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Double-Blind Switch Study of Imipramine Or Sertraline Treatment of Antidepressant-Resistant Chronic Depression

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Double-Blind Switch Study of Imipramine Or Sertraline Treatment of Antidepressant-Resistant Chronic Depression ORIGINAL ARTICLE Double-blind Switch Study of Imipramine or Sertraline Treatment of Antidepressant-Resistant Chronic Depression Michael E. Thase, MD; A. John Rush, MD; Robert H. Howland, MD; Susan G. Kornstein, MD; James H. Kocsis, MD; Alan J. Gelenberg, MD; Alan F. Schatzberg, MD; Lorrin M. Koran, MD; Martin B. Keller, MD; James M. Russell, MD; Robert M. A. Hirschfeld, MD; Lisa M. LaVange, PhD; Daniel N. Klein, PhD; Jan Fawcett, MD; Wilma Harrison, MD Background: Although various strategies have been pro- verse effects. Although sertraline treatment also re- posed to treat antidepressant nonresponders, little con- sulted in significantly higher response rates in the intent- trolled research has been published that examines pro- to-treat samples (60% in the sertraline group and 44% spectively the use of switching to an alternate antidepressant. in the imipramine group), neither the intent-to-treat re- mission rates nor the response and remission rates among Methods: This was a multisite study in which outpa- study completers differed significantly. Moreover, after tients with chronic major depression (with or without considering the effect of attrition, there were no signifi- concurrent dysthymia), who failed to respond to 12 weeks cant treatment effects on the more comprehensive gen- of double-blind treatment with either sertraline hydro- eralized estimating equation analyses of the continuous chloride (n=117) or imipramine hydrochloride (n=51), dependent measures. were crossed over or switched to 12 additional weeks of double-blind treatment with the alternate medication. Conclusions: More than 50% of chronically depressed Outcome measures included the 24-item Hamilton Rat- antidepressant nonresponders benefited from a switch ing Scale for Depression and the Clinical Global Impres- from imipramine to sertraline, or vice versa, despite a high sions–Severity and Improvement scales. degree of chronicity. As in the initial trial, sertraline was generally better tolerated than imipramine. Switching to Results: The switch from sertraline to imipramine (mean a standard antidepressant of a different class is a useful dosage, 221 mg/d) and from imipramine to sertraline treatment strategy for antidepressant nonresponders and (mean dosage, 163 mg/d) resulted in clinically and sta- could be considered a standard of comparison for fu- tistically significant improvements. The switch to ser- ture studies of novel alternate strategies. traline treatment was associated with fewer adverse effect complaints and significantly less attrition owing to ad- Arch Gen Psychiatry. 2002;59:233-239 T LEAST 40% of patients is important to document the efficacy of each treatedfordepressiondonot medicationclass,insequence,whentheother respond to the initial trial of has failed. antidepressant medication.1 Despite the public health importance ThaseandRush2,3 character- of antidepressant nonresponse, surpris- Aized this as stage I antidepressant resistance, ingly few switch studies2,3 have been con- the first of a sequence of 5 stages defined by ducted. Only a handful have confirmed pro- treatment history. Numerous treatment op- spectively the adequacy of the ineffective tions are available for such individuals, in- medication trial or have used controlled, cluding switching between or within classes double-blind methods. We report herein the of medications, as well as various augmen- results of a large, double-blind study of pa- tation strategies. In fact, the major issue fac- tients with chronic forms of major depres- ing clinicians is trying to decide which “next sion who, after failing to respond to 12 step” strategy to choose.3,4 Some clinicians weeks of double-blind treatment with ser- favoraugmentationstrategiesbecauseofease traline hydrochloride or imipramine hy- ofimplementation(eg,notaperingisneeded), drochloride, were crossed over or switched whereas others view switching to a different to the alternate compound. antidepressant, especially one from a differ- 3 ent class, as a more prudent option. In an RESULTS era in which selective serotonin reuptake in- Author affiliations are listed hibitors and tricyclic antidepressants are the Of the 207 nonresponders who com- at the end of this article. most widely prescribed antidepressants,5-7 it pleted the acute-phase trial, 168 (81%) be- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 59, MAR 2002 WWW.ARCHGENPSYCHIATRY.COM 233 ©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 SUBJECTS AND METHODS INITIAL TREATMENT TRIAL After providing written informed consent, a complete medi- SUBJECTS cal history, physical