Effectiveness of Electroconvulsive Therapy in Community Settings Joan Prudic, Mark Olfson, Steven C. Marcus, Rice B. Fuller, and Harold A. Sackeim Backgrollnd· Clinical Jl;als indicate that electroconvulsive therapy (Ecn is fbe most effeclive treatment lor mOjO" depression, but its effectiveness in community sellings has 110t been Met/Jods: In aprospective, naturalistic study involving 347patients at seven bospitals, clinical outcomes immediately after ECT and over a 24-weekJollow-ufJ period were exami/7ed in relation to patient cbarne/ensUes and treatment van'ables. Results: 'I11e sites differed markedly in patie11ljeatlt1t!s and HCf administration but did not differ in clinical outcomes. In contrast to fbe 70%-9096 remission 1"ates wit/] EeT, remission. rales, depending on criteria, were 30.]%-46.796. L017ger episode duration, comorbid personality disorder, and sCbizoaffectiue disorder were associated with poorer outcome, Among remitters, tbe relapse rate dUring/allow-up was 64396. Relapse was more/requent in patients with ps)'cbotic depression or comorhid Axis I or Axis n disorders. Only 23.4% 0/ ECT non remitters bad sltStained remission dUring follow-up. Conclusions: 11JC remission rate with ECTin communUy settings is substantially less tban that in clinical tn"als" Pl'Oviders/requently end tile ECTcourse witb tbe view thatpatients have benefited/tilly, yet jonnal assessment sllows Significant residual symptoms. Patients who do not remit witb ECTbave a poor prognosis; tbis underscores tile 1leed to achieve ma:dmal impmvcment with this modality. Key Words: Electroconvulsive therapy, efficacy, effectiveness, re- lapse, major depression, outcome prediction M edictl treaUllents frequendy do not perform as well in routine practice as in controlled clinical trials (Hewitt et al 1999; Hoekstr.1 et al 2002; U.S. Institme of Medicine 2001). In a variety of conte",-"tS, the effectiveness of pharmacologic and psychological treatments of psychiatric disorders delivered in community settings also falls below that achieved in controlled research (Dixon et a11995; Schoenbaum et a12oo1; Unutzer et al 1999; Weersing and Weisz 2002). This gap between patient outcomes in clinical trials and routine practice poses a central challenge to programs seeking to improve d1e quality of mental health care (National AdVisory Menml Health Council 1999; U.S. Department of Health and Human Services 1999). In the acute treatment of major depression, a vast literature has documented d1e efficacy of antidepressant medications (Nelson 1999; Thase 3nd Ninan 2002) and some forms of psychotherapy CCasacalenda et al 2002i Markowitz 1999). Elec- troconvulsive therapy (ECf) is a vital treatment for this disorder. Patients who receive this modality are typically more severely ill, with more chronic and treatment-resistant conditions, dlan pa- tients who receive other antidepressant treatments (Abrams 2002; American Psychiatric Association 2000, 2001; U.S. Department of Health and Human Services 1999). Nonetheless, conrrolled com- parisons with antidepressant medications generally find superior clinical outcome with ECf (Folkerts et al 1997; Gangadhar et al 1982; )anicak et a11985; Medical Research Council 1965). Largeiy on the basis of results from controlled clinical trials, it is estimated that the remission rate after ECf is on the order of 70%t--900k and From the Departments of Biological Psychiatry UP. RBF, HAS) and Clinical and Genetic Epidemiology (MO), New York State Psychiatric Institute, and the Departments of Psychiatry UP, MO, HAS) and Radiology (HAS), College of Physicians and Surgeons, Columbia University, New York, New York; and the School of Social Work (SCM), University of Pennsylva- nia, Philadelphia, Pennsylvania. Address reprint requests to Joan Prudic, M.D., New York State Psychiatric Institute, Department of Biological Psychiatry, 1051 Riverside Drive, Unit 126, New York NY 10032. Received June 26, 2003; revised September 25, 2003; accepted September 26, 2003. 0006-3223/04/$30.00 doi,10.10l6/j.biopsych.2003.09.015 substantially exceeds that of any other form of antidepressant treatment O• .merican Psychiatric Association 2000, 2001; Petrides et al 2001; Sackeim et al 1993. 2000). In community pmctice, patients who receive ECf, like those treated with other modalities, vary in demographic features, comorbid psychiatric and medical conditions, cognitive status, treatment history, and other clinical characteristics (Hermann et al 1995; Olfson et a1 1998). Muitiple dimensions impact on ECf referral (e,g., treatment reSistance, chronicity) illness severity, sUicidality, and medication intolerance. Thus variability in patient femures might be particularly pronounced in ECT community samples. Although some patient characteristics, such ::IS comor- bid substance abuse and personality disorders, are Widely be- lieved to predict poor acute clinical Olucome with ECf (Black et al 1988; DeBattista and Mueller 200n, there is limited empirical support for these impressions. At the same time, ECf adminis- tration in the community varies in important technical character- istics, including electrical waveform, dosing strategy, and num- ber and frequency of treaUllents CPippard 1992; Prudic et al 2001). These technical features are readily identifiable and have been shown in controlled research to have marked impact on short-term efficacy and the magnitude of cognitive Side effects (McCall et al 2oo0b; Sackeim er al 1987, 1993, 2000; Shapira et al 1998). The e:\1:ent to which variation in patient characteristics and Eer technique influence outcomes in community settings is unknown. Early investigators remarked that virtually all patients with major depreSSion remit with ECT (Kalinowsk-y and Hoch 1946), but these claims were impressionistic. Subsequent inves- tigation of community practice has involved self-report surveys (Farah and McCall 1993; Prudic et al 200l) and audits examining variation in treatment technique (Halliday and Johnson 1995; L31ey and Fahy 1985; O·Dea er al 1991; Pippard 1992; Pippard and Ellam 1981). Despite 65 years of use, there has been no systematic documentation of the effectiveness of ECf In commu- nity practice. A high rate of relapse has been observed in recent studies of patients who remit with ECf (Grunhaus et al 2001; Sackeim et al 1990, 1993, 2000, 2001). The e"'-1:ent to which this occurs in community settings is also unknown. Funhermore, regardless of setting, there has never been a prospective follow-up of a substantial number of patients who do not remit when treated BIOL PSYCHIATRY 2004;55'301-312 itl 2004 Society of Biological PsychiatIy
Transcript
Effectiveness of Electroconvulsive Therapy inCommunity SettingsJoan Prudic, Mark Olfson, Steven C. Marcus, Rice B. Fuller, and Harold A. SackeimBackgrollnd· Clinical Jl;als indicate that electroconvulsive therapy (Ecn is fbe most effeclive treatmentlor mOjO" depression, but itseffectiveness in community sellings has 110t been e~,,·amined.
Met/Jods: In a prospective, naturalistic study involving 347patients at seven bospitals, clinical outcomes immediately after ECT andover a 24-weekJollow-ufJ period were exami/7ed in relation to patient cbarne/ensUes and treatment van'ables.Results: 'I11e sites differed markedly in patie11ljeatlt1t!s and HCf administration but did not differ in clinical outcomes. In contrastto fbe 70%-9096 remission 1"ates e~'\pected wit/] EeT, remission. rales, depending on criteria, were 30.]%-46.796. L017ger episodeduration, comorbid personality disorder, and sCbizoaffectiue disorder were associated with poorer outcome, Among remitters, tberelapse rate dUring/allow-up was 64396. Relapse was more/requent in patients with ps)'cbotic depression or comorhid Axis I or Axisn disorders. Only 23.4% 0/ECT nonremitters bad sltStained remission dUring follow-up.Conclusions: 11JC remission rate with ECTin communUy settings is substantially less tban that in clinical tn"als" Pl'Oviders/requentlyend tile ECTcourse witb tbe view thatpatients have benefited/tilly, yetjonnal assessment sllows Significant residual symptoms. Patientswho do not remit witb ECT bave a poor prognosis; tbis underscores tile 1leed to achieve ma:dmal impmvcment with this modality.
Medictl treaUllents frequendy do not perform as well inroutine practice as in controlled clinical trials (Hewitt etal 1999; Hoekstr.1 et al 2002; U.S. Institme of Medicine
2001). In a variety of conte",-"tS, the effectiveness of pharmacologicand psychological treatments of psychiatric disorders deliveredin community settings also falls below that achieved in controlledresearch (Dixon et a11995; Schoenbaum et a12oo1; Unutzer et al1999; Weersing and Weisz 2002). This gap between patientoutcomes in clinical trials and routine practice poses a centralchallenge to programs seeking to improve d1e quality of mentalhealth care (National AdVisory Menml Health Council 1999; U.S.Department of Health and Human Services 1999).
