QUEST - Electroconvulsive Therapy

• Clinical Outcome of ECT in Patients With Major Depression and Comorbid Borderline Personality Disorder 

• Electroconvulsive Therapy in Depressive Disorders

• Comparing ECT to TMS, Which is More Effective in Major Depression

• Electroconvulsive Treatment Compared with Lithium in Mania

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AUTHOR

Lena Irvine 

Clinical Outcome of ECT in Patients With Major Depression and Comorbid Borderline Personality Disorder 

Chairman’s Rounds, June 4, 2007 

Citation: Feske U, Mulsant BH, Pilkonis PA, Soloff P, Dolata D, Sackeim HA et al (2004).  Clinical outcome of ECT in patients with major depressive disorder and comorbid borderline personality disorder.  American Journal of Psychiatry 161, 2073-80.

Clinical question:  Does having Borderline personality disorder affect one’s response to ECT in patients with Major depressive disorder?

Methods:
Diagnosis:
            DSM-III-R: Major depressive disorder
Personality disorder: Personality Disorder Examination before ECT (68 subjects)
Structured Clinical Interview for DSM-III-R Personality Disorders after ECT
(71 subjects)
No difference by chi-square tests in rates of personality disorder
Statistically significant difference by t tests of certain non-Borderline personality disorders
Wash out period
Usually received RUL, could switch to bilateral, no preset number of ECT treatments

Question type:  Prognosis

Validity criteria:
Sample of population:  (table 1) Population appears to be similar to that of clinical practice
Homogeneity:  Patients with Borderline personality disorder were overwhelmingly female and medication resistant
Similar point in disease progression:  Borderline personality disorder had higher 24-item HAM-D scores, but unknown if statistically significant
Follow up:  None (4-8 days after receiving ECT)
Similarity of treatment:  All patients were treated similarly
All patients accounted for:  All but 4 patients had final HAM-D score
Outcome criteria:  Outcome criteria were objective and unbiased (24-item HAM-D score, had independent evaluators)

Study design type:  Prospective case cohort
Appropriate design:
Setting:  Western Psychiatric Institute and Clinic (psychiatric institute at academic hospital)
Patient population:  139 patients total (table 1), 14.4% patients with Borderline personality disorder, 30.2% patients with another personality disorder, 55.4% patients without personality disorder
            Inclusion criteria:  Major depressive disorder (24-item HAM-D score at least 20), not describe recruitment
            Exclusion criteria:  Schizophrenia, schizoaffective disorder, other psychosis, neurological disorder or dementia, substance abuse, ECT within past 6 months
            No drop outs, but 4 subjects without final HAM-D score, not explained how they dropped out
Secondary prognostic factors:  Gender, race, marital status, medication resistance, prior history of ECT, age, duration of episode, Cumulative Illness Rating Scale—Geriatrics, Number of previous depressive episodes
Exposures:  ECT (usually RUL, some bilateral)
Outcomes:  HAM-D score to determine remission
Follow up period:  4-8 days 

Main results: (table 2)
Patients with Borderline personality disorder (dimensional score) had poorer response to ECT
Remission = HAM-D score < 10
            Borderline personality disorder: 22% remission (p=0.001)
            Other personality disorder: 56% remission (p=0.001)
            No personality disorder: 72% remission (p=0.001)
Younger age was predictor of negative response
*No long term follow up*
*Ascertainment bias*
*Severity of depression was predetermined*
Medication resistance
Gender
Qualitative difference in depression among groups

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AUTHOR:
Maria Almond 

Efficacy And Safety Of Electroconvulsive  Therapy In Depressive Disorders  

Chairman’s Rounds, August 14, 2006 

Citation:  Efficacy and safety of electroconvulsive  therapy in depressive disorders: a systematic review and meta-analysis.  The Lancet. March 2003. 361: 799-808. 

Clinical Question: Is ECT an effective short-term treatment for depressive disorders compared to other drug therapies? 

Clinical Case or Background Info: A 38yo male w/ ESRD admitted to 9B with symptoms of catatonic depression and initially treated with ECT without good effect.  

