The

NEW ENGLA ND JOURNAL

of

MEDICINE

Perspective
may 12, 2011

Electroconvulsive Therapy in the Spotlight

Wayne K. Goodman, M.D.

n January, the Food and Drug Administration (FDA) convened a meeting of its Neurological Devices Advisory Panel to help it decide how to classify electroconvulsive therapy (ECT) devices,
induce a seizure, was first performed in 1938, but its safety has since been enhanced by the use of general anesthesia, cardiopulmonary support, muscle relaxa tion, waveform and energy dosing, electroencephalographic monitoring, and varied electrode placement. Nevertheless, it has significant effects on cognitive function. The degree and duration of adverse cognitive effects are domainspecific and vary with ECT settings. Disorientation is common but usually resolves within minutes after each treatment. Anterograde amnesia inability to create new memories is also common but generally disappears within days after a treatment course. The primary safety

a decision that could determine the future of ECT in the United States.1 The meeting revealed sharp differences of opinion about ECTs effectiveness and safety. Although ECT has long been controversial, refinements in the procedure some of which were introduced by the mid1950s might have been expected to correct impressions based on terrifying but inaccurate Hollywood depictions. Whereas most psychiatrists embrace ECT as the gold standard for treating severe depression (and other serious mental disorders2), many other physicians remain dubious about its riskbenefit ratio. ECT, the therapeutic application of electricity to the scalp to

concern is the possible persistence of retrograde amnesia inability to recall events before ECT.3 A course of ECT is typically 6 to 12 treatments, administered three times weekly (in the United States) or twice weekly (in Britain). The indications for use include depression, schizophrenia, bipolar mania, and catatonia. The treatment is usually reserved for patients in whom pharmacotherapy has failed or caused adverse reactions or those with severe symptoms such as suicidality, psychosis, or grave functional impairment.2 It is widely used in geriatric depression. ECT devices are among the few remaining class III (highestrisk) medical devices that were grandfathered through a regulatory pathway requiring no premarket approval application (PMA). Since 2009, the FDA has been examining whether such devices should be reclassified as
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PERSPE C T I V E

Electroconvulsive Therapy in the Spotlight

Potential Mitigating Factors for Cognitive and Memory Dysfunction.* ECT Parameter Electrode placement Waveform Energy level Frequency Reduces Risk Right unilateral Brief pulse Ultra-brief pulse Low Twice a week Increases Risk Bilateral Sine-wave High Three times a week Comments Several variations for anatomical location of electrodes exist. Use of alternating current (sine wave) is strongly discouraged. Measured in multiples of seizure threshold. Twice weekly is standard practice in Britain.

* These findings vary according to the specific domain examined and the measure used. Domains influenced by these electroconvulsive therapy (ECT) settings include disorientation immediately after treatment and anterograde memory. There is less evidence that risk of retrograde amnesia can be altered. For several variables, there is a trade-off between side effects and effectiveness.

class II (intermediate-risk) or remain in class III, in which case PMAs would be required. The Neurological Devices Advisory Panel, of which I was a member, evaluated evidence on safety, efficacy, and controls that might mitigate ECTs risks. Although no formal vote was taken, the majority of the members recommended that ECT devices remain in class III. In general, the panels psychiatrists and anesthesiologist favored reclassification into class II, whereas the neurologists, psychologists, biostatisticians, and public representative advised retaining class III status. Reclassification would require establishing procedural and regulatory measures to mitigate risk primarily that of retrograde memory loss. By a narrow majority, the panel was unconvinced that sufficient information exists to manage this potential hazard. If the FDA decides to keep ECT devices in class III, PMAs will be required for each indication, possibly necessitating additional randomized, sham-controlled trials. Some fear that trials costs could prove prohibitive for the two relatively small manufacturers of ECT devices for sale in the United

States. There are also concerns about the ethicality and feasibility of a sham-controlled study in conditions such as severe depression, with its high risk of suicide. If the manufacturers dont submit acceptable applications within 30 months after the PMA requirements are issued, the devices could be withdrawn from the market. In my view, this is the worst-case scenario: ECT devices exit the market before safety and effectiveness issues are resolved and before viable alternatives are identified for the estimated 100,000 U.S. patients who receive ECT each year.1 The FDA review of ECTs effectiveness concentrated on randomized, controlled trials using sham-procedure, pill-placebo, or active-drug controls; it concluded that active ECT was more effective than sham ECT, placebo, and some antidepressants during the acute treatment phase (up to 4 weeks) but not longer. Limitations of the sham-controlled studies may help to explain the failure to show a longer-term advantage: in some studies longerterm outcome measures were not obtained; in others comparisons were confounded by allowing

