0271-0749/01/2105-0516/0
`Journal of Clinical Psychopharmacology
`Copyright © 2001 by Lippincott Williams & Wilkins, Inc.
`
`Vol. 21, No. 5
`Printed in U.S.A.
`
`BRIEF REPORTS
`
`Rapid Reversal of Psychotic Depression Using
`Mifepristone
`
`JOSEPH K. BELANOFF, MD, BENJAMIN H. FLORES, MD, MICHELLE KALEZHAN, PHD, BRENDA SUND, BS, AND
`ALAN F. SCHATZBERG, MD
`
`Department of Psychiatry, Stanford University Medical Center, Stanford, California
`
`The rationale for treating psychotic major de-
`pression with glucocorticoid receptor (GR) antag-
`onists is reviewed. Five patients with psychotic ma-
`jor depression were given 600 mg of mifepristone in
`a 4-day, double-blind, placebo-controlled crossover
`study. All the patients completed the protocol and
`adverse effects were not observed or reported. All
`of the five patients showed substantial improve-
`ments in their Hamilton Rating Scale for Depres-
`sion scores while they were receiving mifepristone,
`and four of the five patients showed substantial im-
`provement in their Brief Psychiatric Rating Scale
`scores. Little, if any, improvement was seen with
`placebo. These preliminary results suggest that
`short-term use of GR antagonists may be effective
`in the treatment of psychotic major depression and
`that additional study, perhaps using higher doses or
`more treatment days, seems warranted. (J Clin
`Psychopharmacol 2001;21:516–521)
`
`T HERE IS STRONG evidence to support the theory
`
`that psychotic major depression (PMD) is a distinct
`syndrome.1 Statistically significant differences between
`psychotic and nonpsychotic major depression have
`been noted along many axes, including presenting fea-
`tures,2–7 biology,8 familial transmission,9, 10 course and
`outcome,11 as well as response to treatment.5, 6, 12–16
`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
`
`Received February 8, 2000; accepted after revision August 23, 2000.
`Address requests for reprints to: Joseph K. Belanoff, MD, Stanford
`University Medical Center, Department of Psychiatry, 401 Quarry
`Road, Stanford, CA 94305. Address e-mail to: afschatz@leland.stan-
`ford.edu.
`
`on the dexamethasone suppression test (DST),8–18 and
`many of them have markedly elevated postdexametha-
`sone cortisol levels. A recent meta-analysis of 12 different
`studies, with a combined sample size of 700 patients, in-
`dicated that when inpatient status was controlled, psy-
`chosis, but not melancholic symptoms, were associated
`with DST nonsuppression rates.17 Significant elevations
`in 24-hour measures of urinary free cortisol levels have
`also been observed in patients with psychotic major
`depression.18
`Patients with nonaffective psychoses, such as schizo-
`phrenia, do not show high DST nonsuppression rates.19, 20
`Patients with PMD respond differently to pharmacologic
`therapies in comparison with patients with nonpsychotic
`major depression.5, 6, 12–16 Important findings include a
`very low placebo response rate in PMD, as well as a poor
`response to antidepressant therapy alone.21, 22 Patients
`with PMD do respond to electroconvulsive therapy, or a
`combination of currently available antipsychotic and an-
`tidepressant medication.4, 7, 23 However, both of these
`methods act relatively slowly, which results in an interim
`period of high morbidity.
`The progesterone-receptor antagonist mifepristone
`(17␤-hydroxy-11␤-(4-dimethylaminophenyl)17␣-(1 pro-
`pynyl) estra-4,9-dien-3-one) is also, at higher concentra-
`tions, an effective antagonist of glucocorticoid action in
`vitro and in vivo.24, 25 It is specifically a GR-II receptor an-
`tagonist and has very little affinity for the GR-I receptor.
`The effects of GR-II blockade have been studied fairly
`extensively in humans26; an antiglucocorticoid effect is
`not associated with peripheral cortisol suppression.