Question Type: Therapy

Validity Criteria:

Clinical Question: Authors used a single search technique to answer a broad two-pronged question about 1) efficacy and 2) safety of ECT treatment for depression.  ECT was compared both to placebo and drug therapy.  Several secondary questions were also asked regarding ECT technique—bilateral vs unilateral, dosing, frequency of dosing, type of wave used.

Literature Search: Exhaustive search done through several well-respected databases, including a database of the grey literature (i.e. unpublished). Uncertain if specialists in the field were consulted. Entire search methodology was listed in appendix. Relevant studies were unlikely to be omitted.

Inclusion/Exclusion criteria: Of the 624 reports obtained from the search, 73 reports met criteria for “properly randomized, unconfounded, controlled trials” comparing ECT to no ECT, ECT versus pharmacology or different forms of ECT on pts with depressive illness. Did not specifically define “depressive illness,” but primary outcome in paper needed to have a continuous depressive symptoms scale.  Exclusion criteria were not made explicit in the paper.

Methodological Quality of Primary Studies: The primary studies were of uncertain quality. The authors indicated the methods used for assessing quality—reporting of allocation concealment, masking, loss to follow-up and length of follow-up—but did not report in  detail on what the investigators found. Authors did reveal that for the RCTs selected, few described their allocation concealment methods.  Most did use some form of masking the outcome assessor to limit ascertainment bias.

Reproducibility: The search techniques and process of data abstraction were well-outlined in the appendix. However, exclusion criteria were not well-defined, raising possibility of selection bias.

Homogeneity of studies: Very heterogeneous—different interventions, designs with largely different methods of performing ECT (doses and forms of administration) and with a variety of subjects. However, plotting effect estimates against sample sizes (funnel plot) showed no publication bias.

Study Design Type: Systematic Review w/ meta-analysis

Data Sources: Obtained data from the Cochrane Collaboration Depressive Anxiety and Neurosis and Schizophrenia Group Controlled trial registers, Cochrane Controlled Trials register, Biological Abstracts, CINAHL, EMBASE, LILACS, MEDLINE, PsychINFO, and SIGLE, reference lists, and specialist textbooks.  Entire search methodology was listed in appendix.

Study Selection Criteria: As listed above in Inclusion/Exclusion criteria

Outcomes: Change in symptoms on continuous depressive symptoms scale at end of course of ECT. Change in symptoms at 6 months. Immediate and long-term effect on cognitive functioning.  Mortality.

Main Results: ECT as compared to placebo is an effective treatment for adult patients with depressive symptoms in the short term, translating to a mean difference on HDRS of  9.7 (95% CI 5.7-13.5).  Unable to comment on effectiveness of drug therapy vs  ECT due to heterogeneity of studies and inability to adequately separate out confounders such as anesthesia and nursing care. In the analysis performed, results show significant difference of 5.2 points on HDRS (95% CI 1.4-8.9).   Bilateral ECT more effective than unilateral with change of 3.6 on HDRS (95% CI 2.2-5.2). No significant differences were found in frequency of dosing.  High dose more effective than low dose with difference of 4.1 pts on HDRS (95% CI 2.4-5.9). No difference in stimulus wave form was found.

Conclusions:  These trials are older with small sample sizes and also heterogeneous in nature, but the searching technique itself was effective (i.e. adequate funnel plot).  Unfortunately, the authors did not focus on a single clinical question, but attempted several using the same search technique. Good! Also while they stated they used one primary outcome measurement, this is only true of the RCTs analyzed. The authors also used several different outcome measurements depending on type of trial. And some of the secondary clinical questions asked had only small numbers of trials to examine. The heterogeneity of the studies makes it difficult to combine results in a meaningful way.  Authors basically indicated that the general weight  of the evidence for ECT efficacy was “reasonably consistent.” Also generally difficult to pin the results simply to the shock of ECT alone, given that  nursing care and the anesthesia are also involved in the procedure. As for utility, none of the studies adequately reflects clinical practice with short trial of ECT followed by treatment of residual symptoms and relapse prevention.

