ORIGINAL ARTICLE A Double-blind Randomized Controlled Trial of Olanzapine Plus Sertraline vs Olanzapine Plus Placebo for Psychotic Depression The Study of Pharmacotherapy of Psychotic Depression (STOP-PD) Barnett S. Meyers, MD; Alastair J. Flint, MD; Anthony J. Rothschild, MD; Benoit H. Mulsant, MD; Ellen M. Whyte, MD; Catherine Peasley-Miklus, PhD; Eros Papademetriou, MA; Andrew C. Leon, PhD; Moonseong Heo, PhD; for the STOP-PD Group Context: Evidence for the efficacy of combination phar- Results: Treatment with olanzapine/sertraline was as- macotherapy has been limited and without positive trials sociated with higher remission rates during the trial than in geriatric patients with major depression (MD) with psy- olanzapine/placebo (odds ratio [OR], 1.28; 95% confi- chotic features. dence interval [CI], 1.12-1.47; PϽ.001); 41.9% of sub- jects who underwent combination therapy were in re- Objectives: To compare remission rates of MD with psy- mission at their last assessment compared with 23.9% of ␹2 chotic features in those treated with a combination of subjects treated with monotherapy ( 1=9.53, P=.002). atypical antipsychotic medication plus a serotonin reup- Combination therapy was comparably superior in both take inhibitor with those treated with antipsychotic mono- younger (OR, 1.25; 95% CI, 1.05-1.50; P=.02) and older therapy; and to compare response by age. (OR, 1.34; 95% CI, 1.09-1.66; P=.01) adults. Overall, tol- erability was comparable across age groups. Both age Design: Twelve-week, double-blind, randomized, con- groups had significant increases in cholesterol and tri- trolled trial. glyceride concentrations, but statistically significant in- creases in glucose occurred only in younger adults. Setting: Clinical services of 4 academic sites. Younger adults gained significantly more weight than older subjects (mean [SD], 6.5 [6.6] kg vs 3.3 [4.9] kg, Patients: Two hundred fifty-nine subjects with MD with P=.001). psychotic features randomized by age (Ͻ60 or Ն60 years) (mean [standard deviation (SD)], 41.3 [10.8] years in 117 Conclusions: Combination pharmacotherapy is effica- younger adults vs 71.7 [7.8] years in 142 geriatric par- cious for the treatment of MD with psychotic features. ticipants). Future research must determine the benefits vs risks of continuing atypical antipsychotic medications beyond 12 Intervention: Target doses of 15 to 20 mg of olanza- weeks. pine per day plus masked sertraline or placebo at 150 to 200 mg per day. Trial Registration: clinicaltrials.gov Identifier: NCT00056472 Main Outcome Measure: Remission rates of MD with psychotic features. Arch Gen Psychiatry. 2009;66(8):838-847 AJOR DEPRESSION (MD) residual disability, and greater mortality than with psychotic fea- MD without psychosis.2,4,5,8,9 tures is a severe but po- Expert guidelines10,11 recommend treat- tentially treatable dis- ment of MD with psychotic features with order.1 Epidemiological either electroconvulsive therapy (ECT) or studies2,3 and studies of large samples of psy- pharmacotherapy that combines an anti- M4,5 chiatric patients indicate that 15% to 20% depressant with an antipsychotic medica- of individuals with major depression have tion. The guidelines were based on stud- psychotic features. Higher prevalence rates ies demonstrating low response rates of approximating 45% have been reported MD with psychotic features to tricyclic an- Author Affiliations are listed at 12-16 the end of this article. among elderly inpatients with depres- tidepressant (TCA) monotherapy and 6,7 16 Group Information: The sion. Major depression with psychotic fea- results from both a small controlled trial STOP-PD group members are tures is associated with poorer short-term and pooled analyses17-20 favoring combi- listed on page 845. outcomes, a longer time to recovery, greater nation treatment or ECT. (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 66 (NO. 8), AUG 2009 WWW.ARCHGENPSYCHIATRY.COM 838 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 A recent meta-analysis demonstrating that combina- belief. The presence of at least 1 clearly defined delusion was tion therapy was superior to antipsychotic mono- required, with or without hallucinations, as studies of MD with therapy included the only 3 controlled trials available.21 psychotic features have generally considered delusional depression and MD with psychotic features to be synony- The limited evidence for the efficacy of combination treat- 35-37 ment for MD with psychotic features may contribute to mous. The presence of moderately severe to severe depres- 22 sion was assured by requiring scores of 21 or higher on the 17- the underrecognition of delusions in patients with MD item Hamilton Depression Scale (HAM-D),38 which was and the low use of antipsychotic medications to treat MD administered using the GRID-HAM-D method.39 23,24 with psychotic features in community settings. In con- This study focused on the treatment of MD with psychotic trast to trials in young adults,16 geriatric trials have not features rather than syndromes in which psychotic and depres- demonstrated