In the acute treatment of major depression, a vast literaturehas documented d1e efficacy of antidepressant medications(Nelson 1999; Thase 3nd Ninan 2002) and some forms ofpsychotherapy CCasacalenda et al 2002i Markowitz 1999). Electroconvulsive therapy (ECf) is a vital treatment for this disorder.Patients who receive this modality are typically more severely ill,with more chronic and treatment-resistant conditions, dlan patients who receive other antidepressant treatments (Abrams 2002;American Psychiatric Association 2000, 2001; U.S. Department ofHealth and Human Services 1999). Nonetheless, conrrolled comparisons with antidepressant medications generally find superiorclinical outcome with ECf (Folkerts et al 1997; Gangadhar et al1982; )anicak et a11985; Medical Research Council 1965). Largeiyon the basis of results from controlled clinical trials, it is estimatedthat the remission rate after ECf is on the order of 70%t--900k and
From the Departments of Biological Psychiatry UP. RBF, HAS) and Clinicaland Genetic Epidemiology (MO), New York State Psychiatric Institute,and the Departments of Psychiatry UP, MO, HAS) and Radiology (HAS),College of Physicians and Surgeons, Columbia University, New York,New York; and the School of Social Work (SCM), University of Pennsylvania, Philadelphia, Pennsylvania.
Address reprint requests to Joan Prudic, M.D., New York State PsychiatricInstitute, Department of Biological Psychiatry, 1051 Riverside Drive, Unit126, New York NY 10032.
Received June 26, 2003; revised September 25, 2003; accepted September 26,2003.
substantially exceeds that of any other form of antidepressanttreatment O•.merican Psychiatric Association 2000, 2001; Petrideset al 2001; Sackeim et al 1993. 2000).
In community pmctice, patients who receive ECf, like thosetreated with other modalities, vary in demographic features,comorbid psychiatric and medical conditions, cognitive status,treatment history, and other clinical characteristics (Hermann etal 1995; Olfson et a1 1998). Muitiple dimensions impact on ECfreferral (e,g., treatment reSistance, chronicity) illness severity,sUicidality, and medication intolerance. Thus variability in patientfemures might be particularly pronounced in ECT communitysamples. Although some patient characteristics, such ::IS comorbid substance abuse and personality disorders, are Widely believed to predict poor acute clinical Olucome with ECf (Black etal 1988; DeBattista and Mueller 200n, there is limited empiricalsupport for these impressions. At the same time, ECf administration in the community varies in important technical characteristics, including electrical waveform, dosing strategy, and number and frequency of treaUllents CPippard 1992; Prudic et al2001). These technical features are readily identifiable and havebeen shown in controlled research to have marked impact onshort-term efficacy and the magnitude of cognitive Side effects(McCall et al 2oo0b; Sackeim er al 1987, 1993, 2000; Shapira et al1998).
The e:\1:ent to which variation in patient characteristics andEer technique influence outcomes in community settings isunknown. Early investigators remarked that virtually all patientswith major depreSSion remit with ECT (Kalinowsk-y and Hoch1946), but these claims were impressionistic. Subsequent investigation of community practice has involved self-report surveys(Farah and McCall 1993; Prudic et al 200l) and audits examiningvariation in treatment technique (Halliday and Johnson 1995;L31ey and Fahy 1985; O·Dea er al 1991; Pippard 1992; Pippardand Ellam 1981). Despite 65 years of use, there has been nosystematic documentation of the effectiveness of ECf In community practice.
A high rate of relapse has been observed in recent studies ofpatients who remit with ECf (Grunhaus et al 2001; Sackeim et al1990, 1993, 2000, 2001). The e"'-1:ent to which this occurs incommunity settings is also unknown. Funhermore, regardless ofsetting, there has never been a prospective follow-up of asubstantial number of patients who do not remit when treated
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302 BIOL PSYCHIATRY 2004;55;301-312
with Eer. Determining longer-term clinical outcome in ECTnonremitters is important, especially because ECT is most commonly given to patients who have not benefited from pharmacotherapy (American Psychiatric Association 2000, 2001; Prudicet al 1990).
Here we report the results of a prospective, naruralistic studyof a large sample of patients treated for major depression withECT in diverse community settings. We determined the overallclinical effectiveness of ECf and assessed the effects of variationin patient and practice characteristics on short-term clinicaloutcome. The sample was followed for 24 weeks after ECf, andlong-term outcome was examined in all patients, both those whowere remitters and those who were nonreminers immediatelyafter ECf. Patient and practice features associated with risk ofrelapse were also examined.
Methods and Materials
Study Sites and Study ParticipationThe study was conducted at seven hospitals in the New York
City metropolitan area. The sites included two private psychiatrichospitals, three community general hospitals, and two hospitalsat university medical centers. A clinical outcomes evaluator wasaSSigned to each hospital and collected all the research information. These evaluators conducted clinical and neuropsychological research assessments and obtained data on clinical andtreatment history. They had no involvement or impact on thecare patients received because the goal was to document patientoutcomes at each facility with minimal influence on the outcomes. The study was directed by investigators at the New YorkState Psychiatric Institute (NYSPI), but patients at this facility didnot participate. The study was approved by the institutionalreview board at NYSPI and each of the seven hospitals.
Participants were recruited from those referred for ECT ateach hospital who had a provisional psychiatric diagnosis of adepressive disorder. Over a 26-month period, 751 patients wereso referred (Figure D. To be included, patients had to meetDSM-N criteria (American Psychiatric Association 1994) for amajor depressive episode (unipolar or bipolar) or schizoaffectivedisorder, depressed, on the basis of the Structured ClinicalInterview for DSM-N Axis I Disorders (SCID-I/P; First et a11996a). Patients were excluded if they had received ECf in thepast 2 months, had a Mini·Mental State Examination (MMSE)CFolstein et al 1975) score of less than 15, spoke neither Englishnor Spanish, or had previously participated in the study (Figuren. Patients were at least 18 years of age and proVided informedconsent.
Study MeasuresPatients who consented to study participation were adminis
tered a battery of assessments to evaluate clinical status andtreatment history. The primary instrument to assess severity ofdepressive symptoms was the 24-item Hamilton Rating Scale forDepression (HRSD; Hamilton 1967). Self-reports of depressivesymptoms were also assessed with the Beck Depression Inventory-II (BDI; Beck et a1 1996). The Global Assessment of Functioning (GAF) was used to estimate global impairment (AmericanPsychiatric Association 1994). Comorbid DSM-IV psychiatric A.xisI disorders, including substance abuse or dependence, weredetermined from administration of the full SCID-I1P interview.Medical comorbidity was assessed with the Cumulative IllnessRating Scale (Miller et al 1992). Global cognitive status wasassessed with the MMSE (Folstein et al 1975).
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5crlllned Patients IN" 7511 INon·p,artlclpanl$(N .. 353} I
Mat Exclusion Crftllrla (N ., 128) Potentially SJliIlbl, (N c 225)
Nol Depronive Disorder (N '" 48) lnsufficlcnt limo for E...:ilu:lUon (N '" 84)ECTWlthln Past 2 Moo\h$ IN c 27) Rofu:lcd PartJcjpnllon CN <> 741Minl-Mental Slate Exnm < 15 (N '" 25) Phy$lcal UmililUons (N" 45)Nel E~1isII Dr SpanlsllSpeaklng IN '" 23 Attending Raquosted f./on·partlcIpaUon {N '" 14)PrevIously Pnrticipallld In SllJdy (N '" 7) Pl;ych!alrlc Cond:Uoo ProcItldad EVOlIualion IN c 5)
OIher FadDl'S (N '" J)
Entered Study {N" 3981
Excluded from All Analysas {N" 51)
18 Did Not Rccoivo ECT35 Ne ClinlQ] OtJIccnUt Eor.JllIilUon
19 Unable to Conlllet14 Refu5ed PoslEGTE...aluulJon .
9 Dropped Out Wilhoul Relapse 29 Remitted end Relapsed8 Did Not Pilrilcillllle In FoIOW-UD 7 Rem!lled and Relapso 5l:1tus Unknown
20 In:;,llff"dont FollCM'<lJp
Figure 1. Participant flow through the study. ECT, electroconvulsive therapy.
Consent was obtained to contact previous health care providers to gather information on the psychiatric treatments receivedduring the current depressive episode, including dosage andduration of psychotropic medications. This information, coupledwith patient interviews and medical records review, was used tocomplete the Antidepressant Treatment History Fonn (ATHF)CPrudic et al 1990; Sackeim 2001; Sackelm et aI1990). The ATHFquantifies the adequacy of antidepressant treatments by evaluating the adequacy of each treatment trial in episode with respectto dose and duration. DemographiC information was collected onall patients, including socioeconomic status of the household(Hollingshead 1975). At pre-ECT baseline, immediately after theECT course, and at 24-month follow-up, an e:x1:ensive neuropsychological battery was administered. The findings regardingcognitive outcomes will be the subject of a separate report.
The outcomes evaluators attended ECT treatments and documented the type and doses of medications administered beforeanesthesia induction, agents used for anesthesia and their doses,type of physiologic and seizure monitoring, and the ECT devicemodel, electrical waveform, electrode placement, stimulus dosing strategy, and the specific parameters used for stimulation.The duration of the motor convulsion and, when monitored, theelectroencephalogram (EEG) seizure were also recorded. Complications during the procedure and in the immediate postictalperiod were documented, as well as any additional medicationsadministered after each treatment.
