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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) FREE

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 ; STOP-PD Group
[+] Author Affiliations

Author Affiliations: Department of Psychiatry, Weill Medical College of Cornell University and New York Presbyterian Hospital, Westchester Division, White Plains, New York (Drs Meyers, Peasley-Miklus, Leon, and Heo, and Mr Papademetriou); Department of Psychiatry, University of Toronto and University Health Network, Toronto, Ontario, Canada (Drs Flint and Mulsant); Geriatric Program and Research Institute, Toronto Rehabilitation Institute, and Toronto General Research Institute, Toronto (Dr Flint); University of Massachusetts Medical School and University of Massachusetts Memorial Health Care, Worcester (Dr Rothschild); Centre for Addiction and Mental Health, Toronto (Dr Mulsant); and Western Psychiatric Institute and Clinic, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Drs Mulsant and Whyte). Dr Heo is now at Albert Einstein College of Medicine, Bronx, New York.


Arch Gen Psychiatry. 2009;66(8):838-847. doi:10.1001/archgenpsychiatry.2009.79.
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Published online

Context  Evidence for the efficacy of combination pharmacotherapy has been limited and without positive trials in geriatric patients with major depression (MD) with psychotic features.

Objectives  To compare remission rates of MD with psychotic features in those treated with a combination of atypical antipsychotic medication plus a serotonin reuptake inhibitor with those treated with antipsychotic monotherapy; and to compare response by age.

Design  Twelve-week, double-blind, randomized, controlled trial.

Setting  Clinical services of 4 academic sites.

Patients  Two hundred fifty-nine subjects with MD with psychotic features randomized by age (<60 or ≥60 years) (mean [standard deviation (SD)], 41.3 [10.8] years in 117 younger adults vs 71.7 [7.8] years in 142 geriatric participants).

Intervention  Target doses of 15 to 20 mg of olanzapine per day plus masked sertraline or placebo at 150 to 200 mg per day.

Main Outcome Measure  Remission rates of MD with psychotic features.

Results  Treatment with olanzapine/sertraline was associated with higher remission rates during the trial than olanzapine/placebo (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.12-1.47; P < .001); 41.9% of subjects who underwent combination therapy were in remission at their last assessment compared with 23.9% of subjects treated with monotherapy (χ21 = 9.53, P = .002). Combination therapy was comparably superior in both younger (OR, 1.25; 95% CI, 1.05-1.50; P = .02) and older (OR, 1.34; 95% CI, 1.09-1.66; P = .01) adults. Overall, tolerability was comparable across age groups. Both age groups had significant increases in cholesterol and triglyceride concentrations, but statistically significant increases in glucose occurred only in younger adults. Younger adults gained significantly more weight than older subjects (mean [SD], 6.5 [6.6] kg vs 3.3 [4.9] kg, P = .001).

Conclusions  Combination pharmacotherapy is efficacious for the treatment of MD with psychotic features. Future research must determine the benefits vs risks of continuing atypical antipsychotic medications beyond 12 weeks.

Trial Registration  clinicaltrials.gov Identifier: NCT00056472

Figures in this Article

Major depression (MD) with psychotic features is a severe but potentially treatable disorder.1 Epidemiological studies2,3 and studies of large samples of psychiatric patients4,5 indicate that 15% to 20% of individuals with major depression have psychotic features. Higher prevalence rates approximating 45% have been reported among elderly inpatients with depression.6,7 Major depression with psychotic features is associated with poorer short-term outcomes, a longer time to recovery, greater residual disability, and greater mortality than MD without psychosis.2,4,5,8,9

Expert guidelines10,11 recommend treatment of MD with psychotic features with either electroconvulsive therapy (ECT) or pharmacotherapy that combines an antidepressant with an antipsychotic medication. The guidelines were based on studies demonstrating low response rates of MD with psychotic features to tricyclic antidepressant (TCA) monotherapy1216 and results from both a small controlled trial16 and pooled analyses1720 favoring combination treatment or ECT.

A recent meta-analysis demonstrating that combination therapy was superior to antipsychotic monotherapy included the only 3 controlled trials available.21 The limited evidence for the efficacy of combination treatment for MD with psychotic features may contribute to the underrecognition of delusions in patients with MD22 and the low use of antipsychotic medications to treat MD with psychotic features in community settings.23,24 In contrast to trials in young adults,16 geriatric trials have not demonstrated greater efficacy for combined TCA/conventional antipsychotic therapy compared with TCA/placebo for either acute25 or post-ECT continuation treatment26 but did demonstrate poorer tolerability of combination therapy.

The present study investigated the efficacy of combination treatment in patients with systematically diagnosed MD with psychotic features across a broad spectrum of illness severity and compared the efficacy and tolerability between persons aged 18 to 59 years and those aged 60 years and older. We compared olanzapine (an atypical antipsychotic medication reported to have acute antidepressant effects in placebo-controlled trials27,28) combined with placebo relative to olanzapine combined with sertraline hydrochloride, a selective serotonin reuptake inhibitor antidepressant reported to be effective for MD with psychotic features.29 The design encouraged aggressive dosing of both medications during a 12-week trial to maximize remission rates that could be compared with the high remission rates associated with ECT.14,17,18,30,31 The following hypotheses were tested: whether (1) combination therapy would be more effective than atypical antipsychotic monotherapy; (2) younger adults would achieve higher remission rates than older adults; and (3) younger adults would tolerate treatment better than older adults.

PARTICIPANTS

Patients aged 18 years or older who were admitted to the inpatient or ambulatory services of the 4 participating academic sites between December 2002 and June 2007 were eligible for recruitment. The institutional review boards of the participating institutions and a data safety monitoring board at the National Institute of Mental Health approved study consent forms and monitored the study's progress. Informed consent was obtained from all subjects, either directly or through locally approved surrogate consent procedures. Strategies to identify eligible patients varied by institution and included review of new admissions, advertisements, and direct referrals by community psychiatrists.

Potentially eligible consenting subjects were assessed with the Structured Interview for Clinical Diagnosis32 to assure that DSM-IV-TR1 criteria for unipolar MD with psychotic features were met. Inclusion required the presence of at least 1 delusional belief (a fixed idea that was held contrary to the laws of logic), a score of 2 or higher on 1 of the conviction items of the Delusional Assessment Scale,33 and a score of 3 or higher on the delusion severity rating item of the Schedule of Affective Disorders and Schizophrenia (SADS).34 A SADS delusion severity score of 3 is assigned when there is no more than a transient ability to consider the implausibility of an irrational belief. The presence of at least 1 clearly defined delusion was required, with or without hallucinations, as studies of MD with psychotic features have generally considered delusional depression and MD with psychotic features to be synonymous.3537 The presence of moderately severe to severe depression was assured by requiring scores of 21 or higher on the 17-item Hamilton Depression Scale (HAM-D),38 which was administered using the GRID-HAM-D method.39

This study focused on the treatment of MD with psychotic features rather than syndromes in which psychotic and depressive symptoms accompany dementia. Therefore, patients with dementia or histories of impaired cognition prior to the current depressive episode were excluded. Patients were excluded if they met criteria for another Axis I psychotic or mood disorder; current body dysmorphic disorder or obsessive-compulsive disorder; or substance abuse during the preceding 3 months. Additional exclusion criteria were the presence of an unstable medical condition that might interfere with completion of the 12-week trial; a neurological disease that might affect neuromuscular functioning, such as Parkinson disease; and ongoing need for medications known to cause depression or psychosis. Patients with known hyperlipidemia or diabetes mellitus, including insulin-dependent diabetes, were allowed to enroll if their metabolic conditions were stable. Patients were excluded if immediate ECT was indicated because of their refusal to eat or drink or imminent risk for suicide. Patients who demonstrated current suicidal ideation without immediate intent and those who had made a suicide attempt during the current episode were allowed to begin the study on an inpatient basis. Screening also involved baseline laboratory assessments, including measurement of thyroid-stimulating hormone, folate, and B12 concentrations; an electrocardiogram; and a toxicology screen to detect undisclosed illicit drug use. Finally, patients were excluded if they had received 15 mg or more of olanzapine per day for a minimum of 4 weeks during the current episode or if they were benefiting from their current psychotropic medications regimen.

