WO2011140608A1 - Régimes de traitement neuropsychopharmacologiques pour le traitement de troubles psychologiques - Google Patents

Régimes de traitement neuropsychopharmacologiques pour le traitement de troubles psychologiques Download PDF

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WO2011140608A1
WO2011140608A1 PCT/AU2011/000561 AU2011000561W WO2011140608A1 WO 2011140608 A1 WO2011140608 A1 WO 2011140608A1 AU 2011000561 W AU2011000561 W AU 2011000561W WO 2011140608 A1 WO2011140608 A1 WO 2011140608A1
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depressant
depression
oxytocin
cyclic
ssri
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Charlotte L. Keating
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Keating Charlotte L
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Publication of WO2011140608A1 publication Critical patent/WO2011140608A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present disclosure relates generally to neuropsychopharmacological treatment regimes for a range of psychological illnesses and their sub-threshold forms. Particularly, the present disclosure describes a combination of treatment protocols which target the stress-linked and/or reproductive-linked biological system and anti-depressant therapy.
  • the neuropsycho-pharmacological approach may be used alone or in combination with other neuropsychobehavioral modification protocols.
  • Psychological disorders represent a broad spectrum of conditions, which have a variety of behavioral and clinical manifestations. These manifestations extend from mild to heavily debilitating symptoms. Particular conditions such as major depression and anorexia nervosa often present co-morbidly and share similar symptoms despite having different phenotypes (Wade et al, American Journal of Psychiatry 157 (3) :469 -471 , 2000). Both illnesses frequently onset around the age of puberty. Patients have traditionally been prescribed anti-depressant drugs. However, the efficacy of these drugs has been contentious (Kaye et al., Nature Reviews Neuroscience 70:573-584, 2009). There is a gender bias in the onset of some psychiatric disorders.
  • MDD Major Depressive Disorder
  • TRD is presumed when at least two trials of anti-depressants from different classes fail to produce significant improvements (Berlim and Turecki, Can J Psychiatry 52(7 :46-54, 2007; Ananth, Psych Psychos 67(2):6 ⁇ -70, 1998; Rush et al, Biol Psychiatry 53 (3 ⁇ 4 : 743 -753, 2003; Keller, J Clin Psychiatry 66(8):5- ⁇ 2, 2005). Without successful treatment, patients remain severely disabled, have little hope of recovery and suffer one of the highest risks of suicide and mortality of any psychiatric condition (Fava, 2003 supra).
  • HPA hypothalamopituitary adrenal
  • psychological illness includes a “neuropsychological illness” and encompasses a neurological ⁇ psychological and/or psychiatric condition, state, disorder or sub-threshold form thereof in which a subject exhibits a behavioral or clinical phenotype characterized by abnormalities in dopamine, serotonin and/or reproductive- or stress-linked biological systems.
  • HPG hypothalamopituitary gonadal
  • Agents which facilitate normalization include agents which ultimately (but not solely) result in reduced Cortisol production.
  • agents include oxytocin or an agonist thereof, a corticotropin-releasing hormone (CRH) antagonist, a CRH receptor antagonist, an arginine vasopressin antagonist, a adrenocorticotropin hormone (ACTH) antagonist, glucocorticoid antagonist, an anti-psychotic and a dopamine antagonist or mood stabilizer.
  • CRH corticotropin-releasing hormone
  • ACTH adrenocorticotropin hormone
  • anti-depressants includes selective serotonin re-uptake inhibitors (SSRIs), selective serotonin noradrenergic re-uptake inhibitors (SSNRIs), tetra-cyclic and tri-cyclic antidepressants and a monoamine oxidase inhibitor (MAOI).
  • Agents which facilitate normalization of the HPG-axis include estrogens as well as progestogens.
  • the two or more drugs may be administered simultaneously or sequentially and in any order. When sequentially administered, the period of time between administration of each drug may be nanoseconds, milliseconds, seconds, a minute or minutes, hours or days. The drugs may be administered via the same or different routes.
  • An aspect enabled herein is a method for treating a human subject diagnosed with. symptoms of depression, the method comprising administering to the subject, effective amounts of oxytocin and estrogen for a time and under conditions sufficient to amelioratethe symptoms of depression.
  • the treatment protocol further comprises the administration of an anti-depressant such as selected from an SSRI, SSNRI, tri-cyclic anti-depressant and a tetra-cyclic anti-depressant.
  • the depression is treatment resistant depression.
  • the depression is chronic depression.
  • the depression is associated with another illness.
  • Taught herein is a pharmaceutical composition
  • an anti-depressant such as selected from an SSRI, SSNRI, a tri-cyclic anti-depressant and a tetra-cyclic anti-depressant; (ii) oxytocin; and (iii) estrogen.
  • an SSRI include escitalopram, sertraline, citalopram, fluoxetine and agomelatine.
  • SSNRI include esmertazapine, venlafaxine, desvenlafaxine and duloxetine.
  • a tri-cyclic anti -depressant include amitriptyline and imip ' ramine.
  • a terra-cyclic anti -depressant examples include amoxapine and mirtazapine.
