ORIGINAL CONTRIBUTION
`
`Efficacy and Safety of Mifepristone for the
`Treatment of Psychotic Depression
`
`Christine M. Blasey, PhD, MS,*Þ Thaddeus S. Block, MD,*Þ Joseph K. Belanoff, MD,*
`and Robert L. Roe, MD*
`
`Abstract: Open-label studies and randomized clinical trials have sug-
`gested that mifepristone may be effective for the treatment of major
`depression with psychotic features (psychotic depression). A recent study
`reported a correlation between mifepristone plasma concentration and
`clinical response.
`The current study aimed to evaluate the safety and efficacy of mi-
`fepristone and, secondarily, to test whether response was significantly
`greater among patients with mifepristone plasma concentrations above
`an a priori hypothesized threshold.
`A total of 433 patients who met criteria for psychotic depression were
`randomly assigned to receive 7 days of either mifepristone (300, 600, or
`1200 mg) or placebo. Response was defined as a 50% reduction in psy-
`chotic symptoms on both days 7 and 56. Cochran-Mantel-Haenszel tests
`compared (1) the proportion of responders among patients assigned mi-
`fepristone versus placebo and (2) the proportion of responders among the
`subset of patients with plasma concentrations greater than 1660 ng/mL
`versus placebo.
`Mifepristone was well tolerated at all 3 doses. The proportion of re-
`sponders randomized to mifepristone did not statistically differ from pla-
`cebo. Patients with trough mifepristone plasma concentrations greater than
`1660 ng/mL were significantly more likely to have a rapid and sustained
`reduction in psychotic symptoms than those who received placebo.
`The study failed to demonstrate efficacy on its primary end point.
`However, the replication of a statistically significant linear association
`between mifepristone plasma concentration and clinical response indi-
`cates that mifepristone at sufficient plasma levels may potentially be ef-
`fective in rapidly and durably reducing the psychotic symptoms of patients
`with psychotic depression.
`
`Key Words: psychotic depression, glucocorticoid receptor antagonists,
`mifepristone, cortisol, hypothalamic-pituitary-adrenal axis, ROC
`analyses, signal detection
`(J Clin Psychopharmacol 2011;31: 436Y440)
`
`M ajor depression with psychotic features (psychotic de-
`
`pression) is a common and debilitating psychiatric ill-
`ness, which affects up to 25% of depressed patients admitted to
`a psychiatric hospital.1 It carries a 0.4% prevalence across the
`United States and Europe.2 Psychotic depression differs from
`nonpsychotic depression in several ways, including increased
`
`From *Corcept Therapeutics Incorporated, Menlo Park; and †Department of
`Psychiatry & Behavioral Sciences, Stanford University School of Medicine,
`Stanford, CA.
`Received November 1, 2010; accepted after revision May 9, 2011.
`Reprints: Christine M. Blasey, PhD, MS, Stanford University School of
`Medicine, Stanford, and Corcept Therapeutics Menlo Park, CA
`(e-mail: cblasey@corcept.com).
`Drs Blasey and Block are joint primary authors.
`The study was funded by Corcept Therapeutics. The authors are employees
`of Corcept Therapeutics.
`Copyright * 2011 by Lippincott Williams & Wilkins
`ISSN: 0271-0749
`DOI: 10.1097/JCP.0b013e3182239191
`
`risk of mortality,3 increased severity and chronicity of depressive
`episodes, increased impairment, increased psychiatric comor-
`bidity, increased suicidality,4 and increased rate of relapse.5,6
`Some have argued that psychotic depression is a different clinical
`entity from nonpsychotic depression, despite being diagnostically
`coded as a subtype of major depression.7,8 In addition, patients
`with psychotic depression tend to have a poor response to stan-
`dard antidepressants,9,10 often requiring more complex treatments
`such as electroconvulsive therapy (ECT) or combination phar-
`macotherapy with antipsychotics and antidepressants.