When the treating psychiatrist indicated that the acute courseof ECT treatment was completed, the post-ECT assessment was
]. Prudic et .1
conducted. TIle HRSD and BDI were repeated. The StructuredClinical Interview for DSM-rv A.xis II Personality Disorders(SCID-lIj First et al 199Gb) was administered to derive DSM-lVdiagnoses of personality disorders. TIle treating psychiatristdocumented the reason for renninating dle ECf course. Thechoices included "full response," "nonresponder and 3dditionalECT not expected (Q benefit clinically," and a variety of otherreasons related to premature tennination, including withdrawalof consent, intercurrent illness, medical complication, excessivecognitive impainnent, and medical insurance limitations,
Classification of Clinical OutcomesPatients were classified as having met response or remission
criteria immediately after the ECT course. Responders had areduction in HRSD scores at post-ECT relative to pre-ECf baseline of 500Al or greater. Although this dichotomization is commonly used to characterize outcome in ph:umacotherapy trials(Frank et .1 1991), it is rareLy applied to Ecr. This is partlybecause the high baseline symptom severity of ECT patientsoften makes a 50% reduction an inadequate clinical end point.Moreover, because persistent depressive symptoms are assodated with continued functional impainnent and a high rate ofrelapse, the standard in the treatment of depression has movedfrom achieving response to achieving remission (Paykel 2002;TI13se and Ninan 2002). In this study, remission was definedaccording to both moderate and strict criteria. The moderatecriteria (remltterl~' corrunonly used in Ecr trials) required aminimum 60% reduction in HRSD scores and a post-ECT score of10 or less (Petrides et a12001; Sackeim et a12000, 2001). The strictcri[eria (remitter7) were identical to the remltterlO criterJa butrequired a post-ECf score of 7 or less. Some have argued thatbecause an HRSD threshold of 10 might allow for significantresidual symptoms, a HRSD score of 7 or less corresponds to fullremission (Frank et a11991; McIntyre et al 2002; 111ase and Ninan2002).
Patients who met remitter10 criteria were monitored forrelapse dUring follow-up. To be considered provisionally relapsed, patients had to have at least a la-point increase in rheirHRSD score at a follow-up interview relative to the scoreimmediately after ECf and a minimum score of 16. Patients whomet these criteria were re-interviewed 1 week later; they wereconsidered relapsed if they continued to meet these criteria.Relapse 'Vo':lS :lIsa declared whenever patients were hospiL1.lizedfor treatment of depression, received another acute course ofECf, attempted suicide, or manifested psychotic symptoms.
Follow-up ProceduresPatients were clinically monitored for a period of 24 weeks
after the end of the acute Ecr course. They were administeredthe HRSD at 4-week intervals and interviewed regarding thetreatments received since last contact. The adequacy of thesetreatments was scored according to ATHF criteri:l (Sackeim2001), except that a minimal erial duration was not required.Nonreminers at post-Ecr were classified into three groups on thebasis of subsequent course: not meeting remitlo criteria at anytime during follow-up; meeting remi[1O cri[eria on only oneoccasion; meeting these criteria on two or more conseculiveoccasions. A£ the final foUow-up visit, all patients were classifiedby reapplication of the response and remit lO criteria.
Clinical Outcomes EvaluatorsThe clinical outcome evaluators were hired expressly for [his
project and were principally masters-level technicians who had
310L PSYCHIATRY 2004;55:301-312 303
prior experience working in clinical and/or research settings withpsychiatric patients. The evaluators participated in a 6-1O-weektraining program rhat involved didnctics, observation of clinicalin[erview videotapes, observation of expert evaluators assessingpatients at NYSPI, and expert observation and critique of assessments conducted by each of the evaluators. The bulk of thetraining was proVided by three of the authors QP, MO, and HAS),although orher faculty at the New York State Psychiatric Institutealso participated. Throughout the study, supervision occurred atleast weekly. Before collecting data, evaluators met reliabilitycri[eria for HRSD ratings. Each of the 10 evaluators rated 35videotapes of HRSD interviews conducted in patients referred forECf. The intraclass correlation coefficient for these ratings was.97.
Statistical MethodsThe intent-to-trea[ sample comprised all patients who con
sented to study participation and participated in at least onepost-ECf assessment of symptom status. The completer samplecomprised the subset in which the treating psychiatrist indicatedthat a complete course of ECT had been given. These werepatients for whom me reason for ending ECf was that fullimprovement had been achieved or that improvement wasincomplete but additional ueatments were not expected toproduce further benefit. Patients for whom the treating psychiatrist considered the ECT course to be premarurely terminared,whatever the reason, were not included in the completer sample.The complete set of statistical analyses was conducted in boththe intent-to-treat and completer samples.
The sites were compared with regard to patient demographicand clinical features and treatment methods by one-way analysesof variance (ANOVAs) on continuous measures and X2 tests oncategoric measures. For all analyses, the criterion for statisticalSignificance (ex) was .05, except for the post hoc comparisons ofsite differences, for which ex was reduced to .01, given thenumber of possible pair-wise comparisons. Post hoc TukeyKramer comparisons identified pair-wise differences among thesites. Infonnation regarding the adequacy of antidepressanttreatments during dle index episode was not available for 245%of the sample. Therefore, t.he influence of [reatmen[ history wasnot examined in this report.
The primary clinical outcome measures were the rates ofremission (remit lO and remit,) and the percentage change inHRSD scores over the ECf course. Secondary outcome measureswere rates of response, absolute post-ECT scores on the HRSDand BDI, and the percentage change in BD! scores.
To compare the sites in clinical outcome after Ecr, logisticregressions were performed on response and remission rates,with site as a between-subjects factor and the interval betweenlast treatment and outcome assessment as a covariare. Analysesof covariance CANCOVAs) were conducted on the absolutesymptom scores CHRSD and BOI-[1) after treatment, with site asthe between-subjects factor and the baseline symptom score andintelVal [0 assessment as covariates. In ANCQVAs on percentagechange in symptom scores from baseline to after ECf the sameANCOVA model was used but without the baseline symptomscore as a covariate.
An a priori set of patient features was tested for associationswith the primary clinical outcomes. These variables served aspredictors in a simuJ[aneous linear regression analysis on thepercentage change in HRSD scores and in logistic regressionanalyses on remit IO and remit7 rates. The Significant relationshipsin these multivariate analyses were retested for bivariate associ-
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304 BIOL PSYCHIATRY 2004;55:301-312
ations with t tests and XZ analyses. Similar analyses were cooduered to examine the relationship to clinical outcome of an apriori set of predictor variables characterizing ECf treatmentparameters. These variables included electrical waveform (briefpulse YS. sine wave), electrode placement (right unilateral [RUt]only, bilateral [BLJ only, RUL and BL, and other), stimulus dosingstrategy (individually titrated eleccrical dose V5. fLxed arbit.rarydose), the intemction of electrode placement and dosing st.rategy, electrical dosage (percent of ma.ximal device output, averaged across all treatments), and number of treatments in the ECTcourse.
Site differences in relapse over the 24-week follow-up wereexamined with rionparamctric estimates of the survival distribution function, by the Kaplan-Meier product-limit method and thelog-rank test. A parnmetric simultaneous regression model was fitto the relapse-time dam with use of the Weibull distribution(Sackeim et al 1990, 2001). Covariate5 in the regression modelwere site, patient age, post-ECf HRSD score, duration of thedepressive episode, presence or absence at study intake ofpsychotic depression, comorbid A."ds I disorder, comorbid A.xis IIdisorder, number of treaunents in the acUle ECf phase, receipt ofcontinuation Eer (before relapse or completion of follow-up),strength of continuation pharmacotherapy (at point of relapse orcompletion of follow-up), and the interaction between these lasttwo variables. The regression parameters were estimated withthe partial likelihood method. Scores on the HRSD from all timepoints were submitted to a longitudinal mixed-model analYSiS,with post-ECf remit lO status as a fLxed between-subjects factorand time point as a fLxed repeated-measures faceor. On the basisof actual 24-week scores (17. = 263), or where missing (n = 83)on those predicted by the mixed model, perceneage improvement at the 24-week end point was determined for dle groupswho did or did not meet pose-ECT remie lO criteria.
Results
Ofdle 751 patients scheduled to receive ECf at dle 7 sites, 398(53.0%) consented to srudy participation (Figure 1). Of the 353patients who did not enter the study, 128 <36.3%) patients metone or more exclusion criteria, with a psychiatric diagnosis odlerthan a depreSSive disorder being the most common (n = 46,13.(010). Of the remaining 225 patients who might have beeneligible, the most common reasons for nonpanicipation wereinsufficient time before the frrst Eer treaunent to conduct thebaseline evaluation (11 = 84, 37.3%) and patients declining toenroll (n = 74, 32.9%), TIlere was no evidence that the 225pOlentially eligible nonparticipants differed from the 398 panicipants in demographic features, such as age, gender, or race. Ofd,e 398 patients who completed the baseline evaluation, 51patients (12.8%) did not contribute to analyses of outcomes. Thisincluded patients who did not receive ECf (n = 16, 4.0%) and alarger number who did not participate in any post-Eer assessment owing to loss to follow-up (n = 19, 4.8%) or refusal offurther participation en = 14, 3.5%). Only 2 (,5%) of the 398patients who entered the study had a level of cognitive impairment during the week after ECf that precluded d,e pose-ECToutcome evaluation. Thus, the intent-to-treat sample comprised347 (46.2%) of the 751 patients referred for ECf and screened forthe study.
