PRIORITY COMMUNICATION
`An Open Label Trial of C-1073 (Mifepristone) for
`Psychotic Major Depression*
`
`Joseph K. Belanoff, Anthony J. Rothschild, Frederick Cassidy, Charles DeBattista,
`Etienne-Emile Baulieu, Clifford Schold, and Alan F. Schatzberg
`
`Background: The rationale for treating patients with
`psychotic major depression (PMD) with glucocorticoste-
`roid receptor (GR) antagonists is explained.
`Methods: Thirty patients with PMD, with Hamilton Rat-
`ing Scale for Depression (HAMD-21) scores of 18 or
`greater, were assigned in an open label trial to receive 50
`mg, 600 mg, or 1200 mg of mifepristone for 7 days.
`Results: All the subjects completed the protocol; there
`were no dropouts. Side effects were mild and sporadic. Of
`19 subjects in the combined 600- and 1200-mg group, 13
`had a 30% or greater decline in their Brief Psychiatric
`Rating Scale (BPRS) scores, compared with 4 of 11 in the
`50-mg group. In the 600- and 1200-mg group, 12 of 19
`subjects showed a 50% decline in the BPRS positive
`symptom subscale, a more sensitive index for the symp-
`toms seen in PMD, compared with 3 of 11 in the 50-mg
`group; 8 of 19 subjects in the 600- and 1200-mg group
`had a 50% decline in the HAMD-21, compared with 2 of
`11 in the 50-mg group.
`Conclusions: These results suggest that short term use
`of GR antagonists may be effective in the treatment of
`psychotic major depression and that
`further blinded
`are warranted. Biol
`Psychiatry
`2002;52:
`studies
`386 –392 © 2002 Society of Biological Psychiatry
`
`Key Words: C-1073 Mifepristone, psychotic major de-
`pression, cortisol
`
`*See accompanying Commentary, in this issue.
`
`Introduction
`
`There is strong evidence to support the hypothesis that
`
`psychotic major depression (PMD) is a distinct syn-
`drome. Statistically significant differences between psy-
`chotic and nonpsychotic major depression have been noted
`
`From Corcept Therapeutics Inc. (JKB), Menlo Park, California; the Department of
`Psychiatry, University of Massachusetts Medical School (AJR), Worcester,
`Massachusetts; the Department of Psychiatry, Duke University (FC), John
`Umstead Hospital, Butner, North Carolina; Department of Psychiatry, Stanford
`University, (CD, AFS), Stanford, California; Ste´roı¨des et Syste`me Nerveux,
`Institut National de la Sante´ et de la Recherche Me´dicale (E-EB), Le
`Kremlin-Biceˆtre Cedex, France; Duke Clinical Research Institute (CS),
`Durham, North Carolina.
`Address reprint requests to Joseph K. Belanoff, M.D., Corcept Therapeutics Inc.,
`275 Middlefield Road, Suite A, Menlo Park CA 94025.
`Received January 7, 2002; revised April 15, 2002; accepted April 17, 2002.
`
`© 2002 Society of Biological Psychiatry
`
`along many axes including presenting features (Charney
`and Nelson 1981; Coryell et al 1984; Frances et al 1981;
`Glassman and Roose 1981; Lykouras et al 1986; Nelson
`and Bowers 1978; Schatzberg and Rothschild 1992),
`neuropsychologic features (Belanoff 2001; Schatzberg et
`al 2000), biological features (Nelson and Davis 1997),
`familial transmission (Leckman et al 1984; Nelson et al
`1984), course and outcome (Robinson and Spiker 1985),
`as well as response to treatment (Anton and Burch 1990;
`Chan et al 1987; Glassman and Roose 1986; Kantor and
`Glassman 1977; Nelson and Bowers 1978; Rothschild
`1985; Spiker et al 1985).
`Many centers have reported specific abnormalities in
`the hypothalamic-pituitary-adrenal (HPA) axis activity of
`patients with psychotic depression. Patients with PMD are
`among those with the highest rates of nonsuppression on
`the dexamethasone suppression test (DST; Anton 1987;
`Anton and Burch 1990; Chan et al 1987; Kantor and
`Glassman 1977; Leckman et al 1984; Nelson and Davis
`1997; Nelson et al 1984; Robinson and Spiker 1985;
`Rothschild 1985; Schatzberg et al 2000; Spiker et al 1985),
`and many have markedly elevated postdexamethasone
`cortisol
`levels. A meta-analysis of 12 studies, with a
`combined sample size of approximately 1000 depressed
`patients, indicated that when inpatient status was con-
`trolled for, psychosis, but not melancholic symptoms, was
`associated with increased DST nonsuppression rates (Nel-
`son and Davis 1997). Significant elevation in 24-hour
`measures of urinary free cortisol levels and plasma adre-
`nocorticotropin hormone (ACTH) have also been ob-
`served in patients with PMD (Anton 1987). Patients with
`nonaffective psychoses, such as schizophrenia, generally
`do not show a high DST nonsuppression rate (Arana et al
`1983; Rothschild et al 1982), but not all studies concur
`(Muck-Seler et al 1999). We hypothesized a number of
`years ago that excessive glucocorticosteroid activity re-
`sulted in alterations in dopamine metabolism and the
`development of delusions (Schatzberg et al 1985). More
`recent data point to glucocorticoid administration causing
`cognitive deficits in humans and nonhuman primates that
`mirror impairments in PMD (Lyons 2000; Newcomer et al
`1999).
