Perspective TheNEWENGLANDJOURNALofMEDICINEmay 12, 2011n engl j med 364;19nejm.orgmay 12, 20111785adecisionthatcoulddetermine the future of ECT in the United States.1Themeetingrevealed sharpdifferencesofopinion aboutECTseffectivenessand safety.AlthoughECThaslong been controversial, refinements in the procedure some of which wereintroducedbythemid-1950smighthavebeenex-pectedtocorrectimpressions basedonterrifyingbutinaccu-rate Hollywood depictions. Where-asmostpsychiatristsembrace ECTasthegoldstandardfor treatingseveredepression(and otherseriousmentaldisorders2), many other physicians remain du-bious about its riskbenefit ratio.ECT,thetherapeuticapplica-tion of electricity to the scalp to induceaseizure,wasfirstper-formed in 1938, but its safety has sincebeenenhancedbytheuse ofgeneralanesthesia,cardiopul-monarysupport,musclerelaxa-tion, waveform and energy dosing, electroencephalographicmonitor-ing,andvariedelectrodeplace-ment. Nevertheless, it has signifi-cant effects on cognitive function. Thedegreeanddurationofad-verse cognitive effects are domain-specificandvarywithECTset-tings.Disorientationiscommon butusuallyresolveswithinmin-utes after each treatment. Antero-gradeamnesiainabilityto createnewmemoriesisalso commonbutgenerallydisap-pearswithindaysafteratreat-ment course. The primary safety concernisthepossiblepersis-tence of retrograde amnesia in-ability to recall events before ECT.3AcourseofECTistypically 6 to 12 treatments, administered three times weekly (in the United States) or twice weekly (in Britain). Theindicationsforuseinclude depression, schizophrenia, bipolar mania,andcatatonia.Thetreat-mentisusuallyreservedforpa-tients in whom pharmacotherapy hasfailedorcausedadversere-actions or those with severe symp-toms such as suicidality, psychosis, orgravefunctionalimpairment.2 Itiswidelyusedingeriatricde-pression.ECTdevicesareamongthe few remaining class III (highest-risk)medicaldevicesthatwere grandfatheredthrougharegu-latory pathway requiring no pre-marketapprovalapplication (PMA).Since2009,theFDAhas been examining whether such de-vicesshouldbereclassifiedas Electroconvulsive Therapy in the SpotlightWayne K. Goodman, M.D.In 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, The New England Journal of Medicine Downloaded from nejm.org on July 27, 2015. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved. PERSPECTI VEn engl j med 364;19nejm.orgmay 12, 20111786class II (intermediate-risk) or re-maininclassIII,inwhichcase PMAswouldberequired.The NeurologicalDevicesAdvisory Panel, of which I was a member, evaluatedevidenceonsafety,ef-ficacy,andcontrolsthatmight mitigateECTsrisks.Although noformalvotewastaken,the majorityofthemembersrecom-mended that ECT devices remain inclassIII.Ingeneral,thepan-elspsychiatristsandanesthesiol-ogist favored reclassification into class II, whereas the neurologists, psychologists, biostatisticians, and publicrepresentativeadvisedre-taining class III status. Reclassi-ficationwouldrequireestablish-ingproceduralandregulatory measures to mitigate risk pri-marily that of retrograde memory loss.Byanarrowmajority,the panelwasunconvincedthatsuf-ficient information exists to man-age this potential hazard.If the FDA decides to keep ECT devices in class III, PMAs will be required for each indication, pos-sibly necessitating additional ran-domized, sham-controlled trials. Some fear that trials costs could prove prohibitive for the two rela-tively small manufacturers of ECT devicesforsaleintheUnited States.Therearealsoconcerns about the ethicality and feasibil-ity of a sham-controlled study in conditions such as severe depres-sion, with its high risk of suicide. Ifthemanufacturersdontsub-mit acceptable applications with-in30monthsafterthePMAre-quirements are issued, the devices couldbewithdrawnfromthe market.Inmyview,thisisthe worst-case scenario: ECT devices exit the market before safety and effectivenessissuesareresolved andbeforeviablealternatives areidentifiedfortheestimated 100,000 U.S. patients who receive ECT each year.1 TheFDAreviewofECTsef-fectivenessconcentratedonran-domized,controlledtrialsusing sham-procedure, pill-placebo, or active-drug controls; it concluded thatactiveECTwasmoreeffec-tivethanshamECT,placebo, and some antidepressants during the acute treatment phase (up to 4weeks)butnotlonger.Limita-tionsofthesham-controlled studiesmayhelptoexplainthe failure to show a longer-term ad-vantage:insomestudieslonger-term outcome measures were not obtained;inotherscomparisons wereconfoundedbyallowing treating psychiatrists to freely pre-scribeantidepressanttreatments (including ECT) during follow-up. Inpractice,ECTisusedwhen rapidonsetofactioniscritical, and ongoing antidepressant ther-apy follows.The panel was concerned about risksofcognitiveandmemory dysfunction. The FDAs safety re-viewincludedtrialscomparing the moderating effects of various ECTtechniques(seetable).The ECTsettingsassociatedwith greatercognitiveandmemory impairmentwerebilateraland dominant-hemisphereelectrode placement,sine-wavestimulus, and high energy doses; converse-ly, right unilateral placement with brieforultra-briefpulsewasas-sociated with fewer cognitive and memory problems.The review found no evidence ofpersistentdisorientation,and anterograde memory disturbances usuallyclearedwithin2weeks after an ECT course. Global cog-nitivefunctionwaseitherun-changed or improved from base-lineby3to6monthsafterthe completion of ECT; improvement mayreflecttheunderlyingdis-ordersresponsetotreatment, sincemajordepressionisfre-Electroconvulsive Therapy in the SpotlightPotential Mitigating Factors for Cognitive and Memory Dysfunction.