Continuation Pharmacotherapy in the Prevention of Relapse Following Electroconvulsive Therapy - Continuation Pharmacotherapy Following Electroconvulsive Therapy

Written by JAMA

RESULTS

Of the 290 patients who completed the ECT phase, 159 (54.8%) patients were remitters (Table 1 and Figure 1). There was no difference among the sites in remitter rate (^≤222=3.75, P=.15). Immediately following ECT, 17 patients (5.9%) met initial remitter criteria, but not at the 4- to 8-day reassessment. The remitter rate may have been negatively influenced by the stringency of the remission criteria and the fact that 262 patients (90.3%) started with right unilateral ECT, with the minimum dosage only 150% above seizure threshold. Subsequent research has shown that the efficacy of right unilateral ECT improves at a higher dosage relative to seizure threshold.15, 59

Of the 159 remitters, 84 (52.8%) patients entered the randomized continuation trial. Of the 75 remitters who did not participate, 22.7% had medical exclusions for nortriptyline or lithium; 26.7% had travel limitations; and 50.7% preferred treatment by their referring physician, were receiving other medications or ECT, or were unwilling to receive placebo.

Comparisons of remitters who did or did not enter the continuation trial yielded no differences in pre- or post-ECT HRSD, Clinical Global Impression, or Global Assessment Scale scores, number of episodes, duration of current episode, number of ECT treatments, strength of the most potent antidepressant trial during the index episode, sum or average potency of all trials, number of trials, or number of adequate trials. The groups also did not differ in sex, race, history of previous ECT, use of right unilateral or bilateral ECT, or classification of medication resistance. Trial participants were younger (mean [SD], 57.4 [17.2] years) than nonparticipants (64.2 [16.3] years) (t₁₅₇=2.54; P=.01); had more previous psychiatric hospitalizations (2.4 [2.6]) than nonparticipants (1.5 [1.6]) (t₁₅₇=2.82; P=.005); a higher rate of psychotic depression (41.7% vs 16.0%) (^≤2₁=12.54, P <.001); and less total medical burden (Cumulative Illness Rating Scale score, 6.1 [4.2] vs 8.0 [3.9]) (t₁₅₇=2.91; P=.004). The medical exclusions for the continuation trial and travel limitations likely accounted for the higher age and greater medical burden of nonparticipants.

The continuation treatment groups were compared in demographic and clinical features (Table 2). There were no significant differences.

Eleven (13.1%) of the 84 patients dropped out of the trial before completing 24 weeks or meeting relapse criteria. The reasons for noncompletion are described in Figure 1. Dropout rates were evenly distributed among the 3 treatment groups (4 placebo, 2 nortriptyline, and 5 nortriptyline-lithium).

The overall model in the parametric analysis on survival time was significant (likelihood ratio, ^≤2₆=27.3; P<.001) (Table 3). The treatment groups differed markedly (P<.001). Both nortriptyline alone (P=.01) and nortriptyline-lithium (P<.001) were superior to placebo in survival time, and nortriptyline-lithium was superior to nortriptyline alone (P=.04).

The Kaplan-Meier survival function was computed for each treatment group (Figure 2). Across the sample, 45 (61.6%) of 73 completers relapsed. This confirmatory nonparametric analysis yielded a log-rank ^≤2₂ of 9.12 (P=.01). The relapse rates for completers were 84.0% (21/25) for placebo (95% confidence interval [CI], 70%-99%); 60.0% (15/25) for nortriptyline (95% CI, 41%-79%); and 39.1% (9/23) for nortriptyline-lithium (95% CI, 19%-59%). Only 1 patient relapsed while taking nortriptyline-lithium after 5 weeks, while relapse steadily continued with placebo and nortriptyline throughout the 24-week trial (Figure 2). Nonparametric survival analyses comparing each active treatment condition with placebo yielded a significant effect for nortriptyline-lithium (^≤2₁=8.52; P=.004), but only a trend for nortriptyline (^≤2₁=3.33; P=.07).

The parametric survival analysis indicated that across the treatment conditions, medication-resistant nonpsychotic patients had a higher relapse rate than patients with psychotic depression. The relapse rates were 50.0% for psychotic patients (n=28), 55.6% for nonpsychotic patients without medication resistance (n=9), and 72.2% for nonpsychotic medication-resistant patients (n=36). The significant effect of sex was due to a higher relapse rate among women (77.8%) than men (53.6%). Patients who relapsed had higher mean (SD) HRSD scores at trial entry (6.0 [3.1]) than patients who did not relapse (5.0 [2.8]). There were no additional significant effects in the parametric survival analysis when treatment with right unilateral, right unilateral and bilateral, or bilateral ECT (P=.89), and number of ECT treatments (P=.96) were entered as additional terms.

Study site (WPIC vs combined Carrier Foundation and University of Iowa) was entered as a term in both the parametric and nonparametric survival analyses. There were no site effects. The relapse rates at WPIC for placebo, nortriptyline, and nortriptyline-lithium were 88.9%, 60.0%, and 41.2%, respectively, and for the combined Carrier Foundation and University of Iowa they were 71.4%, 60.0%, and 33.3%, respectively.

The high rate of relapse across the treatments could have been due to excessively sensitive relapse criteria. Clinical ratings at continuation trial entry and end point were compared as a function of relapse status. Relapsed patients showed marked symptomatic worsening. Fifteen (33%) of the 45 relapsed patients were hospitalized and received ECT, 6 patients (13%) received outpatient ECT, and all other relapsed patients (53%) were switched to other pharmacotherapies. The severity of relapse did not differ among the continuation treatments.

No effects approached significance in the analyses of variances of nortriptyline and lithium levels on final visit. At final visit, the mean (SD) nortriptyline level was 89.9 (38.2) ng/mL for the nortriptyline group, 89.2 (32.2) ng/mL for the nortriptyline-lithium group, and the simulated levels reported for the placebo group averaged 93.0 (27.5) ng/mL. For lithium, the levels were 0.59 (0.2) mEq/L for the nortriptyline-lithium group, with simulated levels of 0.54 (0.2) mEq/L and 0.62 (0.2) mEq/L for the nortriptyline and placebo groups, respectively. Relapse was not associated with nortriptyline or lithium plasma levels.