  • the present disclosure further contemplates a neuropsychopharmalogical medicament comprising two or more drugs selected from an agent which facilitates normalization of a stress-linked biological system and anti-depressant and anti-psychotic and mood stabilizer and reproductive linked system-modulator, for use in treating a psychological illness, phenotype, state, condition or sub-threshold form thereof.
  • Psychological conditions contemplated herein include depression (including major depressive disorder [MDD] and postnatal depression as well as treatment resistant depression [TRD], chronic depression, psychotic depression or melancholic depression), eating disorders (such as anorexia nervosa and bulimia nervosa), bipolar disorder, anxiety disorders, addiction, dementia, epilepsy, schizophrenia, Tourette's syndrome, obsessive compulsive disorder (OCD), panic disorder, PTSD, phobias, acute stress disorder, adjustment disorder, agoraphobia without history of panic disorder, alcohol dependence (alcoholism), amphetamine dependence, brief psychotic disorder, cannabis dependence, cocaine dependence, cyclothymic disorder, delirium, delusional disorder, dysthymic disorder, hallucinogen dependence, nicotine dependence, opioid dependence, paranoid personality disorder, Parkinson's disease, schizophrenia, schizoaffective disorder, schizoid personality disorder, schizophreniform disorder, schizotypal personality disorder, sedative dependence, shared psychotic
  • the drugs may be given alone or as part of another therapeutic program and/or behavioral modification therapy or counseling.
  • aspects taught herein include a method for treating a male or female subject with a psychological illness, phenotype, state, condition or sub-threshold form thereof, the method comprising administering to the subject two or more drugs selected from an agent which facilitates normalization of a stress-linked biological system and an anti-depressant and mood stabilizer and anti-psychotic and reproductive linked system-modulator, in amounts and under conditions sufficient to ameliorate symptoms of the psychological, illness, phenotype, state, condition or sub-threshold form thereof.
  • Figure 1 is a schematic representation of hypothalamopituitary adrenal (HPA)-axis showing sites of proposed action of oxytocin or synthetic oxytocin agonist and CRH antagonist.
  • Oxytocin restrains CRH and AVP neurones in the hypothalamus thus reducing synthesis and secretion of these neuropeptides, hence decreasing HPA-axis activity.
  • the CRH antagonist blocks the actions of CRH on coriicotropes, decreasing stimulation of ACTH, ultimately reducing adrenal Cortisol production.
  • a color photograph of Figure 1 is available from the Patentee upon request or from an appropriate Patent Office. A fee may be imposed if obtained from a Patent Office.
  • An empiricaly-based protocol is taught herein based on the use of a combination of agents which facilitates normalization of a stress-linked biological system, act as an antidepressant, an anti-psychotic and a reproductive linked system-modulator to treat a psychological illness.
  • the stress-linked biological system includes the HPA-axis.
  • Agents which normalize the HPA-axis include agents which reduce overactivity such as any agent which reduces Cortisol production.
  • agents contemplated herein include oxytocin or agonist thereof, a CRH antagonist, a CRH receptor antagonist, a AVP antagonist and an ACTH antagonist, a glucocorticoid antagonist, an anti-psychotic and a dopamine antagonist.
  • Reference to an anti-depressant includes tetra-cyclic and tri-cyclic agents, monoaminoxidase inhibitors and SSRIs and SSNRIs.
  • Reference to an- anti -psychotic includes dopamine antagonists.
  • the present disclosure provides a therapeutic protocol comprising: (i) an agent which normalizes HPA-axis activity; (ii) an SSRl or SSNRI or other anti-depressant; (iii) an anti-psychotic or (iv) mood stabilizer and/or (v) a reproductive linked modulator such as estrogen an estrogen analog or agonist or a selective estrogen receptor modulator (SERM) or estrogen pro-drug, and/or (vi) a progestogen or progestogen analog or agonist, for use in treating or ameliorating the symptoms of a psychological illness or condition.
  • a reproductive-linked biological system includes the HPG-axis.
  • An aspect enabled herein is a method for treating a human subject diagnosed with symptoms of depression, the method comprising administering to the subject effective amounts of oxytocin and estrogen for a time and under conditions sufficient to ameliorate the symptoms of depression.
  • the treatment protocol further comprises the administration of an anti-depressant such as selected from an SSRI, SSNRI, tri-cyclic anti-depressant and a tetra-cyclic anti-depressant.
  • the depression is treatment resistant depression.
  • the depression is chronic depression.
  • the depression is associated with another illness.
  • Taught herein is a pharmaceutical composition
  • an anti -depressant such as selected from an SSRI, SSNRI, a tri-cyclic anti -depressant and a tetra-cyclic anti-depressant; (ii) oxytocin; and (Hi) estrogen.
  • an SSRI include escitalopram, sertraline, citalopram, fluoxetine and agomelatine.
  • SSNRI include esmertazapine, venlafaxine, desvenlafaxine and duloxetine.
  • Examples of a tri-cyclic anti-depressant include amitriptyline and imipramine.
  • a tetra-cyclic anti-depressant include amoxapine and mirtazapine.