*ECT Parameter Reduces Risk Increases Risk CommentsElectrode placement Right unilateral Bilateral Several variations for anatomical location of elec-trodes exist.Waveform Brief pulseUltra-brief pulseSine-wave Use of alternating current (sine wave) is strongly discouraged.Energy level Low High Measured in multiples of seizure threshold.Frequency Twice a week Three times a week Twice weekly is standard practice in Britain.* These findings vary according to the specific domain examined and the measure used. Domains influenced by these electro-convulsive therapy (ECT) settings include disorientation immediately after treatment and anterograde memory. There is less evidence that risk ofretrograde amnesia can be altered. For several variables, there is a trade-off between side effects and effectiveness.The New England Journal of Medicine Downloaded from nejm.org on July 27, 2015. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved. n engl j med 364;19nejm.orgmay 12, 2011PERSPECTI VE1787quentlyassociatedwithrevers-ible cognitive impairments.3Themosttroublingfinding was impaired retrieval of past per-sonalmemories(retrogradeauto-biographical memory), as opposed to impersonal memories (e.g., his-toricalorfactualinformation). The review revealed no significant changes in retrograde impersonal memory from baseline to 6 months afterECT,buttheevidencethat retrograde personal memory def-icitsresolvedby6monthswere deemed inconclusive. Bilateral, as comparedwithlow-energyuni-lateral, ECT increased the risk of personal memory deficits during the 2 weeks after treatment.Autobiographical memory is a complexconstructthatisdiffi-cult to characterize and measure. Ithasanepisodiccomponent involvingmemoriesofunique, personaleventssituatedintime andspacethatarehardtoau-thenticate.4Objectivemeasures would require baseline validation by family members or others. Be-cause depression can impair auto-biographicalmemory,3themost appropriatebaselinemaybebe-foretheonsetofdepression, ratherthanimmediatelybefore ECT.5 The primary instrument for assessing autobiographical mem-ory has several limitations, includ-ing the unverifiability of baseline information.5Moreover,objectivemeasures andsubjectiveaccountsofper-sonalmemorydeficitsoftendo notagree,5andself-reportsof memorylossmaybeinfluenced bydepressivesymptoms.3,5In geriatricpatients,itmaybedif-ficult to disentangle possible ad-verseeffectsofECTfrommani-festationsofconditionssuchas cerebrovascularordegenerative braindisease.3Thecombination ofmeasurementproblemsand potentialconfounderscouldac-countforsomeofthelong-term personalmemorydeficitsattri-butedtoECT.3Nevertheless,re-portsofpermanenterasureof somepersonalmemoriesafter ECT cannot be ignored.Unfortunately, the relevant data are inconclusive, and new studies wonthelpwithoutobjective, standardized,user-friendlymea-suresofautobiographicalamne-sia.Giventheprobablelowfre-quency of this adverse effect and need for long-term follow-up, large sample sizes will be required, as will suitable comparison groups, topermitexaminationofpossi-ble confounding effects of mood, medicalillness,andagingon memory assessments.3Meanwhile, the uncertain risk ofmemorylossmustbeconsid-ered in the context of the gravity oftheunderlyingillness.Many patientsundergoECTonlyafter othertreatmentoptionshave been exhausted.2 Decisions about ECTrequirefullparticipationof thepatientinarobustinformed consentprocessthatacknowl-edgesgapsinourknowledge abouttheextentofpersonal memory loss.If ECT devices remain in class III,aPMArequirementfornew trialsisnottheonlyoption.The FDAcouldclearECTforcertain indications, such as depression, on the basis of further review of ex-istingdataandidentificationof conditionsofuseprovidingrea-sonableassuranceofsafetyand effectiveness. Yet a favorable deci-sion wouldnt obviate the need for additional research, including the development of safer alternatives. Promisingnewdevicesorrapid-actingdrugscouldbecompared withECTinrandomized,con-trolled trials providing oppor-tunities to reevaluate the compar-ativesafetyandeffectivenessof ECT without violating equipoise.Disclosure forms provided by the author are available with the full text of this arti-cle at NEJM.org.From the Department of Psychiatry and Fried-manBrainInstitute,MountSinaiSchoolof Medicine, New York.1.FoodandDrugAdministration.Meeting to discuss the classification of electroconvul-sivetherapydevices(ECT).Executivesum-mary.2011.(http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeeting Materials/MedicalDevices/MedicalDevices AdvisoryCommittee/NeurologicalDevices Panel/UCM240933.pdf.)2.Committee on Electroconvulsive Therapy. Thepracticeofelectroconvulsivetherapy: recommendationsfortreatment,training, andprivileging.2nded.Washington,DC: American Psychiatric Association, 2001.3.Weiner RD. Retrograde amnesia with elec-troconvulsive therapy: characteristics and im-plications. Arch Gen Psychiatry 2000;57:591-2.4.Piolino P, Desgranges B, Eustache F. Epi-sodicautobiographicalmemoriesoverthe courseoftime:cognitive,neuropsychologi-calandneuroimagingfindings.Neuropsy-chologia 2009;47:2314-29.5.Fraser LM, OCarroll RE, Ebmeier KP. The effect of electroconvulsive therapy on auto-biographical memory: a systematic review. J ECT 2008;24:10-7.Copyright 2011 Massachusetts Medical Society.Electroconvulsive Therapy in the SpotlightThe New England Journal of Medicine Downloaded from nejm.org on July 27, 2015. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved.