magnetic resonance spectroscopic imaging study. 

 McCormick LM, Yamada T, Yeh M, et al. Antipsychotic effect of electroconvulsive therapy is related to normalization of subgenual cingulate theta activity in psychotic depression. 

 Perrin JS, Merz S, Bennett DM, et al. Electroconvulsive therapy reduces frontal cortical connectivity in severe depressive disorder. 

 Abbott CC, Lemke NT, Gopal S, et al. Electroconvulsive therapy response in major depressive disorder: a pilot functional network connectivity resting state fMRI investigation. 

 Beall EB, Malone DA, Dale RM, et al. Effects of electroconvulsive therapy on brain functional activation and connectivity in depression. 

 Christ M, Michael N, Hihn H, et al. Auditory processing of sine tomes before, during and after ECT in depressed patients by fMRI. 

 Andrade C. A primer for the conceptualization of the mechanism of action of electroconvulsive therapy, 1: defining the question. 

 Andrade C. A primer for the conceptualization of the mechanism of action of electroconvulsive therapy, 2: organizing the information. 

 Nahas Z, Short B, Burns C, et al. A feasibility study of a new method for electrically producing seizures in man: focal electrically administered seizure therapy [FEAST]. 

Articles

Simply telling patients “we don’t know how ECT works” neglects our abundant knowledge of what this treatment does. The authors review biological actions of ECT and discuss future directions for research.

Contemporary ECT, Part 2: Mechanism of Action and Future Research Directions

[[{"type":"media","view_mode":"media_crop","fid":"32074","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_1540772424833","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4028","media_crop_rotate":"0","media_crop_scale_h":"125","media_crop_scale_w":"106","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]Electroconvulsive therapy (ECT) remains an indispensable part of the treatment armamentarium in psychiatry.

 In recent decades, technical advances have made ECT safer and better-tolerated while its well-known effectiveness has been maintained. Ongoing research into the mechanism of action of ECT has led to better understanding of its effects on brain physiology. The explosion of interest in other brain stimulation technologies-primarily repetitive transcranial magnetic stimulation-has yet to produce an alternative clinically viable treatment for the seriously ill population for whom ECT is an appropriate choice; there is still no other equally effective therapy for our most severely ill patients.

This review covers recent advances in ECT technique, post-ECT management, and theories of mechanism of action. It will focus on the use of ECT in depression, the most common indication for ECT in clinical practice.

Three electrode placements have become standard in contemporary ECT practice: bitemporal (bilateral), right unilateral, and bifrontal. A body of clinical trial evidence suggests that, overall, bilateral placement is somewhat more effective and provides quicker response, while unilateral placement results in fewer cognitive effects.

Contemporary ECT for Depression, Part 2: Mechanism of Action and Future Research Directions

In the early decades of ECT practice, standard electrode placement was bilateral. Modifications to this technique were introduced in an effort to decrease the adverse effect of memory loss, based on the theory that the electrical stimulus should not be passed directly through the dominant hemisphere for language. Research in the 1950s demonstrated that therapeutic efficacy with unilateral electrode placement was similar to that with bilateral placement but with less cognitive impairment. Modern studies by Sackeim and colleagues

 introduced the concept that the antidepressant efficacy of right unilateral ECT is sensitive to stimulus dosing.

The theory underlying the development of bifrontal placement was that concentrating electrical current in the frontal rather than the temporal lobes would result in less cognitive impairment. A comprehensive meta-analysis of the literature on bifrontal electrode placement concluded that the overall efficacy of bifrontal placement is similar to that of bitemporal and unilateral placements, assuming adequate stimulus dosing for unilateral.

A large multisite study that compared unilateral, bitemporal, and bifrontal placements found equivalent efficacy and no cognitive advantage for bifrontal placement, although the latter finding is at odds with earlier studies.

 Thus, there currently is no compelling reason to favor bifrontal placement for treatment of depression. However, it remains in widespread clinical use, partly because it is easier to perform technically. Henceforth in this review, “bilateral” refers to bitemporal placement only.