  • psychological illness or "psychological condition” is meant a psychological, neurological and psychiatric condition, disorder, phenotype, state or sub-threshold form thereof in which a subject exhibits a behavioral or clinical phenotype characterized by abnormalities in the stress-linked biological system and/or reproductive-linked biological system.
  • the term "psychological illness” or “psychological condition” encompasses all such neuropsychological and neuropsychiatric phenotypes.
  • the present disclosure teaches a method of ameliorating the symptoms of neurobiological anomalies such as associated with major depression including major depressive disorder (MDD), treatment resistant depression, chronic depression, schizophrenia, anorexia nervosa, bulimia nervosa, anxiety disorder subtypes and other psychiatric conditions.
  • Major depressive disorder MDD
  • Treatment resistant depression chronic depression
  • schizophrenia, anorexia nervosa bulimia nervosa
  • anxiety disorder subtypes and other psychiatric conditions.
  • Terms which are also applicable to these phenotypes include psychiatric, psychological and neurological illnesses.
  • the term "illness” does not necessarily mean that a subject is medically incapacitated. Rather, it includes the full spectrum of psychological conditions, disorders, phenotypes, states or sub-threshold forms thereof which manifest in from complete debilitation to minor behavioral, physiological and/or clinical abnormalities.
  • Examples of psychological illnesses contemplated by the present disclosure include but are not limited to depression (including major depression and MDD postnatal depression, treatment resistant depression, chronic depression, psychotic or melancholic depression), eating disorders (such as anorexia nervosa and bulimia nervosa), bipolar disorder, anxiety disorders, addiction, dementia, epilepsy, schizophrenia, Tourette's syndrome, obsessive compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), phobias, acute stress disorder, adjustment disorder, agoraphobia without history of panic disorder, alcohol dependence (alcoholism), amphetamine dependence, brief psychotic disorder, cannabis dependence, cocaine dependence, cyclothymic disorder, delirium, delusional disorder, dysthymic disorder, hallucinogen dependence, nicotine dependence, opioid dependence, paranoid personality disorder, Parkinson's disease, schizophrenia, schizoaffective disorder, schizoid personality disorder, schizophreniform disorder, schizotypal personality disorder, sedative dependence,
  • MDD which includes treatment resistant depression.
  • Reference to “depression” includes “major depressive disorder” (MDD).
  • Reference to “anxiety disorder” includes “generalized anxiety disorder”. Depression may also be associated with another illness.
  • the present disclosure contemplates the use of a combination of agents which facilitates normalization of a stress-linked biological system and an anti-depressant or anti-psychotic and/or reproductive system modulator (ie., estrogen) in the treatment or prophylaxis or clinical or behavioral management of subjects with or at risk of developing a psychological illness.
  • Estrogen may also be administered.
  • the drug combinations include in one embodiment: (1) an HPA-axis-normalizing agent selected from oxytocin or an agonist thereof; a CRH antagonist; a CRH receptor antagonist; an AVP antagonist; and a ACTH antagonist, a glucocorticoid antagonist, an anti-psychotic and a dopamine antagonist: and (2) an anti-depressant selected from an SSRI, SNRI/SSNRI and other anti-depressants or mood stabilizer.
  • a modulator of the reproductive-linked biological system such as the HPG-axis is also provided.
  • An example includes estrogen, or other agent inducing estrogens and pro-estrogen drugs, as well as progestogens or agents that induce progestogens.
  • particular combinations include:
  • an anti-depressant selected from SSRI, SSNRl, a tri-cyclic anti-depressant and a tetra-cyclic anti-depressant + oxytocin + estrogen;
  • Components and combinations include tri- and tetra-cyclic anti-depressants, monoamine oxidase inhibitors, antipsychotics including dopamine antagonist, mood stabilizer and estrogen (or selective estrogen receptor modulator, SERM, or estrogen prodrug) and all combinations may further include super-active agonists (or inverse agonists) of CRH or AVP or ACTH or glucocorticoids as well as super-active antagonists of oxytocin
  • estrogen includes an estrogen analog, estrogen agonist and an agent which facilitates or -promotes estrogen production as well a SERM (including but not limited to raloxifene) as well as estrogen pro-drugs (ie., tibolone) or plant-like estrogens (ie., phytoestrogen). '
  • progestogen includes a progesterone or progestogen analog, progestogen agonist and an agent which promotes progesterone (or other precursor or derivative) production. This includes but is not limited to naturally occurring and synthetic progestogens.
  • a progestogen or “an agent” includes a single progestogen or a single agent as well as two or more progestogens or agents.
  • the present disclosure teaches a selection of neuropsychopharmacological agents based on an understanding of the interaction these drugs have on the stress-linked biological system.
  • the combination of drugs can, in one aspect, be considered synergistic, since the combination of the drugs has more efficacious outcomes than the use of the single drugs above. Hence, the combination is functionally synergistic.
  • an aspect taught herein contemplates a method for treating a subject, male or female, with a psychological illness, phenotype, state, condition or sub-threshold form thereof, the method comprising administering to the subject an agent which facilitates normalization of a stress-linked biological system and an anti-depressant in amounts and under conditions sufficient to ameliorate symptoms of the psychological, illness, phenotype, state, condition or sub-threshold form thereof.