`Dysregulation of the hypothalamic-pituitary-adrenal axis has
`been postulated in the pathophysiology of psychotic depression
`for many years.11 Patients with psychotic depression have high
`rates of dexamethasone suppression test nonsuppression12 and
`abnormalities in diurnal fluctuation of cortisol.13 Mifepristone,
`an antagonist of the type 2 glucocorticoid receptor, has been
`proposed as a possible pharmacologic treatment of psychotic
`depression based on these biologic observations.14 Prior studies
`of mifepristone in the treatment of psychotic depression have
`included both open-label and randomized controlled trials and
`have produced varying results.15Y19 In a previous randomized
`clinical trial published in 2006, efficacy of mifepristone was
`demonstrated in this patient population, particularly among
`patients with moderate to severe psychotic symptoms.16
`Results from another previous randomized clinical trial of
`mifepristone testing the reduction of psychotic features in patients
`with psychotic depression were published in 2009. In this trial,
`there was a statistically significant correlation between plasma
`mifepristone level and clinical response.19 Specifically, 42% of
`patients with mifepristone plasma concentrations greater than
`1660 ng/mL versus 23% of patients randomized to placebo met
`the response criteria (a 50% reduction from baseline in psy-
`chotic symptoms at both study days 7 and 56). The plasma
`concentrationYefficacy relationship was detected as statistically
`significant despite considerable background noise owing to the
`presence of a statistically significant site-by-treatment interaction.19
`The current study was a placebo-controlled randomized
`clinical trial designed to evaluate the safety and efficacy of mi-
`fepristone for the reduction of psychotic symptoms in patients
`with psychotic depression. Secondarily, based on findings from
`a previous, separate clinical trial reported in 2009,19 it was hy-
`pothesized that patients whose mifepristone plasma concentra-
`tions were greater than 1660 ng/mL would be significantly more
`likely to meet responder criteria when compared with placebo-
`treated patients.
`
`MATERIALS AND METHODS
`Participants
`Participants were 433 patients who met current Diagnostic
`and Statistical Manual, Fourth Edition, Text Revision, diagnostic
`criteria for major depressive disorder with psychotic features by
`Structured Clinical Interview for DSM Disorders and had min-
`imum baseline raw scores of 38 on the Brief Psychiatric Rating
`
`436
`
`www.psychopharmacology.com
`
`Journal of Clinical Psychopharmacology & Volume 31, Number 4, August 2011
`
`Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
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`Journal of Clinical Psychopharmacology & Volume 31, Number 4, August 2011
`
`Mifepristone and Psychotic Depression
`
`Scale (BPRS) total score, 12 on the BPRS Positive Symptom
`Subscale (PSS), and 20 on the 24-item Hamilton Depression
`Rating Scale. Eligible participants were between 18 and 75 years
`and were not on antidepressants, antipsychotics, and/or mood
`stabilizers for at least 7 days before randomization. Potential
`patients were excluded who had a primary psychiatric diagno-
`sis of schizophrenia, schizoaffective disorder, or bipolar disor-
`der. Other exclusion criteria included the following: presence of
`a major medical problem; history of clinically significant liver
`disease including viral hepatitis, steatohepatitis, and alcohol- or
`drug-induced liver disease; ECT within 3 months before ran-
`domization; currently taking medications known to significantly
`induce or inhibit the metabolism of CYP 3A4; used illicit drugs
`within 30 days before screen as per patient report and urine drug
`screen; history of drug dependence within 6 months of ran-
`domization; history of alcohol dependence within 6 months of
`randomization, in the judgment of the investigator at immedi-
`ate risk of suicide or at risk for harming others; had received
`investigational therapy within 30 days of randomization; and
`previously participated in a mifepristone clinical trial.
`Patients were enrolled in 40 outpatient clinical research
`centers across the United States and 5 sites in eastern Europe.
`After complete description of the study to subjects, written in-
`formed consent was obtained. The study protocol was reviewed
`at all research centers by a local or central institutional review
`board.
`
`Design
`This was a 56-day, double-blinded, 4-arm randomized clin-
`ical trial. Patients were randomly assigned 1:1:1:1 to receive either
`active treatment of mifepristone at 1 of 3 dose levels (300 mg, n =
`107; 600 mg, n = 107; 1200 mg, n = 109) or placebo (n = 110).
`Patients were randomized to receive either mifepristone or pla-
`cebo daily for 7 days. Throughout the study, patients were ad-
`ministered one of the following antidepressant medications at
`standard clinical doses: bupropion, venlafaxine, fluoxetine, ci-
`talopram, escitalopram, mirtazapine, paroxetine, or sertraline.
`Blood samples were obtained on day 7, the last day of ac-
`tive dosing. After solvent extraction, trough plasma concentra-
`tions of mifepristone were measured using high-performance
`reverse-phase liquid chromatography followed by tandem mass
`spectrometry (MicroConstants, San Diego, Calif ). The internal
`standard was mifepristone-d4. Liquid chromatographic separa-
`tions were achieved using a ZORBAX (Agilent Technologies,
`Santa Clara, Calif ) SB phenyl column (150  2.1 mm, 5 Km).