Because there is considerable variation in clinical presentations and patient response (both antidepressant response and sensitivity to cognitive and other adverse effects) there is no single “best” electrode placement for all. In general, the more severely and urgently ill a patient is, the more likely he or she is to be treated initially with bilateral electrode placement. Conversely, the more concerned a patient is about adverse cognitive effects, the more likely he is to be treated initially with right unilateral placement. Patients who do not show adequate response to unilateral elec- trode placement should generally be crossed over to bilateral electrode placement after approximately 6 treatments.

Modern ECT electrical stimuli consist of a series of brief pulses of electricity generated by the ECT device and delivered through the electrodes (either metal or disposable adhesive) placed on the scalp. The total amount of electricity (stimulus dose) can be increased or decreased by manipulation of the following parameters:

• Duration of each pulse (pulse width) in milliseconds

• Total duration of the pulse train in seconds

• Frequency of pulses in hertz (cycles per second, 2 consecutive pulses constituting a “cycle”)

The total amount of electrical charge delivered to the patient can be quantified in units of millicoulombs, conceptually analogous to a dose of a medication in milligrams. The minimum charge necessary to elicit a seizure varies from patient to patient and is termed the “seizure threshold.” It can be determined at the first session in a course of treatments, by starting with a low setting on the ECT device and re-stimulating the patient at progressively higher doses until a seizure ensues (dose titration).

With unilateral placement, the degree to which electrical dose exceeds initial seizure threshold at subsequent treatments correlates with antidepressant outcome and cognitive effects. Doses in the range of 6 times seizure threshold and higher have demonstrated efficacy equal to that of bitemporal placement.

 Clinical data also show that cognitive effects increase as the electrical dose increases, for both unilateral and bilateral placements. In current practice, using dose titration, at the second treatment and beyond, a multiple of the initial threshold stimulus is used to elicit seizures, typically approximately twice seizure threshold for bilateral or approximately 6 times threshold for right unilateral electrode placement. Ongoing research will likely clarify whether this approach to stimulus dosing is optimal or whether more nuanced, or different, approaches will yield even better efficacy and tolerability.

Manipulations of individual stimulus parameters may affect therapeutic and cognitive outcomes in ECT, independent of total electrical dose. The necessary pulse width to depolarize neurons is much shorter than that traditionally used on ECT devices, which is in the range of 0.5 to 1.5 milliseconds. Sackeim and colleagues

 randomly assigned depressed patients to ultrabrief (0.3 millisecond) or brief (1.5 milliseconds) pulse stimuli. Electrode placement was further randomized to unilateral at 6 times threshold or bitemporal at 2.5 times threshold. Remission rates were approximately 70% for all groups except bitemporal ultrabrief pulse, which unexpectedly had very low efficacy. Cognitive adverse effects were markedly reduced in the ultrabrief pulse width groups.

Response/remission rates have varied considerably in other studies of depressed patients treated with right unilateral ultrabrief pulse ECT.

 In contrast to the findings of Sackeim and colleagues,

 other data indicate approximately equal memory performance for brief and ultrabrief pulse width right unilateral placement.

 Thus, it is still unclear whether the ultrabrief technique truly provides a cognitive advantage over standard pulse width unilateral treatment. Enthusiasm in the ECT community for right unilateral ultrabrief pulse technique has grown, and it is now commonly used.

Augmenting ECT with antidepressant medications

A common clinical question is whether to use antidepressant medications concomitantly with ECT. Although several early studies found no advantage to adding the medications, Lauritzen and colleagues

 found that the addition of imipramine to acute ECT, vis-Ã -vis paroxetine or placebo, resulted in lower posttreatment depression ratings.

 randomly assigned patients to receive concomitant placebo, venlafaxine, or nortriptyline along with ECT. Both antidepressants improved remission rates compared with placebo; nortriptyline was slightly better than venlafaxine. Interestingly, anterograde and retrograde amnesia were less severe with nortriptyline than with venlafaxine or placebo. Thus, the two most methodologically sound studies of concomitant antidepressant medications indicate that a TCA may enhance acute response rates with ECT.

