Major Studies on ECT for Depression: What Have We Learned?

October 1, 2007
Max Fink, MD

Volume 24, Issue 12

Early relapse is a limiting defect in electroconvulsive therapy (ECT). Although more than 80% of patients with a severe depressive illness who complete an acute course of ECT are relieved within three weeks, up to 60% relapse within six months, despite continuation treatments with antidepressant medications.1,2 In a large, government-supported, collaborative study led by the Columbia University Consortium (CUC), patients with unipolar major depression that had failed to respond to multiple trials of medications were treated with ECT to clinical remission and then randomly assigned to one of three continuation treatments--placebo, nortriptyline (Aventyl, Pamelor) alone, or the combination of nortriptyline and lithium (Eskalith, Lithobid). The patients were monitored for adequacy of blood levels.1 Within the six-month follow-up period, 84% of patients treated with placebo, 60% of patients treated with nortriptyline, and 39% of patients treated with the combination medications had relapsed.

These findings were verified in the multisite Consortium for Research in ECT (CORE) collaborative study that used the same populations with the same inclusion and exclusion criteria, evaluations, and time periods as the CUC study.2-8 After remission, the patients were randomly assigned to continuation treatment with the same combination of lithium and nortriptyline or with ECT. The six-month relapse rates for the two treatments were not statistically different from that of the lithium and nortriptyline combination in the CUC study.2

The benefit exhibited with continuation ECT confirms the experience of clinical practice. While medications are easier to administer and are preferred by both patients and practitioners, the efficacy of continuation ECT supports its use in patients who relapse despite the prescription of medications and in those who may not tolerate medications' adverse effects.

Populations and treatments

The studies differed in treatment strategies. In the CORE study, seizures were induced with bitemporal electrode placement (BT) at 50% above a measured seizure threshold (ST). In the CUC study, electrode placement was right unilateral (RUL), with dosages 150% above the ST.

The CUC collaboration enrolled 349 patients and the CORE enrolled 531 patients with severe depression. Clinical characteristics were comparable, with mean ages ranging from 55 to 59 years; 70% were female and the mean pretreatment Hamilton Rating Scale for Depression (HAM-D) scores were 34 (± 7). At treatment end point (remission), HAM-D scores were between 5 and 6 (± 3) in both studies. The episode duration at the time of referral was from 24 to 31 weeks in the CUC study and from 45 to 49 weeks in the CORE study.

ECT efficacy

ECT was effective in both studies. Remission-defined as greater than 60% reduction in HAM-D scores and final scores less than 10-was 87% in CORE and 55% in CUC completers. These rates compared favorably with the 30% remission rate in patients taking citalopram (Celexa), and the 18%, 21%, and 25% reduction rates in patients tak- ing bupropion (Wellbutrin), sertraline (Zoloft), and venlafaxine (Effexor), respectively, in the STAR*D study of patients with nonpsychotic major depression that was diagnosed using DSM-IV criteria.9

The difference in remission rates between the CUC and CORE studies is best ascribed to the technical differences in electrode placement and energy dosing. When the CUC study was designed, RUL electrode placement with energy dosing set at 150% above the calibrated ST was considered effective. These settings were used as the primary treatment in more than 90% of CUC study patients. Recent studies found that stimulating energies must be increased considerably in RUL placements, to at least 500% above the calibrated ST, to match the efficacy of BT electrode placement.10,11 The difference in efficacy is also noted in the number of treatments needed to achieve remission. In the CUC study, the patients received a mean number of 10.2 to 10.8 treatments; of these, 6.6 to 7.7 were RUL treatments. In the CORE study, the mean number of treatments to remission was 7.2 to 7.5-a significant savings in time and cost of an average of three treatments.

Clinical lesson: psychosis

In the data analyses, the populations were stratified by the presence of psychosis.2 Slightly more than one third of the patients were considered to have psychosis as well as depression. In the CORE study, remissions appeared earlier and were more robust-95% of the patients who had psychosis and depression remitted compared with 83% of patients who had nonpsychotic depression (Figure 1).

In the literature on psychotic depression, the efficacy of antidepressants alone is estimated at 30%, antipsychotics alone at 50%, and the combination of two agents at 70%.12 The response to ECT is sufficiently greater than that of medications for clinicians to recommend its use as a primary treatment in preference to repeated trials with medications. Such primary use ensures early relief of mood, thought, vegetative signs, and suicide risk.