INTERVENTION

Eligible subjects were randomized to sertraline plus olanzapine or olanzapine plus placebo using computer-generated lists, with investigators and raters blind to treatment assignments. Randomization was stratified by site and age, with a block size of 4. Subjects taking antidepressant or antipsychotic medications at entry had these tapered prior to randomization, though a washout period was not enforced because of the severity of illness anticipated in study participants. Subjects began taking 5 mg of olanzapine per day and 50 mg of sertraline hydrochloride or matching placebo per day, with dose increases permitted every 3 days as tolerated. Frail elderly subjects initially received 2.5 mg of olanzapine and 25 mg of sertraline or placebo (one-half of a 50-mg or placebo tablet). Olanzapine was administered openly, sertraline and placebo under double-blind conditions. An attempt was made to reach minimum doses of 10 mg of olanzapine per day and 100 mg of sertraline or placebo per day before the end of week 1. Doses were increased to 15 mg of olanzapine per day and 150 mg of sertraline or placebo per day during week 2, with further increases allowed to a maximum of 20 mg of olanzapine per day and 200 mg of sertraline per day, as tolerated, beginning in week 3. Slower titration or temporary dose reductions of 1 or both medications was allowed if adverse effects were suspected; however, subsequent dose increases were required to attempt to achieve minimum daily target doses of 15 mg of olanzapine per day and 150 mg of sertraline or placebo per day. For data analytic purposes, the subject's dose was considered the last one taken for a minimum of 7 days. Adjunctive lorazepam of up to 4 mg per day was allowed to control anxiety or agitation, and up to 2 mg of benztropine per day to control extrapyramidal symptoms. No other psychotropic drugs were allowed.

STUDY ASSESSMENTS

Baseline assessments were completed within 7 days of obtaining consent. Follow-up research assessments were conducted weekly for the first 6 weeks and then every other week until week 12 or termination. Research assessments included overall symptom severity using the Clinical Global Impressions, Severity of Illness Scale (CGI-S),40 HAM-D, assessments for delusional ideation using the Delusional Assessment Scale and the SADS delusional item, the Brief Psychiatric Rating Scale,41 and the Scale for Positive Symptoms.42 At baseline, the Cumulative Illness Burden Scale43 was used to assess general medical burden, and the Mini-Mental State Examination44 was used to assess global cognitive functioning. Raters were trained to achieve adequate reliability prior to conducting study assessments and interrater reliability reassessed annually thereafter.

OUTCOME CRITERIA

Remission was defined as a HAM-D score of 10 or lower at 2 consecutive assessments. This criterion was applied to assure that remission from mood symptoms was sustained and to allow for comparability with ECT studies that typically use a 2-week HAM-D criterion.31 Remission also required the absence of delusions (SADS delusional item score of 1) at the second remission of depression assessment. A 1-week remission of delusions criterion was applied to make the remission of psychosis outcome compatible with the standard duration criterion used in MD with psychotic features pharmacotherapy trials.21 Subjects who were not delusional at both of 2 consecutive HAM-D assessments were considered remitted at both points; subjects who had been delusional at the first of the HAM-D assessments were considered to be remitted at the second assessment only, and subjects who were not delusional at the first assessment but had SADS scores higher than 1 at the second were classified as not remitted at either assessment. A HAM-D cutoff of 10 or lower was used because this has been a standard in geriatric antidepressant trials45,46 and ECT studies.31 Subjects who achieved a HAM-D score of 10 or lower without delusions for the first time at week 12 were assessed again at week 13 to determine whether the 2-week duration criterion was met.

Investigators were allowed to withdraw subjects for either clinically significant worsening or insufficient clinical improvement after 5 weeks of randomized treatment. Insufficient clinical response was operationally predefined as having both a CGI-Improvement scale score of 2 or less (no or minimal improvement) and a CGI-S score of 4 or more (moderately or more severely ill). Discontinuations initiated by subjects were categorized as perceived poor response, poor tolerability, or withdrawal of consent.

Safety and tolerability assessments considered the incidence of adverse events and evaluations conducted by the investigators. Adverse events were identified at each visit using research assistant interviews and subject reports. Increases of 2 points on a Udvalg for Kliniske Undersogelser (UKU) scale item47 or scores of 3 on an item were classified as adverse events. Research psychiatrists quantified extrapyramidal symptoms using the Simpson Angus Scale48 and incident akathisia using the Barnes Akathisia Scale.49 Tardive dyskinesia was assessed using the Abnormal Involuntary Movement Scale,50 applying modified Schooler-Kane criteria51 without requiring a 2-week duration.

STATISTICAL ANALYSIS

Comparisons of baseline variables between the 2 treatment groups were made using χ2 and t tests. Baseline factors that differed significantly between the 2 treatment conditions were identified to be used in sensitivity analyses of the efficacy results. We applied intent-to-treat principles to include all randomized subjects in the primary and secondary efficacy analyses. The primary analyses of treatment efficacy examined the longitudinal binary outcome of remission using mixed-effects logistic regression52 with a random intercept that included treatment and time (ie, weeks from baseline) as fixed effects and a treatment × time interaction effect. The hypothesized difference in remission rates between the 2 treatment conditions over time was assessed by testing for the significance of an interaction between treatment assignment and time in the trial. The hypothesized age effect on treatment efficacy was tested by assessing the significance of a 3-way interaction between treatment, age, and time in a full model. The model used in the efficacy analysis was applied subsequently in each age group to assess the consistency of the efficacy results across the age groups. Also, site × treatment interactions were tested to evaluate site differences in efficacy.

Tolerability comparisons examined the incidence of adverse events and discontinuation rates due to poor tolerability in the 2 treatment arms and the 2 age groups. The young and old subgroups were compared for changes in metabolic parameters and for mean and maximum extrapyramidal symptoms scores during the trial. Secondary analyses compared remission rates between the 2 groups among subjects who completed the 12-week trial using the χ2 test and changes in CGI-S score using mixed-effects linear regression models. Exploratory analyses for group differences in changes on HAM-D scores and SADS delusional rating item scores used mixed-effects linear regression.

We assessed data distribution for normality prior to conducting analyses. When necessary, data transformation or nonparametric tests were applied. Each statistical test used a 2-tailed α level of .05. Data are expressed as mean (standard deviation [SD]) except where noted.

SAMPLE SIZE AND POWER CALCULATIONS

Based on predicted remission rates of 40% in subjects who underwent combination therapy and 20% in subjects who underwent monotherapy, 260 subjects randomized into the 2 treatment groups would provide more than 80% power at a 2-tailed α level of .05. This power analysis was based on a simulation study using the mixed-effects model under an anticipated total attrition rate of 45% and a within-subject outcome correlation of 0.5 or less.

DISPOSITION OF SUBJECTS

Of the 375 patients who consented to participation, 65 (17.3%) were found not to meet criteria for unipolar MD with psychotic features. As illustrated in Figure 1, 51 of the 310 subjects who met psychiatric inclusion criteria either withdrew consent, met an exclusion criterion, or were excluded for other reasons prior to randomization. The intent-to-treat sample consisted of 259 subjects, of whom 129 were randomized to combination treatment and 130 to olanzapine plus placebo.

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Figure 1.

Study flowchart.

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Clinical and sociodemographic characteristics of the randomized sample are presented in Table 1. The 2 groups were comparable for most major baseline variables, but differed by race and inpatient status at study entry. Among subjects in the olanzapine/sertraline group, 85.3% were white, 13.2% were African American, and 1.6% were Asian, compared with 83.1%, 9.2%, and 7.7%, respectively, in the olanzapine/placebo group (χ21 = 6.21, P = .05). Frequencies of inpatient status at study entry were 75.2% in the olanzapine/sertraline group and 63.1% in the olanzapine/placebo group (χ23 = 7.8, P = .05). The high baseline HAM-D and Brief Psychiatric Rating Scale scores and 18.5% frequency of suicide attempts during the current episode document the severity of illness in study participants. The mean ages of the 117 younger and 142 older subjects were 41.3 years (10.8 years) and 71.7 years (7.8 years), respectively.

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of 259 Randomized Subjects
DOSING

At the end of the study, mean daily doses of sertraline or placebo (168.9 mg [44.1 mg] vs 169.7 mg [35.0 mg]; t229 = 0.15; P = .88) and olanzapine (14.3 mg [5.3 mg] vs 14.7 mg [4.7 mg]; t234 = 0.55; P = .59) were comparable between the olanzapine/placebo and olanzapine/sertraline treatment groups, respectively. However, younger subjects received significantly higher mean daily doses of olanzapine compared with older subjects (15.7 mg [4.7 mg] vs 13.4 mg [5.1 mg]; t237 = 3.53; P < .001). Younger subjects also tended to receive higher mean daily sertraline/placebo doses (174.3 mg [34.1 mg] vs 165.7 mg [43.4 mg]; t237 = 1.72; P = .08), but the difference was not statistically significant.

PRIMARY EFFICACY ANALYSIS
Olanzapine/Sertraline vs Olanzapine/Placebo

The treatment × time effect was statistically significant (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.12-1.47; P < .001), demonstrating that the increase in rates of remission over the course of the trial was greater in the olanzapine/sertraline group than in the olanzapine monotherapy group. The significantly greater efficacy of combination therapy was apparent between weeks 8 and 12 (Figure 2). Fifty-four of the 129 participants (41.9%) assigned to combination therapy were in remission at their last assessment compared with 31 of the 130 (23.9%) who received olanzapine monotherapy (χ21 = 9.53, P = .002). Expressed as number needed to treat, 1 additional patient achieved remission with combination treatment than with olanzapine monotherapy for every 5.5 patients treated. The effect of treatment × site interactions on efficacy were not significant (log-likelihood ratio = 4.1, df = 3, P = .25). Treatment interactions with the hypothesized confounding variables of race (log-likelihood ratio = 0.0, df = 1, P > .99) and inpatient status (log-likelihood ratio = 0.1, df = 1, P > .75) were not significant either.