`The use of mifepristone has been reported to amelio-
`rate psychosis and depression in patients with Cushing
`syndrome. Relatively high doses of mifepristone (400–
`800 mg/day) were useful in rapidly reversed psychosis
`
`516
`
`

`

`Rapid Reversal of Psychotic
`
`J CLIN PSYCHOPHARMACOL, VOL 21/NO 5, OCTOBER 2001
`
`517
`
`and suicidal thinking in two patients with Cushing
`syndrome (caused in this case, by metastatic adrenal
`cancer).27 Nieman and associates28 have also reported a
`patient with Cushing syndrome who had PMD symp-
`toms that were unresponsive to antidepressants alone,
`and only partially responsive to an antidepressant/
`antipsychotic combination. However, treatment with
`high doses of mifepristone (up to 1,400 mg every day) re-
`sulted in both his physical and psychiatric symptoms re-
`solving quickly.
`Few adverse effects from mifepristone have been ob-
`served in studies in which patients were given 10 mg/kg
`a day for as many as 7 days.29 Mifepristone given at daily
`doses of 200 mg, for more than 7 days, has been associ-
`ated with fatigue, anorexia, and nausea (although not
`uniformly).30, 31 Mifepristone induced a maculopapular
`erythematous cutaneous eruption in 8 of 11 healthy 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
`meningioma at 200 mg daily for a median of 27 months.31,
`32 The cause of this spontaneously resolving rash is un-
`known. At higher doses (up to 22 mg/kg a day) given to
`patients with Cushing syndrome, no exanthema was
`seen, although nausea was common in these patients.33
`Unfortunately, neither extensive nor blinded studies
`of mifepristone as a treatment for PMD have taken
`place.34 We are conducting such a study. In this article
`we present preliminary data, suggesting that mifepris-
`tone may potentially benefit PMD patients.
`
`Materials and Methods
`
`Five newly admitted patients, with an admitting diag-
`nosis of major depression with psychotic features
`(DSM-IV criteria) were studied. The diagnoses at ad-
`mission were confirmed independently by two psychia-
`trists. The patients served as their own controls in a ran-
`dom- assignment, double-blind crossover design. They
`were given either 600 mg of mifepristone for 4 days fol-
`lowed by 4 days of placebo, or 4 days of placebo fol-
`lowed by 600 mg of mifepristone. Routine biological and
`hematologic studies were conducted daily to watch for
`possible signs of relative adrenal insufficiency, such as
`hypoglycemia and eosinophilia.
`The patients were required to be between the ages of
`18 and 75, and without major medical problems. Apart
`from hypercortisolemia, patients were excluded if they
`had any signs of Cushing syndrome. Furthermore, be-
`cause mifepristone, in the dose range we used, is re-
`ported to cause an abortion rate approaching 85%,
`women of childbearing potential were excluded from
`the study. All patients who admitted to having used il-
`licit drugs within the month before admission, or who
`consumed in excess of 2 ounces of alcohol daily were
`
`also excluded. All patients had normal physical exams
`and normal routine labs at hospital admission.
`Patients were required not to take antipsychotic med-
`ication for 3 days before entering the study. Concurrent
`antidepressant use did not lead to exclusion from the
`study, however, no patients were taking antidepressant
`medication upon entering the mifepristone trial. No pa-
`tient was started on an antidepressant medication while
`participating in the study. Benzodiazepines were per-
`mitted for insomnia and acetaminophen for headaches.
`If a patient’s condition was such that they could not tol-
`erate the drug-free period (for example, if they were in-
`tensely suicidal), they were not eligible for the study. Fi-
`nally, all patients were required to give written consent
`to a protocol approved by the Institutional Review
`Board at Stanford University Medical Center.
`Formal psychiatric assessments, including the Hamil-
`ton Rating Scale for Depression (HAM-D),35 Brief Psy-
`chiatric Rating Scale (BPRS), and Clinical Global Im-
`pression Scale, were carried out on days 1, 3, 5, 7, and 9
`at 10 a.m. Paragraph recall was tested at 11:30 a.m., cor-
`tisol levels were measured serially every half-hour from
`1:00 p.m. to 4:00 p.m., and plasma adrenocorticotropic
`hormone (ACTH) was measured serially every hour
`from 1:00 p.m. to 4:00 p.m., on days 1, 5, and 9. Blood
`samples were spun down and plasma were frozen at
`⫺80⬚F in the General Clinical Research Center Labora-
`tory. Plasma cortisol determinations were made by ra-
`dioimmunoassay in the Endocrinology Laboratory at
`Brigham and Women’s Hospital (Harvard University).
