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An open label trial of C-1073 (mifepristone) for psychotic major depression*

      Abstract

      Background

      The rationale for treating patients with psychotic major depression (PMD) with glucocorticosteroid receptor (GR) antagonists is explained.

      Methods

      Thirty patients with PMD, with Hamilton Rating 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 symptoms 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 studies are warranted.

      Keywords

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      References

        • Ammar S.
        • Allilaire J.-F.
        • Lecrubier Y.M.
        • Widlocher D.
        • Baulieu E.E.
        Letter.
        Am J Psychiatry. 1986; 143: 129-130
        • Anton R.F.
        Urinary free cortisol in psychotic depression.
        Biol Psychiatry. 1987; 22: 24-34
        • Anton R.F.
        • Burch E.A.
        Amoxapine versus amitriptyline combined with perphenazine in the treatment of psychotic depression.
        Am J Psychiatry. 1990; 147: 1203-1208
        • Arana G.W.
        • Barreira P.J.
        • Cohen B.M.
        • Lipinski J.F.
        • Fogelson D.
        The dexamethasone suppression test in psychotic disorders.
        Am J Psychiatry. 1983; 140: 1521-1523
        • Avery D.
        • Lubrano A.
        Depression treated with imipramine and ECT.
        Am J Psychiatry. 1979; 136: 559-562
        • Belanoff J.
        • Flores B.
        • Kalezhan M.
        • Sund B.
        • Schatzberg A.
        Rapid reversal of psychotic major depression using mifepristone.
        J Clin Psychopharmacol. 2001; 21: 516-521
        • Belanoff J.K.
        • Kalehzan M.
        • Sund B.
        • Fleming Fice K.S.
        • Schatzberg A.F.
        Cortisol activity and cognitive changes in psychotic major depression.
        Am J Psychiatry. 2001; 158: 1612-1616
        • Bertagna X.
        • Escourolle H.
        • Pinquier J.L.
        • Coste J.
        • Roux-DeMay M.C.
        • Perles P.
        • et al.
        Administration of RU486 for 8 Days in normal volunteers.
        J Clin Endocrinol Metab. 1994; 78: 375-380
        • Chan C.H.
        • Janicak P.G.
        • Davis J.M.
        • Altman E.
        • Andriukaitis S.
        • Hedeker D.
        Response of psychotic and nonpsychotic depressed patients to tricyclic antidepressants.
        J Clin Psychiatry. 1987; 48: 197-200
        • Charney D.S.
        • Nelson J.C.
        Delusional and nondelusional unipolar depression.
        Am J Psychiatry. 1981; 138: 328-333
      1. 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 J.W.
        • Matthias D.F.
        • Belanoff J.
        • Schatzberg A.
        • Hoffman A.R.
        • Feldman D.
        Successful long-term treatment of refractory Cushing’s disease with high-dose mifepristone (RU 486).
        J Clin Endocrinol Metab. 2001; 86: 3568-3573
        • Coryell W.
        • Pfohl B.
        • Zimmerman M.
        The clinical and neuroendocrine features of psychotic depression.
        J Nerv Ment Dis. 1984; 172: 521-528
        • Croxatto H.B.
        • Salvatierra A.M.
        • Croxatto H.D.
        • Fuentealba B.
        Effects of continuous treatment with low dose mifepristone throughout one menstrual cycle.
        Hum Reprod. 1993; 8: 201-207
        • Frances A.
        • Brown R.P.
        • Kocsis J.H.
        • Mann J.J.
        Psychotic depression.
        Am J Psychiatry. 1981; 138: 831-833
        • Gaillard R.C.
        • Riondel A.
        • Muller A.F.
        • Herrmann W.
        • Baulieu E.E.
        RU 486.
        Med Sci. 1984; 81: 3879-3882
        • Gatti F.
        • Bellini L.
        • Gasperini M.
        • Perez J.
        • Zanardi R.
        • Smeraldi E.
        Fluvoxamine alone in the treatment of delusional depression.
        Am J Psychiatry. 1996; 153: 414-416
        • Glassman A.H.
        • Kantor S.J.
        • Shostak M.
        Depression, delusions, and drug response.
        Am J Psychiatry. 1975; 132: 716-719
        • Glassman A.H.
        • Roose S.P.
        Delusional depression.
        Arch Gen Psychiatry. 1981; 38: 424-427
        • Glassman A.H.
        • Roose S.P.
        Delusional depression.
        Arch Gen Psychiatry. 1986; 43: 1014
        • Grunberg S.M.
        • Weiss M.H.
        • Spitz I.M.
        • Zaretsky S.
        • Kletzky O.
        • Groshen S.
        Long-term treatment with the oral antiprogestational agent mifepristone (RU486).
        in: Adjuvant Therapy of Cancer VII. Vol. VII. J. B. Lippincott, Philadelphia1993
        • Halbreich U.
        • Zumoff B.
        • Kream J.
        • Fukushima D.K.
        The mean 1300–1600 h plasma cortisol concentration as a diagnostic test for hypercortisolism.
        J Clin Endocrinol Metab. 1982; 54: 1262-1264
        • Hamilton M.
        A rating scale for depression.
        J Neurol Neurosurg Psychiatry. 1960; 23: 56-62
        • Herrmann W.
        • Riondel A.
        • Philibert D.
        Effet d’un steroide anti-progesterone chez la femme.
        Comtes Rendus. 1982; 294: 922-938
        • Kane J.M.
        • Honigfeld G.
        • Singer J.
        • Meltzer H.Y.
        • Group CCS
        Clozapine for the treatment-resistant schizophrenic.
        Arch Gen Psychiatry. 1988; 45: 789-796
        • Kantor S.J.
        • Glassman A.H.
        Delusional depressions.
        Brit J Psychiatry. 1977; 131: 351-360
        • Kettel L.M.
        • Murphy A.A.
        • Morales A.J.
        • Ulmann A.
        • Baulieu E.E.
        • Yen S.S.C.
        Treatment of endometriosis with the antiprogesterone mifepristone (RU486).
        Fertil Steril. 1996; 65: 23-28