`Patients with PMD respond differently to pharmaco-
`logic therapies in comparison with patients with nonpsy-
`
`0006-3223/02/$22.00
`PII S0006-3223(02)01432-4
`
`

`

`Open Label Trial of C-1073
`
`BIOL PSYCHIATRY
`2002;52:386 –392
`
`387
`
`chotic major depression (Anton and Burch 1990; Chan et
`al 1987; Glassman and Roose 1986; Kantor and Glassman
`1977; Nelson and Bowers 1978; Rothschild 1985; Spiker
`et al 1985). Important findings include a very low placebo
`response rate in PMD, as well as a poor response to
`antidepressant therapy alone (Avery and Lubrano 1979;
`Glassman et al 1975). Patients with PMD do respond to
`electroconvulsive therapy, or a combination of antipsy-
`chotics and antidepressants. (Charney and Nelson 1981;
`Frances et al 1981; Minter and Mandel 1979). In addition,
`some recent European trials suggest that there may be a
`role for monotherapy with selective serotonin reuptake
`inhibitors, particularly fluvoxamine (Gatti et al 1996;
`Zanardi et al 1996, 1997, 2000). There has been some
`debate as to whether these European patients may have
`represented depressed patients with obsessive features
`rather than classic PMD patients (Rothschild and Phillips
`1999). In any case, both pharmacologic strategies and
`electroconvulsive therapy (ECT) may take weeks to
`months to be effective, and this results in an interim period
`of high morbidity.
`The steroid mifepristone, also known as RU486 (C-
`1073),
`(17(-hydroxy-11(-(4-dimethylaminophenyl)17((1-
`propynyl)estra-4,9-dien-3-one), is not only an antiproges-
`terone but also, at higher concentrations, an effective
`antagonist of glucocorticosteroid action in vitro and in
`vivo (Gaillard et al 1984; Herrmann 1982; Lamberts et al
`1984; Proulx-Ferland et al 1982). It is a potent antagonist
`at the low-affinity GR (glucocorticosteroid receptor, pre-
`viously named GR-II) and with little affinity for the MR
`(mineralocorticosteroid receptor, previously named GR-I).
`Past studies have mapped GR-II in the nonhuman primate
`brain and have found GR-II in high concentrations in the
`prefrontal cortex (Sanchez 2000; Patel et al 2000). The
`effects and kinetics of GR-II blockade have been explored
`fairly extensively in humans (Bertagna et al 1994; Gaillard
`et al 1984) and do not appear to be associated with
`suppression of glucocorticosteroid actions peripherally.
`Mifepristone may be useful in revealing disturbance of the
`HPA neuroendocrine rhythm in major depressive disor-
`ders (Ammar et al 1986).
`The use of mifepristone has been reported to ameliorate
`psychosis and depression in patients with Cushing’s dis-
`ease. Relatively high doses of mifepristone (400 mg to 800
`mg/day) rapidly reversed psychosis and suicidal thinking
`in two patients with Cushing’s syndrome (caused by
`metastatic adrenal cancer; Van der Lely et al 1991).
`Mifepristone use has also been reported in a patient with
`Cushing’s syndrome who had both depressive and psy-
`chotic symptoms that were unresponsive to antidepres-
`sants alone and only partially responsive to an antidepres-
`sant–antipsychotic combination. Treatment with high
`doses of mifepristone (up to 1400 mg/day) resulted in both
`
`his physical and psychiatric symptoms resolving quickly.
`(Nieman et al 1985). We recently reported on an extremely
`ill patient with refractory Cushing’s disease who was
`treated with high doses of mifepristone (up to 2000 mg)
`for almost a year before the positive effects of radiother-
`apy took hold. His medical and psychiatric symptoms
`resolved completely on mifepristone (Chu et al 2001).
`Mifepristone and other antiglucocorticoids have also
`been shown to have some benefit in major depression
`without psychotic features. For example, Murphy et al
`(1993) found that three of four patients with MDD had
`modest improvement with mifepristone when treated with
`200 mg/day for up to 8 weeks. In addition, cortisol
`synthesis inhibitors such as ketoconazole have also shown
`some benefit in the treatment of MDD (Wolkowitz et al
`1993, 1999).
`Few adverse effects from mifepristone have been ob-
`served in studies in which subjects were given 10 mg/kg/
`day for up to 7 days (Nieman 1993). At daily doses of 200
`mg, given for more than 7 days, mifepristone has been
`associated with fatigue, anorexia, and nausea (although
`not uniformly; (Grunberg et al 1993; Lamberts et al 1991).