  • Another aspect enabled herein provides a method for treating a subject with a psychological illness, phenotype, state condition or sub-threshold form thereof, the method comprising administering to the subject a drug combination selected from: (i) an HPA-axis normalizing agent selected from oxytocin or an agonist thereof, a CRH or CRH receptor antagonist, a AVP antagonist, a ACTH antagonist; a glucocorticoid antagonist, an antipsychotic and a dopamine antagonist; (ii) an SSRI, SSNRI or other anti-depressant; (ie., a tri- or tetra-cyclic anti-depressant or a monoamine oxidase inhibitor) (iv) a mood stabilizer; and optionally (iii) an estrogen, estrogen analog or estrogen agonist or a SERM , estrogen pro-drug and or (iv) a progestogen or progestogen analog or agonist.
  • a drug combination selected from: (i) an
  • Still another aspect described herein is directed to a method of treating a human subject diagnosed with symptoms of depression, the method comprising administering to the subject effective amounts of oxytocin and estrogen.
  • the method further comprises administering to the subject an effective amount of an anti-depressant such as selected from an SSRJ, SSNRI, a tri-cyclic anti-depressant and a tetra-cyclic antidepressant.
  • Examples of a "selective serotonin re-uptake inhibitor" and a selective serotonin and noradrenergic re-uptake inhibitor include citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline as well as pharmacologically acceptable derivatives, analogs, homologs and formulated forms thereof.
  • Other serotonin inhibitors or serotonin or noradrenergic uptake inhibitors include 1 -
  • Selective serotonin and noradrenergic re-uptake inhibitors include psychoactive drugs which antagonize various adrenergic and serotonin receptors and include esmirtazapinej mianserin, mirtazapine, setiptiline, such agents are also referred to as "tetracyclic anti-depressants”.
  • Other anti-depressants include tricyclic anti-depressants.
  • Such agents include serotonin and/or norepinephrine re-uptake inhibitors including amitriptyline, amitriptylinoxide, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dosulepin/dothiepin, doxepin, imipramine, imipraminoxide, lofepramine, melitracen, metapramine, nitroxazepine, nortriptyline, noxiptiline, pipofezine, propizepine, protriptyline, and quinupramine.
  • serotonin and/or norepinephrine re-uptake inhibitors including amitriptyline, amitriptylinoxide, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dosulepin/dothi
  • Monoamine oxidase inhibitors include phenelzine, tranylcypromine.
  • Anti-psychotics include dopamine receptor antagonists which antagonize dopamine (and serotonin). Examples of D2 and D2/D3 antagonists include first generation anti- psychotics (typical anti-psychotics) and second generation antipsychotics (atypical antipsychotics). Pimozide is also a dopamine receptor antagonist.
  • dopamine receptor antagonists include amisulpride (D2/D3 antagonist), nemonapride, remoxipride (D2 antagonist), sultropride and Iriapride as well as pharmacologically acceptable derivatives, analogs, homologs, salts and formulated forms thereof and any typical or atypical antipsychotics with full or partial dopamine antagonist actions.
  • dopamine antagonists include (5,6-dimethoxyindan-2-yl)dipropylamine; 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline; 1 -methyl-4-(2'-methylphenyl)- 1 ,2,3,6- tetrahydropyridine; 3-((4-(4-chlorophenyl)piperazin-l -yl)methyl)-l H-pyrrolo(2,3- b)pyridine; 3-iodo-2-hydroxy-6-methoxy-N-((l-ethyl-2-pyrrolidinyl)methyl)benzamide; 5- methoxy-l -methyl-2-(n-propylamino)tetralin; 8-iodo-2,3,4,5-tetrahydro-3-methyl-5- phenyl-l H : 3-benzazepine-7-ol; acepromazine; amoxapine; azaperone; ben
  • Reference to mood stabilizers includes inter alia antimania, anticonvulsants, antipsychotics and antihypertensives. Examples include lithium carbonate, divalproex sodium, tiagabine, levetiracetam, lamotrigine, gabapentin, carbamazepine, oxcarbazepine, topiramate, zonisamide, olanzapine, verapamil, clonidine, propranolol, mexiletine and guanfacine.
  • Naturally occurring synthetic modified, and steroidal and non-steroidal forms of estrogens as well as plant-like compounds which induce estrogens, and estrogen pro-drugs are contemplated for use in accordance with the present disclosure.
  • Examples include 2,3- bis(3'-hydroxybenzyl)butane-l,4-diol; 2,3-bis(3'-hydroxybenzyl)butyrolactone; 4- octylphenol; 8-prenylnaringenin; biochanin; bisphenol A; chlorotrianisene; coumestrol; daidzein; dienestrol; diethylstilbestrol; diethylstilbestrol dipropionate; cpimestrol; equol; estradiol; estrogenic steroids, alkylated; estrogens, conjugated (USP); phytoestrogens; estrogens, conjugated synthetic A; estrogens, conjugated synthetic B; estrogens, esterified (USP); estrone; ethinyl estradiol
  • Selective estrogen receptor modulators include: clomifene, femerelle, ormeloxifene. raloxifene, tamoxifen and toremifene.