`The mobile phase consisted of solvent A (0.1% formic acid in
`water) and solvent B (0.1% formic acid in acetonitrile) and was
`delivered at a flow rate of 0.033 mL/min. The lower limit of
`quantitation (sensitivity) of the assay was 10 ng/mL. The gradient
`of mobile phase A/phase B = 59:49. The MS instrument settings
`were as follows: mass transition = 430.4 9 372.35; cone (V) =
`50; collision (eV) = 21; and dwell time (seconds) = 0.2. There is
`a single charge associated with the compound mifepristone: the
`expected mass/charge (m/z) = MW + 1.
`Plasma measurements were available for 87% of study par-
`ticipants. Missing data analysis indicated that patients with mis-
`sing plasma data (13%) did not statistically differ from patients
`with valid data on baseline parameters.
`Efficacy was measured using the BPRS-PSS, a Likert-type
`ratings scale with 4 items: conceptual disorganization, suspi-
`ciousness, hallucinatory behavior, and unusual thought content.20
`Responses are rated from 1 (not present) to 7 (extremely severe).
`Scores on PSS are derived by summing the ratings across the
`4 items and then subtracting 4, such that the derived scale scores
`range from 0 (no symptoms present) to 24 (all symptoms pres-
`
`ent at a severe level). The BPRS was administered by raters who
`were clinical researchers with at least 1 year of experience per-
`forming the BPRS and who completed training every 6 months
`throughout the study. Raters were certified by using online test-
`ing methods that evaluated rater scores against a criterion standard
`test (Hillicon Technologies, Austin, Tex).
`
`Primary End Point
`Responders were defined as patients with a 50% or greater
`reduction in their baseline PSS score on days 7 and 56. Patients
`with less than a 50% reduction from baseline at either day 7 or 56
`were defined as nonresponders. Patients requiring rescue treat-
`ment with antipsychotic or mood stabilizer medications were also
`defined as nonresponders.
`
`Statistical Analyses
`The primary efficacy end point was the comparison of the
`proportion of responders in the active group (all 3 dose groups
`combined) versus the placebo group using the Cochran-Mantel-
`Haenszel procedure, with site used as a stratification variable.
`Efficacy analyses were conducted for 3 populations: intent to
`treat (ITT), modified intent to treat (mITT), and observed cases
`(OC). For the primary end point, missing BPRS scores were im-
`puted using a mixed model for repeated measurements, with terms
`for treatment group, baseline PSS score, and time as categorical
`variables. The mITT population was defined a priori to the un-
`blinding and comprised the ITT population minus the patients
`enrolled at 1 study site (n = 35). Quality control analyses con-
`firmed that patients assigned to receive active treatment at this site
`had mifepristone plasma concentrations below the minimum mea-
`surable quantity. The OC population was defined as those patients
`with observed efficacy data on days 7 and 56. Missing data anal-
`yses were conducted to compare the 3 analysis populations on all
`study parameters.
`Secondary efficacy analysis compared the proportion of
`responders among patients with plasma concentrations of mi-
`fepristone greater than 1660 ng/mL versus patients who received
`placebo using Pearson W2 test. The level of 1660 ng/mL provided
`maximal sensitivity and specificity for differentiating responders
`from nonresponders in a previous clinical trial using signal
`detection analysis of receiver operating characteristic (ROC)
`curves.19,21 Exploratory analyses using ROC analyses21 were
`conducted to determine the plasma level cut point for maximal
`discrimination between responders and nonresponders in this
`study.
`Safety analyses were conducted on the population of all
`patients who were randomized and received at least 1 dose of
`study medication. All adverse events were tabulated and com-
`pared between treatment groups.
`
`RESULTS
`Table 1 shows the baseline characteristics of study
`participants.
`
`Primary End Point: Mifepristone Versus Placebo
`The Cochran-Mantel-Haenszel test adjusted for site indi-
`cated no statistically significant difference in the proportion of
`responders between those patients who received mifepristone
`(all dose groups combined) and those who received placebo on
`the primary end point. Figure 1 shows the response rates on the
`primary end point for the ITT, mITT, and OC populations. Post
`hoc analyses indicated that the 3 active dose groups did not differ
`from each other or from placebo in the proportion of responders.
