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Medication was administered in sealed capsules containing 25 mg of nortriptyline, 300 mg of lithium, or microcrystalline cellulose (placebo). The capsules containing nortriptyline or lithium were distinct in appearance, and each was matched with placebo capsules identical in size, weight, appearance, and taste. Each patient was given 2 sets of pills. On the first study day, 50 mg of nortriptyline or its placebo and 600 mg of lithium or its placebo were administered. Blood samples were obtained 24 hours later and estimates were determined for the oral dose needed to produce steady-state levels of 100 ng/mL of nortriptyline and 0.7 mEq/L of lithium.52-54 On days 3 and 4, depending on the estimate, oral doses were adjusted and maintained until plasma levels were again taken on days 9 through 11. The goal was to maintain nortriptyline levels between 75 and 125 ng/mL and lithium levels between 0.5 and 0.9 mEq/L. During the 24-week trial, plasma levels were determined on 10 occasions. A yoked-control procedure was used, with a psychiatrist at NYSPI reporting simulated nortriptyline and lithium values for patients receiving placebo, based on matching by sex, age, and weight with patients who were receiving active medication.
Patients were evaluated at weekly intervals for the first 4 weeks, at 2-week intervals for the next 8 weeks, and at 4-week intervals for the remaining 12 weeks. They were contacted by telephone at weekly intervals between visits. Clinical ratings during the continuation phase were obtained by the same blinded evaluator (continuous rater) who evaluated patients throughout the ECT course. During the continuation trial, a blinded study psychiatrist assessed adverse effects and vital signs, adjusted medication or placebo dosage (based on plasma levels reported by NYSPI and adverse effects), and completed clinical ratings. To evaluate the adequacy of the blinding, patients guessed their treatment assignment as placebo, nortriptyline, or nortriptyline-lithium at study exit. Patients who dropped out of the study or relapsed were offered clinical care by a psychiatrist at the research site not affiliated with the study or the follow-up evaluation of the particular patient.
Time to relapse was the main outcome measure. The criteria for relapse were a mean HRSD score (continuous rater and study psychiatrist) of at least 16 that was maintained for at least 1 week (over 2 consecutive visits) and a mean absolute increase of at least 10 points at 2 consecutive visits relative to continuation trial baseline. These criteria reflected a clinical worsening for which most clinicians would abandon the current treatment in favor of an alternative.
At the pre-ECT evaluation, a research nurse completed ratings on the Cumulative Illness Rating Scale55 to assess medical comorbidity. At all major time points (pre-ECT, post-ECT, start of continuation trial [day 0], week 12, week 24, and relapse), the HRSD, Clinical Global Impression,56 and Global Assessment Scale43 scores were completed by the continuous rater and the study psychiatrist. At each site, intraclass correlation coefficients for the 2 raters exceeded 0.97, 0.93, and 0.90 for HRSD, Clinical Global Impression, and Global Assessment Scale scores, respectively. A site-independent, time-blind clinician at NYSPI rated 239 videotapes of continuous rater interviews conducted at random intervals during the ECT and continuation phases. The intraclass correlation coefficients were 0.97, 0.96, and 0.95 for HRSD, Clinical Global Impression, and Global Assessment Scale scores, respectively. The HRSD, Clinical Global Impression, and Global Assessment Scale scores reported below are the continuous rater evaluations.
At each visit in the continuation phase, a blinded study psychiatrist completed the Treatment Emergent Symptom Scale.56 Forty-eight possible adverse effects were rated for severity, relationship to study medication, and action taken. Clinically significant adverse effects were defined as those rated as moderate in severity, possibly related to study medication, and, at minimum, those requiring increased surveillance.
Statistical Methods
Patients who met remitter criteria following ECT and who did or did not participate in the continuation trial were compared in demographic, clinical, and previous treatment features with t tests for continuous measures and  2 analyses for dichotomous variables. The randomized continuation pharmacotherapy groups were compared on baseline variables using analyses of variance or 2 analyses.
The primary analysis of the continuation trial used survival analysis for right-censored failure-time data. A simultaneous regression model was fit to the relapse-time data using the Weibull distribution.10, 15 Covariates in the regression model were the randomized treatment condition (3 levels), strata (3 levels), sex, and HRSD score at the start of the trial. In a secondary analysis, ECT treatment modality (right unilateral only vs right unilateral and bilateral ECT vs bilateral ECT only) and number of ECT treatments were added as additional covariates. To confirm the findings from the parametric analysis regarding treatment group differences, nonparametric estimates of the survival distribution function for each group were computed, using the Kaplan-Meier method57 and contrasted with the log-rank test (Mantel-Cox).58
Early in the study, 1 site (Carrier Foundation) was closed when the hospital discontinued its research division, so another site (University of Iowa) was added late. These 2 sites entered 21 patients in the continuation trial compared with 63 patients at WPIC. To determine whether the effects were not unique to WPIC, the Carrier Foundation and the University of Iowa were pooled for analysis. A site term (WPIC vs Carrier Foundation and University of Iowa) was entered into both secondary parametric and nonparametric survival analyses.
To assess the adequacy of pharmacotherapy, separate analyses of variances were conducted on the last plasma levels for nortriptyline and lithium obtained in completers (24-week or time of relapse), using the assayed values for active medication and the simulated values for placebo, and treatment group (3 levels) and relapse status as between-subject factors. A logistic regression was conducted on the patients' guess of treatment condition with relapse status and actual treatment assignment as predictors.
References
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