  • An example of an estrogen pro-drug is tibolone or a pharmaceutically acceptable salt or functional equivalent thereof.
  • the present disclosure enables the use of any naturally occurring, synthetic and chemically modified progestogens as well as their functional equivalents including plant progesterone-like compounds.
  • the present disclosure also includes any compounds which induce a naturally occurring progestogen or which are metabolized into a functional progestogen, or slow release progestogen patches and implants. Examples include but are not .
  • P5 P4 pregn-4-ene-3,20-dione
  • pregnenalone cholesterol; lepidium meyenii
  • dihydroprogesterone 17-acetyl-lO, 13 -dimethyl- 1 ,2 ,8, 9,1 1 ,12,14,15, 16, 17- decahydrocyclopenta[a] phenanthren- 3-one; 6,17-dimethylpregna-4,6-diene-3,20-dione; androstenedione; progestin; progestogenic steroids; progesterone (USP); dienogest; dydrogesterone; medrogestone; medroxyprogesterone acetate; drospirenone; ormiloxifene.
  • the drugs may be simultaneously or sequentially administered.
  • the drugs may be provided in a single formulation or in a multipart form in which the contents are admixed prior to the administration. Where sequential administration occurs, the drugs may be provided within nanoseconds, milliseconds, seconds, a minute or minutes, hours or days apart.
  • the present disclosure further teaches a therapeutic or medicament kit comprising two or more drugs selected from: (i) an HPA-axis normalizing agent selected from oxytocin or an agonist thereof, a CRH or CRH receptor antagonist, a AVP antagonist, a ACTH antagonist, a glucocorticoid antagonist, and a dopamine antagonist; (ii) an SSRI, SSNRI or other anti-depressant (iii) anti-psychotic; and optionally (iv) an estrogen, estrogen analog or estrogen agonist or SERM, estrogen pro-drug and or (iv) a progestogen or progestogen analog or agonist.
  • the formulation comprises oxytocin and estrogen.
  • the disclosure comprises oxytocin, estrogen and an anti-depressant such as selected from an SSRI, SSNRI, a tri-cyclic anti-depressant and a tetra-cyclic anti-depressant.
  • formulations may also be in a form requiring reconstitution or admixing with a pharmaceutically acceptable carrier, diluent or excipient prior to use.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • Pharmaceutical compositions taught therein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion.
  • compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredien with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound- moistened with an inert liquid diluent.
  • the drugs taught herein may be administered orally, parenterally (including by subcutaneous, intravenous, intra-arterial, intramuscular, intrasternal, intra-peritoneal injection or infusion techniques), topically such as via ophthalmic and mucus membranes, by inhalation, by intranasal spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, excipients, diluents and/or other vehicles.
  • Pharmaceutical compositions and formulations for topical administration include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders,
  • compositions When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • Intravenous administration includes both bolus and infusion when administered by injection
  • the injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parenterally-acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • compositions When rectal ly administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyeeride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyeeride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • the effective dosage of the agents employed in therapy may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated.
  • the dosage regimen utilizing the compounds of the present disclosure is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the rerial and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or clinician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages may vary depending on the relative potency of individual agents, and can generally be estimated based on EC50S found to be effective in in vitro and in vivo animal models. In general, dosage is from 0.01 ⁇ g to 100 g per kg of body weight, and may be given once or more daily, weekly, monthly or six monthly or as required. Persons of ordinary skill in the art can readily estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues.
  • Variations may include daily, twice daily, thrice daily, weekly, multiple weekly and dosage may include a range of 1 - 1 ,000 international units (IUs).
  • IUs international units
  • Variations may include daily, twice daily, thrice daily, weekly, multiple weekly and dosage may include a range of 1 - 1 ,000 international units (IUs).
  • the pharmaceutical formulations enabled herein, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry.
  • Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s).
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • compositions described herein may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas.
  • the compositions herein described may also be formulated as suspensions in aqueous, non-aqueous or mixed media
  • Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran.
  • the suspension may also contain stabilizers.
  • the drugs proposed to be used in accordance with the subject method may also be referred to as medicaments, agents, therapeutics, actives, vaccines, compounds and the like.
  • Reference to a “medicament”, “agent”, “therapeutic”, “active”, “vaccine” and “compound” includes a single drug or a combination of two or more drugs.
  • the drugs may also be referred to as neuropsychopharmacological ' agents. This term is not to exclude agents which modulate signaling targets within the stress-linked biological system or reproductive linked system.
  • the subject contemplated herein is generally a human subject and may also be referred to as a patient, individual or recipient.
  • the human subject may be an infant, child, adolescent, teenager, young adult, adult or elderly adult of male or female gender.
  • the present disclosure extends to the use of the drug combinations in a variety of small to large animal models such as mice, rats, guinea pigs, hamsters, cats, dogs, pigs, sheep, cattle, horses, camels, monkeys and other non-human primates.