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Figure 2.

Remission rates in the intent-to-treat sample of 259 subjects randomized to olanzapine plus placebo vs olanzapine plus sertraline. *Statistically significant, using the Hochberg α level adjustments with a 2-sided family-wise α level of .05 from χ2 analysis.53

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Analysis for Age Effect

The nonsignificant 3-way interaction between age, treatment, and time (OR, 1.05; 95% CI, 0.80-1.37; P = .75) indicated that the treatment × time effect was comparable across age groups. Subgroup analyses showed that the treatment × time effect was statistically significant and comparable in the younger (OR, 1.25; 95% CI, 1.05-1.50; P = .02) and older subgroups (OR, 1.34; 95% CI, 1.09-1.66; P < .01).

SECONDARY EFFICACY ANALYSES

Differences in CGI-S scores in the intent-to-treat sample significantly favored the olanzapine/sertraline group (F1,1460 = 5.63; P = .02). Subjects allocated to olanzapine/sertraline in the intent-to-treat sample also had significantly lower HAM-D scores than those randomized to olanzapine/placebo at most points and during the trial overall (F1,1722 = 14.32; P < .001) (Figure 3). However, decreases in the score for the SADS delusional item were comparable in the 2 treatment groups without significant differences at any point (F9,1720 = 1.25; P = .26).

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Figure 3.

Hamilton Depression Scale (HAM-D) scores in subjects randomized to receive olanzapine plus placebo vs olanzapine plus sertraline. Overall treatment effect: F1,1722 = 14.32, P < .001. *Statistically significant using the Hochberg α level adjustments53 with a 2-sided family-wise α level of .05 from post hoc t tests.54

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The planned analysis of study completers demonstrated that the remission rate was significantly greater in the subjects randomized to olanzapine/sertraline who continued to week 12 than in those randomized to olanzapine/placebo (66.7% vs 49.2%; χ21 = 4.40; P = .04).

ATTRITION AND TOLERABILITY

The overall attrition rate was 45.2% (Figure 1), with 88 of 117 noncompleters (75.2%) exiting the trial at or before the midpoint at week 6. Attrition was significantly lower in the olanzapine/sertraline than in olanzapine/placebo group (37.2% vs 53.1%; χ21 = 6.58; P = .01). The frequencies of reasons for attrition in the 2 treatment groups were statistically comparable. Fourteen percent of subjects randomized to olanzapine/sertraline compared with 21.5% of subjects randomized to olanzapine/placebo withdrew themselves from the study (χ21 = 2.55, P = .11); 12.4% vs 10.0% of subjects in the combination therapy vs the monotherapy group, respectively, were withdrawn because of significant clinical worsening (χ21 = 0.38, P = .54); 4.7% vs 10.0% were withdrawn because of insufficient response (χ21 = 2.73, P = .1); and 3.1% vs 6.9% discontinued treatment because of intolerable adverse effects (χ21 = 1.98, P = .16). Similarly, there were no significant treatment group differences in rates of adverse events that occurred in more than 10% of study subjects, with 54.3% of subjects treated with olanzapine/sertraline meeting the UKU for significant weight gain (defined as an increase of ≥2.70 kg during the previous month) compared with 53.4% of subjects randomized to receive olanzapine/placebo (χ21 = 0.005, P = .95); 28.7% vs 30.8% of subjects in the combination therapy vs the monotherapy group, respectively, experienced somnolence/sedation (χ21 = 0.14, P = .72); 15.5% vs 12.3% experienced at least 1 fall (χ21 = 0.55, P = .46); and 15.5% vs 10.0% had orthostatic light-headedness (χ21 = 1.76, P = .84).

Serious adverse events involving increased suicidal thinking or behavior occurred in 5 subjects (2%), 4 of whom had been treated with olanzapine/sertraline, including a completed suicide at week 4 (3.1% vs 0.7%; Fisher exact, P = .21).

Table 2 summarizes the comparisons between younger and older subjects for the most common and clinically significant adverse events. Younger subjects were significantly more likely than older subjects to meet UKU criteria for significant weight gain (65.0% vs 45.1%, χ21 = 10.21, P = .001) but less likely to experience pedal edema (4.3% vs 13.4%, χ21 = 6.33, P = .01). There were no differences in incident akathisia or tardive dyskinesia by age group. Although older subjects had higher extrapyramidal symptom scores during the trial, the interaction between age group and extrapyramidal symptom severity was not significant (F3,498 = 1.89, P = .21). Two younger subjects and 3 older subjects were prescribed adjunctive benztropine (Fisher exact test, P > .99). Rates of attrition due to poor tolerability in younger and older subjects were statistically comparable (4.3% vs 5.6%, respectively, χ21 = 0.25, P = .62).

Table Graphic Jump LocationTable 2. Adverse Effects and Extrapyramidal Symptoms by Age

Changes in metabolic parameters in the younger and older subjects from baseline to week 12 or termination are shown in Figure 4. Cholesterol and triglyceride concentrations increased significantly over time in both age groups (F1,205 = 34.85, P < .001; and F1,201 = 22.11, P < .001, respectively) without significant interactions with age (F1,205 = 0.89, P = .35; and F1,201 = 0.74, P = .39, respectively). Although a statistically significant increase in glucose concentrations was observed only in the younger adults, the interaction between age group and glucose increases was not significant (F1,205 = 1.97, P = .16). Consistent with the UKU analysis, both age groups experienced significant increases in weight, with subjects younger than 60 years having significantly greater weight gain (6.5 kg [6.6 kg] vs 3.3 kg [4.9 kg], F1,221 = 11.10, P = .001).

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Figure 4.

Metabolic values at baseline and week 12 (or termination) in young adult and older subjects. * Young age × time effect: t205 = 2.76, P = .006; †young age × time effect: t 201 = 3.73, P < .001; ‡ old age × time effect: t 201 = 2.88, P = .004 (analysis was performed after log transformation owing to nonnormality); § young age × time effect: t 205 = 4.58, P < .001; ∥ old age × time effect: t 205 = 3.73, P = .002; ¶ interaction between time and age group: F1,221 = 11.1; P = .001; # young age × time effect: t 221 = 10.98, P < .001; ** old age × time effect: t 221 = 7.28, P < .001.

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Combination treatment with olanzapine plus sertraline was associated with a greater remission rate than with olanzapine monotherapy among patients with MD with psychotic features. The benefits of the combination therapy became more apparent as the 12-week trial progressed, with separation favoring olanzapine/sertraline from week 8 to the end of the trial. The higher categorical remission rate observed with olanzapine/sertraline compared with olanzapine/placebo was consistent with the significantly greater decreases in HAM-D scores observed with combination therapy.

Our hypothesis that pharmacotherapy would be more efficacious in the younger group was not supported. The greater efficacy of olanzapine/sertraline was comparable in both age groups; furthermore, the subgroup analyses demonstrated the efficacy of combination treatment compared with olanzapine alone in both the younger adults and geriatric subjects.

The rates and severity of adverse effects were similar in the 2 treatment groups. Older subjects did not demonstrate poorer overall tolerability. With the exception of a greater frequency of pedal edema, older subjects were not more likely to experience falls or sedation/somnolence or to have greater extrapyramidal symptoms.

Both age groups experienced significant increases in weight and both triglyceride and cholesterol levels. Fasting glucose levels increased significantly among younger adults only. The observed metabolic changes are consistent with those reported during olanzapine treatment among younger adults with schizophrenia.55 In the absence of reliable measures of premorbid weight, we cannot estimate how much of the weight gained during the trial was due to the recovery of weight lost during the depressive episode. Our finding that older age was associated with less weight gain is consistent with other reports with atypical antipsychotic medications56 and with olanzapine specifically.57,58 In an analysis of data from a subgroup of subjects from this trial, we have shown that the lower weight gain experienced by older subjects is partially explained by their lower cumulative olanzapine dose.59

The positive findings must be considered in relation to the absence of an antidepressant monotherapy arm and previous combination pharmacotherapy trials for MD with psychotic features. Although most studies1214,16,6062 report poor response rates of MD with psychotic features to TCA monotherapy, positive trials exist in patients with delusions that are congruent with depressed mood treated with high doses of amitriptyline63 or imipramine.64,65 The generally poor responsiveness to TCA monotherapy has contributed to the conceptualization of MD with psychotic features as a distinct entity15,35,61 and the recommendation for combination therapy,10,11 including in geriatric patients.66 Nevertheless, a meta-analysis of the only 2 trials comparing combination therapy with antidepressant monotherapy did not demonstrate the superiority of combination treatment. Although this meta-analysis did demonstrate greater efficacy for combination therapy compared with antipsychotic monotherapy,21 only 1 of the 2 trials that used an atypical antipsychotic medication19 had positive results. Therefore, these results confirm and extend those of the meta-analysis.