`Plasma ACTH was assayed by immunoradiometric as-
`say in the same laboratory.
`
`Brief patient histories
`
`Patient 1. This 50-year-old man had no prior psy-
`chiatric history, and had received no mental health
`treatment, except for career-counseling in graduate
`school. He was employed as an executive in the high-
`tech industry, was in excellent physical health, and was
`married with no children. He took no medications other
`than daily vitamins. Three months before his entry into
`the study he noted increasing feelings of depression
`with anhedonia, insomnia, decreased appetite, and de-
`creased concentration. A stressor at that time was his
`mother’s entry into a skilled nursing facility because of
`advanced Alzheimer’s disease. One month before entry
`into the study he began to grow increasingly suspicious
`that coworkers were talking about him and planning to
`get him fired. At entry into the study, he was extremely
`guarded with mood-congruent delusions that the hospi-
`tal might be a prison where he would be executed. He
`had received no psychiatric care to that point.
`At admission, the patient’s mean afternoon cortisol
`level was 12.0 ␮g/dL and did not decline throughout the
`
`

`

`518
`
`J CLIN PSYCHOPHARMACOL, VOL 21/NO 5, OCTOBER 2001
`
`Belanoff and Associates
`
`afternoon collection period. He received mifepristone
`first, and by day 5 his mean afternoon cortisol level was
`37.7 ␮g/dL and, in a striking example, the normal
`rhythm of a steady decline of cortisol levels throughout
`the afternoon had resumed (Table 1). His HAM-D scores
`declined from 29 to 21, and his BPRS declined from 47
`to 40. Moreover, from day 5 to day 9, while receiving
`placebo, his HAM-D continued to decrease (21 to 10), as
`did his BPRS (40 to 25), suggesting that mifepristone
`continued to be active in his system, as indicated by the
`continued elevation of his afternoon cortisol values. At
`this time, his normal cortisol rhythm continued. The pa-
`tient experienced no adverse effects and no lab values,
`other than cortisol and ACTH, changed significantly.
`The patient began taking paroxetine at discharge and
`returned to work 2 weeks later. His depressed mood re-
`solved over the next several weeks and his paroxetine
`was discontinued 9 months after conclusion of the
`study. He remains asymptomatic 2 years later.
`Patient 2. A 44-year-old European-American mar-
`ried woman and mother of two, had a past psychiatric
`history that was limited to one previous episode of
`PMD, 3 years before study admission, for which she had
`been hospitalized for 1 week. During this initial episode
`of PMD, she acknowledged being very depressed, and
`felt that the devil was controlling her. She knew this to
`be true because her bed was very cold and thought there
`might have been a machine under her bed. Against med-
`ical advice, she left the hospital because she came to be-
`lieve that one of her physicians was also being con-
`trolled by the devil. After leaving the hospital, she
`continued to be severely depressed with both auditory
`hallucinations and somatic delusions. She tried paroxe-
`tine for several weeks but there was no change in her
`condition. The paroxetine was decreased and nortripty-
`line was started. Eventually lithium was added to her
`treatment regimen, and her depression improved, al-
`though her somatic delusions remained.
`One year before study admission, all of her symptoms
`had resolved. Two months later, against medical advice,
`she discontinued her medications. For 9 months she re-
`mained asymptomatic, but then became depressed again.
`
`TABLE 1. Results of the afternoon cortisol test (patient 1)
`Cortisol Levels (␮g/dl)
`
`Time
`
`1:00 p.m.
`1:30 p.m.
`2:00 p.m.
`2:30 p.m.
`3:00 p.m.
`3:30 p.m.
`4:00 p.m.
`Mean
`
`Day 1
`
`11.8
`14.4
`11.6
`10.4
`11.6
`12.7
`11.8
`12.0 ␮g/dl
`
`Day 5
`
`56.0
`40.9
`34.4
`34.2
`34.6
`35.7
`28.4
`37.7 ␮g/dl
`
`Day 9
`
`22.1
`22.7
`16.9
`14.1
`13.4
`12.6
`18.7
`17.2 ␮g/dl
`
`She could not identify any particular precipitating event.
`She reported increasingly depressed mood, weight loss,
`decreased concentration, memory, and energy, anhedo-
`nia, and insomnia.