  • One useful animal model is the Forced Swim Test (or Porsolt Test). This model is useful inter alia for testing drug combinations for acute and chronic conditions.
  • the present disclosure further enables a combination of drugs selected from: (i) an HPA-axis normalizing agent selected from oxytocin or an agonist thereof, a CRH or CRH receptor antagonist, a AVP antagonist, a ACTH antagonist, a glucocorticoid antagonist, an anti-psychotic and a dopamine antagonist; (ii) an SSRI, SSNRI or other anti-depressant; (iii) a mood stabilizer and optionally (iv) an estrogen, estrogen analog or estrogen agonist or SERM or estrogen pro-drug, and/or (v) progestogen, progestogen analog, progestogen agonist in the manufacture of a medicament for the treatment or prophylaxis of a psychological illness.
  • an HPA-axis normalizing agent selected from oxytocin or an agonist thereof, a CRH or CRH receptor antagonist, a AVP antagonist, a ACTH antagonist, a glucocorticoid antagonist, an anti-psychotic
  • the present disclosure further describes a vaccine for use in the treatment of chronic conditions.
  • a vaccine is contemplated which induces antibodies against a particular HPA axis target, e.g, CRH as an antigen to generate antibodies specific for CRH or ACTH as an antigen to generate ACTH-specific antibodies.
  • HPA axis target e.g, CRH as an antigen to generate antibodies specific for CRH or ACTH as an antigen to generate ACTH-specific antibodies.
  • HPA axis target e.g, CRH as an antigen to generate antibodies specific for CRH or ACTH as an antigen to generate ACTH-specific antibodies.
  • a range of other HPA axis components may be used in a vaccine formulation.
  • the present disclosure further contemplates active and passive immunization protocols.
  • the term "vaccine” or "vaccine formulation” includes a preparation of antigens to induce a humoral (antibody) response as well as preparation of antibodies for use in passive immunization.
  • Antigens may need to be conjugated to a larger foreign molecule such as keyhole impact hemocyanin (KLH) or bovine serum albumin (BSA).
  • KLH keyhole impact hemocyanin
  • BSA bovine serum albumin
  • the complex (including the immunization target) is usually administered to the subject as a primary injection, followed by one or more booster injections, as required for treatment and maintenance.
  • antibodies are contemplated from any source such as humans, horses, goats, sheep, pigs, etc.
  • Non-human antibodies are generally de-immunized or humanized for use in human patients.
  • Immunoglobulin-like molecules from marine vertebrate animals such as sharks and rays may also be employed.
  • sharks and rays may also be employed.
  • One particular type is a shark -derived antibody referred to as an "IgNAR" (immunoglobulin new antigen receptor).
  • IgNAR shark -derived antibody
  • This approach may be useful for the treatment of acute symptoms (
  • treatment includes aspects of prevention (prophylaxis) such as in subjects at risk of developing a psychological condition. Such as genetically or environmentally predisposed individuals.
  • Hyperactivity of the HPA-axis response to stress in MDD is illustrated via increased levels of Cortisol in saliva, plasma and urine and increased size (and activity and responsivity) of the pituitary and adrenal glands (Nemeroff and Vale, 2005 supra). Normalization of the HPA-axis is required for a response to antidepressant treatment in some patients (Binder et ai, 2009 supra. Young et ai, 2004 supra; Juruena et ai, 2009 supra) therefore, the HPA-axis in MDD is an important target to understand in relation to anti-depressant treatment response.
  • Hyperactivity of the HPA-axis prevents a response to anti-depressant treatment in some patients (Binder et al, 2009 supra, Young et al, 2004 supra; Juruena et al, 2009 supra). This is supported by evidence that in an inpatient setting, individuals (Young et al., 2004 supra; Juruena et al, 2009 supra) who subsequently failed to respond to two antidepressant interventions (including SSRIs) showed elevated HPA-axis activity at baseline, failed to normalize at treatment follow-up (Young et al, 2004 supra; Juruena et al, 2009 supra). Furthermore in some patients (versus healthy controls) excessive concentrations of ACTH were reported (Young et al, 2004 supra).
  • Oxytocin is a neuropeptide with a wide spectrum of actions in the brain and body (Heinrichs and Domes, Prog Brain Res 770:337-350, 2008). Oxytocin binds significantly in the hypothalamus (see Figure 1) and the limbic system, including the amygdale (Huber et al.
  • Oxytocin in an intranasal form (enabling its effects on the central nervous system to be determined), has been shown in several randomized controlled trials (RCTs) to effectively treat symptoms in social phobia and autism spectrum disorder (Guastella et al, Psychoneuroendocrinology 34(6):9 ⁇ 7-923, 2009; Guastella el al, Biol Psychiatry, 2009; Andari et al, Proc of the Nat Acad of Sci; 2010).
  • the drug showed no impact on weight gain or plasma leptin concentrations (Kunzel et al, J Psychiatr Res 39(2): ⁇ 3- ⁇ , 2005), gonadal and rennin-angiotensisn systems, prolactin or arginine vasopressin secretion (Kunzel et al., J Psychiatr Res 37 (6) :525-533, 2003).