Site Differences in Patient Features and TreatmentAdministration
There were statistically Significant differences among the sitesin patient age, education, estimated verbal intelligence quotient,
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J. Prudic et al
familial socioeconomic starus, duration of current episode, ageat-onset of mood disorder, severity of cumulative medical burden, camorbid Axis I disorders, and the percent41ge treated asinpatients (Table 1).
The sites also varied markedly in methods of ECf administration (Table 2). Sine wave stimulation was in use at two sites, and1;.3% of the total intent-to-treat sample was treated with thiswaveform, with all other patients receiVing constant-current,brief-pulse, bidirectional stimulation. Three sites mainly used BLelectrode placement, two sites mainly treated widl RUt ECT, andtwo sites used a mi>..1:ure of electrode placements. Titration ofelectrical dosage to the individual patient's seizure threshold wasused to determine subsequent stimulus dosing in 48.1% ofpatients; an arbitrary fLxed dosage was used in the remaining51.9% of patients, There were marked differences among thesites in dle intenSity of the electrical stimulus, and at two sitesnearly all patients were treated at the ma.ximal device output. Thesites differed in the average number of treatments patientsreceived, which ranged from SA to 8.6. There were also substantial site differences in the medications administered at ECT beforeanesthesia, especially the use of anticholinergic and ~-blocking
agents, and in seizure monitoring (data not shown). Two sitesused neither the "cuff" technique to block the diStribution of themuscle rela.xant to aid the timing of the motor convulsion(American PsychiatriC Association 2001) nor EEG seizure moniloring Ix'(6) = 431.9, P < .00011.
Clinical Outcome Immediately after ECT: Intent-to-TreatSample
Despite the differences among the sites in patient charncteriSlics and treatment and monitoring methods, there were nodifferences in any of the primary or secondary observer-ratedmeasures of shon-term clinical outcome (Table 3). There was asmall but Significant difference among the sites in the change inpalient ratings of symptoms on the BDI, but none of thepair-wise comparisons were Significant. Across the intent-to-treatsample, 162 patients (46.7%) met remission lO and 105 patients(30.3%) met remission, criteria. Most patients had substantialclinical improvement, with 221 (63.70;6) patients classified asresponders.
In the nnalyses examining parential site differences, theinterval between final treatment and the assessment of post-ECfoutcome was strongly associated with the percentage changefrom baseline in depreSSion scores [HRSD: J(1,339) = 56.6, P <.0001; BD!: J{1,310) = 14.0, P = .00021 and rate of responseIx'(l) = 31.6, P < .00011, remissionw IX'(l) = 27.2, P < .00011,and remission7 (X2(l) = 14.6, P = ,0007]. The median assessmenttook place 3 days after ECf (mean = 4.6 days; SD = 4.3), with318 of 347 patients (91.6%) evaluated widlin 10 days. A longerinterval to assessment was associated with less improvement andlower rates of response and remission. \Vhen the sample wasrestricted to patients assessed within 10 days of ECf termination,a regression analysis on dle percentage change in HRSD scoresindicated that with each day since the end of ECT until assessment there was a decrease of 4.0% (SE = .62) in dle percentageof symptomatic improvement. TIlliS, this analysis suggested that,on avernge, 10 days after ECf, patients had lost 409'0 of theimprovement that accrued over the Eer course.
Several patient features and the interval between last treatment and the assessment of clinical outcome were associatedwith the e:x1:ent of improvement and remission rates (Table 4).The presence of a comorbid personality disorder, longer duration of current episode of mood disorder, diagnosis of schizoaf-
Demographic and Clinical Characteristics for the Intent-to-Treat Sample by Site"
Total Site I Site II Site III Site IV Site V 5ite VI Site VII(n ~ 347) (n ~ 92) (n = 62) (n~48) (n ~ 471 (n=41) (n = 35) (n =22) F"or?
lUOUS variables are expressed as mean (SDj unless otherwise noted; categoric variables are expressed as %.elligence quotient; ECT, electroconvulsive therapy.I sites with different superscript symbols above the mean or percentage values differed significantly in post hoc comparisons, whereas study sites sharing one or more superscriplFor example, for the mean age of patients, only Site Vhad the superscript ..., indicating that patients were oldest at this site. Sites 1, III and IV had the superscript ..t·, indicating that.; differed significantly from single site with superscript ....... In contrast, Sites II, VI, and VII had superscript "*,t". Each ofthese three sites did not differ in the age of patients from an!! each of the other sites were specified by ..... or "t".I Pvalues refer to the effect of study site in one-way analyses of variance conducted on each continuous variable (df = 6, 340).:he effect of study site in x: analyses conducted an each categoric measure. and the p value is the significance level from the Likelihood Ratio test (df = 6).
306 BIOL PSYCHIATRY 2004;55:301-312 ]. Prudic et al
Table 2. Characteristics of ECT Administration in the lntent-to·Treat Sample by Sileo
Total Sample Site [ Site II Site III Site IV Site V Site VI Site VIIVariables (n ~ 347) (n ~ 92) (n =62) (n =48) (n ~ 47) (n =41) (n ~ 35) (n =22) Xl!> or~ p
Data are expressed as % or mean (SO).ECT, electroconvulsive therapy."Average stimulus dosage Is the average electrical dosage across all treatments ofa patient, and is expressed as a percentage of maximal device output.
High dosage reflects an average charge per treatment that was 80% or greater of maximal device output. ECT treatment period is the number of days fromstart to end oftheacute treatment phase with ECT. Duration per treatment is the treatment period divided by the number of treatments the patient received.Study sites with different superscript symbols (-,tJ.l above mean or percentage values differed significantly in post hoc comparisons, whereas study sItes withoverlap in superscript symbols did not differ.
bJ? and p values refer to the main effect ofstudy site In >! analyses conducted with categoric measures (df =6).;? analyses were conducted on all variablesexcept average intensity of electrical stimulation, number of treatments received, and the treatment duration measures.
cF and p values refer to the main effect of study site in one-way analyses of variance (ANOVAs) on continuous variables (df = 6,340). ANOVAs wereconducted on the average intensity of electrical stimulation, number of treatments received, and the treatment duration measures.
fective disorder, and more days intervening between last treatment and clinical assessment were consistent predictors ofinferior clinical outcome. In bivariate analyses, each of thesevariables was significantly associated with each of the primaryclinical outcome measures (data not shown).
The presence of a comorbid personality disorder was dlepatient variable widl the largest and most consistent associationswith clinical outcome. 111 the intent-to-teem sample, the response,remit lO, and remit7 rates in those without versus those with acomorbid Axis II disorder were 68.95% versus 50';1%, ;2.4~1l
versus 32.32%, and 3;.08~bversus 18.18%, respectively. Althoughthe diagnosis of a comorbid A.xis II disorder had a subSL1ntiaieffect on clinical outcome, the response and remission rates werestill markedly below those expected for ECf among patients whodid not have :1 comorbid A.x.is II disorder. Furthermore, theassociations of A.x.is II comorbidity and ECf clinical outcomeswere undoubtedly exaggerated. The scrO-II interview was conducted immediately after the ECf course. This timing confounded the identification of A.xis II disorders wilh the effects ofEer on depressive symptoms and memory. \Vhen the intent-te>treat sample was further restricted to patients without :1 comorbidA.xis I or A.xis II disorder (n = 157), dle response and remissionrates were still below expectations (response: 72.6%, remit lO:
54.1000, and remit7 : 37.8%). Thus, the relatively Jow rates ofresponse and remission could not be attribured to greaterprevalence of comorbid A.xis I or Axis II disorder in thiscommunity sample.
TIle treatment variables did not have significant associationswith any of the three primary outcome measures, except for acomponent of the interaction between elecrrode placement and
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stimulus dose titration (Table 5). Among patients treated withRUL ECf, titrarion of electrical dose was associated with higherrates of remission w Ix'(l) = 4.79, P< .03; odds ratio (OR) = .54,95% confidence interval (el) .31-.941 and remission7 (X2(l) =4.79, P < .03; OR = .54,95% CI .31-.941, relative to use of a fLxed(nontitrated) electrical dose. These analyses also indicated thatdlere were no site differences in the primary outcome measures.
Reasons for Terminating ECTThe low remission rates and the absence of associations
between clinical outcome after ECT and the number of treatments administered (Table 5) raised the issue of the rationale fordiscontinuing treatment. rn research conte},.'1S, as a consequenceof ensuring that an adequate treatment trial is given beforedeclaring lack of benefit, patients who do not remit typictllyreceive more treatment than remitters (Petrides et al 2001jSackeim et al 1993, 2000).