`One month after the onset of this depressive episode,
`she attempted suicide by hanging. The attempt failed be-
`cause her feet reached the floor. She then made a second
`suicide attempt by taking an overdose of the previously
`prescribed nortriptyline. At this point, she was brought to
`the emergency department and stabilized. During her ex-
`amination, she revealed that she had recently been hear-
`ing strange noises in her house and seeing shadows. She
`also stated that the devil was manipulating her body and
`that she had been unwilling to drive because the devil had
`the power to destroy her. Her examination in the emer-
`gency department was also notable for significant psy-
`chomotor retardation. Her only long-standing medical
`problems were irritable bowel syndrome and back pain.
`Findings from her physical examination wer within nor-
`mal limits, and she was receiving estradiol and medrox-
`yprogesterone for perimenopausal symptoms.
`She received placebo first, and then mifepristone.
`While receiving placebo, her HAM-D increased from 33
`to 35 and her BPRS from 51 to 57. While receiving
`mifepristone, her HAM-D declined from 35 to 21 and her
`BPRS from 57 to 44. At the end of the 9-day study, the
`patient was no longer delusional and felt well enough to
`go home. She declined follow-up antidepressant med-
`ication. Six weeks after leaving the study, she was re-
`ported to be experiencing symptoms of PMD and did
`not return for follow-up.
`Patient 3. The patient, a 67-year-old woman with a
`history of recurrent PMD, was admitted after taking 15
`fluoxetine capsules in a suicide attempt. Her first episode
`of PMD was in 1980, during which she experienced delu-
`sions of persecution and reference, and was hospitalized
`after a suicide attempt. One year before study entry, she
`experienced an episode of PMD and was prescribed low-
`dose haloperidol and fluoxetine. Her condition improved
`to the point where she felt “back to normal,” and after 2
`to 3 months of combination therapy she decided to stop
`taking her prescribed haloperidol and fluoxetine. Two
`months before study admission, her condition began to
`deteriorate. She complained of very low energy, poor ap-
`petite, spontaneous crying, poor self-care, and increased
`guilt about being a burden to her family. She also ex-
`pressed increasingly delusional thoughts, including that
`her phones were tapped, her family was trying to poison
`her, her neighbors were observing her through her win-
`dows and, most recently, that white automobiles were
`following her. There was a question of whether she had
`experienced auditory hallucinations, because she com-
`plained of hearing sirens and phones ringing, but this ob-
`servation was complicated by her partial hearing loss.
`
`

`

`Rapid Reversal of Psychotic
`
`J CLIN PSYCHOPHARMACOL, VOL 21/NO 5, OCTOBER 2001
`
`519
`
`The patient’s psychiatric history has been marked by
`long periods when she is fully functional (working as a
`nursing aide) with intermittent episodes of severe de-
`pression and paranoid ideation. At admission, the patient
`was taking no medications of any kind on a regular basis.
`Other than a 65% hearing loss in one ear and a 35% loss in
`the other ear, she had no ongoing medical problems.
`This patient received placebo first and then mifepris-
`tone. She showed little change on either regimen. She
`was discharged and treated with olanzapine and her
`condition continued to improve. Her mean afternoon
`cortisol was 9.4 ␮g/dL at entry into the study, 9.4 ␮g/dL
`after 4 days of placebo and more than 60 ␮g/dL after 4
`days of mifepristone. When she returned for her follow-
`up visit, 8 weeks later, and was feeling well, her after-
`noon cortisol was only 3.1 ␮g/dL, perhaps indicating
`that 9.4 ␮g/dL was quite hypercortisolemic for her.
`Patient 4. This patient was a 57-year-old, male pro-
`fessional, with an 18-month history of severe depres-
`sion characterized by extreme insomnia, low energy,
`poor concentration, and somatic concerns that had re-
`sulted in an extensive medical workup. Despite an ex-
`traordinary physical workup, he could not be convinced
`that he was physically sound and planned even more ex-
`tensive physical testing. He tried virtually all of the an-
`tidepressants currently available, often in combination
`with antipsychotic medication. He also had a round of
`electroconvulsive therapy (ECT), with eight treatments
`that led to a modest and short-lived improvement in his
`condition. He had not been able to work for the past 15
`months, which was in sharp contrast to his very pro-
`ductive career before the onset of his depression. He
`linked the onset of his depression to treatment with
`prednisone for an allergic reaction. He had no previous
`history of depression and no medical problems, but his
`family history was significant for his mother had severe
`late-life depression. He had weaned himself off of all
`medications (with the exception of clonazepam for
`sleep) before study entry.
