(12) United States Patent
`US 6,362,173 Bl
`(10) Patent N0.:
`
`(45) Date of Patent: Mar. 26, 2002
`Schatzberg et al.
`
`USOO6362173B1
`
`(54) METHODS FOR TREATING PSYCHOSIS
`ASSOCIATED WITH COCAINE ADDICTION
`WITH GLUCOCORTICOID RECEPTOR
`ANTAGONISTS
`
`(75)
`
`Inventors: Alan F. Schatzberg, I.os Altos; Joseph
`K. Belanofi‘, Cupertino, both of CA
`(US)
`
`(73) Assignee: The Board of Trustees of the Leland
`Stanford Junior University, Palo Alto,
`CA (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/639,377
`
`(22)
`
`Filed:
`
`Aug. 15, 2000
`
`Related US. Application Data
`
`(63) Continuation of application No. 09/244,457, filed on Feb. 4,
`1999, now Pat. No. 6,150,349, which is a continuation of
`application No. l’C'l'/US98/20906, filed on Oct. 5, 1998.
`Provisional application No. 60/060,973, filed on Oct. 6,
`1997.
`
`(60)
`
`Int. Cl.7 ................................................ A61K 31/56
`(51)
`(52) us. Cl.
`....................................................... 514/179
`(58) Field of Search .......................................... 514/179
`
`(56)
`
`El’
`W0
`W0
`W0
`W0
`W0
`W0
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3/1989 Ravaris
`4,814,333 A
`FOREIGN PAl‘EN T DOCUMENTS
`
`3/1997
`0763541
`11/1993
`WO/9322685
`4/1994
`W'0/408588
`3/1997
`WO/9710827
`10/1997
`WO/9737664
`6/1998
`W0/9826783
`6/1998
`WO9826785
`OTHER PUBLICATIONS
`
`Van der Lely (1993). Derwent Drug File, abstract No.
`1993—29824,
`
`Cadepond et a1. (1997). “RU486 (milepristone): Mecha-
`nisms of action and clinical uses”Anna. Rev. ill/led, vol. 48:
`129—156.
`
`Krishnan et a1. (1992), “RU486 in depression” Prog. Neu-
`ro—Psychopharmacul. & Biol. Psychiat, vol. 16: 913—920.
`Murphy et al. (1993). “Possible use of glucocorticoid recep-
`tor antagonists in the treatment of major depression: Pre—
`liminary results using RU 486” J. Psychiatr. Neurosci, vol.
`18: 209—213.
`
`Murphy (1997). “Antiglucocorticoid therapies in major
`depression: A review” Psychaneuroendorinology, vol. 22:
`125—132.
`
`Nieman et al. (1985). “Successful treatment of Cushing’s
`Syndrome with the glucocorticoid antagonist RU 486” J.
`Clin. Endocrinol. Alemb, vol. 61: 536—540.
`Rothschild et al. (l982). “The dexamethasonc suppression
`test as
`a discriminator among subtypes of psychotic
`patients” Brit. J. Psychiat, vol. 141: 471—474.
`Rothschild et al, (1985). “The effects of a single acute dose
`of dexamethasone on monoamine and metabolite levels in
`rat brain” Life Science, vol. 36: 2491—2501.
`Sartor et al. (1996). “Mifepristone: Treatment of Cushing’s
`Syndrome” Clin. Obstetrics and Gynecol. , vol. 39: 506—510.
`Schatzberg et al. (1983). “The dexamethasone suppression
`test: Identification of subtypes of depression” Am. J. Psy-
`chiat, vol. l40: 88—91.
`“A corticosteriod/doparnine
`Schatzberg et
`a1.
`(1985).
`hypothesis for psychotic depression and related states” J
`Psychiat, Res, vol. 19: 57—64.
`Schatzberg et al. (1988). “The roles of glucocorticoid and
`dopaminergic systems in delusional (psychotic) depression”
`Annals NY. Acad. 0fSci., vol. 537: 462—471.
`Van der Lely et al. (1991). “Rapid reversal of acute psycho—
`sis in the cushing syndrome with the cortisol—reseptor
`antagonist mifepristone (RU 486)” Ann. Intern. filed, vol.
`114: 143—144.