`Mifepristone induced a maculopapular erythematous cu-
`taneous eruption in 8 of 11 normal men receiving the
`medicine at a dose of 10 mg/kg for 9 to 14 days and in 5
`of 28 patients receiving treatment for unresectable menin-
`gioma at 200 mg daily for a median of 27 months
`(Grunberg et al 1993; Laue et al 1990). The cause of this
`spontaneously resolving rash is unknown. In a recently
`completed double-blind randomized placebo-controlled
`study of mifepristone for unresectable meningioma (200
`mg/day for as long as 144 months) in 160 patients,
`mifepristone was well tolerated. Fatigue and hot flashes
`were reported more frequently in the mifepristone group,
`and 16% of the women in the mifepristone group devel-
`oped endometrial hyperplasia (Grunberg et al unpublished
`data). At higher doses (up to 22 mg/kg/day) given to
`patients with Cushing syndrome, exanthema was not seen,
`although nausea was common in these patients (Chrousos
`et al 1989). The patient described earlier, who received up
`to 2000 mg/day, experienced neither a rash nor nausea
`(Chu et al 2001).
`We recently reported a small-blinded study of mifepris-
`tone as a treatment for PMD (Belanoff et al 2001). Five
`patients with PMD participated in a 4-day, double-blind,
`placebo-controlled crossover study using 600 mg of mife-
`pristone as monotherapy for PMD. In these patients, Brief
`Psychiatric Rating Scale (BPRS) scores declined by 34%
`while they were receiving mifepristone but rose 0.4%
`while receiving placebo. Similarly, scores on the Hamilton
`Rating Scale for Depression (HAMD-21) declined by
`25.5% during mifepristone administration versus 6% dur-
`ing placebo administration. Clinical Global Impression
`
`

`

`388
`
`BIOL PSYCHIATRY
`2002;52:386 –392
`
`J.K. Belanoff et al
`
`Table 1. Raw Phase II Data by Mifepristone Dose
`
`(50 mg)
`
`Pt.
`No.
`
`10-01
`10-02
`10-09
`10-15
`03-20
`04-21
`04-22
`04-28
`10-30
`02-31
`04-32
`
`Age G Hx DCE AD AP ADP N BPRS0 BPRS7
`
`BPRS
`RESP POS0 POS7
`
`POS
`RESP HAM0 HAM7
`
`HAM
`RESP
`
`CGI
`CH
`
`CORT
`0
`
`CORT7
`
`F Y
`33
`F Y
`60
`F Y
`32
`53 M N
`38 M Y
`31
`F Y
`38 M ?
`51
`F Y
`60 M N
`40 M Y
`29
`F Y
`
`6
`36
`2
`52
`4
`6
`2
`2
`18
`26
`8
`
`X
`
`X
`
`X
`X
`X
`X
`
`X
`
`X
`
`X
`
`X
`X
`
`25
`43
`32
`37
`33
`44
`33
`34
`47
`30
`27
`
`27
`31
`11
`23
`14
`34
`24
`30
`51
`6
`20
`
`N
`N
`Y
`Y
`Y
`N
`N
`N
`N
`Y
`N
`
`2
`12
`13
`15
`14
`16
`14
`14
`17
`6
`9
`
`2
`4
`0
`10
`11
`11
`11
`11
`14
`0
`7
`
`N
`Y
`Y
`N
`N
`N
`N
`N
`N
`Y
`N
`
`27
`25
`24
`27
`29
`34
`22
`19
`38
`27
`21
`
`24
`17
`14
`19
`8
`25
`15
`19
`28
`8
`14
`
`N
`N
`N
`N
`Y
`N
`N
`N
`N
`Y
`N
`
`6
`2
`2
`3
`2
`3
`3
`3
`4
`1
`3
`
`15.63
`14.28
`9.82
`8.42
`4.45
`6.12
`9.57
`12.26
`16.84
`13.14
`6.36
`
`11.05
`6.05
`3.00
`9.77
`1.90
`12.37
`13.62
`16.90
`22.34
`14.23
`17.89
`
`(600 mg)
`
`Pt.
`No.
`
`02-04
`04-05
`10-11
`02-14
`10-18
`03-23
`04-24
`11-27
`10-29
`02-33
`
`Age G Hx DCE AD AP ADP N BPRS0 BPRS7
`
`BPRS
`RESP POS0 POS7
`
`POS
`RESP HAM0 HAM7
`
`HAM
`RESP
`
`CGI
`CH CORT0 CORT7
`
`40 M Y
`23
`F Y
`59
`F Y
`37 M Y
`46
`F
`?