[n the intent-to·treat sample, the treating psychiatrist indicatedthat ECf was temlmated due to full clinical response in 213 of316 patients (67.4%) for whom a reason for termination wasdocumented (Table 6). In contrast, the treating psychi:l.lristindicated tllat ECf was terminated because of lack of response inonly 31 of 316 patients (9.8%). For these patients, additionaltreatment was not expected to be of benefit. Only 2 of these 31patients were rated by the research evaluator as meeting remission criteria, but 5 of the 31 patients 06.1%) met responsecriteria. Of the 213 patients determined by the treating psychiatrist to have achieved a full response, 81.6% were classified asmeeting the research response criteria; however, only 66.8% and
]. Prudic et al BlOL PSYCHIATRY 2004;55:301-312 307
Table 3. Efficacy of ECTTreatments by SiteO
TotalSample Site I Site II Site III Site IV SiteV Site VI Site VII
Variable n = 347 n = 92 n = 59 n = 48 n =43 n = 41 n = 35 n = 22 For X2b p
Data are expressed as mean (SO) or %.ECT, electroconvulsive therapy; HRSD, Hamilton Rating Scale for Depression; BDI, Seck Depression Inventory.°Pre-ECT and post-ECT refer to scores before and after the completion of treatment with ECT, respectively. Percent change reflects division of the
difference between these scores by the pre-ECT (baseline) score and multiplying the result by 100. In post hoc comparisons there were no significantdifferences among the study sites for any measure.
bFandpvalues for the main effect of study site are reported from one-way analyses of variance (pre-ECT scores) and analyses of covariance (post-ECTandpercent change scores) on the HRSD and Bol measures. Sample size for the SOl was 31 8 forthe total intenHo-treat sample and 230forthe completer sampledue to missing values. Likelihood ratio J? values and associated p values are reported for the main effect of study site in logistic regression analyses oncategoric outcome measures controlling for the number of days between end of ECT and clinical assessment.
49.2% were classified as meeting remit IO and remi~ criteria,respectively.
The discrepancies between the treating psychiatrist and theresearch evaluator could have been due to the evaluator assessing clinical outcome at a later date than the treating psychiatrist,such that some of the improvement observed by the treatingpsychiatrist had been lost. To test whether this possibility contributed to the discrepancy, three ANOVAs were conducted withthe sample restricted to those patients for whom the treatingpsychiatrist stated that ECf was terminated OWing to full response or lack of response (n = 244). In each case, thedependent measure was tile number of days from the end of ECTuntil the research evaluator HRSD interview. The independentvariables were the treating psychiatrist's determination that thepatient did or did not fully respond to ECf and dle researchoutcomes categorization as meeting or not meeting response,remit IO, or remit7 criteria. There were no significant effects in anyof these ANOVAs, thus indicating dlat dle latency to HRSDinterviews was not different among patients for whom thetreating psychiatrist's and research evaluator's outcome deSignations were congruent or discrepant. For example, among dlepatients whom the treating psychiatrist judged as fully respond-
ing to ECf, dle latency to the HRSD interview averaged 3.28 days(SD = 3.07) in patients categorized as meeting remit IO criteria(11 = 134) and 3.91 days (SD = 2.93) in patients who did notmeet remit lO criteria (11 = 79) [1(211) = 1.47, P = ,141.
Another potential cause of the discrepancy bernreen thetreating psychiatrist and the research evaluator in clinical outcome designation was differential effects of comorbid Axis I orA.,js II conditions. Hypothetically, by discounting symptomsattributable to a comorbid psychiatric disorder, the treatingpsychiatrist might have viewed many more patients as fullyresponding to ECf, whereas ratings of the research evaluatormight have been more influenced by the comorbid pathology;however, there was no evidence that A.,js I or II comorbiditycontributed to the discrepancies in outcome classification. Forexample, among the 134 patients who met remit IO criteria andwere judged to have fully responded by the treating psychiatrist,20.15% had a comorbid Axis II condition, whereas this rate was29.11% among the 79 patients who did not meet remit IO criteriabut were judged to be full responders by the treating psychiatrist[X:\l) = 2.2, P = .14]. TIle comparable rates for the presence ofeidler an Axis I or A.,js II cornorbid disorder were 48.5% and55.7%, respectively [X2(l) = 1.0, P = .31l.
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308 BIOL PSYCHIATRY 2004;55:301-312 J. Prudic et .1
Table 4. Relationships of Patient Factors to Primary Clinical Outcome Measures"
HRSD % Change Remission lD Remission7
Variables F p x' P Odds Ratio 95%CI x' P Odds Ratio 95%CI
HRSD, Hamilton RatIng Scale for Depression; cr, confidence interval; Ea, electroconvulsive therapy.QFand pva[ues for HRSD %change refer to the results of the simultaneous linear regression analysis on the percentage change In scores on the HRSDfrom
before the start of the ECT course until after the ECT course. X2 and associated pvalues, and odds ratios and 95% Cis for the odds ratios refer to the results oflogistIc regression analyses conducted on rates of remission, defined by either the remlssion 1o or remission, criteria.
Clinical Outcome Immediately after ECT: Completer SampleThe analyses reponed above were repeated for the completer
group, which comprised patients for whom the treating psychiatrist indiC3ted that a full course of ECf had been given. There
was no meaningful change in the pattern of site differences inpatient demographic and clinical characteristics, and no sitedifferences emerged in rates of response, remission, or the eAlentof clinical improvement (Table 3). TIle response and remission
Table s. Relationships ofTreatment Factors to Primary Clinical Outcome Measures"
HR5D % Change Remission1o RemissIon,
Variables F p x' p Odds Ratio 95%CI x' P Odds Ratio 95%Cl
HRSD, Hamilton Rating Scale for Depression; CI, conlidence interval.QF and pvalues for HRSD %change refer to the results of the simultaneous linear regression analysis on the percentage change in scores on the HRSD from
before the start of the electroconvulsive therapy (Ecn course until after the ECT course.~ and associated p values, and odds ratios and 95% Cis for the oddsratios refer to the results of logistic regression analyses conducted on rates of remission, defined by either the remission 10 or remission, criteria.
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J. Prudic et .1 mOL PSYCHIATRY 2004;55:301-312 309
Table 6. Concordance ofTreating Psychiatrist's Reasons for Termination of ECT with Research Ratings of Clinical Outcome
Withdrawal of Cognitive Illness or InsuranceClinical Research Full Response Lack of Response Consent Impairment Complication Limitations No InformationRating (n = 213) (n ~ 31) (n ~ 311 (n ~ 17) (n ~ 14) (n ~ 5) (n ~ 31)
Data are expressed as n (qb). ECT, electroconvulsive therapy.
rates improved by 7.8%-9.3% in the completer sample relative tothe intenHO-[feat sample, depending on the measure. Amongcompleters, 73.0% were classified as responders, and 5S.~b and38.1% met remit10 and remit7 criteria, respectively. Time fromend of creatInent to HRSD evaluation continued to be associatedwirh clinical outcome (Tables 4 and 5). TIle patient features ofepisode length, diagnosis of scruzoaffeetive disorder, and presence of an Axis ([ disorder continued (0 show associations wirhpoorer outcome (Table 4), and no new associations wirh patientfeatures emerged; however, new associations were seen between treatment variables and clinical outcome. Among com-
pieters, clinical outcome was now poorer among patients whoreceived a larger number of treaUDents. Patients who weretreated exclusively with brief pulse stimulation had superioroutcomes compared with those who received sine wave stimulation. There were indications that patients for whom titrationwas rhe strategy used for dose detennination had outcomessuperior to those of patients who did not receive titr.lted dosing.As before, dosage titration seemed to be of specific benefit whenRUt ECf was administered.
".....
-1- NOt'H'lmitlll'1l_Rornltt.,..
,....
,,\,,\,
\," £ I £ I_ _--1r r r --- £_---
Figure 3. Depression severity scores. Hamilton Rating Scale for Depression(HRSD) scores for patients who did (0 = 162) and did not (n = 185) meetremit 10 criteria immediately after electroconvulsive therapy (Ecn. Scoresare for the period before and immediately after ECT and at 4-week intervalsduring follow-up. Missing observations were imputed with a longitudinalmixed-model analysis.
,,;,---------------------,
Clinical Outcomes during Follow-upOf the 162 patients in the intent-to-treat sample who met
remit lO criteria, 145 patients were clinically monitored until theymet criteria for relapse or ,the completion of the 24-weekfollow-up. Nine patients were followed for a shorter period butwere lost to follow-up without meeting relapse criteria, and eightpatients did not consent to post-ECf clinical monitoring. Ninety-
1.0
.9
.8
..;:
.7mcC..E• .6
"-0~'E .s•..,e..• .4>"•.,E,
.3l.J
.2
.1
00 4 8 12 16 20 24
Time, Wk
Figure 2. Kaplan-MeIer estimates. Proportion of patients who remitted afterelectroconvulsive therapy and remained well during the 24-weekfollow-upperiod forthe total sample (0 = ,54) and for each of the seven sites.
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310 BIOL PSYCHIATRY 2004;55:301-312
nine of the 154 remined patients (64.3%) relapsed (Figure 2). Themedian time to relapse was 8.6 weeks. Patients who relapsed (6.1± 2.6) did not differ from patients who did not relapse (6.3 ±2.6) in post-ECT HRSD scores [1(152) = - .3, P = .791. At the timeof relapse, the mean HRSD score was 23.2 ± 5.4, whereas at theend of follow-up HRSD scores averaged 6.3 ± 4.8 in patientswho did not relapse [1(148) = 19.3, P < .00011. The Kaplan-Meieranalysis indicated that the sites differed in survival time [log-rank,X2(6) = 16.4, P = .011. Across the seven sites, ti,e relapse rateranged from 46.3% to 78.9"Al (Figure 2).