  • a 30-day dose- escalatjon trial e.g., 5-40mg or 40-80mg further confirmed that the drug is safe, efficacious and well tolerated (Zobel et al,, 2000 supra).
  • the drug does not preclude a normal response of the HPA-axis to stressor challenges (Kunzel et al., 2003 supra) but reduces baseline (or resting) HPA-axis hormone concentrations (Kunzel et al., 2003 supra).
  • Other studies have not shown an impact of CRHl antagonism on symptoms of MDD (Binneman et al., Am J Psychiatry 165(5):617-620, 2008) although a different CRHl angatonist was employed (CP-316,31 1). Owing to its demonstrated clinical effect in MDD (Zobel et al., 2000 supra; Kunzel et a!., 2003 supra) the potential for positive effects of CRH modulation, which have not been investigated in TRD, warrant testing.
  • Estrogens to reduce activity of the HPA axis
  • Estrogen can reduce activity of the HPA axis in the context of stress in females ⁇ Young et al, Psychoneuroendocrinology. 29(9): 1198-1204, 2004).
  • estrogen antagonists tamoxifen and CI 628
  • Young et al, 2004 supra demonstrated an increase in ACTH and corticosterone response to restraint stress in female rats.
  • low dose estradiol over 7 days
  • decreased ACTH response to stress Young et al, 2004 supra.
  • Estrogen has not been used to manage treatment resistant depression, however, it is proposed herein to induce inhibition of the HPA axis via its interactions with oxytocin.
  • Estrogen has not been used to manage treatment resistant depression, however, it is proposed herein to induce inhibition of the HPA axis via its interactions with oxytocin.
  • EBP oestrogen-receptor
  • In rats in distinct sub-regions 45-98% of the hypothalamus oxytocin neurons have been shown to exhibit oestrogen-receptor (ERP) immunoreactivity (confined to cell nuclei) [Hrabovszky et al,. J Comp Neurol. 473(3):3 l 5-333: 2004].
  • ERP oestrogen-receptor
  • Double-blind randomized trial of hormone (adjunct) therapies in treatment resistant depression [0078 j
  • the aim is to compare the efficacy and safety of a combined therapeutic protocol, combined agents which normalize HPA-axis activity with an SSRI, escitalopram, in treating symptoms of depression in patients with TRD. That is, patients who have not previously responded to at least two interventions, including SSRI therapy.
  • Escitalopram is chosen due to its highly specific and selective actions on the serotonin system.
  • This example has been designed consistent with the CONSORT guidelines. This is a three-ann double-blinded parallel-group randomized pilot trial to compare the efficacy and safety of 3 different escitalopram adjuncts in patients with MDD that have previously not shown a clinical response to escitalopram (or other SSRI and at least one other intervention). All patients will take the SSRI, escitalopram, and a comparison made on the efficacy and safety of: oxytocin adjunct (Syntocinon or other commercially or non- commercially available alternative/homolog) or corticotropin releasing hormone (CRH) adjunct (561679 or other commercially or non-commercially available alternative/homolog) to placebo adjunct.
  • oxytocin adjunct Syntocinon or other commercially or non- commercially available alternative/homolog
  • CSH corticotropin releasing hormone
  • Group 1 escitalopram + oxytocin agonist (syntocinon);
  • Group 2 escitalopram + CRH antagonist (561679);
  • Group 3 escitalopram + placebo.
  • Participants are patients that have failed to progress clinically on an SSRI (and at least one other intervention) despite an adequate duration and highest tolerated dose (Berlim and Turecki, 2007 supra; Souery et al, Eur Neuropsychopharmacol 9(102):S3-9 ⁇ , 1999) of an SSRI (e.g., any SSRI, such as escitalopram, fluoxetine, paroxetine).
  • an SSRI e.g., any SSRI, such as escitalopram, fluoxetine, paroxetine.
  • the double-blind phase will begin following 4 weeks of monotherapy with escitalopram. Baseline measures are then be completed and patients are randomly allocated to an investigational group (1 , 2 or 3). Patient visits tocollect blood samples and assess changes in clinical symptoms and the HPA-axis will occur at day 28, 56, 84 (ie., every 4 weeks until the trial end-date).
  • Group 1 Oxytocin are intranasally administered at a total dose of 24 IU (international units) (40.32 g). 12 IU will be sprayed into each nostril (three puffs per nostril each with 4 IU oxytocin) each day consistent with established efficacy and tolerability in patients with social phobia (Guastella et al., 2009 supra). SSRl dosing design will be the maximum prescribed dose of escitalopram (20mg).
  • Group 2 CRH (561679 Glaxosmithkline or alternative) are orally administered at a dose of 80mg consistent with manufactures established efficacy and safety in patient trials. SSRl dosing design will be the maximum prescribed dose of escitalopram (20mg).
  • Group 3 Placebo (vehicle) are both intranasally administered in spray form in some patients or orally administered in tablet form in other patients to present appropriate non-active ' treatment controls for oxytocin (instranasal spray) and CRH (orally administered tablet).
  • SSRl dosing design is the maximum prescribed dose of escitalopram (20mg).