The TCA studies cited previously1216 were shorter than the 12-week duration of our Study of Pharmacotherapy of Psychotic Depression (STOP-PD). It is possible that longer antidepressant monotherapy trials would result in higher remission rates. Our trial also differed in applying a criterion of 2 consecutive assessments to assure that remission was sustained, which may have contributed to the absence of separation between olanzapine/sertraline and olanzapine/placebo before week 8. Nevertheless, the HAM-D analysis demonstrated that combination treatment was statistically superior on HAM-D scores from week 2 to week 12 without differences between the treatment arms in changes of SADS delusional scores at any point. Therefore, the benefit of adding sertraline to olanzapine was specific for the rate of improvement of depressive symptoms.

The possible efficacy of selective serotonin reuptake inhibitor monotherapy for unipolar delusional depression was suggested by a reported intent-to-treat remission rate of 72% with 150 mg of sertraline per day compared with only 27% for 40 mg of paroxetine per day.29 Methodological limitations in the trial design67 and a separate report that patients with MD with psychotic features had a markedly lower response rate to 200 mg of sertraline per day than patients with nonpsychotic depression68 highlight the need for additional trials to compare the efficacy of antidepressant monotherapy and combination treatment.

We have reported that prestudy antidepressant therapy was common among the first 100 study participants but that combination therapy was not.24 Without accounting for prestudy treatment, we cannot assess whether resistance to prior antidepressant therapy influenced response to either treatment.

Illness severity of participants, with most recruited as inpatients, rendered randomization to placebo only and use of a placebo lead-in impractical. The low placebo response rates in previous trials of MD with psychotic features (0%69 to 24.5%19) supported not including a placebo arm. Furthermore, the low early remission rate (<10% at week 2) decreases the likelihood that residual effects from pretrial treatment contributed to these results.

Although patients with major depression associated with hallucinations but not delusions meet DSM-IV criteria for MD with psychotic features, STOP-PD required the presence of delusions. Therefore, we cannot assess the efficacy of combination therapy for MD with psychotic features associated with hallucinations only. Also, the study focused on patients with unipolar MD with psychotic features and systematically excluded patients with histories that indicated periods of either mania or hypomania. Therefore, the results cannot be generalized to bipolar psychotic depression.

The 45.2% rate of attrition is a limitation. Attrition was comparable with the 48.1% rate reported in placebo-controlled antipsychotic trials70 but higher than the approximately 35% overall rate estimated for antidepressant studies of nonpsychotic depression.71 Although the severity of illness among study participants, with 69.1% entering as inpatients, presumably contributed to the high rate of attrition, the lack of systematic follow-up data from subjects who prematurely discontinued the study limits both generalizeability and our ability to apply the results to inform clinical practice.71,72 Mixed-effects logistic regression was applied as the primary analytic strategy to allow for the use of all available data under the assumption of ignorable missingness.71

The significantly higher attrition rate among patients treated with olanzapine than those treated with olanzapine/sertraline may be attributable to both more frequent discontinuations by investigators owing to insufficient response and earlier self-withdrawal by individuals who were responding poorly to monotherapy. Also, considering symptoms to be caused by study medications rather than MD with psychotic features may have contributed to the numerically greater frequency of discontinuation attributed to intolerable adverse effects in subjects treated with olanzapine/placebo. The observation that 75.2% of instances of attrition occurred during the first 6 weeks indicates that the 12-week trial length does not explain the high attrition rate

This trial applied an innovative and rigorous approach to defining remission in MD with psychotic features. The remission criterion of 2 consecutive assessments has been used in a previous trial of MD with psychotic features19 and a 2-week remission HAM-D cutoff of 10 points or lower has been used in ECT studies that included subjects with MD with psychotic features.31,73 The current study added a systematic assessment to assure delusions were resolved as a criterion for remission. In the absence of studies that assessed for the absence of delusions at more than 1 assessment, determination that delusions were not present at the second HAM-D remission assessment was considered an appropriately stringent remission criterion.

This study's remission rates, greater than 30% at week 8 and rising to 41.9% at week 12, are comparable with those in studies summarized in recent meta-analyses comparing duloxetine54 and venlafaxine74 with selective serotonin reuptake inhibitors for nonpsychotic depression. The potential benefit of acute combination pharmacotherapy relative to ECT, which is generally considered the treatment of choice for MD with psychotic features, warrants consideration. The efficacy of ECT has been well established, with a response rate of 87% when bilateral ECT is administered in academic centers.31 The public health significance of the acute efficacy of ECT is tempered by the rapid increase in depressive symptoms that occurs within days of completing a course of ECT73,75 and the markedly lower ECT remission rates (30%-47%) reported in community settings.76 Therefore, evidence that a pharmacological treatment is efficacious offers physicians an alternative to ECT that may be preferred by some patients for reasons of stigma and practicality. Nevertheless, the adverse metabolic effects of atypical antipsychotic medications are problematic. Further study of the optimal duration of continued combination therapy is needed to balance the high risk of early relapse of MD with psychotic features77,78 against the metabolic abnormalities and significant weight gain associated with atypical antipsychotic medications.

Correspondence: Barnett S. Meyers, MD, New York Presbyterian Hospital–Westchester, 21 Bloomingdale Rd, White Plains, NY 10605 (bmeyers@med.cornell.edu).

Submitted for Publication: October 3, 2008; final revision received December 22, 2008; accepted January 6, 2009.

Author Contributions: Dr Meyers had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosures: All of the authors received salary contributions from the National Institute of Mental Health grants that supported this study. Dr Meyers has provided legal consultation for AstraZeneca and has received research support or honoraria from Cyberonics, Eli Lilly, Forest Laboratories, Organon, and Pfizer. Dr Flint has received research support or honoraria from Janssen-Ortho, Lundbeck Canada, Organon, and Pfizer Canada. Dr Rothschild has received research support or honoraria from AstraZeneca, Bristol-Myers, Cephalon, Cyberonics, Forest Laboratories, Eli Lilly, Merck, Pfizer, Takeda, Novartis, and Wyeth; has provided expert testimony for Pfizer, GlaxoSmithKline, Forest Laboratories, and Eli Lilly; and has received royalties for the Rothschild Scale for Antidepressant Tachyphylaxis. Dr Mulsant has received research support or honoraria from AstraZeneca, Corcept, Eisai, Eli Lilly, Lundbeck, Forest Laboratories, GlaxoSmithKline, Janssen, and Pfizer. Dr Mulsant owns stock valued at less than $10 000 in Akzo-Nobel, Alkermes, AstraZeneca, Biogen Idec, Ceslsion, Elan, Eli Lilly, Forest, General Electric, and Orchestra Therapeutics. Dr Whyte has received research support or honoraria from Pfizer, Forest Laboratories, and Ortho-McNeil and research support from the National Institute of Mental Health and National Institute of Child Health and Human Development/National Center for Medical Rehabilitation Research. Dr Leon has served as a consultant for the National Institute of Mental Health and the Food and Drug Administration; has served on data safety monitoring boards for AstraZeneca, Dainippon Sumitomo Pharma America, Neurognetics, Organon, Pfizer, and Vanda; and has served as a consultant to Avera, Best Practices, Cadence, Concordant Raters, Cortex Pharmaceuticals, Cyberonics, Eli Lilly, MedAvante, and Noven. Drs Peasley-Miklus and Heo, and Mr Papademetriou do not have financial disclosures to report. Eli Lilly donated olanzapine for this trial and Pfizer donated sertraline and placebo/sertraline.

Funding/Support: This project was supported by grants MH 62446, MH 62518, MH 62565, and MH 62624 from the US Public Health Service; grants MH069430, MH067710, and P30 MH068368 from the National Institute of Mental Health; and grants M01-RR024153, RR000056, and CTSC UL1RR024996 from the National Center for Research Resources.

Role of the Sponsor: The National Institute of Mental Health supported this study and participated in its implementation through the UO1 mechanism. They did not participate in the collection, analysis, or interpretation of study data or in the preparation, review, or approval of this manuscript. A data safety monitoring board at the National Institute of Mental Health provided data and safety monitoring. Neither Eli Lilly nor Pfizer participated in the design, implementation, collection, analysis, or interpretation of data or in the preparation, review, or approval of this manuscript

Additional Contributions: We thank the members of the STOP-PD group for their contributions.

Box Section Ref ID

STOP-PD Group Members

Weill Cornell Medical Center, White Plains, New York

G. S. Alexopoulos, MD; M. L. Bruce, PhD; S. Klimstra, MD; J. English, MA; M. Gabriele, MSW; F. Santana, MSW; G. Addonizio, MD; J. de Asis, MD; X. Y. Baran, MD; and B. Kalyam, MD.