The averaU model in the parametric analysis on survival timewas significant [likelihood ratio, X2 (l6) = 45.5, P < .00011. Site[X"(6) = 14.5, P = .021, psychotic depression [X2(I) = 5.2, P ~
.021, comorbid Axis I disorder (X2(l) = 7.4, P < .0071. comorbidAxis II disorder [X2(I) = 6.5, P = .011, and number of ECTtreatments in the acute phase [X2(I) = 4.3. -p < .041 were eachassociated with survival time. When we retested these variablesafter controlling for site, all except number of ECT treatmentsmaintained Significant associations. Compared with those whodid not relapse, relapsed patients had higher rates of psychoticdepression (31.1% vs. 22.2%) and comorbid A.xis I (43.4% vs.27.0%) and Axis II (23.2% vs. 14.3%) disorders. Strength ofcontinuation pharmacotherapy was not associated with relapse;however, only 46,80/'0 of relapsed patients and 53.3% of nonrelapsed patients were rated as receiving an adequate dosage of anestablished antidepressam medication. Of note, use of continuation ECf was frequent but equally represented among patientswho did (43.9"Al) and did not relapse (49.0%).
Of the 185 patients who did not meet remitlO criteria, 20palienlS did not complete 12 weeks of follow-up and wereexcluded from characterization of post-EO course. Of theremaining 165 patients, 92 55.8%) never met remission criteriaduring follow-up. Of the 26 patients who met remit lO criteria atone follow-up assessment, ; continued through follow-up without meeting relapse criteria, 15 subsequently met relapse criteria,and relapse status could not be determined in 6 patients. Theremaining 47 patients met remit10 criteria at two or moreconsecutive assessments. Of tllis group, 32 patients continuedwithout relapse, 14 patients subsequently met relapse criteria,and relapse status could not be determined for 1 patient. Thus, ofthe 158 patients who did not meet remit lO criteria immediatelyafter ECf and for whom follow-up data were complete, 37(23.4%) met remission criteria and did not relapse during followup.
TIle longitudinal mixed-model analysis indicated lhat amongpatients who did not remit after ECf there was no change inaverage HRSD scores from the end of the acute ECf coursethrough the completion of the 24-week follow-up (Figure 3). Incontrast, among patients who met remit lO criteria, there was amarked increase in HRSD scores at the first follow-up (4 weeks)after the end of ECT [1(1818) = 6.22, P < .00011. The 4th week offollow-up was the modal point of relapse. Compared with the4th week of follow-uPI HRSD scores of ECT remitters werefurther increased at the 20th [1(1818) = 2.59, P < .011 and 24th(1(1818) = 3.11, P < .002J weeks. Relative to pre-ECT baseline,nonreminers (n = 185) had an average improvement in HRSDscores of 36.6% ± 23.3% at post-ECf and of 345% ± 28.8% atthe 24-week follow-up, The Eer remitters averaged a 79.3% ±9.5% decrease in symptom scores after ECT and a 52.3% ± 30.2%decrease at me end of follow-up, Based on HRSD scores atthe end of the 24-week follow-up, 153 of the total sample of347 patients (44.1%) were classified as responders, 78 of 347
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J. Prudic et al
(225%) met remitlO criteria, and 56 of 34706.1%) met remit7
criteria.
Discussion
\Ve have provided evidence that ECf is substantially lesseffective in community practice than previously assumed fromthe results of clinical trials. Whereas the rate of remission inclinical trials is typic'lily reported to be on the order of 70%r-90%(American Psychialric Association 2001; Petrides el al 2001jSackeim et al 1993. 2000), the intent-ta-treat remission rates froma large cohoIt of adults treated with ECT in community facilitieswere in the range of 300;b-47%. The disparity between clinicaloutcomes in research and community settings was more markedfor remission than for response rates. The low rates of remissionare of particular concern given the long-term outcomes ofpatients who did not remit with ECT. Only a small minority ofsuch patients achieved sustained remission during the subsequent 6 months.
The low remission rales in community practice might beexplained by patient selection. Patients with comorbid psychiatric and medical conditions that are associated with poorer EOoutcome might represent a larger proportion of clinical populations than research samples. For example, we found that comorbid personality disorders, which occurred in more than onequarter of the sample, were associated with poor response toECT. In controlled trials of ECf for major depression, patientselection criteria tend to limit the number of participants withvarious complicating comorbid disorders (e.g., neurologic disorders, substance abuse) (McCall et al 2000a); however, broaderpalient selection does not seem sufficient to account for the lowremission rates. Although statistically significant associationswere observed between several patient fearures and immediatepost-ECf outcome, dle amount of variance explained was modest. Indeed, the remission rates were substantially below expectations when the sample was restricted to patients without acomorbid Axis I or A.\:is II disorder.
Treatment adherence is known to impact on clinical outcomes in the pharmacologic and behavioraltreaunent of depression (Katon et al 2002; Sood et al 2000) and more generally inmedicine (Haynes et al 2002; McDonald et al 2002). Indeed,depreSSion has been repeatedly shown to be a risk factor fornonadherence to medical treatment (DiMatteo et al 2000), Poorpalient adherence is unlikely to accounl for the low remissionrates. Unlike pharmacotherapy, which is self-administered, otherthan agreeing to, and in the case of outpatients. showing up fortreallTlent, the administration of ECT requires minimal activepatient participation. \Vithdrawal of consent was lhe leadingcause of premature termination of ECT according to the treatingpsychiatrist's repon; however, when a completer sample wasselected on the basis of the treating psychiatrist's view that acomplete course of ECT had been administered, the remissionrates were still disappointing.
Premature treatment tennination is a more likely explanationof the remission rates. In controlled trials, a minimum number oftreatments is usually required before patients are considerednonreminers, and in those patients who show clinical improvement, ECf is usually continued until detailed symptom assessments show a plateau in additional benefit (Petrides et al 2001;Sackeim et al 1993, 2000). In the community cohort, treatingpsychiamsts often lenninated ECT before remission wasachieved. ApproXimately one half of the cases lhat the treatingpsychiatrists determined to have had a full response did not meet
J. Prudic et al
the strict remission criteria. The frequent termination of ECf inpatients who had considerable residual symptoms might havebeen due to the use of symptom reduction as the target fortreatment, as opposed to remission. Alternatively, some providers might have aimed for more complete improvement but mightnot have been aware of the residual symptoms. Systematic andthorough assessment of symptomatic staNS might help lower therisk of tenninating treatment before remission has beenachieved. In practice, premature treatment termination deprivespatients of the full benefit of ECf and puts them at risk to lose thegains they have achieved. Indeed, in the first systematic follow-up of a large cohort of patients who did not remit with ECf,the rate of sustained remission was low. Because treatmentresistance and intolerance are the leading indications for use ofECf in major depression (American Psychiatric Association2001), it is not surprising that not achieving remission willi ECfaugers a poor prognosis. The guiding principle should be to
deliver no more or less treatments: than are needed to achievema..xiIruJ.I clinical gains. Too few treatments can result in incomplete improvement, chronic symptomatology, and heightenedrisk of relapse. Additional treatments beyond the point ofmaximal improvement do not seem to reduce the relapse risk(Barton et a1 1973) but can contribute to adverse cognitiveeffects.
\Ve found little evidence that technical aspects of ECf administration were associated with clinical outcomes. Although thecommunity sites varied widely in many aspects of ECf administration, there were no site differences in short-term effectiveness.The incomplete symptomatic improvement in many patientsmight have limited the possibility of observing associations withtechnical factors or patient features. In addition, none of the sitesroutinely used forms of ECf that are known to have reducedefficacy (Sackeim et a11987, 1993). Rather, tile site differences infactors such as choice of electrical waveform, electrode placement, and dosing strategy are more likely to produce differencesin cognitive side effects. Relationships between technical factorsand cognitive outcomes will be addressed in a forthcomingreport.
A high rate of relapse shortly after Eer has been observed inmost recent reports (Grunhaus et al 2001; Sackeim et a1 1990,1993, 2000, 2001) and confirmed in this study. Controlled research has shown that intensive pharmacotherapy reduces thisrelapse rate (Sackeim et al 2001). The majority of patients whoremitted after ECT received continuation pharmacotherapy thatwas rated as inadequate. The e:x1:ent to which this low intensity ofpharmacotherapy was due to medication Intolerance or prescribing preferences could not be determined. Other work in community samples has shown that patients often receive inadequatelevels of phannacothernpy and psychotherapy in the acutetreatment of major depression (Keller et al 1982, 1986).
Although the response and remission rates we observedwould be considered high for routine pharmacologic treatmentof major depression, the remission rates were well below e::-..-pectations for ECf. \Vhen coupled with the relapse rate, it wasevident that only a small percentage of patients who receivedECf achieved a sustained remission. We suggest that rather thanintrinsically reflecting limitations of Eer, this panern reflectslimitations in the delivery of care. In parucular, the low remissionrate might be due largely to premature termination of the acuteECf course in patients who show significant but incompletebenefit. The high relapse rate might be due to insufficientintensity of continuation treatment in Eer reminers.
BIOL PSYCHIAmY2004;55:301-312 311
TlJis work was suppa/1ed in pm1 by Grants RaJ MH59069 (/P,,110, HAS), RaJ MH35636 (HAS, jP), and RaJ MH6J609 (HAS,JP) from the National Institute ofMental Health.
\Ve tbank the electroconvulsive therapy directors at the parlicipating institlltio1lS, as well as the medical staffs, for theirassistance in conducting this study.
