Continuation Pharmacotherapy in the Prevention of Relapse Following Electroconvulsive Therapy

A Randomized Controlled Trial

Harold A. Sackeim, PhD; Roger F. Haskett, MD; Benoit H. Mulsant, MD; Michael E. Thase, MD; J. John Mann, MD; Helen M. Pettinati, PhD; Robert M. Greenberg, MD; Raymond R. Crowe, MD; Thomas B. Cooper, MA; Joan Prudic, MD

Context Electroconvulsive therapy (ECT) is highly effective for treatment of major depression, but naturalistic studies show a high rate of relapse after discontinuation of ECT.

Objective To determine the efficacy of continuation pharmacotherapy with nortriptyline hydrochloride or combination nortriptyline and lithium carbonate in preventing post-ECT relapse.

Design Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1998, stratified by medication resistance or presence of psychotic depression in the index episode.

Setting Two university-based hospitals and 1 private psychiatric hospital.

Patients Of 290 patients with unipolar major depression recruited through clinical referral who completed an open ECT treatment phase, 159 patients met remitter criteria; 84 remitting patients were eligible and agreed to participate in the continuation study.

Interventions Patients were randomly assigned to receive continuation treatment for 24 weeks with placebo (n=29), nortriptyline (target steady-state level, 75-125 ng/mL) (n=27), or combination nortriptyline and lithium (target steady-state level, 0.5-0.9 mEq/L) (n=28).

Main Outcome Measure Relapse of major depressive episode, compared among the 3 continuation groups.

Results Nortriptyline-lithium combination therapy had a marked advantage in time to relapse, superior to both placebo and nortriptyline alone. Over the 24-week trial, the relapse rate for placebo was 84% (95% confidence interval [CI], 70%-99%); for nortriptyline, 60% (95% CI, 41%-79%); and for nortriptyline-lithium, 39% (95% CI, 19%-59%). All but 1 instance of relapse with nortriptyline-lithium occurred within 5 weeks of ECT termination, while relapse continued throughout treatment with placebo or nortriptyline alone. Medication-resistant patients, female patients, and those with more severe depressive symptoms following ECT had more rapid relapse.

Conclusions Our study indicates that without active treatment, virtually all remitted patients relapse within 6 months of stopping ECT. Monotherapy with nortriptyline has limited efficacy. The combination of nortriptyline and lithium is more effective, but the relapse rate is still high, particularly during the first month of continuation therapy.

JAMA. 2001;285:1299-1307

Electroconvulsive therapy (ECT) is usually administered to patients with severe and medication-resistant major depression.¹ The number of ECT procedures performed in the United States exceeds coronary bypass, appendectomy, or hernia repair.² While the response rate to ECT in major depression is high, ^{1, 3} relapse is a key problem.4 Naturalistic studies show that the relapse rate during the 6 to 12 months following ECT exceeds 50%.^5-15

Electroconvulsive therapy is the only somatic treatment in psychiatry that is typically discontinued following response, yet patients untreated following ECT response have high rates of relapse.^16-1916-18 Post-ECT monotherapy with antidepressant medication is now standard.^{9, 20-23} However, the evidence supporting this practice is flawed, and the recent naturalistic studies document high relapse rates. Studies in the 1960s suggested that continuation therapy with a tricyclic antidepressant (TCA) or monoamine oxidase inhibitor markedly reduced the 6-month post-ECT relapse rate.

Post-ECT continuation pharmacotherapy has been based on 3 studies conducted in the 1960s.^16-184, ²⁴ At that time, ECT was a treatment of first choice^{.25, 26} Relevance for continuation therapy in medication-resistant ECT responders is uncertain. Second, some patients likely benefited from the concurrent antidepressant during ECT, and continued to benefit from the medication as continuation therapy. Since use of ECT now centers on medication-resistant patients^{,1, 21, 27} the relevance of this early research is questionable. A primary goal of those studies was to determine whether concurrent treatment with TCAs or monoamine oxidase inhibitors reduced the number of ECT treatments needed. Following ECT, patients continued taking active medication or placebo or no subsequent treatment. Using 6-month follow-up periods, the findings were consistent. Patients who received a TCA or monoamine oxidase inhibitor during and following ECT had a relapse rate of approximately 20%, compared with 50% in the control groups. There are major concerns about this research.

We conducted a randomized, double-blind, placebo-controlled trial of continuation pharmacotherapy following ECT response. The treatments were a TCA (nortriptyline hydrochloride), combination treatment with nortriptyline and lithium carbonate, or placebo. A placebo-controlled trial following ECT had never been conducted in the United States. This trial was justified since the relapse rates in recent follow-up studies^5-15 often exceeded those seen with placebo in the controlled investigations from an earlier era.^16-18 A placebo-controlled trial was also justified by our hypothesis that TCA monotherapy, the best documented treatment in post-ECT relapse prevention,^16-18 has limited efficacy. Monotherapy with nortriptyline was tested since (1) early research suggested that TCA continuation therapy was effective in relapse prevention ^16-18; (2) concern that newer agents, such as selective serotonin reuptake inhibitors (SSRIs), may be less effective than TCAs in treatment of the severe episodes characteristic of ECT patients28-33; and (3) given the widespread use of SSRIs and other newer agents as first-line treatments, a low probability that ECT responders would have received an adequate TCA trial during the episode.34 We hypothesized, however, that the nortriptyline-lithium combination would be most efficacious, given the evidence that combined TCA-lithium treatment is particularly effective in medication-resistant major depression,35-41 and the supposition that regimens effective in the acute treatment of medication-resistant major depression exert protective effects as continuation treatment. Nortriptyline-lithium was also selected since few ECT remitters would have received this treatment during the episode.^{34, 42}

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