greater efficacy for combined TCA/ sive symptoms accompany dementia. Therefore, patients with conventional antipsychotic therapy compared with TCA/ dementia or histories of impaired cognition prior to the cur- placebo for either acute25 or post-ECT continuation treat- rent depressive episode were excluded. Patients were ex- ment26 but did demonstrate poorer tolerability of cluded if they met criteria for another Axis I psychotic or mood combination therapy. disorder; current body dysmorphic disorder or obsessive- The present study investigated the efficacy of combi- compulsive disorder; or substance abuse during the preceding 3 months. Additional exclusion criteria were the presence of nation treatment in patients with systematically diag- an unstable medical condition that might interfere with comple- nosed MD with psychotic features across a broad spec- tion of the 12-week trial; a neurological disease that might affect trum of illness severity and compared the efficacy and neuromuscular functioning, such as Parkinson disease; and on- tolerability between persons aged 18 to 59 years and those going need for medications known to cause depression or psy- aged 60 years and older. We compared olanzapine (an chosis. Patients with known hyperlipidemia or diabetes melli- atypical antipsychotic medication reported to have acute tus, including insulin-dependent diabetes, were allowed to enroll antidepressant effects in placebo-controlled trials27,28) com- if their metabolic conditions were stable. Patients were ex- bined with placebo relative to olanzapine combined with cluded if immediate ECT was indicated because of their re- sertraline hydrochloride, a selective serotonin reuptake fusal to eat or drink or imminent risk for suicide. Patients who inhibitor antidepressant reported to be effective for MD demonstrated current suicidal ideation without immediate in- 29 tent and those who had made a suicide attempt during the cur- with psychotic features. The design encouraged aggres- rent episode were allowed to begin the study on an inpatient sive dosing of both medications during a 12-week trial basis. Screening also involved baseline laboratory assess- to maximize remission rates that could be compared with ments, including measurement of thyroid-stimulating hor- 14,17,18,30,31 the high remission rates associated with ECT. mone, folate, and B12 concentrations; an electrocardiogram; and The following hypotheses were tested: whether (1) com- a toxicology screen to detect undisclosed illicit drug use. Fi- bination therapy would be more effective than atypical nally, patients were excluded if they had received 15 mg or more antipsychotic monotherapy; (2) younger adults would of olanzapine per day for a minimum of 4 weeks during the achieve higher remission rates than older adults; and current episode or if they were benefiting from their current (3) younger adults would tolerate treatment better than psychotropic medications regimen. older adults. INTERVENTION METHODS Eligible subjects were randomized to sertraline plus olanza- pine or olanzapine plus placebo using computer-generated lists, PARTICIPANTS with investigators and raters blind to treatment assignments. Randomization was stratified by site and age, with a block size Patients aged 18 years or older who were admitted to the in- of 4. Subjects taking antidepressant or antipsychotic medica- patient or ambulatory services of the 4 participating academic tions at entry had these tapered prior to randomization, though sites between December 2002 and June 2007 were eligible for a washout period was not enforced because of the severity of recruitment. The institutional review boards of the participat- illness anticipated in study participants. Subjects began taking ing institutions and a data safety monitoring board at the Na- 5 mg of olanzapine per day and 50 mg of sertraline hydrochlo- tional Institute of Mental Health approved study consent forms ride or matching placebo per day, with dose increases permit- and monitored the study’s progress. Informed consent was ob- ted every 3 days as tolerated. Frail elderly subjects initially re- tained from all subjects, either directly or through locally ap- ceived 2.5 mg of olanzapine and 25 mg of sertraline or placebo proved surrogate consent procedures. Strategies to identify eli- (one-half of a 50-mg or placebo tablet). Olanzapine was ad- gible patients varied by institution and included review of new ministered openly, sertraline and placebo under double-blind admissions, advertisements, and direct referrals by commu- conditions. An attempt was made to reach minimum doses of nity psychiatrists. 10 mg of olanzapine per day and 100 mg of sertraline or pla- Potentially eligible consenting subjects were assessed with cebo per day before the end of week 1. Doses were increased the Structured Interview for Clinical Diagnosis32 to assure that to 15 mg of olanzapine per day and 150 mg of sertraline or pla- DSM-IV-TR1 criteria for unipolar MD with psychotic features cebo per day during week 2, with further increases allowed to were met.