American Psychiatric Association (1994): Diagnostic andStatistical Manual ofMental Disorders, 4th ed. Washington, DC: American Psychiatric Association.
American Psychiatric Association (2000): Practice guideline for the treatment of patients with major depressive disorder (revision). Am) PsychiotI)'157:1-45.
American Psychiatric Association (2001): The Practice ofECT: Recommendations for Treatment, Training and Privileging, 2nd ed. Washington, DC:American Psychiatric Press.
Barton J, Mehta 5, Snaith R (1973): The prophylactic value of extra ECT Indepressive illness. Ada Psychiatr5cand49:386-392.
Beck AT. Steer RA, Brown GK (1996): Beck Depression Inventory Manuaf, 2nded. San Antonio, TX: Psychological Corporation.
Black OW, Bell 5, Hulbert J, Nasrailah A(1988); The importance of Axis II inpatients with major depression. A controlled study. ) Affea Disord14:115-122.
Casacalenda N, Peny JC, Looper K(2002): Remission In major depressivedisorder: Acomparison of pharmacotherapy, psychotherapy, and control conditions.Am) Psychiatry 159:1354 -1360.
DeBattista C, Mueller K(2001): Is electroconvulsive therapy effective for thedepressed patient with comorbid borderline personality disorder?)fa17:91-98.
DiMatteo MR, Lepper HS, Croghan TW (2000): Depression Is a risk factor fornoncompliance with medical treatment: Meta-analysis of the effects ofanxiety and depression on patient adherence. Arch Inrern Med 160:21 012107.
Dixon LB, Lehman AF, Levine J (t 995): Conventional antipsychotic medications for schizophrenia. Schizophr Bull 21:567-577.
Farah A, McCall WV (1993): Electroconvulsive therapy stimulus dosing: Asurvey of contemporary practices. Convuls Ther 9:90-94.
First MS, Spitzer RL, Gibbon M, Williams JSW (1996a): Strudured ClinicalInterview for Axis I DSM-IV Disorders-Patient Edillon (with PsychoticScreen) (SClD-lIP). New York: Biometrics Research Department, New YorkState Psychiatric lnstitute_
First MB, Spitzer RL. Gibbon M, Williams JBW, BenjamIn L(1 996b): StructuredClinical fnterview for DSM-N Axis 1/ Personality Disorden (SCfD-II). New York:Biometrics Research Department, New York State Psychiatric Institute.
Folkerts HW, Michael N, Tolle R, Schonauer K, Mucke S, 5chulze-Monking H(1997): Electroconvulsive therapy vs. paroxetine in treatment-resistantdepression-a randomized study. Acta Psychiatr Scand 96:334 -342.
Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer OJ, Lavori PW, et al (1991):Conceptualization and rationale for consensus definitions of terms inmajor depressive disorder. Remission, recovery, relapse, and recurrence.Arch Gen Psychiatry48:8S1-SS5.
Gangadhar B, Kapur R, Kalyanasundaram S (1982): Comparison of electroconvulsive therapy with Imipramine in endogenous depression: A double blind study. Sr) Psychiatry 141:367-371.
Grunhaus l, Hirschman S, Dolberg OT, Schreiber S, Dannon PN (200t): Coadministration of melatonin and nuoxetine does not improve the3-month outcome follOWing ECT.) fa17:124-128.
Halliday G, Johnson G (1995): Training to administer electroconvulsive therapy:Asurvey ofattitudes and experiences. Aust NZJPsychiatry 29:133-138.
Hamilton M (1967): Development of a rating scale for primary depressiveillness. Bf) Soc Clin Psychof 6:278-296.
Hermann RC, Dorwart RA, Hoover CW, Brody J (1995): Variation in ECT use inthe United States. Aml Psychiatry 152:869-875.
Hewin ME, Simone JV, U.S. National Cancer Policy Board (1999): EnsuringQuality Cancer Care. Washington, DC: National Academy Press.
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J. Prudic et al
the strict remission criteria. The frequent termination of ECf inpatients who had considerable residual symptoms might havebeen due to the use of symptom reduction as the target fortreatment, as opposed to remission. Alternatively, some providers might have aimed for more complete improvement but mightnot have been aware of the residual symptoms. Systematic andthorough assessment of symptomatic status might help lower therisk of terminating treatment before remission has beenachieved. In practice, premature treatment termination deprivespatients of the full benefit of ECf and puts them at risk to lose thegains they have achieved. Indeed, in the first systematic follow-up of a large cohort of patients who did not remit with ECf,the rate of sustained remission was low. Because treatmentresistance and intolerance are the leading indications for use ofECf in major depression (American Psychiatric Association2001), it is not surprising that not achieving remission with ECTaugers a poor prognosis. The guiding principle should be todeliver no more or less treatments than are needed to achievema:<i.rnal clinical gains. Too few treatments cm result in incomplete improvement, chronic symptomatology, and heightenedrisk of relapse. Additional treatments beyond the point ofmaximal improvement do not seem to reduce the relapse risk(Barton et aI 1973) but can contribute to adverse cognitiveeffects.
We found Iinle evidence that technical aspects of ECf administration were associated with clinical outcomes. Although thecommunity sites varied Widely in ma.ny aspects of Ecr administration, there were no site differences in short-term effectiveness.TIle incomplete symptomatic improvement in many patientsmight have limited the possibility of observing associations widltechnical factors or patient features. Tn addition, none of the sitesroutinely used forms of ECf that are known to have reducedefficacy (Sackeim et al1987, 1993). Rather, the site differences infactors such as choice of electrical wavefoml, electrode place·ment, and dosing straregy are more likely to produce differencesin cognitive side effects. Relationships between rechnical fac(orsand cognitive outcomes will be addressed in a forthcomingreport.
A high rate of relapse shortly after ECf has been observed inmost recent reports (Grunhaus et al 2001; Sackeim et al 1990,1993, 2000, 2001) and confirmed in this study. Controlled research has shown that intensive pharmacotherapy reduces thisrelapse rate (Sackeim et at 200l). The majority of patients whoremitted after Eer received continuation pharmacotherapy thatwas rated as inadequate. The eh'tent to which this low intensity ofpharmacotherapy was due to medication intolerance or prescribing preferences could not be determined. Other work in community samples has shown that patients often receive inadequatelevels of phannacotherapy and psychotherapy in the acutetreatment of major depression (Keller et al 1982, 1986).
Although the response and remission rates we observedwould be considered high for routine pharmacologic treatmentof major depression, the remission rates were well below expectations for Ecr. When coupled with the relapse rate, it wasevident that only 3 small percentage of patients who receivedECf achieved a sustained remission. \Ve suggest that rather thanintrinsically reflecting limitations of ECT, this pattern reflectslimitations in the delivery of care. In particular, the low remissionrare might be due largely (0 premature termination of the acuteECf course in patients who show Significant but incompletebenefit. The high relapse rate might be due to insufficientintensity of continuation treatment in ECf remitters.
BlOL PSYCHIATRY 2004;55:301-312 311
17J!s work was supporled I" parl by Grams RaJ ~m59069 (/P,MO, HAS), ROJ ~m35636 (HAS, jP), and RaJ ~m6J609 (HAS,jP) from the Na/iona/lnstilu/e ofAfental Healtb.
We thank tbe electroconvulsive therapy directors at the partic;paling (nstitu1J'ons, as !vell as tbe medical staffs, for theirassistance in conducJfHg tbis study.
American Psychiatric Association (1994): Diagnostic andStatisticalManualofMental Disorders, 4th ed. Washington, DC: American Psychiatric Association.
American Psychiatric Association (2000): Practice gUideline for the treatment of patients with major depressive disorder (revision). Am ) Psychiatry 157:1 -45.
American Psychiatric Assoc:latlon (2001):The Practice efECT: Recommendations for Treatment. Training and Privileging, 2nd ed. Washington, DC:American Psychiatric Press.
Barton J, Mehta S, Snaith R (1973): The prophylactic value of extra ECf Indepressive illness. Acto PsychiatrScand 49:386-392
Beck AT, Steer RA, Brown GK (1996): Beck Depression Inventory Manual, 2nded. San Antonio, TX: Psychological Corporation.
Black DW, Bell S, Hulbert J, Nasrallah A (1 988): The importance of Axis II inpatients with major depression. A controlled study. J Affect Disord14:115-122.
Casacalenda N, Perry Jc. Looper K (2002): Remission in major depressivedisorder: A comparison of pharmacotherapy, psychotherapy, and control conditions. Am J Psychiatry 1S9:1 354-1360.
DeBattista C, Mueller K(2001): Is electroconvulsive therapy effective forthedepressed patient with comorbid borderline personality disorder? J Ea17:91-98.
DIMatteo MR, Lepper HS, Croghan TW (2000): Depression is a risk factor fornoncompliance with medical treatment: Meta-analysis of the effects ofanxiety and depression on patient adherence. Arch Intern Med 160:21012107.
Dixon LB, Lehman AF, Levine J (1995): Conventional antipsychotic medications for schizophrenia. Schizophr Bull 21:S67-577.
Farah A, McCall WV (1993): Electroconvulsive therapy stimulus dosing: Asurvey of contemporary practices. Convuls Ther 9:90-94.