University of Pittsburgh, Pittsburgh, Pennsylvania

D. J. Kupfer, MD; M. E. Thase, MD; D. J. Cohen, BS; J. E. Emanuel, BS; T. S. Kamara, MPH; B. Kephart, BA; E. R. Mathis, BS; N. M. McLaughlin, RN, BSN; M. McShea, MS; A. G. Gildengers, MD; R. H. Howland, MD; M. D. Miller, MD; and J. Rosen, MD.

University of Massachusetts Medical School, Worcester

P. Appelbaum, MD; P. J. Candilis, MD; D. Guerin, MS; C. Wood, MS; A. Rohrbaugh, MS; S. Fratoni; C. Calkins; J. Grogan; M. Martin; J. Patel, MD; E. Smith, MD; R. Reni, MD; D. Sit, MD; E. Kayatekin, MD; D. Morin, MD; C. Cimpeanu, MD; T. Shteinlukht, MD; M. Vemuri, MD; M. Bell, MD; P. Burke, MD; N. Byatt, MD; R. Cook, MD; K. Deligiannidis, MD; I. Guryanova, MD; A. Jastiniah, MD; and A. Mathur, MD.

University of Toronto–Affiliated Hospitals, Toronto, Ontario, Canada

S. Kasapinovic, MSc; C. Andrade, BA; P. Zuker, BA; S. Rizvi, BSc; A. Schaffer, MD; N. Herrmann, MD; S. Brook, MD; and J. Silveira, MD.

National Institutes of Mental Health, Bethesda, Maryland

J. Olin, PhD (currently at Novartis); E. Zachariah, PhD; and J. Evans, PhD.

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Figures

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Figure 1.

Study flowchart.

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Figure 2.

Remission rates in the intent-to-treat sample of 259 subjects randomized to olanzapine plus placebo vs olanzapine plus sertraline. *Statistically significant, using the Hochberg α level adjustments with a 2-sided family-wise α level of .05 from χ2 analysis.53

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Figure 3.

Hamilton Depression Scale (HAM-D) scores in subjects randomized to receive olanzapine plus placebo vs olanzapine plus sertraline. Overall treatment effect: F1,1722 = 14.32, P < .001. *Statistically significant using the Hochberg α level adjustments53 with a 2-sided family-wise α level of .05 from post hoc t tests.54

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Figure 4.

Metabolic values at baseline and week 12 (or termination) in young adult and older subjects. * Young age × time effect: t205 = 2.76, P = .006; †young age × time effect: t 201 = 3.73, P < .001; ‡ old age × time effect: t 201 = 2.88, P = .004 (analysis was performed after log transformation owing to nonnormality); § young age × time effect: t 205 = 4.58, P < .001; ∥ old age × time effect: t 205 = 3.73, P = .002; ¶ interaction between time and age group: F1,221 = 11.1; P = .001; # young age × time effect: t 221 = 10.98, P < .001; ** old age × time effect: t 221 = 7.28, P < .001.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of 259 Randomized Subjects
Table Graphic Jump LocationTable 2. Adverse Effects and Extrapyramidal Symptoms by Age