Teaching Points (2)

1)       In meta-analyses selection bias can greatly affect a study’s validity.  One way of evaluating selection bias (and other forms of bias that may have smaller studies showing larger effect sizes) is by creating a funnel plot, which weighs study effect against study precision (standard error). A symmetrical funnel indicates less bias.

2)       A priori definitions in studies are important to prevent authors from “data-dredging” or creating multiple hypotheses after data has been collected. Authors in this study defined outcome a priori  as change in symptoms on an unspecific continuous depressive symptom scale. In results they translated these changes to the HDRS.  However, no method for moving from the generic scales to the HDRS were described.

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COMPARING ECT TO TMS, WHICH ONE IS MORE EFFECTIVE TO DIMINISH DEPRESSIVE SYMPTOMS IN NONPSYCHOTIC PATIENTS WITH MAJOR DEPRESSION

Reference: L Grunhaus et al (2003). A Randomized Controlled Comparison of Electroconvulsive Therapy and Repetitive Transcranial Magnetic Stimulation in Severe and Resistant Nonpsychotic Major Depression. Biological Psychiatry 53: 324-331.

Methods:

Design: Randomized controlled trial.
Setting: Referrals for ECT by their treating clinician to a Medical Center in Israel.
Patient Population: 40 patients (inpt and oupt), screened by "senior clinicians." Does not report how many screened vs number enrolled. No psychotropics allowed other than Ativan >_ 3mg /day.

Inclusion Criteria: 1) Dx of unipolar major depression. 2) >_18 on Hamilton Rating Scale (HRSD). 3) >_age 18. 4) Depression not secondary to general medical condition or substance abuse.
Exclusion Criteria: 1) No additional Axis I Dx.

Intervention: ECT (according to protocol-at least 6 treatments) or rTMS (20 sessions in 4 weeks) Blinding: Outside trained research assistants were hired that did not regularly work in the program to blindly rate treatment modalities. Patients not blinded. No sham treatment.

Analysis: Two-sample t tests for continuous data. X² for nominal data. Change of scores with treatment was tested using repeated measures analysis of variance (ANOVA).
Primary Outcomes: Treatment response=decrease of >_50% or a final rating of <_10 in the HRSD and a final GAF rating >_60. HRSD
Secondary Outcomes: BPRS, GAF, GDR, PSQI, MMSE
Follow- Up: All patients completed the study and were evaluated at baseline, 2 weeks into tx, and at the end of tx.

Validity:
Randomized by computer generated list. List was concealed from raters.
Treatment groups were similar except the ECT group was older (61.4 vs 57.6), included more inpts (16/20 vs 11/20), and had a significantly lower Global Assessment of Function (39.8 vs 48.9). All patients accounted for at conclusion.
Patients were not blinded. Only raters were blinded.
Groups were relatively treated similarly outside of intervention, but not adequately reported. Study does not comment on Axis II nor Axis III comorbidities.

Results:
-Overall Response Rate at Conclusion of Treatment=58% (23/40 patients):
-12 responded in the ECT group and 11 responded in the TMS group. (X2 = .01, ns)
-For the HRSD, BPRS, GAF, GDR, PSQI, MMSE, the ANOVA with repeated measures of absolute scores showed a significant effect of treatment, but no group or interaction effect.

Final Ratings of Responders only

	ECT Group (n=12)	TMS Group (n=11)	t	CI	p
HRSD	9.0±3.8	6.8±2.7	1.6	(-.6,5.1)	ns
BPRS	24.3±3.2	22.4±2.2	1.5	(-.5_4.3)	ns
GAF	69.3±7.4	77.2±4.1	-3	(-13.2,-2.5)	.006
GDR	.25±.45	0±3	.9	(-.1, .4)	ns
PSQI	5.5±3.2	8.5±4.6	-1.7	(-6.4,.4)	ns
MMSE	27.4±2.1	28.8±..7	-2	(-2.8_1)	ns

Comments:
Despite the inherent limitations of the study (No sham treatment, determination of the LDPFC is not precise, sample size relatively small), it is a randomized controlled trial with blinded raters that provides further support for the claim that LDPFC rTMS exerts significant acute antidepressant effects comparable to ECT. More studies needed to clarify the administration of TMS and its mechanism of action, and its long-term benefits.