`
`Van der Lely (1993). Pharmacy World and Science, vol. 15:
`89—90.
`
`Primary Examiner—William R. A. Jarvis
`(74) Attorney, Agent, or Firm—Bret E. Field; Bozicevic,
`Field & Francis
`
`(57)
`
`ABSTRACT
`
`This invention generally pertains to the field of psychiatry.
`In particular, this invention pertains to the discovery hat
`agents which inhibit the binding of cortisol to its recep ors
`can be used in methods for ameliorating pathologies or
`conditions associated With psychosis. These pathologies or
`conditions include psychotic major depression, schizoa ec-
`
`tive disorders, Alzheimer’s Disease and cocaine addic ion.
`Mifepristone, a potent glucocorticoid receptor antagonist,
`can be used in these methods. The invention also provides a
`kit for the amelioration of psychosis in a human including a
`glucocorticoid receptor antagonist and instructional material
`teaching the indications, dosage and schedule of adminis—
`tration of the glucocorticoid receptor antagonist.
`
`
`
`12 Claims, N0 Drawings
`
`NEPTUNE GENERICS — Ex. 1026
`
`Page 1
`
`(1997) Chemical Abstracts, abstract No.
`
`a1.
`
`(1996). Chemical Abstracts, abstract No.
`
`Piazza et
`126:84476.
`Behl et
`a1.
`126:55042.
`
`
`Beck et al. (1993). The steroid antagonist RU486 exerts
`
`
`different e ects on the glucocorticoid and progesterone
`receptors Department of Pathology and Program in Molecu—
`lar Biology, University of Colorado Health Sciences Center
`(S,K.N.D.P.E) vol. 123 (2): 728—740.
`Chrousos et a1. (1989). “Clinical applications of RU486, a
`prototype glucocorticoid and progrestin antagonist” In: Bau—
`lieu and Segal, eds. The Antiprogestin Steroid RU 486 and
`Human Fertility Control. New York: Plenum Press, pp.
`273—284.
`
`NEPTUNE GENERICS – Ex. 1026
`Page 1
`
`

`

`US 6,362,173 B1
`
`1
`METHODS FOR TREATING PSYCHOSIS
`ASSOCIATED WITH COCAINE ADDICTION
`WITH GLUCOCORTICOID RECEPTOR
`ANTAGONISTS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`The present application is a continuation of Ser. No.
`09/244,457, filed Feb. 4, 1999, now US. Pat. No. 6,150,349,
`which is a continuation of PCT/US98/20906, filed Oct, 5,
`1998, which is a continuation-in-part of U.S. Provisional
`Application Ser. No. 60/060,973, filed Oct. 6, 1997. The
`aforementioned application is explicitly incorporated herein
`by reference in its entirety and for all purposes.
`
`15
`
`FIELD OF THE INVENTION
`
`This invention generally pertains to the field of psychiatry.
`In particular, this invention pertains to the discovery that
`agents which inhibit the binding of cortisol to its receptor -
`can be used in methods of ameliorating psychosis, including
`the psychotic component of pathologies or conditions with
`psychotic symptoms.
`INTROD UCTION
`
`This invention is directed to a method for treating psy-
`chosis whose pathogenesis is related to glucoeorticoid regu—
`latory dysfunction. The types of psychosis treated by the
`methods of the invention must be distinguished from the
`older definition of psychosis, which referred to schizophre-
`nia and manic states. Schizophrenia and manic states are not
`associated with dysfunction of the glucoeorticoid regulatory
`pathway and there is no basis to believe that possibility.
`Thus, the treatment methods of the invention encompass the
`modem usage of the term psychosis, i.e., non-schizophrenia
`and non-manic state associated psychosis.
`There has been historic confusion in the definition of
`psychosis. This is, in part, based on a lack of understanding
`of a common pathophysiologic mechanism causing psycho-
`sis in various conditions. For example, Oberlander, et al.,
`WO 98/26785, teaches use of an anti-glucoeorticoid to treat
`schizophrenia and manic states. However, schizophrenia and
`manic states are are believed to be the result of abnormal
`nerve structure, i.e., “hard-wiring” problems. In contrast, it
`is believed that the pathophysiology of psychosis (the term
`used in its modem sense, as used in the instant invention) is
`related to neurochemical (glucoeorticoid regulatory) prob-
`lems. This theory is extended by the instant invention, in
`which it was surprisingly discovered that agents which
`inhibit the binding of cortisol to its receptor can be used to
`treat psychosis.