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ECT (Electroconvulsive Therapy) As First Line Treatment for Psychotic Depression
Posted on February 1, 2010
Charles H. Kellner, MD
Mount Sinai School of Medicine
Conflict of Interest: None Declared
Meyers et al (1) report a remission rate of 41.9% for the olanzapine- sertraline combination compared to 23.9% for olanzapine alone at eight weeks in the treatment of delusional depression in their multi-center trial. While we recognize the considerable effort the authors have expended in carrying out this methodologically rigorous trial, we have concerns about the conclusions, both implied, and stated directly, regarding the treatment of delusional depression. They conclude that combination pharmacotherapy is efficacious for treatment of major depression with psychotic features and continue that: "evidence that a pharmacological treatment is efficacious offers physicians an alternative to ECT that may be preferred by some patients for reasons of stigma and practicality." This conclusion both exaggerates the success of the tested pharmacological treatment and unnecessarily diminishes the utility of ECT. Expert guidelines recommend ECT for delusional depression because numerous reports document response and remission rates substantially higher than pharmacotherapy, often >80%, and usually within three weeks.(2-4) Suicidal behavior, perhaps the greatest risk of mortality and morbidity in this patient population, is particularly quickly relieved with ECT.(5) (Meyers et al. report one completed suicide in their study population).
Despite the relatively high relapse rates of 34% to 39% in six months after successful acute ECT, nearly half of remitted patients remain well at six month follow-up.(6) The dropout rates with both acute and continuation ECT6 again compare favorably to the 45.2% dropout rate within 12 weeks in the reported study. The cited single, unreplicated report of lower ECT efficacy in community settings still found remission rates of 55.7% in the completer sample and a response rate of 73%.(7)
The adverse effect profiles of ECT and combined antidepressant- antipsychotic medications, although quite different, do not favor the medications. Meyers et al. confirm the well-known risks of weight gain, lipid and glucose abnormalities, traumatic falls and the development of tardive dyskinesia with antipsychotic medications.
Experts in the field, dedicated to psychopharmacology, should be particularly careful to not perpetuate stigma as an excuse for failure to prescribe the more effective treatment for delusional depression. Indeed, it is the ethical responsibility of practitioners to recommend those treatments with the highest likelihood of success and the most compelling scientific evidence supporting them.
The Meyers et al study does not alter the recommendation that ECT is the first-line treatment for delusional depression.
Charles Kellner Max Fink Kristen Tobias Georgios Petrides
1. Meyers BS, Flint AJ, Rothschild AJ, Mulsant BH, Whyte EM, Peasley -Miklus C, Papademetriou E, Leon AC, Heo M. A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression. Arch Gen Psychiatry. 2009;66(8): 838-847. 2. Avery D, Lubrano A. Depression treated with imipramine and ECT: the DeCarolis study reconsidered. Am J Psychiatry. 1979; 136(4b):559-562. 3. Petrides G, Fink M, Husain MM, Knapp RG, Rush Aj, Mueller M, Rummans TA, O’Connor KM, Rasmussen KG Jr, Bernstein HJ, Biggs M, Bailine SH, Kellner CH. ECT remission rates in psychotic versus non-psychotic depressed patients: a report from CORE. JECT. 2001;17(4):244-253. 4. Birkenhager TK, Pluijms EM, Lucius SAP. ECT response in delusional versus non-delusional depressed inpatients. J Affect Disord. 2003;74(2):191-195 5. Kellner CH, Fink M, Knapp R, Petrides G, Husain M, Rummans T, Mueller M, Bernstein H, Rasmussen K, O’Connor K, Smith G, Rush AJ, Biggs M, McClintock S, Bailine S, Malur C.. Relief of expressed suicidal intent by ECT: a consortium for research in ECT study. Am J Psychiatry. 2005;162(5): 977-982. 6. Kellner CH, Knapp RG, Petrides G, Rummans TA, Husain MM, Rasmussen K, Mueller M, Bernstein HJ, O’Connor K, Smith G, Biggs M, Bailine SH, Malur C, Yim E, McClintock S, Sampson S, Fink M. Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multi-site study from the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry. 2006; 63(12):1337-44. 7. Prudic J, Olfson M, Marcus SC, Fuller RB, Sackeim HA. Effectiveness of electroconvulsive therapy in community settings. Biol Psychiatry. 2004; 55(3):301-312.
Potential Conflicts of Interest:
Charles H. Kellner: Salary support from NIMH grant 55495, loan of ECT device by Somatics, Inc (References 5, 6 in Letter to the Editor) Max Fink: Nothing to disclose Kristen Tobias: Salary support from NIMH grant 55495 (References 5, 6 in Letter to the Editor) Georgios Petrides: Salary support from NIMH grant 55486 (References 5, 6 in Letter to the Editor)
Olanzapine plus Sertraline for Delusional Depression?
Posted on February 5, 2010
Bernard J Carroll, MBBS, PhD
Pacific Behavioral Research Foundation
Conflict of Interest: None Declared
The report by Meyers et al (1) is to be commended for the rigorousness of the outcome assessments. However, the report offers little new information for managing psychotic-delusional depression, because the design fails the test of clinical equipoise. All patients received olanzapine; half also received sertraline, while the other half received placebo. Establishing that olanzapine plus sertraline is superior to olanzapine plus placebo adds little to our knowledge. We knew in early 2001 that olanzapine alone is not efficacious in delusional depression (2), so when the present study was launched (December 2002) there was no genuine uncertainty whether olanzapine plus placebo would be inferior to olanzapine plus sertraline. We also knew that the combination of olanzapine plus fluoxetine was superior to placebo (2), and there was no scientific reason to hypothesize differently for olanzapine plus sertraline. By mid-2003, the inefficacy of olanzapine alone was amply confirmed (3).
In view of olanzapine’s documented lack of efficacy, one wants to ask what information the patients received regarding equipoise before they gave their consent for randomization. Was olanzapine plus placebo presented as a potentially effective treatment? One certainly hopes not. Was the olanzapine-placebo combination presented to the patients as a so- called active placebo? One hopes not, as that would violate the principle of avoiding harm – see below. As this was a NIMH-supported multi-center project, one also wants to ask what the data safety monitoring board convened by NIMH understood about the established inefficacy of olanzapine alone for delusional depression, and why enrollment of patients was allowed to proceed through June 2007 with a scientifically ineffective design that also exposed consenting patients to significant risks.
The study design presents olanzapine as the default or reference drug. The default or reference drug should have been sertraline (or some other recognized antidepressant drug), not olanzapine (or some other antipsychotic drug). The crucial scientific question is whether olanzapine increases the improvement seen with sertraline alone, not whether sertraline increases the negligible improvement expected with olanzapine alone.
I take the following lessons from this report.
1. Olanzapine lacks antidepressant properties. The improvement seen with olanzapine plus placebo appears no better than what would be expected with placebo itself, based on prior results of Dr. Rothschild and others (2, 3).
2. Sertraline has antidepressant properties in delusional depression, beyond the placebo-level antidepressant efficacy of olanzapine, with a Number Needed to Treat of 5.5. However, the time to statistically significant sertraline-attributable improvement was 8 weeks, which is problematic.
3. Olanzapine possesses antipsychotic properties in delusional depression. Both groups received olanzapine and showed equal improvement of delusional symptoms. At the same time, the data clearly show that simply improving the psychotic symptoms is not a sufficient therapeutic goal in delusional depression.
4. We cannot say whether sertraline reduces psychotic symptoms in delusional depression, for example as a consequence of reducing depression severity, because the study design did not include a group treated with sertraline and without olanzapine. That is a serious and scientifically inexplicable limitation of the study.
5. Overall, the olanzapine-sertraline combination is unimpressive in terms of benefit versus risks.
Contrary to statements by the authors, there are other pharmacological options for delusional depression (I leave it to others to address the option of ECT). Imipramine, trimipramine, and combined amitryptiline-haloperidol treatments have shown substantial efficacy in delusional depression in contemporary reports where blood levels were monitored (4-6). In these trials, allowing for criterion differences, the tricyclic antidepressants appeared equally or more efficacious in a shorter time than the olanzapine-sertraline combination in the present report. These recent studies confirm historical reports of tricyclic antidepressant efficacy in delusional depression, e.g. (7). The unmet need for drug treatment of delusional depression is less than suggested by Meyers et al.
Moreover, olanzapine treatment carried notable toxicity. Within a mere 12 weeks in these depressed patients, olanzapine was associated with a 53% dropout rate (only slightly mitigated by the addition of sertraline), a 9% incidence of tardive dyskinesia, a 14% incidence of falls, and a 54% incidence of significant weight gain, in addition to its adverse effects on cholesterol, triglyceride and glucose measures.
Patients will be placed at unnecessary risk without evidence of potential benefit should clinicians infer from the design of this study that olanzapine is acceptable as the default drug for treating delusional depression. That would be a dangerous normative practice, which should not be promoted or implied.
Clinicians also should be cautioned against inferring from this study that the olanzapine-sertraline combination is a realistic option for treating delusional depression. In comparison to patients who received olanzapine plus placebo, at the end of the day only 18% of cases given the olanzapine-sertraline combination achieved a combination-attributable remission, after factoring in dropouts, first-order remission rate, and Number Needed to Treat. Meanwhile, for every 2 patients who achieved combination-attributable remission in this study, 1 patient developed tardive dyskinesia, 6 patients experienced excessive weight gain, and 1.5 patients experienced falls. There can be little question that the low benefit-to-risk ratio of olanzapine plus sertraline precludes any recommendation for general use of this drug combination in delusional depression.
No relevant conflicts of interest.
References
1. Meyers BS, Flint AJ, Rothschild AJ, Mulsant BH, Whyte EM, Peasley- Miklus C, Papademetriou E, Leon AC, Heo M. A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression. Archives of General Psychiatry 2009;66(8):838- 847.
2. Williamson DJ, Andersen DW, Van Campen LE, Sam LM, Sanger TM, Tohen M, Tollefson GD. A double-blind study of olanzapine-fluoxetine combination for treatment of psychotic major depression. Biological Psychiatry 2001;49 (S1):104S.
3. Rothschild AJ, Williamson DJ, Tohen MF, Schatzberg A, Andersen SW, Van Campen LE, Sanger TM, Tollefson GD. A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol 2004;24:365-373.
4. Steiger A, Künzel HE, Uhr M, Ackl N, Hatzinger M, Held K, Holsboer -Trachsler E, Ising M, Kaschka W, Kasper S, Konstantinidis A, Sonntag A. Trimipramine monotherapy in patients with delusional depression is equivalent to combined treatment with amitryptiline and haloperidol. Naunyn-Schmiederbergs Arch Pharmacol 2006;372 (Suppl 1):346.
5. Birkenhager TK, van den Broek WW, Mulder PG, Moleman P, Bruijn JA. Efficacy of imipramine in psychotic versus nonpsychotic depression. J Clin Psychopharmacol 2008;28:166-170.