        • Kettel L.M.
        • Murphy A.A.
        • Mortola J.F.
        • Liu J.H.
        • Ulmann A.
        • Yen S.S.C.
        Endocrine responses to long-term administration of the antiprogesterone RU486 in patients with pelvic endometriosis.
        Fertil Steril. 1991; 56: 402-407
        • Kronig M.H.
        • Munne M.R.
        • Szymanski S.
        • Safferman A.Z.
        • Pollack S.
        • Cooper T.
        • et al.
        Plasma clozapine levels and clinical response for treatment refractory schizophrenic patients.
        Am J Psychiatry. 1995; 152: 179-192
      2. 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 S.W.J.
        • Koper J.W.
        • Jong F.H.
        The endocrine effects of long-term treatment with mifepristone (RU 486).
        J Clin Endocrinol Metab. 1991; 73: 187-191
        • Laue L.
        • Lotze M.T.
        • Chrousos G.P.
        • Barnes K.
        • Loriaux D.L.
        • Fleisher T.A.
        Effect of chronic treatment with the glucocorticoid antagonist RU 486 in man.
        J Clin Endocrinol and Metab. 1990; 71: 1474-1480
        • Leckman J.F.
        • Weissman M.M.
        • Prusoff B.A.
        • Carvso K.A.
        • Meri Kangas K.A.
        • Pauls D.L.
        • Kidd K.K.
        Subtypes of depression family study perspective.
        Arch Gen Psychiatry. 1984; 41: 833-838
        • Ledger W.L.
        • Sweeting V.M.
        • Hillier H.
        • Baird D.T.
        Inhibition of ovulation by low-dose mifepristone (RU 486).
        Hum Reprod. 1992; 7: 945-950
        • Luukkainen T.
        • Heikinheimo O.
        • Haukkamaa M.
        • Lahteenmaki P.
        Inhibition of folliculogenesis and ovulation by the antiprogesterone RU 486.
        Fertil Steril. 1988; 49: 961-963
        • Lykouras E.
        • Malliaras D.
        • Christodoulou G.N.
        • Moussas G.
        • Christodoulou D.
        • Tzonou A.
        Delusional depression.
        Psychopathology. 1986; 19: 157-164
        • Lyons D.M.
        • Lopez J.M.
        • Yang C.
        • Schatzberg A.F.
        Stress-level cortisol treatment impairs inhibitory control of behavior in monkeys.
        J Neurosci. 2000; 20: 7816-7821
        • Minter R.E.
        • Mandel M.R.
        The treatment of psychotic major depressive disorder with drugs and electroconvulsive therapy.
        J Nerv Ment Dis. 1979; 167: 726-733
        • Mitchell P.
        • Smythe G.
        • Torda T.
        Effect of the anesthetic agent propofol on hormonal responses to ECT.
        Biol Psychiatry. 1990; 28: 315-324
        • Muck-Seler D.
        • Pivac N.
        • Jakovljevic M.
        • Brzovic Z.
        Platelet serotonin, plasma cortisol, and dexamethasone suppression test in schizophrenic patients.
        Biol Psychiatry. 1999; 45: 1433-1439
        • Murphy A.
        • Kettel L.M.
        • Morales A.J.
        • Roberts V.
        • Parmley T.
        • Yen S.S.
        Endometrial effects of long-term, low dose administration of RU 486.
        Fertil Steril. 1995; 63: 761-766
        • Murphy A.A.
        • Morales A.J.
        • Kettel L.M.
        • Yen S.S.
        Regression of uterine leiomyomata to the antiprogesterone RU486.
        Fert Steril. 1995; 64: 187-190
        • Murphy B.E.P.
        • Filipini D.
        • Ghadirian A.M.
        Possible use of glucocorticoid receptor antagonists in the treatment of major depression.
        J Psychiatr Neurosci. 1993; 18: 209-213
        • Nelson C.
        • Bowers Jr, M.B.
        Delusional unipolar depression.
        Arch Gen Psychiatry. 1978; 35: 1321-1328
        • Nelson J.C.
        • Davis J.M.
        DST studies in psychotic depression.
        Am J Psychiatry. 1997; 154: 1497-1503
        • Nelson W.H.
        • Khan A.
        • Orr Jr, W.W.
        Delusional depression.
        J Affect Disord. 1984; 6: 297-306
        • Newcomer J.W.
        • Selke G.
        • Melson A.K.
        • Hershey T.
        • Craft S.
        • Richards K.
        • Anderson A.L.
        Decreased memory performance in healthy humans induced by stress-level cortisol treatment.
        Arch Gen Psychiatry. 1999; 56: 527-533
        • Nieman L.K.
        Uses of mifepristone as a glucocorticoid antagonist.
        in: Benet L.Z. Dorflinger L. Dondaldson M.S. Brown S.S. Clinical Applications of Mifepristone (Ru 486 and other Antiprogestins. National Academy Press, Washington, DC1993: 139-147
        • Nieman L.K.
        • Chrovsos G.P.
        • Kellner C.
        • Spitz I.M.
        • Nisula B.C.
        • Cutler G.B.
        • et al.
        Successful treatment of Cushing’s syndrome with the glucocorticoid antagonist RU 486.
        J Clin Endocrinol Metab. 1993; : 536-540
        • Nierenberg A.A.
        • Farabaugh A.H.
        • Alpert J.E.
        • Gordon J.
        • Worthington J.J.
        • Rosenbaum J.F.
        Timing of onset of antidepressant response with fluoxetine treatment.
        Am J Psychiatry. 2000; 157: 1423-1427
        • Nobler M.
        • Sackeim H.A.
        • Moeller J.
        • Prudic J.
        • Petkova E.
        • Waternaux C.
        Quantifying the speed of symptomatic improvement with electroconvulsive therapy.
        Convuls Ther. 1997; 13: 208-221
        • Patel P.D.
        • Lopez J.F.
        • Lyons D.M.
        • Burke S.
        • Wallace M.
        • Schatzberg A.F.
        Glucocorticoid and mineralocorticoid receptor mRNA expression in squirrel monkey brain.
        J Psychiatr Res. 2000; 34: 383-392
      3. Proulx-Ferland Cote L, Philibert D, Deraedt R (1982): Potent antiglucocorticoid activity of RU38486 on ACTH secretion in vitro and in vivo in the rat. J Steroid Biochem 17:27