`Today it is known that psychotic patients can be distin—
`guished from other psychiatric problems in that they have a
`glucocorticoid regulatory dysfunction. In contrast, patients
`with schizophrenia and manic states do not have glucoeor-
`ticoid regulatory dysfunction (see, e.g., Rothschild (1982)
`Br J. Psychiatry 1412471474; Clower (1986) J. Clin.
`Psychopharmacol. 62363—365). Thus, schizophrenia and
`manic states are not within the scope of the definition of
`“psychosis” (as defined either by the medical profession, or,
`as used herein), and thus are not treated by the methods of
`the invention.
`
`In most species, including man, the physiological gluco-
`eorticoid is cortisol (hydrocortisone). Glucocorticoids are
`secreted in response to ACTH (corticotropin), which shows
`both circadian rhythm variation and elevations in response
`
`35
`
`40
`
`55
`
`60
`
`65
`
`
`
`2
`to stress and food. Cortisol levels are responsive within
`minutes to many physical and psychological stresses,
`including trauma, surgery, exercise, anxiety and depression.
`Cortisol is a steroid and acts by binding to an intracellular,
`glucocorticoid receptor (GR). In man, glucoeorticoid recep-
`tors are present in two forms: a ligand—binding GR—alpha of
`777 amino acids; and, a GR-beta isoform which differs in
`
`
`only the last fifteen amino acids. The two types of GR have
`
`high a inity for their specific ligands, and are considered to
`function through the same transduction pathways.
`The Jiologic effects of cortisol, including those caused by
`
`
`hypercortisolemia, can be modu ated at the GR level using
`
`
`receptor antagonists, Several di erent classes of agents are
`able to block the physiologic effects of GR-agonist binding.
`These antagonists include compositions which, by binding
`to GR, block the ability of an agonist to effectively bind to
`and/or activate the GR. One such known GR antagonist,
`mifepristone, has been found to be an effective anti-
`glucocorticoid agent in humans (Bertagna (1984) J. Clin.
`Endocrinol. Metab. 59225). Mifepristone binds to the GR
`with high affinity, with a K of dissociation élO'9 M
`(Cadepond (1997) Annu. Rev. filed. 482129).
`Patients with some forms of psychiatric illnesses have
`been found to have increased levels of cortisol (Krishnan
`(1992) Prog. Neuro-Psychopharrnacol. & Biol. Psychiat.
`162913—920). For example, some patients with depressed
`mood have had their mood improve with treatments which
`lower the levels of cortisol, In some individuals, reversing
`increased cortisol levels using inhibitors of steroid biosyn-
`thesis can be effective in treating depression (Murphy (1991)
`J. Steroid Biochem. Mol. Biol. 392239; Murphy (1991) J.
`Clin. Psychopharmcol. 112121; Dhar (1989) Clin. Invest.
`
`
`Med. 122B27). Alternatively, some depressed individuals
`
`
`can be responsive to treatments which block the e ect of
`cortisol, as by administering GR antagonists (Van Look
`(1995) Human Reproduction Update 1219—34). In one study,
`a patient with depression secondary to Cushing’s Syndrome
`(hyperadrenocorticism) was responsive to a high dose, up to
`1400 mg per day, of GR antagonist mifepristone (Nieman
`(1985) J. Clin Endocrinol. Metab. 612536). Another study
`which used mifepristone to treat Cushing’s syndrome found
`that
`it improved the patients’ conditions,
`including their
`psychiatric status (Chrousos, pp 273—284, In: Baulieu, ed.
`The Antiprogestin Steroid RU 486 and Human Fertility
`Control. Plenum Press, New York (1989), Sartor (1996)
`Clin. Obstetrics and Gynecol. 392506—510). Mifepristone
`has been used to treat major depression. Using from about
`2.5 to 4.4 mg/kg per day for periods up to eight weeks, one
`group found that four patients with chronic severe
`depression, who were resistant to conventional therapies,
`responded to treatment (Murphy (1993) J. Psychiatr. Neu-
`rosci. 182209).