The ultrashort-acting barbiturate methohexital remains the anesthetic agent of choice in ECT because of its overall profile of characteristics that include predictable dosing, rapid onset, brief duration, only moderate anticonvulsant effect, and low cost. Alternative agents include propofol, thiopental, etomidate, and ketamine.

Ketamine is an older anesthetic medication that has generated enormous interest in psychiatry of late because of its intrinsic antidepressant activity. Several randomized comparative trials have assessed ketamine in ECT, either as the primary anesthetic agent or as augmentation to another agent. Loo and colleagues

 reported that 0.5 mg/kg of ketamine added to thiopental as the primary anesthetic agent resulted in an early greater drop in depression scores than thiopental plus placebo, but the effect was small clinically and not sustained.

In a similar study, Abdallah and colleagues

 used thiopental for ECT anesthesia supplemented with placebo or 0.5 mg/kg of ketamine and found no difference in depression outcome ratings. Okamoto and colleagues15 used ketamine 0.8 mg/kg or propofol for ECT anesthesia and monitored depression ratings. They reported slightly faster antidepressant response with ketamine but equal outcomes with propofol after 8 treatments.

 randomized patients to anesthesia with approximately 1 mg/kg of ketamine or methohexital and found no advantage of ketamine. Yoosefi and colleagues

 did find slightly lower depression rating scale scores with ketamine than with thiopental anesthesia after the first treatment, but not later in the treatment course.

To date, the studies of ketamine for ECT anesthesia are mixed, and even those finding an advantage found this only in the first few days of treatment. A recent meta-analysis of studies of adjunctive ketamine in ECT (N = 182 patients) found no antidepressant advantage but higher rates of confusion, disorientation, and prolonged delirium.

 Given this added adverse effect, ketamine is not recommended for routine ECT anesthesia but may still have a role in select patients for seizure enhancement or antidepressant augmentation.

After a successful course of ECT, patients should receive continuation or maintenance treatment to prevent relapse. Maintenance treatment may include pharmacotherapy, additional ECT, and psychotherapy.

Post-ECT relapse rates have increased in recent years, perhaps because ECT is often delayed until patients have remained ill for long periods and exhibited treatment resistance to multiple medication trials. Approximately half of ECT-treated patients given continuation pharmacotherapy will remain well for 1 year.

Findings indicate that monotherapy, with either a TCA or an SSRI, reduces relapse rates. An antidepressant is typically started during or after a course of ECT with the anticipation that it will provide some protection against post-ECT relapse, despite the fact that it, or similar agents, may not have been successful in inducing remission for the current episode. The evidence for any specific antidepressant is limited, thus an agent may be selected because it was not yet tried during the current episode or because it was well tolerated and may have provided some symptomatic improvement.

Combination pharmacotherapy- often an antidepressant and mood stabilizer-has been shown to reduce post-ECT relapse more than antidepressant monotherapy. The combination of nortriptyline and lithium was associated with a 30% to 40% relapse rate at 6 months.

 A recent study suggests comparable efficacy and tolerability of lithium/nortriptyline and lithium/venlafaxine combinations.

Lithium alone or in combination has been shown to be effective in post-ECT relapse prevention, although the details of optimal lithium use for this indication remain to be elucidated and practitioners are reluctant to prescribe it. Other medication classes, particularly atypical antipsychotics, or combinations of medications are often used clinically after successful ECT. However, the evidence base supporting the efficacy of these practices is very small.

Maintenance ECT is usually reserved for patients with a history of multiple depressive relapses or particularly severe illness. Patients typically receive a single treatment, often as an outpatient, at an interval of between 1 and 5 weeks. The schedule is flexible and tailored to the needs of the patient, with the goal of providing relapse protection with the fewest possible treatments.

The need for ongoing ECT should be reassessed at intervals (eg, every 3 or 6 months); a small cohort of severely ill patients may need maintenance ECT indefinitely. The practice of tapering an acute ECT course, rather than stopping it abruptly, has been suggested as a relapse prevention strategy; data from the recently completed Prolonging Remission in Depressed Elderly (PRIDE) study should help to confirm or deny this (ClinicalTrials.gov Identifier: NCT01028508).