6. Künzel HE, Ackl N, Hatzinger M, Held K, Holsboer-Trachsler E, Ising M, Kaschka W, Kasper S, Konstantinidis A, Sonntag A, Uhr M, Yassouridis A, Holsboer F, Steiger A. Outcome in delusional depression comparing trimipramine monotherapy with a combination of amitryptiline and haloperidol – a double-blind, multicenter trial. J Psychiatr Res 2009;43:702-710.
7. Quitkin F, Rifkin A, Klein DF. Imipramine response in deluded depressive patients. American Journal of Psychiatry 1978;135:806-811.
ECT versus Phamacotherapy for Psychotic Major Depression: Meyers et al. reply to Kellner et al.
Posted on February 17, 2010
Barnett S. Meyers, M.D.
Weill Cornell Medical College of Cornell University
Conflict of Interest: None Declared
Based on the results of the Study of the Pharmacotherapy of Psychotic Depression (STOP-PD), we commented that combination pharmacotherapy for major depression with psychotic features (MDpsy) offers physicians an alternative to ECT, which may be preferred by some patients for reasons of stigma and practicality (1). Kellner et al. write that our conclusion “exaggerates the success of the pharmacological treatment and unnecessarily diminishes the utility of ECT”. They argue that “expert guidelines recommend ECT for delusional depression and imply that ECT is the primary treatment indicated for this severe disorder.” However, our findings do not contradict the American Psychiatric Association Treatment Guidelines (2), which state that ECT should be considered as “a” first line treatment of MDpsy (3). Furthermore, our conclusion that combination treatment using an antidepressant and an antipsychotic is efficacious is consistent with the Guidelines position that combination treatment is also effective for MDpsy. We also differ with their suggestion that the STOP-PD report either exaggerates the benefits of combination pharmacotherapy or understates the utility of ECT. Kellner et al. point out that some ECT trials carried out in academic centers have reported >80% response and remission rates in patients with MDpsy, with response often occurring rapidly. Nevertheless, enthusiasm for early responses to ECT is tempered by the rapid return of depressive symptoms and high rates of relapse in the week following an initial remission that have been reported in both community-based ECT studies (4) and trials conducted in academic centers (5-7). Kellner et al. argue that the Prudic et al’s. (5) report of lower efficacy for ECT in community settings is offset by the 55.7% remission rate and 73% response rate among individuals who completed the course of treatment. However, the 41.9% intent-to-treat (ITT) strict remission rate, defined as Ham-D scores of = 10 at two consecutive assessments without delusions, in STOP-PD study (1) is consistent with the 46.7% ITT remission rate, defined as a Ham-D cut-off of =10, in Prudic et al’s. study. Also, the 66.7% remission rate among STOP-PD completers is numerically higher than the 55.7% rate reported by Prudic et al. Further analysis of the STOP-PD data reveals that 82.5% of completers would meet a response criterion of having a 50% improvement in Ham-D scores at their week-twelve assessment, compared to the 73% response rate among completers in the report by Prudic et. al.
The letter from Kellner et al. raises the larger problem of comparing results from randomized controlled trials of pharmacotherapy to the results of ECT studies. ECT trials are conducted openly and often report response and remission rates among subjects who complete a pre-specified number of treatments; in contrast, pharmacotherapy efficacy is determined using a double-blind randomized parallel group design with efficacy determined by comparing response rates across treatment arms and including all randomized subjects. Applying an ITT approach to ECT generates lower response and remission rates. Sackeim et al. found that only 50.3% of 316 participants with a mixture of nonpsychotic and psychotic unipolar major depression who entered his continuation pharmacotherapy trial both completed an initial phase of ECT and achieved the remission criteria of a Ham-D =10 sustained for one week (6). Kellner et al. reported an initial remission rate of 64.2% in 531 subjects with either psychotic or nonpsychotic unipolar major depression who participated in the lead-in phase of the Consortium for Research in ECT (CORE) maintenance ECT trial (7), but that rate would fall to 51% of the ITT sample if subjects who did not sustain remission for a full week were classified as non-remitters.
The substantial relapse rates during the week following a successful course of ECT highlights the importance of continuing treatment immediately following remission and of studying the efficacy of post- remission treatment. Also, results from the CORE trial demonstrated high and statistically comparable relapse and attrition rates following remission achieved with open ECT among subjects randomized to six months of either maintenance ECT or combination pharmacotherapy with therapeutic concentrations of nortriptyline plus lithium (7). Although subjects with baseline psychosis tended to have lower relapse rates than non-psychotic subjects, this difference did not achieve statistical significance. Thus, results were not analyzed for an interaction between psychosis and treatment assignment. Of importance, participants in this continuation trial did not receive post-remission treatment with an antipsychotic medication.
The CORE design raises a methodological question that cuts across post-ECT continuation treatment trials: does randomizing subjects to a treatment that was not associated with initial remission increase the risk for relapse? Although results from the STOP-PD trial raise the possibility that continuing the initially successful combination pharmacotherapy of MDpsy would decrease the risk for relapse, the efficacy and risks of continuation combination pharmacotherapy for MDpsy remain uninvestigated. In this regard, Kellner et al. point out that the adverse effect profile associated with pharmacotherapy in our study, while different from that associated with ECT, is problematic. We agree that the risks and the benefits of both acute and post-acute combination pharmacotherapy are important considerations that merit rigorous further study.
We further agree with Kellner et al. that stigma and misperceptions about ECT are barriers to effective treatment and that clinicians should help patients and other clinicians to overcome these obstacles rather than perpetuating them. Nevertheless, we believe that evidence from STOP PD demonstrating the efficacy of combination pharmacotherapy for MDpsy in both young and older adults serves an important public health benefit by providing an additional treatment option for a serious mental disorder.
References
1. Meyers BS, Flint AJ, Rothschild AJ, Mulsant BH, Whyte EM, Peasley- Miklus C, Papademetriou E, Leon AC, Heo M: A Double-blind randomized controlled trial of olanzapine plus sertraline versus olanzapine plus placebo. Arch Gen Psychiatry 2009; 66(8):838-847
2. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. Apr 2000;157(4 Suppl):1-45.
3. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000.
4. Prudic J, Olfson M, Marcus SC, Fuller RB, Sackeim HA. Effectiveness of electroconvulsive therapy in community settings. Biol Psychiatry. Feb 1 2004;55(3):301-312.
5. Sackeim HA, Prudic J, Devanand DP, et al. Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy. N Engl J Med. Mar 25 1993;328(12):839-846.
6. Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA. Mar 14 2001;285(10):1299-1307.
7. Kellner CH, Knapp R, Petrides G, Rummans,TA Hussain, MM, Rasmussen K, Mueller M, Bernstein HJ, O’Connor K, Smith G, Biggs M, Bailine SH, Malur C, im E, McClintock S, Sampson S: Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression. Arch Gen Psychiatry 2006; 63:1337-1344
Meyers, BS, Flint AJ, Rothschild AJ, Mulsant BH, Whyte EM
Conflict of Interest Statement
This work was supported by grants from the NIMH. Medications for the study were donated by Eli Lilly and Pfizer. Dr. Meyers has received research support from Forest Laboratories and Pfizer. He has provided legal consultation to AstraZeneca. Dr Flint has received honoraria from Janssen-Ortho, Lundbeck Canada, and Pfizer Canada. Dr Rothschild has received research support or honoraria from AstraZeneca, Bristol-Myers, Cephalon, Cyberonics, Forest Laboratories, Eli Lilly, Merck, Pfizer, Takeda, Novartis, and Wyeth; He has provided expert testimony for Pfizer, GlaxoSmithKline, Forest Laboratories, and Eli Lilly; and has received royalties for the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)TM Dr. Whyte has received research support from Pfizer, Forrest Laboratories, Ortho-McNeil Pharmaceutical, and Eli Lilly and Company. Benoit H. Mulsant receives research support from Bristol-Myers Squibb, and Wyeth. During the past five years, he has also received research support or honoraria from Astra-Zeneca, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen, Lundbeck, and Pfizer; he previously directly held stocks (all less than $10,000) of Akzo-Nobel, Alkermes, AstraZeneca, Biogen, Celsion, Elan, Eli Lilly, Forest, Orchestra Therapeutics, and Pfizer.
Combination Pharmacotherapy for Psychotic Depression: Significance of STOP-PD: Meyers et al. reply
Posted on February 17, 2010
Barnett S. Meyers, M.D.
Weill Cornell Medical College of Cornell University
Conflict of Interest: None Declared
Carroll raises important questions about the design of the NIMH Study of the Pharmacotherapy of Psychotic Depression (STOP-PD) trial (1) and the clinical importance of the results. The principal messages of Carroll’s letter are that a study demonstrating the efficacy of combination therapy adds little new information about the managing of psychotic major depression (MDpsy) and that the selection of an atypical antipsychotic medication, and olanzapine in particular, rather than an antidepressant as the reference condition was unfounded. He states that we knew “in early 2001” that olanzapine alone is not efficacious in delusional depression so that there was no “genuine uncertainty” about whether olanzapine plus placebo would be inferior to combination treatment using olanzapine plus a serotonin-reuptake-inhibitor (SSRI) antidepressant when STOP-PD was launched. He writes that olanzapine “lacks antidepressant properties” and suggests that the reference drug should have been sertraline “or some other recognized antidepressant”. Carroll also suggests that evidence for the efficacy of tricyclic antidepressants (TCA’s) for treating MDpsy was sufficient to warrant using a TCA as a comparator. We disagree with Dr. Carroll’s points and would like to further clarify the rationale for the STOP-PD design. First, we do not believe that the superiority of combination treatment using an atypical antipsychotic compared to atypical antipsychotic monotherapy had been established prior to the STOP-PD findings. The 2001 evidence cited by Dr. Carroll is a poster in which olanzapine plus fluoxetine had only “marginally significant” (p=.06) superiority over olanzapine (2). Olanzapine versus placebo comparisons were not described in the poster abstract. The only clearly positive combination versus monotherapy study published prior to the launch of STOP -PD was a 1985 NIMH-funded study which had demonstrated that high doses of the TCA amitriptyline and nearly 50 mg/day of the conventional antipsychotic medication perphenazine had greater efficacy than either medication alone (3) . Carroll cites the paper by Rothschild et al. (4) as “confirming” that olanzapine monotherapy was ineffective, but only one of the two reported trials was positive. Although the numerical superiority of improved depression scores with olanzapine monotherapy compared to placebo in the positive trial failed to reach statistical significance (p=.09), olanzapine was significantly superior to placebo on secondary outcome measures, including changes in overall psychopathology and global impression of severity. There was no separation on measures of efficacy in the second trial (4). Furthermore, Carroll does not cite a 2003 paper demonstrating the greater antidepressant efficacy of olanzapine monotherapy over placebo in a study of bipolar depression that included subjects with MDpsy (5). Therefore, we believe that Dr. Carroll’s statement that “olanzapine lacks antidepressant properties” is not supported in published studies.