`Psychosis has also been associated with Cushing’s syn-
`drome (Gerson (1985) Can. J. Psychiatry 3022234224; Saad
`(1984) Am. J. Med. 762759—766). Mifepristone has been
`used to treat acute psychiatric disturbances secondary to
`Cushing’s syndrome. One study showed that a relatively
`high dose of mifepristone (400 to 800 mg per day) was
`useful in rapidly reversing acute psychosis in patients with
`severe Cushing Syndrome due to adrenal cancers and
`ectopic secretion of ACTH from lung cancer (Van der Lely
`(1991) Ann. Intern.
`.Med. 1142143; Van der Lely (1993)
`Pharmacy World & Science 15 289490; Sartor (1996) supra).
`Psychotic major depression has long been recognized as
`a distinct psychiatric illness, having both psychotic and
`depressive components.
`In a differential diagnosis,
`it
`is
`important that psychotic major depression be distinguished
`
`NEPTUNE GENERICS — Ex. 1026
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`US 6,362,173 B1
`
`3
`from nonpsychotic major depression, because effective
`treatments and patterns of response to pharmacologic thera—
`pies for psychotic major depression are very diIIerent from
`those relating to non- psychotic major depression. Successful
`treatment depends on the accuracy of the initial diagnosis
`(Glassman (1981) Arch. Gen. Psychiatry 3824247427,
`Schatzberg (1992) Am. J. Psychiatr. 149:733—745,
`Schatzberg (1988) Annals NY. Acad. 0f Sci.537:462). Psy-
`chotic major depression is very common. It has been esti-
`mated that twenty five percent of depressed patients admit-
`ted to the hospital have psychotic major depression (Coryell
`(1984) J. Nerv. iMertt. Dis. 1722521).
`Before this invention, there was to fast-acting effective
`treatment without significant side effects for the treatment of
`psychosis or
`the psychotic component of illnesses and
`conditions associated with psychosis, such as psychotic
`major depression.
`Individuals suffering from psychotic
`major depression have a low placebo response rate and
`respond poorly to antidepressant therapy alone, i.e., without
`concurrent
`treatment with antipsychotic medication ~
`(Glassman (1975) Am. J. Psychiatry 132:716—719; Avery
`(1979) Am. J. Psychiatry 135559—562). While psychotic
`depression can respond to electroconvulsive therapy (ECT),
`this form of treatment is controversial, can have significant
`side effects, has a relatively slow response rate and has a
`high level of related morbidity. Similarly, another commonly
`used treatment for psychotic major depression, a combina-
`tion therapy of currently available antipsychotic and anti—
`depressant medications, has a slow onset of action and a
`relatively high rate of morbidity (Minter (1979) J. Nerv.
`.Ment. Dis. 167:726—733).
`Thus, there exists a great need for a more effective and
`safer treatment for psychosis and illnesses and conditions
`associated with psychosis,
`including psychotic major
`depression. There is a great need for a new treatment for
`psychotic major depression which has a quick response
`time, has few side elIects, decreases the amount of time a
`patient must be institutionalized and has a lower rate of
`morbidity. Furthermore, there exists a variety of conditions
`which have a psychotic element for which there is no known
`cure or effective treatment. These include schizoaffective
`disorder, Alzheimer’s Disease and cocaine addiction. Thus,
`there exists a great need for a safe and effective treatment for
`these conditions. The present invention fulfills these and
`other needs.
`
`35
`
`4O
`
`15
`
`30
`
`4
`about 8 to 20 mg per kilogram of body weight per day, or,
`in a daily amount of about 8 to 12 mg per kilogram of body
`weight per day. The glucocorticoid receptor antagonist can
`be administered for about four days. It can be administered
`in a daily amount of about 600 mg per day. The adminis-
`tration can be once per day. Its mode of administration can
`be oral or transdermal.