`25
`F Y
`45
`F Y
`67
`F Y
`31
`F Y
`58 M Y
`
`3
`5
`6
`2
`13
`2
`1
`8
`4
`4
`
`X
`X
`X
`X
`X
`X
`X
`
`X
`
`X
`
`38
`41
`30
`23
`32
`33
`35
`51
`30
`45
`
`X
`
`25
`31
`8
`15
`21
`39
`22
`35
`4
`39
`
`Y
`N
`Y
`Y
`Y
`N
`Y
`Y
`Y
`N
`
`9
`17
`6
`4
`5
`7
`13
`10
`10
`4
`
`4
`12
`0
`2
`2
`12
`10
`2
`0
`3
`
`Y
`N
`Y
`Y
`Y
`N
`N
`Y
`Y
`N
`
`27
`23
`25
`18
`27
`25
`20
`38
`20
`24
`
`21
`4
`6
`9
`15
`29
`13
`22
`3
`12
`
`N
`Y
`Y
`Y
`N
`N
`N
`N
`Y
`Y
`
`2
`3
`1
`3
`2
`2
`3
`3
`1
`2
`
`57.68
`9.13
`35.05
`5.71
`12.01
`9.87
`30.75
`10.79
`9.67
`5.89
`16.82
`5.99
`6.23
`3.13
`46.22
`16.89
`4.16 ⬎60.00
`6.66
`27.94
`
`(1200 mg)
`
`Pt.
`No.
`
`10-03
`10-07
`10-10
`03-12
`08-16
`10-19
`03-25
`08-26
`10-34
`
`Age G Hx DCE AD AP ADP N BPRS0 BPRS7
`
`BPRS
`RESP POS0 POS7
`
`POS
`RESP HAM0 HAM7
`
`HAM
`RESP
`
`CGI
`CH CORT0 CORT7
`
`24
`F N
`56
`F Y 104
`53
`56 M ?
`52
`51 M Y
`12
`64
`F Y
`4
`25 M Y
`5
`39
`F Y
`52
`74
`F Y
`7
`45
`F Y
`17
`
`X
`
`X
`
`X
`
`X
`
`X
`X
`X
`X
`X
`
`32
`30
`37
`38
`26
`24
`28
`42
`20
`
`13
`9
`30
`5
`23
`25
`11
`28
`6
`
`Y
`Y
`N
`Y
`N
`N
`Y
`Y
`Y
`
`12
`13
`7
`13
`10
`8
`10
`9
`4
`
`6
`1
`4
`0
`6
`4
`5
`5
`1
`
`Y
`Y
`N
`Y
`N
`Y
`Y
`N
`Y
`
`19
`21
`31
`23
`18
`19
`21
`26
`19
`
`12
`7
`25
`6
`12
`17
`12
`16
`8
`
`N
`Y
`N
`Y
`N
`N
`N
`N
`Y
`
`3
`2
`2
`1
`4
`3
`4
`2
`2
`
`7.68
`5.96
`2.61
`5.90
`10.50
`7.80
`6.50
`13.56
`8.45
`
`36.97
`41.71
`20.47
`18.21
`41.80
`3.76
`7.00
`31.44
`n/a
`
`Pt. No., patient number (first two digits ⫽ site); G, gender (M, male; F, female); Hx, history of psychotic major depression; DCE, duration of current episode of psychotic
`major depression; AD, antidepressant; AP, antipsychotic; ADP, both antipsychotic and antidepressant; N, neither antipsychotic nor antidepressants; BPRS0 (7), Brief
`Psychiatric Rating Scale Score at day 0 and day 7 (individual items rated from 0 – 6); BPRS RESP, “responder” if 1, indicates 30⫹ % improvement (decline in score); POS0
`(7), subscale of BPRS (items 4, 11, 12, and 15) day 0 and day 7; POS RESP, “responder” 1 indicates 50⫹ % decline in Positive Symptom Scale; HAM0 (7), Hamilton
`Depression Scale at day 0 and day 7; HAM RESP, “responder” if 1, indicates 50%⫹ decline in HAMD score; CGI /CH, Clinical Global Impression change scores; CORT0
`(7), median afternoon cortisol value.
`
`(CGI) scores declined by 33% during mifepristone admin-
`istration and 8% during placebo administration. In this
`article, we present additional data supporting the earlier
`observations that mifepristone rapidly reverses symptoms
`of PMD and is well tolerated.
`
`Methods and Materials
`The subjects comprised 30 patients who met DSM-IV criteria, by
`clinician interview, for a diagnosis of major depression with
`
`psychotic features and had a HAMD-21 score of 18 or greater
`(Hamilton 1960). The subjects were randomly assigned to
`receive 50 mg, 600 mg, or 1200 mg of mifepristone once daily
`for 7 days. (We chose to use a 50-mg dose because the placebo
`response rate in PMD is very low. In addition, a 50-mg/day dose
`does not appear to have significant antiglucocorticoid effects in
`humans but still has antiprogesterone properties (Gaillard et al
`1984). The study was an open-label, inpatient trial. Routine
`biological and hematologic studies were conducted at day 0, day
`7, and day 28, and possible signs of adrenal insufficiency were
`
`

`

`Open Label Trial of C-1073
`
`BIOL PSYCHIATRY
`2002;52:386 –392
`
`389
`
`Table 2. Efficacy Measures: C-1073 (Mifepristone) for Psychotic Major Depression by Dose
`
`HAM-D responders
`BPRS responders
`BPRS Positive Symptom Scale
`
`50 mg
`
`2/11 (18.2%)
`4/11 (36.4%)
`3/11 (27.3%)
`
`600 mg
`
`5/10 (50%)
`7/10 (70%)
`6/10 (60%)
`
`1200 mg
`
`3/9 (33%)
`6/9 (66.7%)
`6/9 (66.7%)
`
`600 mg ⫹ 1200 mg
`
`8/19 (42.1%)
`13/19 (68.4%)
`12/19 (63.2%)
`
`HAMD, Hamilton Rating Scale for Depression; BPRS, brief psychiatric rating scale.