`The patient received placebo first. While receiving
`placebo his HAM-D declined from 31 to 28 and his BPRS
`declined from 53 to 45. While receiving mifepristone his
`HAM-D declined from 28 to 21 and his BPRS from 45 to
`28. He left the hospital at the end of the study and was
`treated with venlafaxine, a drug to which his depression
`had not previously responded. Although his course of re-
`covery was not a straight line, his improvement contin-
`ued over time and he required neither additional hospi-
`talization, nor ECT, and eventually gained full recovery.
`Patient 5. A 45-year-old man with a history of
`obsessive-compulsive disorder, who in the 8 months be-
`fore study entry, became increasingly depressed, expe-
`rienced poor sleep, anhedonia, poor concentration, low
`energy, feelings of guilt, and had developed a fixed be-
`
`lief that his hearing had been irreparably harmed by var-
`ious noises in his environment. These noises included a
`phone ringing, a child’s bell, and a car horn. He became
`convinced that he had lost almost all of his hearing and
`was not dissuaded by the many trips to the audiologist,
`who indicated normal hearing, nor by the fact that he
`could converse in normal tones with those around him.
`Several weeks before study admission, he contem-
`plated suicide and was hospitalized briefly and involun-
`tarily. After trying a first dose of several medications, he
`refused to take any medication because he believed that
`each previous one- or two-pill trial had added to his
`hearing loss. Shortly before study admission, he began
`to believe that the police were trailing him ever since his
`involuntary admission. This patient worked as a college
`professor and was married with three children. He used
`no illicit substances or alcohol, but did have a family
`history of depression, including several siblings with
`major depression and his mother who experienced both
`depression and dementia.
`He received mifepristone first and then placebo. While
`receiving mifepristone, his HAM-D declined from 46 to
`37 and his BPRS from 54 to 41. Particularly significant,
`item 11 (suspiciousness) declined from a 6 (severe) to a
`1, (absent) and item 15 (unusual thought content) de-
`clined from a 6 to a 3, mild. He no longer believed that
`the police were trailing him, nor that his phone was
`tapped. However, he still obsessively believed that he
`had a hearing loss, and his desire to have his hearing
`tested again was even stronger than before. While re-
`ceiving placebo, his HAM-D declined from 37 to 35, but
`his BPRS increased again from 41 to 54, with particularly
`high scores on somatic concern and anxiety. At dis-
`charge, he refused all medications, and he has remained
`quite debilitated with high levels of somatic anxiety.
`
`Results
`
`In all cases, HAM-D scores declined during mifepris-
`tone treatment (see Table 2). In both cases, where the pa-
`tient received mifepristone first, their HAM-D declined
`during the placebo treatment also (case one significantly,
`case five marginally.) In the three cases where placebo
`was given first, HAM-D scores changed very little (rising
`slightly in case two and falling slightly in cases three and
`four.) Ignoring the carryover effect leaves five active
`treatment cells and three placebo cells. The mean decline
`in HAM-D while receiving mifepristone was 8.0 (25.5%),
`whereas while receiving placebo it was 1.7 (5.8%). The
`difference approaches statistical significance (F ⫽ 5.01,
`p ⬍ 0.07).
`In all but one case, BPRS scores declined during
`mifepristone treatment (See Table 2). The exception
`was case three, the patient with the lowest BPRS at
`
`

`

`520
`
`J CLIN PSYCHOPHARMACOL, VOL 21/NO 5, OCTOBER 2001
`
`Belanoff and Associates
`
`TABLE 2. Individual HAM-D and BPRS scoresa
`
`HAM-D
`
`BPRS
`
`Subject No.
`
`Day 1 Day 5 Day 9 Day 1 Day 5 Day 9
`
`1 (mifepristone first)
`2 (placebo first)
`3 (placebo first)
`4 (placebo first)
`5 (mifepristone first)
`
`29
`33
`23
`31
`46
`
`21
`35
`19
`28
`37
`
`10
`21
`17
`21
`35
`
`49
`51
`32
`53
`54
`
`40
`57
`35
`45
`41
`
`25
`44
`36
`28
`54
`
`aHAM-D, Hamilton Rating Scale for Depression; BPRS, Brief Psy-
`chiatric Rating Scale.