        • Robinson D.G.
        • Spiker D.G.
        Delusional depression.
        J Affect Disord. 1985; 9: 79-83
        • Rothschild A.J.
        Delusional depression.
        McLean Hosp J. 1985; 10: 68-83
        • Rothschild A.J.
        • Phillips K.A.
        Selective serotonin reuptake inhibitors and delusional depression.
        Am J Psychiatry. 1999; 156: 977-978
        • Rothschild A.J.
        • Schatzberg A.
        • Rosenbaum A.H.
        • Stahl J.B.
        • Cole J.O.
        The dexamethasone suppression test as a discriminator among subtypes of psychotic patients.
        Am J Psychiatry. 1982; 141: 471-474
        • Sanchez M.M.
        • Young L.J.
        • Plotsky P.M.
        • Insel T.R.
        Distribution of corticosteroid receptors in the rhesus brain.
        J Neurosci. 2000; 20: 4657-4668
        • Sartor O.
        • Cutler Jr, G.B.
        Mifepristone.
        Clin Obstet Gynecol. 1996; 39: 506-510
        • Schatzberg A.
        • Posener J.A.
        • DeBattista C.
        • Kalehzan M.
        • Rothschild A.J.
        • Shear P.K.
        Neuropsychological deficits in psychotic versus nonpsychotic major depression and no mental illness.
        Am J Psychiatry. 2000; 157: 1095-1100
        • Schatzberg A.
        • Rothschild A.J.
        • Langlais P.J.
        • Bird E.D.
        • Cole J.O.
        A corticosteroid/dopamine hypothesis for psychotic depression and related states.
        J Psychiatr Res. 1985; 19: 57-64
        • Schatzberg A.F.
        • Rothschild A.J.
        Psychotic (delusional) major depression.
        Am J Psychiatry. 1992; 149: 733-745
        • Shoupe D.
        • Mishell Jr, D.R.
        • Lahteenmaki P.
        • Heikinheimo O.
        • Birgerson L.
        • Madkour H.
        Effects of the antiprogesterone RU 486 in normal women. 1.
        Am J Obstet Gynecol. 1987; 157: 1415-1420
        • Spiker D.G.
        • Weiss J.C.
        • Dealy R.S.
        • et al.
        The pharmacological treatment of delusional depression.
        Am J Psychiatry. 1985; 142: 430-436
        • Swartz C.
        • Chen J.-J.
        Electroconvulsive therapy-induced cortisol release.
        Convul Ther. 1985; 1: 15-21
      4. Tollefson G (2001): The use of olanzapine-fluoxetine combination in the treatment of major depressive disorder with psychotic features. NIMH Clinical Drug Evaluation Unit Meeting (NCDEU), Phoenix, AZ