`
`monitored daily by specifically asking patients about the occur-
`rence of decreased appetite, nausea or vomiting, fatigue or
`weakness, dizziness, and rash.
`Subjects were between the ages of 18 and 75 and could not
`have an unstable medical problem. Women of childbearing
`potential could be included after a negative serum pregnancy test.
`Patients who admitted to using illicit drugs within the month
`before dosing, who had a positive drug screen at screening, or
`who consumed in excess of two ounces of alcohol daily were
`also excluded.
`Patients were allowed to remain on antidepressants or antipsy-
`chotic medications (or both) if they had been on stable doses for
`at least 1 week. No patient was started on an antidepressant or an
`antipsychotic medication during the week before or during the
`week of dosing. In addition, medication-naı¨ve patients were also
`allowed in the study. Benzodiazapines were permitted for insom-
`nia, as was acetaminophen for headaches. All patients were
`required to give written consent to a protocol approved by their
`academic center’s institutional review board.
`Formal psychiatric assessments, including the HAMD-21, BPRS,
`and CGI were carried out on day 0, day 3, and day 7. The positive
`symptom subscale of the BPRS was used because it focuses on
`symptoms characteristic of PMD. The items of the BPRS included
`in this scale were items 4 (conceptual disorganization), 11 (suspi-
`ciousness), 12 (hallucinatory behavior), and 15 (unusual thought
`content). Our response criteria were a 30% reduction on the BPRS,
`a 50% reduction on the BPRS positive symptom subscale, and a
`50% reduction on the HAMD-21 (Kane et al 1988; Kronig et al
`1995; Nierenberg et al 2000; Nobler et al 1997). On day 0, day
`7, and day 28, cortisol levels were measured serially every half
`hour from 1– 4. (afternoon cortisol test; Halbreich et al 1982),
`and plasma ACTH was measured serially every hour from 1– 4.
`Blood samples were spun down, and plasma was frozen at
`⫺80°F in each center before shipping to the Endocrine Labora-
`tory at Brigham and Women’s Hospital (Harvard University).
`Plasma cortisol determinations were made by radio immunoas-
`say and plasma ACTH by immunoradiometric assay.
`
`Results
`Thirty patients at six academic centers (University of
`Massachusetts, Duke University, Cornell University Med-
`ical College, University of Michigan, University of Texas
`at Galveston, and Stanford University) were enrolled in
`the study. The groups did not differ significantly in age,
`gender, ethnicity, weight, or duration of the current epi-
`sode of illness nor did they differ on baseline cortisol
`level, HAMD or BPRS (Table 1).
`The number and percent of patients who met response
`criteria (50% or greater decline on HAM-D from baseline
`to day 7, 30% or greater decline on the BPRS from
`baseline to day 7, 50% or greater decline on the BPRS
`Positive Symptom Scale) are shown in Table 2.
`Both the 600-mg/day and 1200-mg/day doses resulted
`in statistically significant increases in serum cortisol com-
`pared with the 50-mg dose at day 7 (Table 3). Mifepristone
`was well tolerated by all subjects, and none dropped out
`because of side effects. Two patients in the 600-mg group
`and one in the 1200-mg group reported uterine cramping,
`and one patient in the 50-mg group and one patient in the
`1200-mg group (but none in the 600-mg group) reported a
`rash. The rash developed by the patient in the 50-mg group
`was noted to have completely abated 1 month after study
`completion;
`the rash developed by the patient
`in the
`1200-mg group was noted to have completely abated 2
`months after study completion.
`
`Discussion
`In this open-label study, mifepristone appeared to be effec-
`tive in the patients with PMD. In the higher dose groups (600
`mg and 1200 mg), nearly two thirds of the subjects showed
`
`Table 3. Cortisol and Adrenocorticotropin Hormone (ACTH) Measures: C-1073 (Mifepristone) for Psychotic Major Depression by
`Dose
`
`Baseline cortisol (SD) (ug/dL)
`Day 7 change from baseline cortisol (SD)
`Baseline ACTH (SD) (pg/MI)
`Day 7 change from baseline ACTH (SD)
`
`ap ⬍ .05
`bp ⬍ .01
`
`50 mg n ⫽ 11
`
`600 mg n ⫽ 10
`
`1200 mg n ⫽ 9
`
`11.4 (4.1)
`.5 (6.5)
`23.9 (9.3)
`.5 (9.5)
`
`8.9 (4.3)
`20.5 (16.6)b
`18.4 (9.7)
`19.2 (19.2)a
`
`8.9 (4.4)
`15.7 (13.5)a
`16.4 (7.4)
`15.4 (17.1)a
`
`

`

`390
`
`BIOL PSYCHIATRY
`2002;52:386 –392
`
`J.K. Belanoff et al
`
`significant reductions in their psychosis in a week or less:
`each dose produced roughly equivalent benefits. Although
`the numbers are small, our data indicate that it made little
`difference whether patients were taking concomitant medi-
`cations to experience a clinically meaningful reduction in
`symptoms, (e.g., 9 of 15 patients on concomitant medications
`vs. 3 of 4 patients without other medications met response
`criteria on the BPRS Positive Symptom Subscale.) In addi-
`tion, three investigators noted that they each had a subject
`who was recorded as a nonresponder at day 7 but were
`clinically improved by day 10 (3 days after the last mifepris-
`tone dose.) Although our a priori sense was that mifepristone
`is not predominantly an antidepressant, in this group of
`patients with PMD, the fact that more than 40% of the
`subjects taking higher doses had a greater than 50% reduction
`in their HAM-D scores is noteworthy. Some of the observed
`effect on depression and psychosis could be carry over effects
`from their existing medication regimen, but the mean dura-
`tion of the PMD episode was 17 weeks. Several patients had
`been on their psychotropic regimen for 1 year or longer.