`
`*
`
`2011 Lippincott Williams & Wilkins
`
`www.psychopharmacology.com 437
`
`Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
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`

`Blasey et al
`
`Journal of Clinical Psychopharmacology & Volume 31, Number 4, August 2011
`
`TABLE 1. Baseline Characteristics of Study Participants
`
`Mifepristone 300 mg Mifepristone 600 mg Mifepristone 1200 mg Placebo
`
`mITT, n*
`Age, mean (SD), y
`Sex (% female)
`Raw BPRS-PSS,† mean (SD)
`24-item Hamilton Depression Rating Scale, mean (SD)
`Mifepristone plasma concentration at day 7,
`mean (SD), ng/mL
`
`93
`44 (12)
`60
`14.4 (2)
`36.6 (8)
`1366 (556)
`
`97
`46 (12)
`59
`14.7 (3)
`37.1 (8)
`1819 (842)
`
`104
`47 (10)
`66
`14.8 (2)
`35.5 (8)
`2070 (957)
`
`103
`43 (11)
`65
`14.6 (2)
`36.5 (7)
`0
`
`*Statistics presented in this table describes the mITT population.
`†The scoring method for converting raw BPRS-PSS scores to derived scores is detailed in the Materials and Methods section.
`
`Secondary End Point: Clinical Response and
`Mifepristone Plasma Concentration
`Of patients assigned to active treatment and with observed
`plasma concentrations, 42% (108/255) had mifepristone plasma
`concentrations greater than 1660 ng/mL. As shown in Table 2,
`these patients were significantly more likely than patients as-
`signed to placebo to meet the efficacy response criterion (52% vs
`34%, P = 0.02). Of patients treated with mifepristone, but with
`plasma levels below 1660 ng/mL, 38% met the efficacy response
`criterion.
`Exploratory signal detection analysis21 detected that
`1356 ng/mL was the optimal plasma level cut point for discrim-
`inating responders from nonresponders. Of the patients assigned
`to treatment with mifepristone, and whose plasma concentrations
`exceeded 1356 ng/mL, 51% were responders compared with
`34% of patients assigned to placebo (P = 0.02). Patients treated
`with mifepristone, but with plasma levels below the threshold of
`1356 ng/mL, had a response rate of 31%. Of patients with mea-
`surable plasma mifepristone levels at day 7, 65% had mifepris-
`tone plasma concentrations greater than 1356 ng/mL.
`Table 3 shows the proportion of patients in each dose group
`with mifepristone plasma concentrations greater than the thresholds
`of 1660 and 1356 ng/mL, respectively. Patients in the 1200-mg dose
`
`group were most likely to have plasma levels greater than both
`the 1356- and 1660-ng/mL thresholds.
`
`Safety
`All 3 dose levels of mifepristone seemed to be well toler-
`ated throughout the study, and similar percentages of patients
`experienced 1 or more treatment emergent adverse events
`throughout the study for all treatment groups including placebo
`(Table 4). Rates of headache, dizziness, and dyspepsia were higher
`in the mifepristone group, and rates of nausea and somnolence
`were higher in the placebo group. Sixty-nine percent (307/442) of
`the patients in the safety population (all patients enrolled) had 1
`or more adverse events. There were a total of 18 serious adverse
`event (SAEs; placebo = 5, mifepristone 300 mg = 6, 600 mg = 2,
`and 1200 mg = 5), which occurred among 15 patients (placebo =
`4, mifepristone 300 mg = 5, mifepristone 600 mg = 2, and
`1200 mg = 4). Of the 18 SAEs, 14 were psychiatric in origin
`and included events such as ‘‘worsening psychosis, worsening
`depression, suicidal ideation, and acute anxiety.’’ Four nonpsy-
`chiatric SAEs occurred in 3 patients, namely, gastritis, worsening
`asthma, and rash + bilateral pleural effusions, which occurred in
`the same patient. Sixteen patients experienced either an adverse
`event or SAE that led to premature discontinuation from the
`study (placebo = 6, 300 mg = 3, 600 mg = 3, 1200 mg = 4). Of
`the 15 patients with 1 or more SAEs, 7 terminated the study
`early because of the SAE. In only 1 patient with SAE (rash and
`bilateral pleural effusion) was the SAE judged to be related to
`
`TABLE 2. Proportion of Responders With Plasma
`Concentrations Above Cut points
`
`Mifepristone,
`%
`
`Placebo,
`%
`
`P*
`
`0.14
`0.02
`
`0.02
`
`FIGURE 1. Primary end point: proportion of patients with
`rapid and sustained clinical response. Cochran-Mantel-Haenszel
`tests indicated that active and placebo groups did not differ in
`the proportion of responders (ITT, P = 0.58; mITT, P = 0.60;
`OC, P = 0.14). In each bar cluster, the bar on the left shows the
`response rate for patients assigned to active treatment and the
`right bar shows the response rate for patients assigned to placebo.