`
`study entry. Her BPRS score increased by one point. In
`case one, where the patient received mifepristone first,
`their BPRS continued on a distinct decline during the
`placebo period. In the other patient who received
`mifepristone first (case 5), the patient’s BPRS reversed
`to the pretreatment level during placebo treatment. The
`mean decline in BPRS score while receiving mifepris-
`tone was 10.2 points (34%), whereas while receiving
`placebo, the BPRS increased by 0.3 points (1.2%).
`
`Discussion
`
`Although only a small number of patients have re-
`ceived mifepristone for psychotic major depression, the
`results seem fairly promising. All the patients were dis-
`charged from the hospital at the end of the 9-day study
`period. All of the five patients showed improvement in
`their HAM-D scores while receiving mifepristone, and
`four of the five patients showed improvement in their
`BPRS scores. Moreover, the patient who did not, was the
`least symptomatic to start. The overall decline in BPRS
`scores was 32.5%, which approaches the 40% value fre-
`quently seen in 6- to 8-week trails of effective antipsy-
`chotic medication. None of the patients reported side ef-
`fects of any kind, and both basic lab measures and
`measures of vital signs were unaffected by treatment.
`Although HAM-D scores diminished during treatment,
`all the patients still had significant residual signs and
`symptoms of major depression. We recommended that
`all begin antidepressant treatment at the end of the study.
`We observed that the more significant clinical change
`was that four of the five patients were no longer psy-
`chotic at the end of the study, and all were more cogni-
`tively organized. Additionally, it seemed as if the reason
`that the patients’ HAM-D scores declined was that they
`were more cognitively intact and felt in better control of
`their thinking.
`Cortisol transmission takes place through two recep-
`tors, the mineralocorticoid (type I, MR) and the gluco-
`corticoid receptor (type II, GR). Type I receptors bind
`cortisol with roughly 10 times the affinity of type II re-
`ceptors.36 As a consequence, type I receptors primarily
`regulate cortisol homeostasis and type II receptors do
`
`not fill until cortisol levels are relatively high.37 Mifepri-
`stone is a specific type II antagonist, which means that
`although the creation of the gene product resulting from
`high levels of cortisol is blocked, normal cortisol home-
`ostasis continues forward.38 Perhaps this mechanism
`explains the paucity of patientive complaints and ob-
`served side effects in our study.
`The mechanism of clinical improvement in our pa-
`tients with psychotic major depression is not entirely
`clear. Type II receptors are found in relatively high abun-
`dance in nonhuman, frontal cortex and primate hip-
`pocampus,39 and functions modulated by these regions
`appear to be decreased in PMD patients.40 Blocking
`these receptors may aid in improving cognition. It also
`seems that the abruptly blocking type II-receptors may
`cause a “resetting” of the HPA axis. Cortisol levels rise
`when mifepristone is taken because the feedback mech-
`anism is partially disrupted, however, normal cortisol
`rhythm returns and seems to remain intact after mifepri-
`stone is discontinued. Short-term use of mifepristone
`may prove to be its most effective regimen.
`Although it is generally accepted that many patients
`with psychotic major depression have high levels of cir-
`culating cortisol, it has been noted that some patients do
`not. One explanation may be, because of wide interindi-
`vidual differences in serum cortisol levels and a lack of
`longitudinal observation, some patients with psychotic
`major depression whose cortisol levels seem to be nor-
`mal, actually may be experiencing quite high levels of
`cortisol for them. For instance, patient #3’s average af-
`ternoon cortisol was a modestly elevated 9.4 ␮g/dL when
`she was quite ill. Eight weeks later when she was well,
`her average afternoon cortisol was 3.1 ␮g/dL.
`Although the number of patients we have studied is
`small, their improved condition after just 4 days of treat-
`ment with mifepristone suggests that glucocorticoid an-
`tagonists may be useful for treating psychotic major de-
`pression. In fact, the paucity of adverse effects observed,
`leads us to believe that a slightly longer trial, (i.e., 7 or 8
`days) might be equally safe and even more efficacious.