`Thus, it is unlikely but possible that the responders experi-
`enced a carryover effect in the 7 days of the trial.
`Placebo response rates are quite low in PMD, often in
`the range of 0 –10% for 1 week of placebo run-in (Anton
`and Burch 1990; Glassman et al 1975) and certainly much
`lower than rates of response we observed in our higher
`dose groups. A recently presented study (Tollefson 2001)
`reported a higher placebo response rate in PMD patients,
`but the high placebo response rate (28%) in this trial is
`inconsistent with studies published to date. It should also
`be noted that 50 mg of C-1073 is not a placebo dose.
`Indeed, it is a biologically active dose on the ovarian cycle
`(Croxatto et al 1993; Kettel et al 1991, 1996; Ledger et al
`1992; Luukkainen et al 1988; Murphy et al 1995a, 1995b;
`Shoupe et al 1987).
`This open-label study supports our previously reported
`4-day double-blind study of 600 mg of mifepristone for
`PMD. It also supports the dramatic reduction in psychosis
`and depression reported by investigators using mifepris-
`tone to treat symptoms secondary to Cushing’s disease
`(Sartor and Cutler 1996).
`We hypothesize that the psychosis in PMD is caused by
`excessive activation of the HPA axis. Actively blocking
`GR-II receptors in the prefrontal cortex and other areas in
`the brain with mifepristone may rapidly improve PMD
`patient’s psychosis. Blocking this receptor also causes a
`rapid rise in cortisol (by blocking the feedback loop),
`which could downregulate MR. Perhaps this perturbation
`of the HPA axis causes a resetting of HPA normal rhythm.
`Additional well-controlled scientific research should test
`these possibilities. Interestingly, ECT, a mainstay in the
`treatment of psychotic major depression, creates a similar
`perturbation of the HPA axis (Mitchell et al 1990; Swartz
`
`and Chen 1985). Mifepristone, of course, is much more
`specific than ECT, which probably accounts for its more
`benign side-effect profile. It is also difficult for the patient
`to receive ECT more than every other day or every third
`day as the brain becomes more refractory to seizures and
`side effects, particularly cognitive side effects, increase.
`Mifepristone can be given daily which, compared with
`ECT, cuts down on the length between first and last
`“dosing.” At this time, we know little about repeated
`exposure to mifepristone in patients who relapse. On the
`other hand, ECT is known to be a safe and effective
`strategy for some PMD and appears effective in repeated
`trials. Combination therapy with antipsychotics and anti-
`depressants also appear safe and effective for both acute
`treatment and in repeated exposures; however, both main-
`tenance ECT and maintenance pharmacotherapy may have
`a significant side-effect burden for the PMD patient and
`have a delayed onset of action.
`These data, although based on a relatively small number
`of subjects, raise the possibility that mifepristone, used
`alone or as an adjunct to antidepressant or antipsychotic
`medications, appears to substantially improve the psy-
`chotic and depressive symptoms seen in psychotic major
`depression. This finding adds to the growing body of
`literature indicating that hormonal dysregulation may be
`causally related to the expression of affective disorders.
`We are planning to conduct a large, random-assignment,
`double-blind study of mifepristone in psychotic major
`depression in the near future.
`
`This study was supported by a grant from Corcept Therapeutics. JKB,
`AFS, and AJR have a financial interest in Corcept Therapeutics, a
`pharmaceutical company that is testing antiglucocorticoid treatment for
`psychiatric disorders. The authors also acknowledge related support from
`the NIMH (MH50604 and T-32MH19983) the Pritzker fund, and
`NARSAD.
`
`References
`Ammar S, Allilaire J-F, Lecrubier YM, Widlocher D, Baulieu EE
`(1986): Letter: Afternoon increase in plasma cortisol
`in
`depressed patients receiving an antiglucocorticosteroid in the
`morning. Am J Psychiatry 143:129 –130.
`Anton RF (1987): Urinary free cortisol in psychotic depression.
`Biol Psychiatry 22:24 –34.