`
`438
`
`www.psychopharmacology.com
`
`*
`
`2011 Lippincott Williams & Wilkins
`
`Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`44
`52
`
`51
`
`34
`34
`
`34
`
`All patients†
`Patients with plasma
`concentration 91660 ng/mL‡
`Patients with plasma
`concentration 91356 ng/mL‡
`*Probability values derived from Pearson 2  2 W2 tests.
`†Patients with observed mifepristone plasma concentration and ob-
`served efficacy data.
`‡The concentration 1660 ng/mL was the a priori defined cut point for
`the study, and 1356 ng/mL was defined from post hoc signal detection
`analysis.
`
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`Journal of Clinical Psychopharmacology & Volume 31, Number 4, August 2011
`
`Mifepristone and Psychotic Depression
`
`TABLE 3. Proportion of Patients in Each Dose Group
`With Mifepristone Plasma Concentrations Greater Than
`1356 and 1661 ng/mL
`
`300 mg
`
`21
`52
`
`600 mg
`
`1200 mg
`
`45
`63
`
`55
`81
`
`Plasma Concentration
`91660 ng/mL,* %
`91356 ng/mL,† %
`*The concentration 1660 ng/mL was specified a priori in the current
`study and was detected as an optimal cut point in a previously published
`clinical trial.19
`†The concentration 1356 ng/mL was the threshold in the current
`study, which optimally discriminated responders and nonresponders
`using ROC signal detection methods.
`
`centrations (ie, 91660 ng/mL) were significantly more likely than
`placebo to have a rapid and sustained reduction in their psychotic
`symptoms.
`This was the first clinical trial to use 3 dose levels of
`mifepristone. There was no statistically significant relationship
`between dose of mifepristone (300, 600, or 1200 mg) and clin-
`ical efficacy. Rather, trough plasma concentration of mifepris-
`tone on study day 7, regardless of dose, was positively correlated
`with clinical improvement. Patients receiving 1200 mg were more
`likely than patients receiving the lower doses to have mifepristone
`plasma concentrations greater than the threshold associated with
`response in a previous study (1660 ng/mL).19
`The pharmacokinetics of mifepristone is complex and non-
`linear. For a given population receiving a fixed dose of mifepris-
`tone, the variability of plasma concentrations is large.24 In our
`study, a comparison of plasma concentration distributions across
`dose levels showed substantial overlap (Table 1). However, there
`was an observable linear relationship between dose and plasma
`concentration: 52% of patients dosed with 300 mg, 63% of pa-
`tients dosed with 600 mg, and 81% of patients dosed with 1200 mg
`achieved the plasma threshold of 1356 ng/mL derived in the
`ROC analysis. These results suggest that the higher daily dose
`of mifepristone given to a patient, the higher their probability
`for experiencing a significant reduction in psychotic symptoms.
`Previous work with mifepristone in psychotic depression
`has mostly been conducted with a dose of mifepristone 600 mg.
`This study provided the opportunity to compare the safety profile
`of mifepristone 1200 mg to placebo and lower doses of mi-
`fepristone. These data suggest that mifepristone 1200 mg is as
`safe and well tolerated in this patient population as the lower
`doses of mifepristone, while maximizing the probability of yield-
`ing mifepristone plasma concentrations greater than the ROC-
`defined plasma threshold.
`Given the debilitating nature of psychotic depression, it is
`imperative to search for new treatments that improve on the cur-
`rent mainstays of psychiatric practice. Combination pharmaco-
`therapy (antidepressant + antipsychotic) is often the first-line
`treatment for this patient population, and ECT is usually reserved
`for more severe cases. Although these treatment options have
`
`study drug by the investigator. In all other cases, SAEs were
`judged to be not related to study drug by the investigator.