There is currently little evidence to support psychotherapy as post-ECT maintenance, although a recent randomized trial that included cognitive-behavioral therapy (CBT) plus antidepressant medication showed a protective effect for CBT.

Contemporary ECT practice has evolved such that ECT today is a remarkably safe and effective treatment for severe depression. Its tolerability continues to be improved by refinements in technique. Clinical strategies for relapse prevention are helping patients stay well longer. Such advancements, coupled with better understanding of ECT’s mechanism of action (see Part 2 of this review in a future issue), will help to de-stigmatize this very important treatment in psychiatric medicine.

The authors report no conflicts of interest concerning the subject matter of this article.

 Fink M. Electroconvulsive therapy resurrected: its successes and promises after 75 years. 

 Kellner CH, Tobias KG, Wiegand J. Electrode placement in electroconvulsive therapy (ECT): a review of the literature. 

 Sackeim HA, Prudic J, Devanand DP, et al. A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. 

 McCall WV, Reboussin DM, Weiner RD, Sackeim HA. Titrated moderately suprathreshold vs fixed high-dose right unilateral electroconvulsive therapy: acute antidepressant and cognitive effects. 

 Dunne RA, McLoughlin DM. Systematic review and meta-analysis of bifrontal electroconvulsive therapy versus bilateral and unilateral electroconvulsive therapy in depression. 

 Kellner CH, Knapp R, Husain MM, et al. Bifrontal, bitemporal and right unilateral electrode placement in ECT: randomised trial. 

 Lapidus KA, Kellner CH. When to switch from unilateral to bilateral electroconvulsive therapy. 

 Sackeim HA, Prudic J, Nobler MS, et al. Effects of pulse width and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy [published correction appears in Brain Stimul. 2008;1(3):A2]. 

 Loo CK, Sainsbury K, Sheehan P, Lyndon B. A comparison of RUL ultrabrief pulse (0.3 ms) ECT and standard RUL ECT. 

 Spaans HP, Verwijk E, Comijs HC, et al. Efficacy and cognitive side effects after brief pulse and ultrabrief pulse right unilateral electroconvulsive therapy for major depression: a randomized, double-blind, controlled study.

 Lauritzen L, Odgaard K, Clemmesen L, et al. Relapse prevention by means of paroxetine in ECT-treated patients with major depression: a comparison with imipramine and placebo in medium-term continuation therapy. 

 Sackeim HA, Dillingham EM, Prudic J, et al. Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects. 

 Loo CK, Katalinic N, Garfield JB, et al. Neuropsychological and mood effects of ketamine in electroconvulsive therapy: a randomised controlled trial. 

 Abdallah CG, Fasula M, Kelmendi B, et al. Rapid antidepressant effect of ketamine in the electroconvulsive therapy setting. 

 Okamoto N, Nakai T, Sakamoto K, et al. Rapid antidepressant effect of ketamine anesthesia during electroconvulsive therapy of treatment-resistant depression: comparing ketamine and propofol anesthesia. 

 Rasmussen KG, Kung S, Lapid MI, et al. A randomized comparison of ketamine versus methohexital anesthesia in electroconvulsive therapy.

 Yoosefi A, Sepehri AS, Kargar M, et al. Comparing effects of ketamine and thiopental administration during electroconvulsive therapy in patients with major depressive disorder: a randomized, double-blind study. 

 McGirr A, Berlim MT, Bond DJ, et al. A systematic review and meta-analysis of randomized controlled trials of adjunctive ketamine in electroconvulsive therapy: efficacy and tolerability. 

 Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. 

 Kellner CH, Knapp RG, Petrides G, et al. Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE). 

 Prudic J, Haskett RF, McCall WV, et al. Pharmacological strategies in the prevention of relapse after electroconvulsive therapy. 

 Brakemeier EL, Merkl A, Wilbertz G, et al. Cognitive-behavioral therapy as continuation treatment to sustain response after electroconvulsive therapy in depression: a randomized controlled trial. 