`Anton RF Jr, Burch EA Jr (1990): Amoxapine versus amitripty-
`line combined with perphenazine in the treatment of psy-
`chotic depression. Am J Psychiatry 147:1203–1208.
`Arana GW, Barreira PJ, Cohen BM, Lipinski JF, Fogelson D
`(1983): The dexamethasone suppression test in psychotic
`disorders. Am J Psychiatry 140:1521–1523.
`Avery D, Lubrano A (1979): Depression treated with imipramine
`and ECT: The DeCarolis study reconsidered. Am J Psychiatry
`136:559 –562.
`
`

`

`Open Label Trial of C-1073
`
`BIOL PSYCHIATRY
`2002;52:386 –392
`
`391
`
`Belanoff J, Flores B, Kalezhan M, Sund B, Schatzberg A (2001):
`Rapid reversal of psychotic major depression using mifepris-
`tone. J Clin Psychopharmacol 21:516 –521.
`Belanoff JK, Kalehzan M, Sund B, Fleming Fice KS, Schatzberg
`AF (2001): Cortisol activity and cognitive changes in psy-
`chotic major depression. Am J Psychiatry 158:1612–1616.
`Bertagna X, Escourolle H, Pinquier JL, Coste J, Roux-DeMay
`MC, Perles P, et al (1994): Administration of RU486 for 8
`Days in normal volunteers: Antiglucocorticoid effect with no
`evidence of peripheral cortisol deprivation. J Clin Endocrinol
`Metab 78:375–380.
`Chan CH, Janicak PG, Davis JM, Altman E, Andriukaitis S,
`Hedeker D (1987): Response of psychotic and nonpsychotic
`depressed patients to tricyclic antidepressants. J Clin Psychi-
`atry 48:197–200.
`Charney DS, Nelson JC (1981): Delusional and nondelusional
`unipolar depression: Further evidence for distinct subtypes.
`Am J Psychiatry 138:328 –333.
`Chrousos GP, Laue L, Nieman LK, Udelsman R, Kawai S,
`Loriaux DL (1989): Clinical applications of RU 486, a
`prototype glucocorticoid and progestin antagonist. In: The
`Adrenal and Hypertension: From Cloning to Clinic 57 of
`Serono Symposia. New York: Raven Press, pp 273–284.
`Chu JW, Matthias DF, Belanoff J, Schatzberg A, Hoffman AR,
`Feldman D (2001): Successful long-term treatment of refrac-
`tory Cushing’s disease with high-dose mifepristone (RU 486).
`J Clin Endocrinol Metab 86:3568 –3573.
`Coryell W, Pfohl B, Zimmerman M (1984): The clinical and
`neuroendocrine features of psychotic depression. J Nerv Ment
`Dis 172:521–528.
`Croxatto HB, Salvatierra AM, Croxatto HD, Fuentealba B (1993):
`Effects of continuous treatment with low dose mifepristone
`throughout one menstrual cycle. Hum Reprod 8:201–207.
`Frances A, Brown RP, Kocsis JH, Mann JJ (1981): Psychotic
`depression: A separate entity? Am J Psychiatry 138:831–833.
`Gaillard RC, Riondel A, Muller AF, Herrmann W, Baulieu EE
`(1984): RU 486: A steriod with antiglucocorticosteroid activ-
`ity that only disinhibits the human pituitary-adrenal system at
`a specific time of day. Med Sci 81:3879 –3882.
`Gatti F, Bellini L, Gasperini M, Perez J, Zanardi R, Smeraldi E
`(1996): Fluvoxamine alone in the treatment of delusional
`depression. Am J Psychiatry 153:414 –416.
`Glassman AH, Kantor SJ, Shostak M (1975): Depression, delu-
`sions, and drug response. Am J Psychiatry 132:716 –719.
`Glassman AH, Roose SP (1981): Delusional depression. A
`distinct clinical entity? Arch Gen Psychiatry 38:424 –427.
`Glassman AH, Roose SP (1986): Delusional depression: Tricy-
`clic response. Arch Gen Psychiatry 43:1014.
`Grunberg SM, Weiss MH, Spitz IM, Zaretsky S, Kletzky O,
`Groshen S (1993): Long-term treatment with the oral anti-
`progestational agent mifepristone (RU486). In: Salmon SE,
`editor. Adjuvant Therapy of Cancer VII, Vol. VII. Philadel-
`phia: J. B. Lippincott, 55– 62.
`Halbreich U, Zumoff B, Kream J, Fukushima DK (1982): The
`mean 1300 –1600 h plasma cortisol concentration as a diag-
`nostic test for hypercortisolism. J Clin Endocrinol Metab
`54:1262–1264.
`
`Hamilton M (1960): A rating scale for depression. J Neurol
`Neurosurg Psychiatry 23:56 –62.
`Herrmann W, Riondel A, Philibert D (1982): Effet d’un steroide
`anti-progesterone chez la femme: Interuption du cycle men-
`strul et de la grossese au debut. Comtes Rendus 294:922–938.