        • Van der Lely A.-J.
        • Foeken K.
        • van der Mast R.C.
        • Lamberts S.W.J.
        Rapid reversal of acute psychosis in the Cushing syndrome with the cortisol-receptor antagonist mifepristone (RU 486).
        Ann Int Med. 1991; 114: 143-144
        • Wolkowitz O.M.
        • Reus V.I.
        • Chan T.
        • Manfredi F.
        • Raum W.
        • Johnson R.
        Antiglucocorticoid treatment of depression.
        Biol Psychiatry. 1999; 45: 1070-1074
        • Wolkowitz O.M.
        • Reus V.I.
        • Manfredi F.
        • Ingbar J.
        • Brizendine L.
        • Weingartner H.
        Ketoconazole administration in hypercortisolemic depression.
        Am J Psychiatry. 1993; 150: 810-812
        • Zanardi R.
        • Franchini L.
        • Gasperini M.
        • Perez J.
        • Smeraldi E.
        Double-blind controlled trial of sertraline versus paroxetine in the treatment of delusional depression.
        Am J Psychiatry. 1996; 153: 1631-1633
        • Zanardi R.
        • Franchini L.
        • Gasperini M.
        • Smeraldi E.
        • Perez J.
        Long-term treatment of psychotic (delusional) depression with fluvoxamine: An open pilot study.
        Int Clin Psychopharmacol. 1997; 12: 195-197
        • Zanardi R.
        • Franchini L.
        • Serretti A.
        • Perez J.
        • Smeraldi E.
        Venlafaxine versus fluvoxamine in the treatment of delusional depression.
        J Clin Psychiatry. 2000; 61: 26-29