Physicians who use electroconvulsivetherapy (ECT) need tobe vigilant for unstable medicalconditions before and during the courseof treatment. This brief review is intendedto highlight some basic principlesand specific concerns that maybe encountered in the use of ECT inpatients who have comorbid medicalillness. For more extensive discussions,I refer the reader to recent reviews ofECT in the medically ill by Abrams

 aswell as the recommendations of theAmerican Psychiatric AssociationCommittee on ECT.

Safe use of ECT in the medically illpatient begins with a careful pretreatmentevaluation. The cornerstones ofthis are the medical history, review ofsystems, and physical examination,which together are far more important than blood tests or other diagnostic studies.Any significant abnormalities thatemerge, especially those relevant to thecardiac, respiratory, or neurologic systems,can be investigated with a rationalchoice of diagnostic tests and medicalconsultations. For example, in patientswith unstable heart disease, an echocardiogrammay be helpful in assessinghow the heart will react to the stress ofan ECT treatment and may indicate theneed for pretreatment modification ofthe patient's medication regimen.

Routine pre-ECT tests should includeserum electrolyte levels and anECG. A chest xray study should beconsidered in elderly patients and inthose with pulmonary disorders. Brainimaging studies, such as CT or MRI,are not routinely needed but should beconsidered for those in whom thehistory or physical examination suggestsstructural CNS pathology.

The second principle is careful monitoringof the patient during each treatment.If cardiac medications, glaucomaeyedrops, or inhalers are prescribed,these should be administered beforeeach treatment.

 For patients withsevere cardiac disease, tight control of blood pressure may be advisable;accordingly, antihypertensive medicationscan be used in the treatment suite.

The third basic principle for themedically ill patient receiving ECT is(CHF) who was well compensatedcardiologically before the first treatmentmay be having some pulmonary congestionafter several treatments. Onlyongoing evaluation of the medical statusthroughout treatment to monitor fordestabilization of existing conditions oremergence of new ones. For example,a patient with congestive heart failure through daily history taking and physicalexamination can the physician detectsuch subtle changes.

provide detailed discussions about themedical physiology of ECT seizures, anunderstanding of which helps informmanagement before and during ECT inpatients with medical conditions. I willreview this topic only briefly here. Themain organ systems affected duringseizures are the brain, of course, and theheart. Over the decades, there has beena plethora of research on neurometaboliceffects of electrically induced seizuresin humans and animals, none of whichspecifically has implications at presentfor ECT in medically ill patients.

From a neurovascular standpoint, arapid increase in cerebral perfusionoccurs, resulting in increased permeabilityof the blood-brain barrier as wellas a temporary rise in intracranial pressure.Such changes would be expectedto have implications for patients withspace-occupying lesions and increasedintracranial pressure (eg, brain tumors).Another robust neurophysiologicchange in ECT is a rise in the electricallyinduced seizure threshold (thus,an anticonvulsant effect), an interestingphenomenon that has formed thebasis for the occasional use of ECT toreduce spontaneous seizure frequencyin patients with epilepsy.

The cardiac physiologic effects ofECT have been well characterized.Barbiturate anesthetics have a slightdepressing effect on blood pressure.Immediately after the presentation ofthe electrical stimulus, there is a sometimesprofound parasympathetic stimulationthat leads to a few seconds ofasystole.

 This is rapidly replaced by asympathetic predominance (assumingthat the electrical stimulus was of sufficientintensity to produce a seizure)that leads to a sharp rise in heart rateand blood pressure, effects that abateshortly after the end of the seizure. Inaddition, various arrhythmias, such aspremature ventricular contractions, prematureatrial contractions, and evenvery brief runs of ventricular tachycardiawithout blood pressure compromise,are quite common. These variousphysiologic changes would clearly haveimplications for patients with cardiacconditions such as congestive heart failure,coronary artery disease, cardiomyopathies,and arrhythmias.

Given the physiologic changes associatedwith ECT, it bears repeating thata thorough pre-ECT evaluation, carefulmanagement during treatments, andvigilant intertreatment monitoring formthe bulwark of care for patients withany medical illness who undergo ECT.