`
`DISCUSSION
`There were no statistically significant differences between
`mifepristone and placebo on the study’s primary end point (ie,
`50% or greater reduction in psychotic symptoms at days 7 and
`56). The observed placebo response rate in all analysis popula-
`tions was higher than expected. Previous studies of psychotic
`depression have reported placebo response rates close to zero.22
`However, the higher-than-expected placebo response is consis-
`tent with reports from the larger psychiatric literature, which has
`reported an upward trend in placebo response in studies of major
`depressive disorder. In a review of 75 placebo-controlled studies
`across several decades, Walsh et al23 observed that placebo re-
`sponse rates increased an average of 7% per decade; placebo
`response ranged from 10% to 50% across the time span under
`review.
`In our secondary analyses, a positive linear correlation be-
`tween plasma concentration of mifepristone and efficacy, ob-
`served in a previous clinical trial,19 was replicated and confirmed.
`As hypothesized, patients with higher mifepristone plasma con-
`
`TABLE 4. Patients With Treatment-Emergent Adverse Events*
`
`Adverse Event
`
`Mifepristone 300 mg
`
`Mifepristone 600 mg
`
`Mifepristone 1200 mg
`
`Placebo
`
`n (safety population)
`Headache, n (%)
`Nausea, n (%)
`Dizziness, n (%)
`Dry mouth, n (%)
`Diarrhea, n (%)
`Somnolence, n (%)
`Dyspepsia, n (%)
`Fatigue, n (%)
`Constipation, n (%)
`Vomiting, n (%)
`Decreased appetite, n (%)
`Back pain, n (%)
`Insomnia, n (%)
`Tremor, n (%)
`Anxiety, n (%)
`Patient with any of the listed events, n (%)
`
`110
`20 (18)
`20 (18)
`9 (8)
`5 (4)
`10 (9)
`8 (7)
`2 (2)
`9 (8)
`3 (3)
`5 (4)
`4 (4)
`7 (6)
`4 (4)
`4 (4)
`6 (5)
`73 (66)
`
`109
`21 (19)
`23 (21)
`12 (11)
`10 (9)
`9 (8)
`9 (8)
`4 (4)
`7 (6)
`6 (5)
`7 (6)
`7 (7)
`4 (4)
`7 (6 )
`6 (5)
`5 (5)
`83 (76)
`
`112
`28 (25)
`20 (18)
`18 (16)
`14 (12)
`12 (11)
`5 (4)
`11 (10)
`6 (5)
`8 (7)
`8 (7)
`4 (4)
`4 (4)
`6 (5)
`3 (3)
`6 (5)
`77 (68)
`
`111
`21 (18)
`27 (24)
`7 (6)
`12 (11)
`7 (6)
`11 (10)
`3 (3)
`4 (4)
`6 (5)
`5 (4)
`2 (2)
`3 (3)
`6 (5)
`2 (2)
`3 (3)
`74 (66)
`
`*Adverse events are listed for conditions that are reported by at least 5% of the study’s safety population (all patients enrolled).
`
`*
`
`2011 Lippincott Williams & Wilkins
`
`www.psychopharmacology.com 439
`
`Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`4
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`Blasey et al
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`Journal of Clinical Psychopharmacology & Volume 31, Number 4, August 2011
`
`some utility in this patient population, they also present very real
`drawbacks. The newer-generation antipsychotics often prescribed
`for this condition are known to increase patients’ risk of obesity,
`diabetes, and metabolic syndrome.25 Because patients with mental
`illness already have an approximately 2-fold higher all-cause
`mortality rate relative to the general population,26 it is problematic
`to administer medication regimens known to induce metabolic
`syndrome and obesity. Electroconvulsive therapy is associated
`with cognitive adverse effects, financial burden, and is, unfortu-
`nately, associated with substantial social stigma.
`This study replicated a linear association observed in a prior
`clinical trial19 between trough plasma concentrations of mi-
`fepristone and reduction of psychotic symptoms. Future work
`evaluating the utility of mifepristone in treating psychotic de-
`pression will focus on the optimization of dose and plasma levels
`to increase the percentage of patients achieving a robust response.
`A multisite randomized clinical trial evaluating the 1200-mg dose
`of mifepristone versus placebo is currently underway to further
`elucidate the role mifepristone may play in the treatment of psy-
`chotic depression.
`
`ACKNOWLEDGMENT
`The authors thank Ruth Ann Gover for her administrative
`assistance and support in preparing the article.
`
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`5
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`

`

`
`
`Journal of Clinical
`
`Volume 31
`
`Number4
`
`WS
`
`sugliemental Digital Content is available in the text.
`
`Contents
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`(Continued next page)
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