First MB, Spitzer RL, Gibbon M, Williams JBW (1996a): Structured ClinicalInreNiew for Axis I DSM-IV Disorders-Patient Edition (with PsychoticScreen) (SCID-IIP). New York: Biometrics Research Department, New YorkState Psychiatric Institute..
First MB, Spitzer RL. Gibbon M, Williams JBW, Benjamin L (1996b): StructuredClinical Interview for DSM·/V Axis /J Personality Disorders (SOO-/l). New York:Biometrics Research Department, New York State Psychiatric Institute.
Folkerts HW, Michael N, Tolle R, Schonauer K. Mucke 5, Schulze-Monking H(1997): Electroconvulsive therapy vs. paroxetine in treatment-resistantdepression-a randomized study. Acta Psychiatr Scand96:334-342.
Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, et al (1991):Conceptualization and rationale for consensus definitions of terms Inmajor depressive disorder. Remission, recovery, relapse,and recurrence.Arch Gen Psychiarry 48:85 1-855.
Gangadhar B, Kapur R, Kalyanasundaram S (1 9a2): Comparison of electro·convulsive therapy with imipramine in endogenous depression: A double blind study. Br J Psychiatry 141:367-371.
Grunhaus L. Hirschman 5, Oolberg OT, Schreiber 5, Dannon PN (2001): Coadministration of melatonin and fluoxetine does not improve the3-month outcome follOWing ECT.J fCT 17:124-128.
Halliday G, Johnson G (1995): Training to administer electroconvulsive therapy:Asurvey ofattitudes and experiences.Aust NlJ Psychiatry 29:1 33-138.
Hamilton M (1967): Development of a rating scale for primary depressivel1Iness. Br J Soc Clin Psycho/6:278-296.
Hermann RC, Dorwart RA, HooverCW, Brody J (1995): Variation in ECT use inthe Uni(ed States. Am J Psychiatry 152:869-875.
Hewitt ME, Simone N, U.S. National Cancer Policy Board (1999): EnsuringQuality Cancer Care. Washington, DC: National Academy Press.
www.elsevier.com/locate/biopsych
J. Prudic et al
the strict remission criteria. The frequent termination of ECf inpatients who had considerable residual symptoms might havebeen due to the use of symptom reduction as the target fortreatment, as opposed to remission. Alternatively, some providers might have aimed for more complete improvement but mightnot have been aware of the residual symptoms. Systematic andthorough assessment of symptomatic status might help lower therisk of terminating treatment before remission has beenachieved. In practice, premature treatment termination deprivespatients of the full benefit ofECT and puts them at risk to lose thegains they have achieved. indeed, in the first systematic follow-up of a large cohort of patients who did not remit with Eer,the rate of sustained remission was low. Because treatmentresistance and intolerance are the leading indications for use ofECf in major depresSion (American Psychiatric Association2001), it is not surprising that not achieving remission with Eeraugers a poor prognosis. The guiding principle should be todeliver no more or less treatments than are needed to achievemaximal clinic..tl g:lins. Too few treatments c:ln result in incomplete improvement, chronic symptomatology, and heightenedrisk of relapse. Additional treatments beyond the point ofmaximal improvement do not seem to reduce the relapse risk(Barton et al 1973) but can contribute to adverse cognitiveeffects.
We found little evidence that technical aspects of ECf administration were associated with clinical outcomes. Although thecommunity sites varied Widely in many aspects of Eer administration, there were no site differences in shorr-tenn effectiveness.The incomplete symptomatic improvement in many patientsmight have limited the possibility of observing associations withtechnical factors or patient features. In addition, none of the sitesroutinely used forms of ECf that are known to have reducedefficacy (Sackeim et al1987, 1993). Rather, the site differences infactors such as choice of electrical waveform, electrode placement, and dosing strategy are more likely to produce differencesin cognitive side effects. Relationships berween technical factorsand cognitive ourcomes will be addressed in a forthcomingreport.
A high rate of rei:lpse shortly after ECT has been observed inmost recent reports (Grunhaus et a1 2001; Sackeim et al 1990,1993, 2000, 2001) and confinned in this study. Controlled research has shown that intensive phannacotherapy reduces tllisrelapse rate (Sackeim et al 200l). The majority of patients whoremitted after ECT received continuation pharmacotllerapy th3twas rated as inadequate. The extent to which this low intensity ofpharmacotherapy was due to medication intolerance or prescribing preferences could not be detennined. Other work in community samples has shown that patients often receive inadequatelevels of phannacotherapy and psychotherapy in the acutetreatment of major depression (Keller et al 1982, 1986).
Although the response and remission rates we observedwould be considered high for routine phannacologic treatmentof major depression, the remission rates were well below expecmtions for Ecr. When coupled wirh the relapse rate, it wasevident rhat only a small percentage of patients who receivedECf achieved a sustained remission. We suggest that rather thanintrinsically reflecting limitations of ECT, this panern reflectslimitations in the delivery of care. In particular, the low remissionrate might be due largely to premarure tennination of the acuteECf course in patients who show significant but incompletebenefit. The high relapse rate might be due to insufficientintensity of continuation treatmem in Eer remitters,
BIOLPSYCHIATRY 2004;55:301-312 311
17,is work was slIpporied ill pari by Grallis ROt MH59069 (JP,MO, HAS), ROt MH35636 (HAS, jP), alld ROt MH6J609 (H4S,jP) from the National Institute ofAlental Healtb.
\life thank the electroconvulsive therapy directors at the parlic!paling institutions, as well as the medical staffs, for theirassistance in conducling this study.
American Psychiatric Association (1994): Diagnostic andStatistical Manual ofMental Disorders, 4th ed. Washington, DC: American Psychiatric Association.
American Psychiatric Association (2000): Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry' 57:1-45.
American Psychiatric Association (2001):The Practice afECT: Recommendations for Treatment, Training and Privileging, 2nd ed. Washington, DC:American Psychiatric Press.
Barton J, Mehta 5, Snaith R (1973): The prophylactic value of extra ECT Indepressive illness. Acta PsychiotrScond 49:386-392
Beck AT, Steer RA, Brown GK (1996): Beck Depression Inventory Manual, 2nded. San Antonio, TX: Psychological Corporation.
Black OW, Bell S, Hulbert J, Nasral1ah A (1988): The importance of Axis II Inpatients with major depression. A controlled study. J Affect Disord14:115-122.
Casacalenda N, Perry JC, Looper K (2002): Remission In major depressivedisorder: A comparison of pharmacotherapy, psychotherapy, and control conditions. Am) Psychiatry 159:1354-1360.
De Battista C, Mueller K(2001): Is electroconvulsive therapy effective for thedepressed patient with comorbid borderline personality disorder? J Eer17:91-98.
DIMatteo MR, Lepper H5, Croghan TW (2000): Depression Is a risk factor fornoncompliance with medIcal treatment: Meta-analysis of the effects ofanxiety and depression on patient adherence. Arch Inrern Med 160:21 012107.
Dixon LB, Lehman AF, Levine J (1995): Conventional antIpsychotic medications for schizophrenia. Schizophr Bull 21:567-577.
Farah A, McCall WV (1993): Electroconvulsive therapy stimulus dosing: Asurvey of contemporary practices. Convuls Ther 9:90 -94.
First MB, Spitzer Rl, Gibbon M, Williams JBW (1996a): Structured ClinicallntefV;ew for Axis I DSM-IV Disorders-Patient Edition (with PsychoticScreen) (SCID-IIP). New York: Biometrics Research Department, New YorkState Psychiatric Institute..
First MS, Spitzer Rt.. Gibbon M, Williams JBW, Benjamin L (1 996b): StructuredClinicollnterviev.t for DSM-IVAxis 1/ PenonaJity Disorders (SCID-II). New York:Biometrics Research Department, New York State Psychiatric Institute.
Folkerts HW, Michael N, Tolle R, Schonauer K, Mucke S, Schulze-Monklng H(1997): Electroconvulsive therapy vs. paroxetine in treatment-resistantdepression-a randomized study. Acta Psychiotr Scond96:334-342.
Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavor! PW, et al (1991):Conceptualization and ratlonale for consensus deflnitlons of terms inmajor depressive disorder. Remission, recovery, relapse, and recurrence.Arch Gen Psychiatry 48:851-855.
Gangadhar B, Kapur R, Kalyanasundaram S (1982): Comparison of electroconvulsive therapy with Imipramine in endogenous depression: Adouble blind study. 8rJ Psychiatry 141:367-371.
Grunhaus L, Hirschman 5, Dolberg OT, Schreiber S, Dannon PN (2001): Coadministration of melatonin and Ouoxetine does not improve the3-month outcome following Ea.) Eer 17:124-128.
HallidayG, Johnson G (1995):Training to administer electroconvulsive therapy:Asurvey of attitudes and expenences.Aust NZ) Psychiarry29:133-138.
Hamilton M (1967): Development of a rating scale for primary depressiveillness. Br1Soc Clin Psycho/6:278-296.
Hermann RC, Dorwart RA, Hoover CW, Brody J (1995): Variation in Ea use inthe United States. Am) Psychiatry 152:869 -875.
Hewitt ME, Simone JV, U.S. National Cancer Policy Board (1999): EnsuringQuality Cancer Care. WashIngton, DC: National Academy Press.
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