`Larger, double-blinded trials of mifepristone to treat psy-
`chotic major depression seem warranted in the near fu-
`ture.
`
`Acknowledgment
`
`Supported by a Young Investigators Award from the National Al-
`liance for Research on Schizophrenia and Depression, and grants
`from the Pritzker Foundation, and the NIMH (MH 47473 and T-32
`Biobehavioral Research Training Program).
`
`References
`
`1. Schatzberg AF, Rothschild AJ. Psychotic (delusional) major de-
`pression: should it be included as a distinct syndrome in DSM-IV?
`Am J Psychiatry 1992;149:733–45.
`2. Coryell W, Pfohl B, Zimmerman M. The clinical and neuroen-
`
`

`

`Rapid Reversal of Psychotic
`
`J CLIN PSYCHOPHARMACOL, VOL 21/NO 5, OCTOBER 2001
`
`521
`
`docrine features of psychotic depression. J Nerv Ment Dis 1984;
`172:521–8.
`3. Lykouras E, Malliaras D, Christodoulou GN, et al. Delusional de-
`pression: phenomenology and response to treatment. A prospec-
`tive study. Acta Psychiatr Scand 1986;73:324–9.
`4. Frances A, Brown RP, Kocsis JK, et al. Psychotic depression: a
`separate entity? Am J Psychiatry 1981;138:831–3.
`5. Glassman AH, Roose SP. Delusional depression: a distinct clinical
`entity? Arch Gen Psychiatry 1981;38:424–7.
`6. Nelson JC, Bowers MB. Delusional unipolar depression. Arch Gen
`Psychiatry 1978;35:1321–8.
`7. Charney DS, Nelson JC. Delusional and nondelusional unipolar
`depression: further evidence for distinct subtypes. Am J Psychia-
`try 1981;138:328–33.
`8. Nelson JC, Davis JM. DST studies in psychotic depression: a meta-
`analysis. Am J Psychiatry 1997;154:1497–503.
`9. Nelson WH, Khan A, Orr WW Jr. Delusional depression: phenom-
`enology, neuroendocrine function, and tricyclic antidepressant
`response. J Affect Disord 1984;6:297–306.
`10. Leckman JF, Weissman MM, Prusoff BA, et al. Subtypes of de-
`pression: family study perspective. Arch Gen Psychiatry 1984;41:
`833–8.
`11. Robinson DG, Spiker DG. Delusional depression: a one year fol-
`low-up. J Affect Disord 1985;9:79–83.
`12. Kantor SJ, Glassman AH. Delusional depressions: natural history
`and response to treatment. Br J Psychiatry 1977;131:351–60.
`13. Rothschild AJ. Delusional depression: a review of the literature
`and current perspectives. McLean Hosp J 1985;2:68–83.
`14. Spiker DG, Weiss JC, Dealy RS, et al. The pharmacological treat-
`ment of delusional depression. Am J Psychiatry 1985;142:430–6.
`15. Chan CH, Janicak PG, Davis JM, et al. Response of psychotic and
`nonpsychotic depressed patients to tricyclic antidepressants. J
`Clin Psychiatry 1987;48:197–200.
`16. Anton RF Jr, Burch EA Jr. Amoxapine versus amitriptyline com-
`bined with perphenazine in the treatment of psychotic depres-
`sion. Am J Psychiatry 1990;147:1203–8.
`17. Nelson JC, Davis JM: DST studies in psychotic depression: a meta-
`analysis. Am J Psychiatry 1997;154:1497–1503.
`18. Anton RF. Urinary free cortisol in psychotic depression. Biol Psy-
`chiatry 1987;2:24–34.
`19. Rothschild AJ, Schatzberg AF, Rosenbaum AH, et al. The dexa-
`methasone suppression test as a discriminator among subtypes of
`psychotic patients. Br J Psychiatry 1982;141:471–4.
`20. Arana GW, Barreira PJ, Cohen BM, et al. The dexamethasone sup-
`pression test in psychotic disorders. Am J Psychiatry 1983;140:
`1521–3.
`21. Glassman AH, Kantor SJ, Shostak M. Depression, delusions, and
`drug response. Am J Psychiatry 1975;132:716–9.
`22. Avery D, Lubrano A. Depression treated with imipramine and
`ECT: the DeCarolis study reconsidered. Am J Psychiatry 1979;
`136:559–62.