The most common cardiac conditionsencountered in ECT practice are coronaryartery disease, CHF, and arrhythmias.For the patient with coronaryartery disease, the internist or cardiologistwill want to ask detailed questionsabout exercise tolerance, angina pectoris,and shortness of breath. Cardiac auscultationwill also provide informationabout the stability of myocardial function.Consultation with a cardiologist orwith an internist familiar with ECT issuggested for such patients. Pretreatmentdiagnostic tests, such as echocardiographyor nuclear medicine scanning,may assess how the patient's heart respondsto the increased myocardial workloadthat occurs during seizures.

If evidence of ventricular wall motionabnormalities or ischemic changes ispresent, then cardiac medication changesor even revascularization proceduresshould be considered before ECT. If thecardiologist does not recommend sucha course of action, then considerationmay be given to use of β-blockers duringthe ECT treatments to lessen the increasein myocardial workload. Communicationbetween the attending cardiologistand anesthesiologist is crucial tosettle on a rational management plan.

CHF presents a special challenge in ECT, because patients with CHF are oftenexquisitely sensitive to increases in myocardialoxygen demand.

 Again, cardiologicconsultation is recommended forsuch patients to optimize their medicationregimen before ECT is begun; a marginallycompensated patient may easilyproceed to frank decompensation aftera few treatments.

 It is important to administerthe patient's prescribed cardiacmedication regimen, including diuretics,on the morning of each ECT treatment.

The most common arrhythmia inpatients receiving ECT is atrial fibrillation.There are numerous reports ofsafe use of ECT in patients with atrialfibrillation, but conversion to normalsinus rhythm has been described andthe risk of thrombus/embolus formationis also present.

 Thus, maintaininganticoagulation with warfarin or heparinduring ECT is usually recommended insuch patients. If the heart rate is notcontrolled at baseline, the cardiologistwill probably recommend treatment tocontrol it before proceeding with ECT.Patients with pacemakers or implantablecardioverter-defibrillators (ICDs) can betreated safely with ECT; recommendedmanagement includes pretreatmentdevice interrogation to ensure properfunction and turning off of ICDs (aftercontinuous ECG monitoring has beenstarted) under the guidance of competentpersonnel.

The most common neurologic illnessin patients receiving ECT is dementia,usually of the Alzheimer or Lewy bodytype. Numerous case series have documentedthat demented patients can attainsignificant benefit in mood and disruptivebehaviors with ECT without apparentlong-term worsening of thedementing process.

 I recommend thatdemented patients be treated with unilateralor bifrontal electrode placement tolessen cognitive effects. Patients whohave Parkinson disease (PD) often experiencemotoric improvement with ECT,possibly as a result of enhanced dopaminergicfunction.

On the other hand, some evidencesuggests that in patients with basalganglia dysfunction, such as those withPD, ECT may have excessive cognitiveeffects, so either unilateral or bifrontalelectrode placement is recommendedin these patients. There may also bedyskinesias during ECT in patients withPD who are taking levodopa, so thedosage of that drug may need to bereduced temporarily during the courseof treatments.

Because of the increase in intracranialpressure during seizures, braintumors or other intracranial masses--especially those associated with increasedintracranial pressure--may posea substantial risk of neurologic deterioration deteriorationduring ECT.

 Several case reportsdo seem to indicate that meningiomasnot associated with edema or mass effectmay pose no increased risk during ECT.

There is no evidence that ECT worsensthe course of epilepsy; in fact, it mayreduce the frequency of spontaneousseizures in patients with epilepsy.

However,seizure induction may be difficultif the patient is taking anticonvulsant medication.Cautious dose reduction of suchmedications, if deemed safe by thepatient's neurologist, may result in enhancedseizure expression during ECT.

Patients with neuroleptic malignantsyndrome (or other forms of malignantcatatonia) may experience dramaticimprovement with ECT.

 Patients witha wide variety of other neurologic conditions,as documented in an extensive casereport literature, can be treated safelywith ECT.

 A possible exception is multiplesclerosis, especially with gadoliniumenhancinglesions on MRI; there is onereport of neurologic worsening withECT in a patient with such lesions.

