Pilot Trial

The initial study was an open-label pilot trial of imipramine in a consecutive series of depressed methadone patients (Nunes et al. 1991) at a university-affiliated, community-based methadone clinic (site 1). Depression was diagnosed only if the patient met criteria for current DSM-III-R major depression or dysthymia that was either primary, had persisted during a past abstinence, or was at least of 6 months’ duration in the current episode. Diagnosis was made through clinical history by experienced research psychiatrists. Twenty-four patients (10 men, 14 women) entered and 17 (7 men, 10 women) completed a minimum adequate trial of at least 6 weeks of imipramine at doses ranging from 100 to 300 mg/day (median: 250 mg/day). Of the 17 completers, 16 were using illicit drugs at baseline, 9 of 17 intravenously, and one was abstinent but experiencing strong drug cravings. Baseline Hamilton Depression (HAM-D) Scale scores ranged from moderate to severe, with a mean of 17+4. Nine patients (53 percent) were judged "responders," with marked reductions in both depression (mean posttreatment HAM-D 2+1) and illicit drug use. All patients gave weekly urines. For each patient, the percentage of urines positive for any drug, using a mirror image historical control (i.e., 6 months prior to initiation of the imipramine trial), was compared to the proportion of positive urines in a followup period of up to 11 months during which patients were maintained on imipramine. Among responders the percentage of positive urines was 54+26 at pretreatment, which dropped to 15+17 during treatment. The nine responders in the open trial were offered continuing psychiatric treatment at the methadone clinic. Chart review of their treatment course over 4 years of followup (Nunes et al., in press) showed that depression remained improved during imipramine treatment, but relapses often occurred during attempts to taper the medication. This finding suggests that imipramine exerted a continuing antidepressant effect, although drug use recurred intermittently for several patients despite ongoing imipramine treatment, and suggests a less robust effect of the antidepressant on drug abuse. Double-Blind, Placebo-Controlled Trial

Because the uncontrolled trial suggested that antidepressant treatment had a substantial effect on both mood and drug use in carefully selected, depressed methadone patients, the authors conducted a larger, placebo- controlled imipramine trial. Following is a preliminary analysis of outcome for the first 80 patients to complete the study. Sample and Methods. The design was a prospective, parallel groups,

randomized, placebo-controlled trial of imipramine in methadone patients with current depression who met lifetime historical criteria similar to those described for the open-label trial. Because of the high placebo response rates experienced in other trials, patients were required to have been in methadone treatment for at least 1 month preceding study onset in order to be included, which was a further effort to exclude transient mood syndromes. The trial was conducted at the same site as the open-label trial, as well as at a second universityaffiliated, community-based methadone clinic. Global Outcome. The primary outcome measure, defined a priori, was

a dichotomous response criterion requiring both a rating of at least much improved on the Clinician's Global Impression scale score for depression and at least a 75 percent reduction in self-reported drug use or of abstinence. Twenty-four of 40 (60 percent) of completers on imipramine were responders, compared to 3 of 40 (8 percent) on placebo (02 = 24.3, 1 df, p < 0.0001). The imipramine-placebo difference was equally robust among men, women, whites, and minorities and was similarly unaffected by clinic site or type of depression (major versus nonmajor depression, or primary versus nonprimary depression). Thus, imipramine continued to be effective, and low placebo response rate suggests that the diagnostic approach succeeded in excluded patients with transient, self-limited mood disturbances. Continuous Outcome Measures. Preliminary analysis of continuous

outcome measures reveals a mixed picture. There is a robust difference between imipramine (7.3+6.6) and placebo (13.5+6.3) on the post- treatment HAM-D Scale total score (effect size = 0.96) (F = 23.3, 75 df, p < 0.001). For self-reported days of use per week of each patient's most frequently abused drug, the difference between imipramine (1.6+2.1) and placebo (3.3+3.2) (effect size = 0.64), (F = 5.38, 76 df, p < 0.03), is less robust, although still significant. F tests reported are for main effect of medication, in an analysis of covariance (ANCOVA) with the baseline level of the dependent measure entered as a covariate. For each patient, the proportion of urines negative for all drugs (by EMIT assay) during the last 4 weeks of the study was calculated and treated as a continuous measure. There was no difference between imipramine (0.47+0.41) and placebo (0.44 + 0.41) in the proportion of drug-negative urines. This preliminary analysis suggests that imipramine exerts a strong antidepressant effect in carefully selected methadone patients, but that its effect on illicit drug use is less robust, being manifest in self-report, but not in the urine-based measure. Replication is indicated with quantitative urinalysis, which might provide an objective measure of reduced drug use short of abstinence.