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Author:
Matthew Rosa

ELECTROCONVULSIVE TREATMENT COMPARED WITH LITHIUM IN THE MANAGEMENT OF MANIC STATES

Reference: J.G. Small, MD;M.H. Klapper, MS; J.J. Kellmans, MD; M.J. Miller, MD; V.Milstein, PhD; P.H. Sharpley, MD; I.F. Small, MD Electroconvulsive Treatment Compared With Lithium in the Management of Manic States Archives of General Psychiatry 1988;45:727-732

Design: Randomized Controlled Trial

Setting: Study was conducted during a five year period at an academic tertiary care facility at the Indiana University School of Medicine. Subjects were newly hospitalized adults presenting in manic or mixed phases referred from community mental health centers, private psychiatrists and family physicians.

Inclusion Criteria: Subjects all had established diagnoses of bipolar disorder and met criteria for DSM III diagnosis of a manic episode with or without coexisting symptoms of depression and had a history of at least one affective episode within the previous 2.5 years. They were not otherwise selected for treatment resistance or lithium failure. All pts had bipolar I disorders as defined by Research Diagnostic Criteria. Furthermore, a score of 7 or more (range 3-15) on manic subsection of the Severity of Depression and Mania Scale-Depression and Mania Ratings as well as a score of 60 or below on the Global Assessment Scale were required for inclusion. Diagnosis was established with the Schedule for Affective Disorders and Schizophrenia-Lifetime version in interviews with pts and by independent interviews with relatives. Exclusion criteria included pts with other Axis I DSM III diagnosis, significant medical problems, affective episodes associated with physical illnesses or any contraindication to ECT or Lithium.

Methods: 44 pts met inclusion and exclusion criteria. Pts were assigned to treatment arm by table of random numbers. 22 pts entered each group, 10 dropped out before the start for reasons of remission (4), conversion to depression (1) and withdrawal of consent (5). No other athition for the first eight weeks occurred; however, during the maintenance phase there were 11 dropouts for re hospitalization and 13 "for other reasons". 

Lithium therapy was discontinued for 10-14 days and neuroleptic doses were tapered and discontinued "whenever possible" prior to initiation of treatment. After the drug washout, baseline evaluations were performed. Table 1 in the paper lists demographic and historical data on pts. No significant differences were noted in the 2 groups. Before study, 2 clinicians achieved rater agreement of >80% that was rechecked periodically throughout study. Most of the ratings of psychopathology were done by blinded clinician but in certain instances the raters learned of the group assignment. For the first 8 weeks, ratings were done weekly and included the Bech Rafaelson Manic Rating Scale (MRS), the 24 item Hamilton Dep. Scale (HDS), the Brief Psychiatric Rating Scale (BPRS) expanded by 19 items to include elevated mood, and the Clinical Global Impression Scale (CGI). The Nurses Observation Scale for Inpt Eval (NOSIE) and Shopsin-Gershon Social Behavior Checklist (SCGL) were performed by nurses. Interviews covering topics necessary for completion of CGI,MRS,HDS,BPRS were persevered on videotape for "time-blind" analysis. An independent psychiatrist who was blind to treatment group rated patients from these tapes after the references to group assignment were edited from the tapes.

Table 2 in paper provides an overview of the first 8 weeks. Initially ECT group received unilateral ECT. However first six pts demonstrated no benefit and some pts actually worsened so the design was changed to bilateral ECT. (The comparison of unilateral vs bilateral ECT results were reported elsewhere). ECT was administered 3 times weekly. The decision when to terminate ECT treatments was made by clinicians without reference to the rating scale data. Two days after discontinuing ECT pts were titrated to lithium levels between 0.6 and 1.5 mmol/L with a 1.2 mmol/L ceiling in those pts receiving neuroleptics. Pts in the lithium group were titrated in the same manner at the outset. Both groups dosages were increased to optimal therapeutic response, side effects, or ceiling levels. Throughout this period, the only concomitant medication use was neuroleptic use, used in the lowest possible dosage. The mean dose of neuroleptics in pts receiving them was not statistically significant between the groups.