examination, electrocardiography, and laboratory screening battery were completed to confirm This protocol was part of a multiphase, collaborative re- medical eligibility. Patients began a 1-week, single-blind search program studying chronic depressive disorders. A placebo lead-in, during which the only psychotropic medi- full description of the study design, rationale, and meth- cations permitted were chloral hydrate or temazepam, used ods has been previously published.8 Briefly, outpatients aged sparingly for severe insomnia. Patients whose Clinical Global 21 to 65 years were eligible to enroll at 1 of 12 centers if Impressions–Improvement (CGI-I)14 score was 3 or higher they met DSM-III-R criteria for chronic major depressive and whose score on the 24-item Hamilton Rating Scale for disorder (ie, current major depressive episode of Ն2 years Depression (HAM-D)15 was 18 or higher at the end of the in duration) or “double depression” (ie, a current major lead-in period were randomized to double-blind treat- depressive episode superimposed on an antecedent dys- ment with either sertraline (n=426) or imipramine (n=209). thymic disorder). The findings of the main study9-11 have This 2:1 proportion was used because responders to ser- been described elsewhere. traline, but not imipramine, could subsequently partici- Intake diagnoses were based on interviews using pate in a placebo-controlled maintenance-phase trial.11 the Structured Clinical Interview for DSM-III-R12 and All patients were seen initially for 6 weekly visits, Structured Clinicial Interview for DSM-III-R Personality followed by visits every other week for the balance of the Disorders.13 Patients were excluded if they had organic 12-week trial. Imipramine was started at 50 mg/d and ti- mental syndromes, bipolar disorder or cyclothymia, trated by 50 mg/d per week, as tolerated, up to a maxi- schizophrenia or other psychotic disorder, obsessive mum of 300 mg/d. Sertraline was also initiated at 50 mg/d, compulsive disorder, or schizotypal, antisocial, or severe but a dosage increase was not permitted until the end of borderline personality disorder. Those with principal week 3. Thereafter, weekly increases of 50 mg/d were pos- current diagnoses of panic, generalized anxiety, or post- sible, if indicated and tolerated, up to a maximum of 200 traumatic stress disorders were also excluded. Patients mg/d. Therefore, maximum dosages of either study drug were not eligible if they had abused alcohol or other could be reached by week 6. Patients who could not tol- drugs within 6 months or had experienced bulimia or erate at least 50 mg/d of either study medication were with- anorexia nervosa within 1 year of intake. Patients con- drawn from the trial. Mean±SD dosages of 141±59 mg/d sidered to be an immediate suicide risk, to have medical of sertraline and 200±82 mg/d of imipramine were achieved contraindications to antidepressant therapy, or to have at the end point of the initial acute-phase trial. significant, unstable general medical disorders were also excluded. Patients who had not responded previously to ASSESSMENT OF RESPONSE minimally adequate trials of sertraline or imipramine (ie, at least 4 weeks of Ն50 mg of sertraline or Ն150 mg of Vital signs and adverse events (volunteered or observed) were imipramine daily) were ineligible. Patients could not assessed at each visit. The principal dependent measures, the have been treated with anxiolytic or other antidepressant CGI-I (Improvement) and the 24-item HAM-D, were obtained medication within 2 weeks, monoamine oxidase inhibi- at each visit. Secondary measures included the CGI-S (Sever- tors within 3 weeks, fluoxetine hydrochloride within 1 ity), Montgomery-A˚ sberg Depression Rating Scale,16 Cornell month, electroconvulsive therapy within 3 months, or Dysthymia Scale,17 and self-report 21-item Beck Depression depot neuroleptics within 6 months. Psychotherapy was Inventory.18 All clinical ratings were completed by a blinded, permitted during the study only if it had been ongoing independent evaluator. A satisfactory therapeutic response for at least 3 months before intake. (hereafter referred to as response) was noted if the final CGI-I gan the alternate antidepressant. There were no signifi- and sertraline received at the end point of the second trial cant differences in sociodemographic or clinical measures were 221±84 mg/d and 163±48 mg/d, respectively. between those who did or did not participate in the sec- ond treatment trial. Reasons for not enrolling in the switch ATTRITION AND TOLERABILITY phase were not recorded systematically. However, sev- eral patients improved significantly during the washout Thirty-four patients dropped out, including 10% (5/51) period, and 1 patient experienced a significant clinical of those switched to sertraline treatment and 25% worsening necessitating emergency hospitalization. (29/117) of those switched
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