`23. Minter RE, Mandel MR. The treatment of psychotic major depres-
`sive disorder with drugs and electroconvulsive therapy. J Nerv
`Ment Dis 1979;167:726–33.
`24. Proulx-Ferland L, Cote J, Philibert D. Potent anti-glucocorticoid
`activity of mifepristone on ACTH secretion in vitro and in vivo in
`the rat. J Steroid Biochem Mol Biol 1982;17:xvii.
`
`25. Lamberts SW, Bons EG, Uitterlinden P. Studies on the glucocorti-
`coid receptor blocking action of RU 38486 in cultured ACTH-se-
`creting human pituitary tumor cells and normal rat pituitary cells.
`Acta Endocrinologica 1985;109:64–9.
`26. Bertagna X, Escovrolle JL, Pinquier L. Administration of RU 486
`for 8 days in normal volunteers: antiglucocorticoid effect with no
`evidence of peripheral cortisol deprivation. J Clin Endocrinol
`Metab 1994;78:375–80.
`27. van der Lely AJ, Foeken K, van der Mast RC, et al. Rapid reversal
`of acute psychosis in the Cushing syndrome with the cortisol-
`receptor antagonist mifepristone (RU 486). Ann Intern Med 1991;
`114:143–4.
`28. Nieman LK, Chrousos GP, Kellner C. Successful treatment of
`Cushing syndrome with the glucocorticoid antagonist mifepris-
`tone. J Clin Endocrinol Metab 1985;61:536–40.
`29. Nieman LK. Uses of RU 486 as an antiglucocorticoid. In: Donald-
`son MS, Dorflinger L, Brown SS, et al., eds. Clinical applications
`of mifepristone (RU 486) and other antiprogestins : assessing the
`science and recommending a research agenda. Washington, DC:
`National Academy Press, 1993:229–42.
`30. Lamberts SW, Koper JW, de Jong FH. The endocrine effects of
`long-term treatment with mifepristone. J Clin Endocrinol Metab
`1991;73:187–91.
`31. Grunberg SM, Weiss MH, Spitz IM, et al. Long-term treatment with
`the oral antiprogestational agent mifepristone. In: Salmon SE, ed.
`Adjuvant therapy of cancer VII: proceedings of the Seventh Inter-
`national Conference on the Adjuvant Therapy of Cancer, Tucson,
`Arizona, March, 1993. Philadelphia: JB Lippincott, 1993.
`32. Laue L, Lotze MT, Chrousos GP, et al. Effect of chronic treatment
`with the glucocorticoid antagonist mifepristone in men: toxicity,
`immunological, and hormonal aspects. J Clin Endocrinol Metab
`1990;71:1474–80.
`33. Chrousos GP, Lavue L, Nieman LK, et al. Clinical applications of
`mifepristone, a prototype glucocorticoid and progestin antago-
`nist. In: Mantero F, Scoggins BA, Takedu R, et al., eds. The
`Adrenal and hypertension: from cloning to clinic. New York:
`Raven Press 1989:273–84.
`34. Murphy BEP, Filipini D, Ghadirian AM. Possible use of glucocor-
`ticoid antagonists in the treatment of major depression: prelimi-
`nary results using Mifepristone. J Psychiatry Neurosci 1993;18:
`209–13.
`35. Hamilton M. A rating scale for depression. J Neurol Neurosurg
`Psychiatry 1960;23:56–62.
`36. de Kloet ER. Brain corticosteroid receptor balance and homeo-
`static control. Front Neuroendocrinol 1991;12:95–104.
`37. Holsboer F, Barden N. Antidepressants and hypothalamic-
`pituitary-adrenocortical regulation. Endocr Rev 1990;17:187–
`205.
`38. Lamberts SWJ, Koper JW, de Jong FH. The endocrine effects of
`long-term treatment with mifepristone (RU 486). J Clin Endocrinol
`Metab 1991;73:187–91.
`39. Patel PD, Lopez JF, Lyons DM, et al. Glucocorticoid and mineralo-
`corticoid receptor mRNA expression in squirrel monkey brain. J
`Pysch Res 2000;0:1–10.
`40. Schatzberg AF, Posener JA, DeBattista DMH, et al. Neuropsycho-
`logical deficits in psychotic versus non