If inhalers have been prescribed for apatient with chronic obstructive pulmonarydisease or asthma, these shouldbe administered before each treatment.Theophylline in patients receiving ECThas been associated with status epilepticus,and if the patient is taking this medication, blood levels should bechecked regularly.

Patients with diabetes who are takinginsulin can be given half their usualmorning dose and treated promptlywith ECT, then given the remaining halfand fed breakfast. Non-insulin-dependentpersons should not be given theirmorning oral hypoglycemic agent untilafter the treatment, when they can eata meal. Blood sugar should be checkedbefore each treatment by fingerstick.

In the third trimester of pregnancy,the sympathetic stimulation associatedwith the seizure may be associated withabruptio placentae or premature labor.In such cases, noninvasive fetal monitoringis recommended; ECT shouldonly be conducted if obstetric servicesare readily available.

Dr Rasmussen is associate professor, departmentof psychiatry, Mayo Clinic, Rochester,Minn. He reports no financial conflicts regardingthe subject matter of this article.

 Abrams R. Electroconvulsive Therapy. 4th ed. NewYork: Oxford University Press; 2002.


 Rasmussen KG, Rummans TA, Tsang TS, et al.ECT in the medically ill. In: Levenson J, ed. AmericanPsychiatric Publishing Textbook of PsychosomaticMedicine. Washington, DC: American PsychiatricPublishing; 2004.


 American Psychiatric Association Committeeon Electroconvulsive Therapy. The Practice ofElectroconvulsive Therapy: Recommendations forTreatment, Training, and Privileging. 2nd ed. Washington,DC: American Psychiatric Publishing; 2001.


 Griesemer DA, Kellner CH, Beale MD, Smith GM.Electroconvulsive therapy for treatment of intractableseizures: Initial findings in two children. Neurology.1997;49:1389-1392.


 Rasmussen KG, Jarvis MR, Zorumski CF, et al.Low-dose atropine in electroconvulsive therapy. JECT. 1999;15:213-221.


 Goldberg RJ, Badger JM. Major depressive disorderin patients with the implantable cardioverter defibrillator:two cases treated with ECT. Psychosomatics.1993;34:273-277.


 Petrides G, Fink M. Atrial fibrillation, anticoagulation,and electroconvulsive therapy. Convuls Ther.1996;12:91-98.


 Dolenc TJ, Barnes RD, Hayes DL, et al.Electroconvulsive therapy in patients with cardiacpacemakers and implantable cardioverter defibrillators.Pacing Clin Electrophysiol. 2004;27:1257-1263.


Rao V, Lyketsos CG. The benefits and risks of ECTfor patients with primary dementia who also suffer fromdepression. Int J Geriatr Psychiatry. 2000;15: 729-735.


 Rasmussen K, Abrams R. Treatment of Parkinson'sdisease with electroconvulsive therapy.Psychiatr Clin North Am. 1991;14:925-933.


 Maltbie AA, Wingfield MS, Volow MR, et al.Electroconvulsive therapy in the presence of braintumor: case reports and an evaluation of risk. J NervMent Dis. 1980;168:400-405.


 McKinney PA, Beale MD, Kellner CH.Electroconvulsive therapy in a patient with a cerebellarmeningioma. J ECT. 1998;14:49-52.


 Mattingly G, Baker K, Zorumski CG, et al. Multiplesclerosis and ECT: possible value of gadoliniumenhancedmagnetic resonance scans for identifyinghigh-risk patients. J Neuropsychiatry Clin Neurosci.1993;4:145-151.


 Rasmussen KG, Zorumski CF. ECT in patients takingtheophylline. J Clin Psychiatry. 1993;54:427-431.

Physicians who use electroconvulsivetherapy (ECT) need tobe vigilant for unstable medicalconditions before and during the courseof treatment. This brief review is intendedto highlight some basic principlesand specific concerns that maybe encountered in the use of ECT inpatients who have comorbid medicalillness.

Author | Keith G. Rasmussen, MD

Articles

Contemporary ECT, Part 2: Mechanism of Action and Future Research Directions

Contemporary ECT for Depression Part 1: Practice Update

Electroconvulsive Therapy and Medical Illness