`Kane JM, Honigfeld G, Singer J, Meltzer HY, Group CCS
`(1988): Clozapine for the treatment-resistant schizophrenic:
`A double-blind comparison with chlorpromazine. Arch Gen
`Psychiatry 45:789 –796.
`Kantor SJ, Glassman AH (1977): Delusional depressions: Natu-
`ral history and response to treatment. Brit J Psychiatry
`131:351–360.
`Kettel LM, Murphy AA, Morales AJ, Ulmann A, Baulieu EE,
`Yen SSC (1996): Treatment of endometriosis with the anti-
`progesterone mifepristone (RU486). Fertil Steril 65:23–28.
`Kettel LM, Murphy AA, Mortola JF, Liu JH, Ulmann A, Yen
`SSC (1991): Endocrine responses to long-term administration
`of the antiprogesterone RU486 in patients with pelvic endo-
`metriosis. Fertil Steril 56:402–407.
`Kronig MH, Munne MR, Szymanski S, Safferman AZ, Pollack
`S, Cooper T, et al (1995): Plasma clozapine levels and clinical
`response for treatment refractory schizophrenic patients. Am J
`Psychiatry 152:179 –192.
`Lamberts SWJ, Bons EG, Uitterlinden P (1984): Studies on the
`glucocorticoid receptor blocking action of mifepristone in
`clultured ACTH-secreting human pituitary tumor cells and
`normal rat pituitary cells. J Steroid Biochem 17.
`Lamberts SWJ, Koper JW, Jong FH (1991): The endocrine
`effects of long-term treatment with mifepristone (RU 486).
`J Clin Endocrinol Metab 73:187–191.
`Laue L, Lotze MT, Chrousos GP, Barnes K, Loriaux DL,
`Fleisher TA (1990): Effect of chronic treatment with the
`glucocorticoid antagonist RU 486 in man: Toxicity, immu-
`nological, and hormonal aspects. J Clin Endocrinol and
`Metab 71:1474 –1480.
`Leckman JF, Weissman MM, Prusoff BA, Carvso KA, Meri
`Kangas KA, Pauls DL, Kidd KK (1984): Subtypes of depression
`family study perspective. Arch Gen Psychiatry 41:833–838.
`Ledger WL, Sweeting VM, Hillier H, Baird DT (1992): Inhibi-
`tion of ovulation by low-dose mifepristone (RU 486). Hum
`Reprod 7:945–950.
`Luukkainen T, Heikinheimo O, Haukkamaa M, Lahteenmaki P
`(1988): Inhibition of folliculogenesis and ovulation by the
`antiprogesterone RU 486. Fertil Steril 49:961–963.
`Lykouras E, Malliaras D, Christodoulou GN, Moussas G,
`Christodoulou D, Tzonou A (1986): Delusional depression:
`Phenomenology and response to treatment. Psychopathology
`19:157–164.
`Lyons DM, Lopez JM, Yang C, Schatzberg AF (2000): Stress-
`level cortisol treatment impairs inhibitory control of behavior
`in monkeys. J Neurosci 20:7816 –7821.
`Minter RE, Mandel MR (1979): The treatment of psychotic
`major depressive disorder with drugs and electroconvulsive
`therapy. J Nerv Ment Dis 167:726 –733.
`Mitchell P, Smythe G, Torda T (1990): Effect of the anesthetic
`agent propofol on hormonal responses to ECT. Biol Psychi-
`atry 28:315–324.
`
`

`

`392
`
`BIOL PSYCHIATRY
`2002;52:386 –392
`
`J.K. Belanoff et al
`
`Muck-Seler D, Pivac N, Jakovljevic M, Brzovic Z (1999):
`Platelet serotonin, plasma cortisol, and dexamethasone sup-
`pression test
`in schizophrenic patients. Biol Psychiatry
`45:1433–1439.
`Murphy A, Kettel LM, Morales AJ, Roberts V, Parmley T, Yen
`SS (1995a): Endometrial effects of long-term,
`low dose
`administration of RU 486. Fertil Steril 63:761–766.
`Murphy AA, Morales AJ, Kettel LM, Yen SS (1995b): Regres-
`sion of uterine leiomyomata to the antiprogesterone RU486:
`Dose-response effect. Fert Steril 64:187–190.
`Murphy BEP, Filipini D, Ghadirian AM (1993): Possible use of
`glucocorticoid receptor antagonists in the treatment of major
`depression: Preliminary results using RU 486. J Psychiatr
`Neurosci 18:209 –213.
`Nelson C, Bowers MB Jr (1978): Delusional unipolar depression.
`Arch Gen Psychiatry 35:1321–1328.
`Nelson JC, Davis JM (1997): DST studies in psychotic depres-
`sion: A meta-analysis. Am J Psychiatry 154:1497–1503.
`Nelson WH, Khan A, Orr WW Jr (1984): Delusional depression:
`Phenomenology, neuroendocrine function, and tricyclic anti-
`depressant response. J Affect Disord 6:297–306.
`Newcomer JW, Selke G, Melson AK, Hershey T, Craft S,
`Richards K, Anderson AL (1999): Decreased memory per-
`formance in healthy humans induced by stress-level