Clinical lesson: suicide risk

Suicide is common in persons with depressive mood disorders. The risk is reduced with lithium treatment and with ECT.12 In the CORE study, 29.5% of the patients expressed suicidal thoughts or reported suicidal acts at baseline.4 The HAM-D scores for suicidal intent were reduced to zero in 38% of the patients after one week of treatment, in 61% after two weeks, and in 81% at the end of the course (Figure 2). These findings are supported by comparable CUC data.13

Clinical lesson: "treatment resistance" no bar

The failure of a depressive illness to respond to antidepressant treatments estimated to have been prescribed at adequate dosages for adequate treatment periods has been labeled "treatment resistance." To define treatment adequacy, scientists at Columbia University developed an antidepressant treatment history form (ATHF).14

In patients treated with ECT, they concluded that those whose depressive illness had failed to respond to adequate pre-ECT pharmacotherapy were substantially less likely to respond to ECT than patients who had not received adequate therapy.15 In the CORE study, the adequacy of prior treatment bore no relation to treatment efficacy, a finding that is confirmed in other studies.8

Using ATHF evaluations, only 2 of 52 patients with psychosis and depression (4%) in the CUC study and only 5 of 106 patients (5%) in the CORE study had received adequate trials of antidepressant and antipsychotic medications before referral for ECT.6,16 It is not clear whether the clinicians in these leading academic medical centers failed to identify the psychotic form of the depressive illness or had failed to apply adequate treatment algorithms. The identification of psychosis in patients with depression is difficult and is essential in ensuring adequate treatment.

Confirming the literature: role of age

Experienced clinicians find that older patients with depression exhibit better clinical outcomes than younger patients when treated using ECT. In the CORE study, dividing the sample by age into 18 to 45, 46 to 64, and 65 to 85 years supported this result. While 53% of the patients aged 18 to 45 years remitted, approximately 89% did so in the two older-aged samples.5

Lessons

What do these studies teach and confirm? ECT, when optimally induced, is an effective treatment for patients with the most severe forms of depressive illness, regardless of the adequacy or inadequacy of their previous medication treatments. There is no difference in response rates to ECT in patients who are deemed medication resistant-that is, patients whose depression has failed to respond to adequate trials of antidepressant treatments-when they are adequately treated.

Apparently, severely depressed patients with psychosis are often inadequately treated before referral for ECT. The primary use of ECT in these patients is to be encouraged, since it ensures effective relief of depressed mood, vegetative features, psychosis, and suicide risk in the shortest time.

Preoccupation with suicide is a principal risk in psychiatric patients. When symptoms are recognizable, such as when patients are restricted to continuous observation or when they are readmitted after multiple suicide attempts, ECT is a very effective intervention that should be considered early.

Rapid relapse is a principal risk after a course of ECT. Major depression and bipolar mood disorders are chronic illnesses. At best, clinicians relieve the overt syndrome temporarily. Few clinicians expect medications to relieve a severe mood disorder in one or a few months. Common practice is to prescribe medications for months and even years. In ECT practice, the stigma and the complexities of the treatment encourage clinicians to prescribe a fixed, limited number of treatments and to specify lesser effective forms of the procedure (asking for RUL ECT), and continue treatment with medications that had already been tried and failed. Such practices do not serve patients well. Relapse rates after successful ECT are reduced by either the combination of lithium and nortriptyline or by continuation ECT. Prescribing a single tricyclic antidepressant as continuation treatment offers only a slightly greater benefit than placebo.

The benefits of continuation ECT are well sustained, even when prescribed in the rigid schedule selected in the CORE study-once weekly for four treatments, once biweekly for four treatments, and monthly thereafter. This rigid ECT continuation treatment schedule was selected to ensure equivalent dosing across treatment sites, even though the scientists knew that clinical practice encouraged treating patients as soon as symptoms surfaced. A flexible treatment schedule that offers treatments as needed minimizes relapse rates.

We have little information for continuation treatment after ECT with SSRIs, serotonin-norepinephrine reuptake inhibitors, or atypical neuroleptic medications. A single report found that remission rates after ECT were reduced to 10% with paroxetine (Paxil), to 30% with imipramine (Tofranil), and to 65% with placebo.17 This unusual finding for paroxetine has not been confirmed. The best evidence is for the combination of lithium and nortriptyline, both monitored with serum blood levels. However, even this strategy is unsatisfactory. It is a difficult and expensive prescription to manage well, but it is the preferred medication when continuation ECT is not available or is refused.

Some clinicians argue for the preferential use of RUL electrode placement and dosing according to measured seizure threshold estimates. The lower efficacy with unilateral ECT when dosing is less than 500% above the seizure threshold-levels at which the cognitive effects are indistinguishable from bitemporal electrode placement-argues against the use of this electrode placement in standard clinical practice.10 ST calibration for energy dosing is a prerequisite in applying RUL electrode placement, ensuring that the first treatment is clinically ineffective, and increasing the number of treatments for remission.1,11 The alternative of bilateral electrode placement and half-age dosing estimates, monitored by EEG adequacy, ensures greater efficacy for the first treatment and overall with fewer treatments.18 Modern ECT devices are calibrated in percent of total energy. As the seizure threshold rises with age, a simple formula selecting the percent energy as half the patient's age delivers effective first treatments. Adjustments in dosing are made on the basis of the duration and quality of the seizure electroencephalogram.19

We need more rigorous systematic assessments of other continuation treatment strategies after successful ECT, especially antidepressant, atypical anti- psychotic, and mood-stabilizing agents that are widely prescribed. For the present, continuation ECT offered on a symptom-relief basis is an effective, albeit difficult, way to sustain the benefits of successful ECT.

References:

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