Ratings were performed weekly for the first 8 weeks. The same ratings (except ward behavior scales and drug levels) were then obtained every 4 to six weeks for up to 2 years Statistical analysis consisted of 2 way ANOVA for repeated measures of all the clinical ratings followed by t test comparisons where main effects of group and time were significant ay p< 0.05.

Validity:

1) Were the pts randomize? Yes
2) Were the pts analyzed in the groups to which they were assigned? Yes
3) Were baseline characteristics similar between the two groups? Yes
4) Were all parties in the study blinded? No, while "the raters tried to avoid learning which treatment pt's received, this was not always possible".
5) Were both groups treated equally? No, in fact pts in the ECT group were changed to alternate mode of therapy (bilateral from unilateral ECT) after unilateral placement failed to achieve results in the first 6 pts.
6) Was follow up complete in both groups? Yes in the 8 week arm for those who began treatment, no in the 2 year follow-up period.

Results: Comparisons of the CGI item 1 rating of severity of illness and GAS rating over 1' 8 weeks of the study are presented in Figs. 1 and 2. Both global ratings indicated that ECT group favored lithium group with statistically significant differences at weeks 6,7 and 8. By the end of the 8 weeks Lithium group rated between "borderline and mildly mentally ill", whereas the pts who underwent ECT were rated between "normal and borderline". Pts in ECT arm received a mean of 9 treatments over 3-5 weeks. Those who started with unilateral ECT had mean of 5.2 unilateral treatments followed by a mean of 5.3 bilateral treatments. None of the differences between the unilateral and bilateral groups were statistically significant by report.

Table 3 shows average total scores on the major clinical ratings at baseline and at the end of the 8 weeks. Both groups improved significantly. A major exception was the SDMS-D which showed worsening with lithium, whereas the ECT group showed no change. On the HDS the lithium group did not change but the ECT group significantly improved. Neither p values or CI's are provided along with this data.

The t test comparisons of data from the edited videotapes (not shown in paper) confirm that improvement occurred in both groups on most of the rating scales (GAS, CGI, MRS, HDS, BPRS). However statistically significant differences between the lithium and ECT groups were found at 8 weeks only on the CGI item I (mean scores Lithium = 2.8 vs ECT = 1.89 ) and the Hamilton Somatization "superfactor" (mean scores Lithium = 2.7 vs ECT = 1.8) however in this item the scores were significantly different at the outset (Lithium 2.4 and ECT 1.8)

Regarding the longitudinal follow up, only 10 pts remained in study at end of two years with approx half re hospitalized and a majority lost to follow up. They state that there were no significant differences between the two groups during this period however interviews were only possible with 10 pts, and it is unclear how authors evaluated data (or lack of data) from the dropouts.

Comments:
Strengths: Study of a difficult pt population, withdrawn from lithium at the outset and randomized with full follow up through 8 weeks. Authors conclude that an average of 9 bilateral ECT treatments were effective in treating acute mania, particularly in mixed or severe mania with unilateral ECT being not being effective at the outset, but nonetheless reducing the total number of bilateral treatments in the long run.

Weaknesses: Study was not completely double blind and the independent video review at start and 8 week showed only one real statistically significant difference between the two groups (the CGI item 1), whereas the raters during the study concluded far more differences.

The selection criteria may have biased against lithium given that pts had to be manic and have had a mood episode within last 2.5 years, though authors note that none of the pts were refractory to lithium as evidenced by the response in the lithium group.

There was a high dropout rate both before (but after randomization) and during the study which limits value of the data obtained.

Another limitation is the concomitant use of neuroleptics which confound the results despite authors claims that their use was not significantly different between the groups.

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