Dr. Carroll’s points raise the important question about whether comparator medications used in studies of severely ill patients should have therapeutic activity. We believe that the illness severity of our subjects, which is reflected by the high proportions recruited from inpatient services (69.1%) and recent suicide attempters (18.5%) dictated that our reference condition balance the needs to protect subjects from significant clinical worsening and offer the potential for some clinical benefit against the need for sufficient power to demonstrate a significant difference between treatment arms. We selected olanzapine as the comparator because published evidence supported this expectation (1).
Carroll questions how STOP-PD managed the consent process and discussed the question of scientific equipoise with potential participants. Investigators informed patients and family members that consensus guidelines recommended the treatment of psychotic major depression with electroconvulsive therapy (ECT) or combination pharmacotherapy. Potential participants were also informed that the study was being conducted because of the limited evidence for the efficacy of combination treatment, particularly for combining an SSRI antidepressant and an atypical antipsychotic medication. The need for a pharmacotherapy trial of geriatric MDpsy was particularly salient because the only two published studies comparing combination treatment with a TCA for geriatric psychotic depression had been negative (6,7). Finally, the options of open treatment with doctor’s choice combination therapy or ECT and the known risks of both SSRI’s and olanzapine were discussed with potential subjects and family members.
Regarding Carroll’s suggestion that “the default or reference drug should have been a sertraline or another “recognized antidepressant”, the initial STOP-PD design did incorporate a third arm that would use sertraline monotherapy to assess the efficacy of antidepressant monotherapy. We agree with Carroll that the absence of a sertraline monotherapy arm is a limitation. However, concerns were expressed during the NIMH peer review process and by NIMH leadership about the ethical and clinical appropriateness of randomizing the severely ill and delusional target population to antidepressant monotherapy led the investigators to agree to drop the sertraline arm. In retrospect, this decision may have enhanced recruitment and retention as well as providing additional power. Trials published subsequent to STOP-PD support this decision. High dose sertraline was found to be inferior in MDpsy compared to nondelusional depression (8). Subsequent to the launch of STOP-PD, a pooled analysis based on the three studies described above found that combination therapy was significantly superior to antipsychotic monotherapy (9); however, these results were strongly influenced by the large effect identified in the 1985 study using a conventional antipsychotic as a comparator (3). More recently, Wijkstra and colleagues reported that combination treatment with venlafaxine plus quetiapine was superior to high dose monotherapy with venlafaxine (10). Although the imipramine monotherapy arm of this three-armed trial did not separate from combination therapy on the primary outcome of 50% improvement in depression scores, combination therapy was associated with a significantly greater remission rate of 41.5% compared to 28.2% for venlafaxine and 21.4% with imipramine monotherapy. The intent-to-treat remission rate with combination therapy was highly comparable to both the 41.9% reported in STOP-D PD and remission rates in antidepressant trials of nonpsychotic major depression.
We believe that Carroll’s comment that recent TCA studies “confirm historical reports of TCA antidepressant efficacy in delusional depression” is incorrect. Carroll’s historical reference considers a 1978 imipramine trial that had retrospectively classified subjects as delusional based on scores on a multi-dimension rating scale (11). This method was challenged more than thirty years ago by Glassman and co- workers (12), who had been the first to report that therapeutic concentrations of imipramine were ineffective in major depression with delusions that were identified through a direct clinical interview (13). Carroll does cite a more recent study demonstrating significantly greater response rates, but not remission rates, in patients with mood congruent psychotic depression compared to nondelusional depressed patients with high target concentrations of imipramine (14). However, the significance of the second TCA study cited by Carroll (15), which reported the non-inferiority of trimipramine to combined haloperidol and amitriptyline, is limited because the presence of delusions had been determined using item scores on a standard depression rating scale and because efficacy criteria did not specifically assess whether delusions had resolved. We believe that STOP-PD differs from these treatment studies by systematically assessing for the presence of delusions at entry and termination using a direct interview and applying anchor points for conviction with established reliability (16). STOP-PD also differs from the most of the TCA studies cited by Carroll by including subjects with both mood congruent and incongruent delusions and by stratifying recruitment to allow for assessment of the efficacy of combination treatment in geriatric MDpsy.
Finally, Carroll raises questions about olanzapine toxicity and warns that using olanzapine for the treatment of delusional depression “would be a dangerous normative practice”. We believe that Carroll overstates the significance of adverse events during the trial. Carroll refers to the 53% rate of attrition, but this rate occurred with olanzapine monotherapy. The 37.2% attrition rate with combination therapy was significantly lower (1). Furthermore, the reasons for attrition were systematically assessed. As reported in the manuscript (1), attrition was largely related to illness severity and attributed to withdrawal of consent, perhaps because of prolonged inpatient care under double-blind conditions, or subjects’ meeting operationalized criteria for insufficient response at week five or for clinical worsening. In fact, only 6.9% of combination subjects and 3.1% of monotherapy subjects withdrew because of poor tolerability. We also believe that the 8.5% incidence of meeting conservative research criteria for incident tardive dyskinesia at termination did not constitute a persistent clinically significant adverse event. We agree with Carroll that the 54% incidence of significant weight gain and the changes of metabolic parameters during the trial have important health implications. Nevertheless, we would assert that the metabolic disturbances raise the question of how long olanzapine should be continued following remission in association with combination treatment but does not warrant concluding that treating severely ill MDpsy patients with olanzapine combination therapy is a “dangerous” practice.
In summary, we continue to believe that delusional depression represents a disturbance in a non-affective domain of psychopathology rather than a particularly severe form of major depression and that the STOP-PD results support the treatment of MDpsy with combination therapy or ECT. While we agree that the metabolic consequences of atypical antipsychotic medications may be problematic, we believe that the STOP-PD results support their short-term use. We argue that the risks versus benefits for continuing an atypical antipsychotic medication beyond the point of a stable remission must be determined empirically. Also, in choosing an atypical antipsychotic medication, clinicians should consider evidence that these agents may differ in antidepressant activity (17), the risks associated with specific medications, and the anticipated duration of the combination treatment.
Meyers BS, Flint AJ, Rothschild AJ, Mulsant BH, Whyte EM.
REFERENCES
1. Meyers BS, Flint AJ, Rothschild AJ, Mulsant BH, Whyte, EM, Peasley -Miklus C, Papdemertiou E, Leon AC, Heo M: 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). Arch Gen Psychiatry. 2009; 66(8): 838-847.
2. Williamson DJ, Andersen DW, Van Campen LE, Sam LM, Sanger TM, Toeh M, Tollefson GD. A double-blind study of olanzapine-fluoxetine combination for treatment of psychotic major depression. Biological Psychiatry 2001; 49(S1): 104S.
3. Spiker DG, Weiss JC, Dealy RS, et al. The pharmacological treatment of delusional depression. Am J Psychiatry. Apr 1985;142(4):430-436.
4. Rothschild AJ, Williamson DJ, Tohen MF, et al. A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol. Aug 2004;24(4):365-373.
5. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. Nov 2003;60(11):1079-1088.
6. Mulsant BH, Sweet RA, Rosen J, et al. A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life. J Clin Psychiatry. Aug 2001;62(8):597-604.
7. Meyers BS, Klimstra SA, Gabriele M, et al. Continuation treatment of delusional depression in older adults. Am J Geriatr Psychiatry.l 2001;9(4):415-422.
8. Wijkstra J, Lijmer J, Balk FJ, Geddes JR, Nolen WA: Pharmacological treatment of unipolar psychotic depression.
9. Wijkstra J, Burther H, van den Broek W.W., Birkenhager TK, Janzing JGE, Boks MPM, Buijn JA, vn der Loos MLM, Breteler LMT, Ramaekers GMGI, Verkes RJ, Nolen WA. Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imimpramine, venlafaxine and venlafaxine plus quetiapine. Acta Psychiatr Scand 2009; 1(11) (Epub ahead of print)
10. Simpson GM, El Sheshai A, Rady A, Kingsbury SJ, Fayek M. Sertraline as monotherapy in the treatment of psychotic and nonpsychotic depression. J Clin Psychiatry. Aug 2003;64(8):959-965.
11. Quitkin F, Rifkin A, Klein DF: Imipramine response in deluded depressed patients. Am J Psychiatry 1978; 135:806-811
12. Glassman AH, Shostak M, Kantor SJ: Imipramine and delusional depressions. Am J Psychiatry, 1979; 136(4A) 462-463.
13. Glassman AH, Perel JM, Shostak M, Kantor SJ, Fleiss JL. Clinical implications of imipramine plasma levels for depressive illness. Arch Gen Psychiatry. Feb 1977;34(2):197-204.
14. Birkenhager TK, van den Broek WW, Mulder PG, Moleman P, Bruijn JA: Efficacy of imimpramine in psychotic versus nonpsychotic depression. J Clin Psychopharacol, 2008; 28:166-170.
15. Kunzel HE, Acki N, Hatzinger M, Held K, Holsboer-Trachsler E, Ising M, Kascha W, Kaasper S, Konstaidis A, Sonntag A, Uhr M, Yassouridis A, Holsboer F, Steiger A: Outcome in delusional depression comparing trimipramine monotherapy with a combination of amitriptyline and haloperidol – a double-blind multi-center trial. J Psychiatr Res 2009; 43:702-710
16. Meyers BS, English J, Gabriele M, et al. A delusion assessment scale for psychotic major depression: Reliability, validity, and utility. Biol Psychiatry. 2006;60(12):1336-1342.
17. Cruz N, Sanchez-Moreno J, Torres F, Gokolea JM, Valenti M, Vieta E: Efficacy of modern antipsychotics in placebo-controlled trials in bipolar depression: a meta-analysis. Int J Neuropsychopharmacol, 2009; 29:1-10 (Epub, ahead of print).
This work was supported by grants from the NIMH. Medications for the study were donated by Eli Lilly and Pfizer. Dr. Meyers has received research support from Forest Laboratories and Pfizer. He has provided legal consultation to AstraZeneca. Dr Flint has received honoraria from Janssen-Ortho, Lundbeck Canada, and Pfizer Canada. Dr Rothschild has received research support or honoraria from AstraZeneca, Bristol-Myers, Cephalon, Cyberonics, Forest Laboratories, Eli Lilly, Merck, Pfizer, Takeda, Novartis, and Wyeth; He has provided expert testimony for Pfizer, GlaxoSmithKline, Forest Laboratories, and Eli Lilly; and has received royalties for the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT)TM Dr. Whyte has received research support from Pfizer, Forrest Laboratories, Ortho-McNeil Pharmaceutical, and Eli Lilly and Company. Benoit H. Mulsant receives research support from Bristol-Myers Squibb, and Wyeth. During the past five years, he has also received research support or honoraria from Astra-Zeneca, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen, Lundbeck, and Pfizer; he previously directly held stocks (all less than $10,000) of Akzo-Nobel, Alkermes, AstraZeneca, Biogen, Celsion, Elan, Eli Lilly, Forest, Orchestra Therapeutics, and Pfizer.
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