`
`the invention relates to a
`In a preferred embodiment,
`method of ameliorating psychotic depression comprising
`administering a mifepristone in a daily amount of about 8 to
`12 mg per kilogram of body weight per day, wherein the
`administration continues for a period of about four days
`The invention also relates to a kit for the amelioration of
`psychosis in a human, the kit comprising: a glucocorticoid
`receptor antagonist; and, an instructional material teaching
`the indications, dosage and schedule of administration of the
`glucocorticoid receptor antagonist. The kit’s instructional
`material can indicate that the glucocorticoid receptor antago-
`nist can be administered in a daily amount of about 8 to 12
`mg per kilogram of body weight per day. The instructional
`material can indicate that the administration of the gluco—
`corticoid receptor antagonist can continue for a period of
`about four days.
`In one embodiment, the kit is for the amelioration of
`psychosis as a component of psychotic major depression and
`the instructional material indicates that the glucocorticoid
`receptor antagonist can be used for the treatment of psy—
`chotic major depression. In a preferred embodiment, the
`kit’s glucocorticoid receptor antagonist
`is mifepristone,
`which can be in tablet form.
`
`The invention also relates to a novel means of diagnosing
`and assessing treatments for psychosis using color-word
`recognition tests. In one embodiment, the Stroop Color and
`Word Test, or variations thereof,
`is used to objectively
`determine whether an individual is psychotic, the degree of
`psychosis and the ellicacy of an antipsychotic treatment
`regimen. The invention also provides a color-word test to
`differentially diagnose psychotic major depression from
`non—psychotic major depression.
`A further understanding of the nature and advantages of
`the present invention is realized by reference to the remain-
`ing portions of the specification, the figures and claims.
`All publications, patents and patent applications cited
`herein are hereby expressly incorporated by reference for all
`purposes.
`
`SUMMARY OF THE INVENTION
`
`DEFINITIONS
`
`The invention is directed to a method of treating psycho-
`sis associated vvith glucocorticoid related dysfunction by
`administration of an amount of a glucocorticoid receptor
`antagonist elfective to ameliorate the psychosis, with the
`proviso that the patient not be sulfering from Cushing’s
`Syndrome. In alternative embodiments of this method, the
`psychosis is associated with psychotic major depression,
`schizoaffective disorder, Alzheimer’s Disease and cocaine
`addiction.
`
`the glucocorticoid receptor
`In further embodiments,
`antagonist used in the methods can comprise a steroidal
`skeleton with at least one phenyl—containing moiety in the
`11-beta position of the steroidal skeleton. The phenyl-
`containing moiety in the 11-beta position of the steroidal
`skeleton can be a dimethylaminophenyl moiety.
`In alternative embodiments of the invention, the gluco-
`corticoid receptor antagonist can comprise mifepristone
`(RU486), RU009 or RU044. The glucocorticoid receptor
`antagonist can be administered in a daily amount of between
`
`50
`
`55
`
`60
`
`65
`
`The term “ameliorating” or “ameliorate” refers to any
`indicia of success in the treatment of a pathology or
`condition, including any objective or subjective parameter
`such as abatement, remission or diminishing of symptoms or
`an improvement in a patient’s physical or mental well-being.
`Amelioration of symptoms can be based on objective or
`subjective parameters;
`including the results of a physical
`examination and/or a psychiatric evaluation. For example, a
`clinical guide to monitor the effective amelioration of a
`psychiatric disorder, such as psychosis or depression,
`is
`found in the Structured Clinical Interview for DSM—IV Axis
`I mood disorders (“SCID-P") (see fourth edition of Diag-
`nostic and Statistical Manual of Mental Disorders (1994)
`Task Force on DSM-IV, American Psychiatric Association
`(“DSM—IV”); Kaplan, Ed. (1995) Comprehensive Textbook
`OfPsychiatry/VI, vol. 1, sixth ed., pp 621—627, Williams &
`Wilkins, Balt., Md.).
`The term “glucocorticoid receptor antagonist" refers to
`any composition or compound which partially or completely
`
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`US 6,362,173 B1
`
`5
`inhibits (antagonizes) the binding of a glucocorticoid recep-
`tor (GR) agonist, such as cortisol, or cortisol analogs,
`synthetic or natural,
`to a GR. A “glucocorticoid receptor
`antagonist” also refers to any composition or compound
`which inhibits any biological response associated with the
`binding of a GR to an agonist.
`The term “glucocorticoid receptor” (“GR”) refers to a
`family of intracellular receptors also referred to as the
`cortisol receptor, which specifically bind to cortisol and/or
`cortisol analogs. The term includes isoforms of GR, recom-
`binant GR and mutated GR.