treating psychiatrists to freely prescribe antidepressant treatments (including ECT) during follow-up. In practice, ECT is used when rapid onset of action is critical, and ongoing antidepressant therapy follows. The panel was concerned about risks of cognitive and memory dysfunction. The FDAs safety review included trials comparing the moderating effects of various ECT techniques (see table). The ECT settings associated with greater cognitive and memory impairment were bilateral and dominant-hemisphere electrode placement, sine-wave stimulus, and high energy doses; conversely, right unilateral placement with brief or ultra-brief pulse was associated with fewer cognitive and memory problems. The review found no evidence of persistent disorientation, and anterograde memory disturbances usually cleared within 2 weeks after an ECT course. Global cognitive function was either unchanged or improved from baseline by 3 to 6 months after the completion of ECT; improvement may reflect the underlying disorders response to treatment, since major depression is fre-

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PERSPECTIVE

Electroconvulsive Therapy in the Spotlight

quently associated with reversible cognitive impairments.3 The most troubling finding was impaired retrieval of past personal memories (retrograde autobiographical memory), as opposed to impersonal memories (e.g., historical or factual information). The review revealed no significant changes in retrograde impersonal memory from baseline to 6 months after ECT, but the evidence that retrograde personal memory deficits resolved by 6 months were deemed inconclusive. Bilateral, as compared with low-energy unilateral, ECT increased the risk of personal memory deficits during the 2 weeks after treatment. Autobiographical memory is a complex construct that is difficult to characterize and measure. It has an episodic component involving memories of unique, personal events situated in time and space that are hard to authenticate.4 Objective measures would require baseline validation by family members or others. Because depression can impair autobiographical memory,3 the most appropriate baseline may be before the onset of depression, rather than immediately before ECT.5 The primary instrument for assessing autobiographical memory has several limitations, including the unverifiability of baseline information.5 Moreover, objective measures and subjective accounts of personal memory deficits often do not agree,5 and self-reports of memory loss may be influenced

by depressive symptoms.3,5 In geriatric patients, it may be difficult to disentangle possible adverse effects of ECT from manifestations of conditions such as cerebrovascular or degenerative brain disease.3 The combination of measurement problems and potential confounders could account for some of the long-term personal memory deficits attributed to ECT.3 Nevertheless, reports of permanent erasure of some personal memories after ECT cannot be ignored. Unfortunately, the relevant data are inconclusive, and new studies wont help without objective, standardized, user-friendly measures of autobiographical amnesia. Given the probable low frequency of this adverse effect and need for long-term follow-up, large sample sizes will be required, as will suitable comparison groups, to permit examination of possible confounding effects of mood, medical illness, and aging on memory assessments.3 Meanwhile, the uncertain risk of memory loss must be considered in the context of the gravity of the underlying illness. Many patients undergo ECT only after other treatment options have been exhausted.2 Decisions about ECT require full participation of the patient in a robust informed consent process that acknowledges gaps in our knowledge about the extent of personal memory loss. If ECT devices remain in class III, a PMA requirement for new

trials is not the only option. The FDA could clear ECT for certain indications, such as depression, on the basis of further review of existing data and identification of conditions of use providing reasonable assurance of safety and effectiveness. Yet a favorable decision wouldnt obviate the need for additional research, including the development of safer alternatives. Promising new devices or rapidacting drugs could be compared with ECT in randomized, controlled trials providing opportunities to reevaluate the comparative safety and effectiveness of ECT without violating equipoise.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Department of Psychiatry and Friedman Brain Institute, Mount Sinai School of Medicine, New York. 1. Food and Drug Administration. Meeting to discuss the classification of electroconvulsive therapy devices (ECT). Executive summary. 2011. (http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeeting Materials/MedicalDevices/MedicalDevices AdvisoryCommittee/NeurologicalDevices Panel/UCM240933.pdf.) 2. Committee on Electroconvulsive Therapy. The practice of electroconvulsive therapy: recommendations for treatment, training, and privileging. 2nd ed. Washington, DC: American Psychiatric Association, 2001. 3. Weiner RD. Retrograde amnesia with electroconvulsive therapy: characteristics and implications. Arch Gen Psychiatry 2000;57:591-2. 4. Piolino P, Desgranges B, Eustache F. Episodic autobiographical memories over the course of time: cognitive, neuropsychological and neuroimaging findings. Neuropsychologia 2009;47:2314-29. 5. Fraser LM, OCarroll RE, Ebmeier KP. The effect of electroconvulsive therapy on autobiographical memory: a systematic review. J ECT 2008;24:10-7.
Copyright 2011 Massachusetts Medical Society.

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