`
`
`
`6
`success of a particular treatment schedule or regimen. For
`example, measuring changes in cognitive ability aids in the
`diagnosis and treatment assessment of the psychotic patient.
`Any test known in the art can be used, such as the so—called
`“Wallach Test,” which assesses recognition memory (see
`below, Wallach (1980) J. Gemm‘nl 35:371—375). For
`example, as described in Example 1, when the Wallach
`Recognition Test was used to measure the degree of ame—
`lioration of psychosis in the study’s subjects, on the average,
`test subjects identified fewer distracters over words they had
`actually heard before. The number of distracting words
`mis—identified as words actually presented in the test
`declined between 25% and 100% after treatment. Another
`example of an objective text which can be used to determine
`whether an individual is psychotic and to measure efficacy
`of an anti—psychotic treatment is the Stroop Color and Word
`Test (“Stroop Test”) (see Golden, C. 1., Cat. No. 30150M, In
`A Manualfor Clinical and Experimental Uses, Smelling,
`Wood Dale, Ill.) The Stroop Test is an objective neuropsy-
`chiatric test that can differentiate between individuals with
`psychosis and those without, and is described in detail
`below.
`The term “psychosis” refers to a psychiatric symptom,
`condition or syndrome in its broadest sense, as defined in the
`DSM-IV (Kaplan, ed. (1995) supra), comprising a “psy-
`chotic” com aonent, as broadly defined above. The term
`psychosis can refer to a symptom associated with a general
`medical concition, a disease state or other condition, such as
`
`a side effect of drug abuse (a substance-induced disorder) or
`
`as a side e ect of a medication. Alternatively,
`the term
`psychosis can refer to a condition or syndrome not associ-
`ated with any disease state, medical condition, drug intake or
`the like. Psychosis is typically defined as a mental disorder
`or condition causing gross distortion or disorganization of a
`person’s mental capacity, affective response, and capacity to
`recognize reality, communicate, and relate to others to the
`degree of interfering with his capacity to cope with the
`ordinary demands of everyday life.
`Historically, the term “psychosis” was sometimes used to
`describe schizophrenia and manic states (these conditions
`are separately described in the DSM-IV, supra). However,
`the current medical View, as embraced by the DSM—IV,
`supra, does not
`include these psychiatric conditions as
`including psychosis. There is a physiologic basis for this
`discrimination, which was recognized as early as
`Rothschild, et al. (1982) “The dexamethasone suppression
`test as a discriminator among subtypes of psychotic
`patients,” Br. J. Psychiatry 141:471—474; and, Clower
`(1986) “The 2-mg dexamethasone suppression test in dif-
`ferentiating major depression with psychosis from
`schizophrenia,” J. Clin. Psychopharmacol. 62363—365. The
`dexamethasone suppression (DS) test indicates a dysfunc—
`tion in the glucocorticoid regulatory feedback pathway,
`which is controlled by the hypothalamic—pituitary-adrenal
`(HPA) axis (non-responsiveness in the test means a patient
`cannot suppress (negatively feedback) cortisol production
`when challenged with a test dose of a synthetic
`glucocorticoid, dexamethasone). Most psychotic patients
`have a glucocorticoid regulatory dysfunction (as indicated
`by non-responsiveness in the DS test). In contrast, patients
`with, e.g., schizophrenia (including those historically
`described as “psychotic schizophrenics”) and manic states,
`do not have glucocorticoid regulatory dysfunction (as indi-
`cated by responsiveness in the DS test). It is widely believed
`that schizophrenia and manic states are caused by abnormal
`nerve structure, i.e., a “hard-wiring” problem. In contrast, it
`is believed that the pathophysiology of psychosis is related
`
`NEPTUNE GENERICS — Ex. 1026
`
`Page 4
`
`The term “cortisol” refers to a family of compositions also
`referred to hydrocortisone, and any synthetic or natural
`analogues thereof.
`The term “mifepristone” refers to a family of composi-
`tions also referred to as RU486, or RU38.486, or 17—beta—
`hydroxy—11—beta—(4—dimethyl—aminophenyl)—17—a1pha—(1—
`propynyl)-estra-4,9-dien-3-one), or 11-beta-
`(4dimethylaminophenyl)-17-beta-hydroxy-17-alpha-(1-
`propynyl)-estra-4,9-dien-3-one), or analogs thereof, which -
`bind to the glucocorticoid receptor,
`typically with high
`affinity, and inhibit the biological effects initiated/mediated
`by the binding of any cortisol or cortisol analogue to a
`receptor. Chemical names for RU-486 vary; for example,
`RU486 has also been termed: 11B—[p—(Dimethylamino)
`phenyl]—17B—hydroxy—17—(1—propynyl)—estra—4,9—dien—3—
`one, 11B-(4-dimethyl-aminophenyl)-17B-hydroxy-17A-
`(prop-1-ynyl)-estra-4,9-dien-3-one; 17B-hydroxy-1lB-(4-
`dimethylaminophenyl-l)-17A-(propynyl-1)-estra-4,9-
`diene—3—one; 17B—hydroxy—11B—(4—dimethylaminophenyl—
`1)-17A-(propynyl-1)-E;
`(11B,17B)-11[4-dimethylamino)-
`phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one,
`and 11B-[4-(N,N-dimethylaino)phenyl]-17A-(prop-1-ynyl)-
`D—4,9—estradiene—17B—ol—3—one.
`The term “psychotic” as used herein refers to a psyc 1iatric
`condition in its broadest sense, as defined in the DSM—WV
`
`(Kaplan, ed. (1995) supra) and described below. The term
`
`“psychotic” has historically received a number of di erent
`definitions, ranging from narrow to broadly described. A
`psychotic condition can include delusions or prominent
`hallucinations, including prominent hallucinations that the
`individual realizes are hallucinatory experiences, and those
`with hallucinations occurring in the absence of insight into
`their pathological nature. Finally, the term includes a psy-
`chotic condition characterized by a loss of ego boundaries or
`a gross impairment in reality testing. Unlike this definition,
`which is broad and based primarily on symptoms, charac-
`terization of psychosis in earlier classifications (e.g., DSM-
`II and ICD-9) were more inclusive and focused on the
`severity of functional im 3airment (so that a mental disorder _
`was termed “psychotic” if it resulted in “impairment” that
`grossly interferes with the capacity to meet ordinary
`
`demands of life). Different disorders which have a psychotic
`
`component comprise di erent aspects of this definition of
`“psychotic.” For example,
`in schizophreniform disorder,
`schizoaffective disorder and brief psychotic disorder,
`the
`term “psychotic” refers to delusions, any prominent
`hallucinations, disorganized speech, or disorganized or cata-
`tonic behavior.
`In psychotic disorder due to a general
`medical condition and in substance-induced psychotic
`disorder, “psychotic” refers to delusions or only those hal-
`lucinations that are not accompanied by insight. Finally, in
`delusional disorder and shared psychotic disorder, “psy—
`chotic” is equivalent to “delusional” (see DSM—IV, supra,
`page 273).
`Objective tests can be also be used to determine whether
`an individual is psychotic and to measure and assess the
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`NEPTUNE GENERICS – Ex. 1026
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`US 6,362,173 B1
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`to neurochemical problems, particularly, HPA axis regula-
`tory dysfunction (this theory is extended by the instant
`invention, in which it was discovered that that agents which
`inhibit
`the binding of cortisol
`to its receptor will
`treat
`psychosis). Thus, schizophrenia and manic states are not
`within the scope of the definition of “psychosis" (as defined
`either by the medical profession, or, as used herein), and thus
`are not treated by the methods of the invention.
`The term “psychotic major depression,” also referred to as
`“psychotic depression” (Schatzberg (1992) Am. J. Psychia-
`try 149:733—745), “psychotic (delusional) depression”
`(Ibid.), “delusional depression” (Glassman (1981) supra)
`and, “major depression with psychotic features" (see the
`DSM—III—R), refers to a distinct psychiatric disorder which
`includes both depressive and psychotic features. Individuals
`manifesting both depression and psychosis,
`i.e. psychotic
`depression, are herein referred to as “psychotic depressives.”
`It has been long—recognized in the art as a distinct syndrome,
`as described, for example, by Schatzberg (1992) supra.
`Illustrative of this distinctness are studies which have found ~
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`significant di erences between patients with psychotic and
`nonpsychotic depression in glucocorticoid activity,
`dopamine—beta—hydroxylase activity, levels of dopamine and
`serotonin-me abolites, sleep measures and ventricle to brain
`ratios. Psychotic depressives respond very differently to
`treatment compared to individuals with other forms of
`depression, such as “non—psychotic major depression.” Psy—
`chotic depressives have a low placebo response rate and a
`respond poorly to antidepressant
`therapy alone (Without
`concurrent anti-psychotic treatment). Psychotic depressives
`are markedly unresponsive to tricyclic (anti—depressive)
`drug therapy (Glassman, et al. (1975) supra). While psy—
`chotic depressives can respond to electroconvulsive therapy
`(ECI'), their response time is relatively slow and the EC'I‘
`has a high level of related morbidity. Clinical manifestations
`and diagnostic parameters of “psychotic major depression”
`is described in detail in the DSM-IV (Kaplan, ed. (1995)
`supra). Thus, due to its unique pathophysiology, high rate of
`morbidity and response to treatment, there is great practical
`need to differentially diagnose and specifically treat psy—
`chotic major depression as compared to non—psychotic
`depression.
`DETAILED DESCRIPTION OF THE
`INVENTION
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`This invention pertains to the discovery that agents that
`can inhibit a biological response caused by an agonist-
`occupied glucocorticoid receptor (GR) are effective for
`ameliorating the mental disorder, or syndrome, of psychosis.
`Because the condition of psychosis can be associated with or
`caused by a variety of conditions and disease processes, the
`methods of the invention also are used to ameliorate the
`psychotic component of pathologies or conditions involving
`psychosis. These pathologies or conditions include psy—
`chotic major depression, schizoaffective disorders, Alzhe—
`imer’s Disease, cocaine addiction, drug side effects and the
`like.
`the methods of the invention use
`In one embodiment,
`agents that act as GR antagonists, blocking the interaction of
`cortisol with GR, thereby ameliorating psychosis. In another
`embodiment, mifepristone, a potent GR antagonist, is used
`in methods to ameliorate psychosis. The invention provides
`a new, effective treatment for psychotic major depression
`which is relatively fast, has fewer side effects, decreases the
`amount of time a patient must be institutionalized and has a
`lower rate of morbidity when compared to alternative treat-
`merits.
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`As psychosis can be manifested as a mental illness in the
`form of a syndrome or as an element of a disease process or
`other condition, various means of diagnosing and assessing
`the success of treatment, i.e., the success and extent the
`psychosis is ameliorated, are set forth below. These means
`include classical psychological evaluations and various
`laboratory procedures. As the methods of the invention
`include use of any means to inhibit the biological effect of
`a GR to ameliorate psychosis, illustrative compounds and
`compositions which can be used to treat psychosis are also
`set forth. Routine procedures that can be used to identify
`further compounds and compositions able to block the
`biological response caused by a GR-agonist interaction for
`use in practicing the methods of the invention are also
`described. As the invention provides for administering these
`compounds and compositions as pharmaceuticals, routine
`means to determine GR antagonist drug regimens and for-
`mulations to practice the methods of the invention are set
`forth below.
`1. General Laboratory Procedures
`A number of general laboratory tests can be used to assist
`in the diagnosis, progress and prognosis of the patient.
`Monitoring of parameters such as blood cortisol, drug
`metabolism, brain function and the like may be needed
`because all patients metabolize and react to drugs uniquely.
`In addition, such monitoring may be important because each
`GR antagonist has different pharmnacokinetics. Different
`disease conditions may require different dosage regimens
`and formulations. Such procedures are well described in the
`scientific and patent literature. A few illustrative examples
`are set forth below.
`a. Determining Blood Cortisol Levels
`Because levels of blood cortisol have been associated
`with psychosis and depression, monitoring blood cortisol
`levels can be a useful laboratory test to aid in the diagnosis,
`treatment and prognosis of the patient. A wide variety of
`laboratory tests exist that can be used to determine whether
`an individual is normal, hypo- or hypercortisolemic. Immu-
`noassays such as rad