  • DSM-IV defined substance dependence, intellectual disability or significant unstable medical illness including epilepsy, diabetes or cardiac related, renal or liver disease or pregnancy.
  • [0086J Screening Patients are screened as soon after referral as possible. Once informed consent is obtained, procedures for the study begin. Patients undergo full psychiatric and medical history examination and non-invasive physical examination. Psychopathology is assessed, to confirm symptom severity and history of failed treatment response. A blood sample is taken in females to confirm hormone profiles, confirm stage of menstrual cycle and pregnancy status.
  • Randomization procedure Following receipt of consent to participate, each participant is allocated an identification number, and randomly assigned to a treatment regimen. The randomization procedure is organized using a (pseudo-randomized) code generated by computer. Equal numbers are assigned to the three treatment arms at a 1 :1 : 1 ratio, where patients, raters, clinicians and researchers are "blind" as to the active (ie., hormone) or non-active (ie., placebo) treatment a patient receives.
  • active ie., hormone
  • non-active ie., placebo
  • Baseline visit Medication is dispensed at baseline, following confirmation by pathology reports (from blood taken at screening visit) that patients meet inclusion criteria. Other procedures performed include: psychopathology and collection of blood for endocrine/hormone assays as well as 24 hour salivary Cortisol tests.
  • Evaluation visits At evaluation visits, the researchers record adherence, adverse events and administer psychopathology rating scales and collect blood for hormone assays. A 10 ml blood sample is taken at each study visit to measure: Oxytocin, CRH, ACTI l, Cortisol, DHEA, progesterone, prolactin, FSH, LH, estrogen, testosterone.
  • Pathology and other tests Physical examination: weight, hip-waist measure. Serum lipids; Liver and renal function; Full blood exam (FBE); Random blood glucose. Hormone analysis in women (only) at baseline: estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, dehydroepiandrosterone (DHEA), progesterone, prolactin, human chorionic gonadotropin hormone (HCG) to determine menstrual status/pregnancy status.
  • DHEA dehydroepiandrosterone
  • HCG human chorionic gonadotropin hormone
  • Medication is dispensed following screening (and pathology tests) at baseline, and each four-weekly study visit thereafter. The prescription is filled according to the randomization relevant to each participant, which will then be collected by the study co-ordinator and given to the participant at each visit.
  • Double-blind randomized trial of hormone (adjunct) therapies in treatment resistant depression [0098]
  • TRD Treatment Resistant Depression
  • HP A hypothalamopituitary adrenal
  • the aim is to compare the efficacy and safety of a combined therapeutic protocol, combined agents which normalize HPA-axis activity with an SSR1, escitalopram, in treating symptoms of depression in patients with TRD. That is, patients who have not previously responded to at least two interventions, including SSRI therapy.
  • Escitalopram is chosen due to its highly specific and selective actions on the serotonin system.
  • All patients are female and take the SSRI, escitalopram, and the efficacy and safety of active adjuncts oxytocin (syntocinon intranasal spray) and tibolone (orally) to non-active adjunct placebo are compared.
  • the use of two active adjuncts and a non-active placebo adjunct is a design that allows investigation of whether novel hormone oxytocin, or oxytocin and tibolone result in better efficacy than placebo in TRD.
  • the endocrine mechanisms contributing to treatment outcomes are systematically studied. The trial Is 12 weeks.
  • Group 1 escitalopram + oxytocin (syntocinon intranasal spray) + tibolone
  • Group 2 escitalopram + oxytocin (syntocinon intranasal spray) + placebo
  • Group 3 escitalopram + placebo (intranasal spray) + placebo (oral)
  • Group 1 Oxytocin will be intranasally administered at a total dose of 24 IU (international units) (40.32 ⁇ g). 12 IU will be sprayed into each nostril (three puffs per nostril each with 4 IU oxytocin) each day consistent with established efficacy and tolerability in patients with social phobia. Escitalopram dosing design will be standard. Patients receive daily oral tibolone 2.5mg/day (dose approved by the TGA for postmenopausal women).
  • Group 2 Oxytocin is intranasally administered as described above. Escitalopram dosing design is standard. A daily oral placebo (vehicle for tibolone) is administered.
  • Group 3 Escitalopram dosing design is standard. Intranasal placebo (vehicle for oxytocin) is administered and daily oral placebo (for tibolone) is administered.
  • Protocols Aspects including exclusion criteria, inclusion criteria, screening, randomization procedure, baseline visit, evaluation visits, instruments for data collection, diagnostic and psychopathology, safety and tolerance, pathology and other tests, medications and concomitant treatments are as per Example 5.
  • Analysis is performed on participants who complete 1) at least one post-baseline treatment visit at week 4 (intention to treat) and 2) per protocol to provide a measure of reliability of the primary analysis. Data are assessed for normality and log- transformed where appropriate. Univariate analysis will be conducted using chi-square test for equal proportion, analysis of variance and non-parametric Kruskal-wallis tests where required. The primary efficacy measure Is the change from baseline to the end of treatment in MADRS score. Primary inferential analysis is conducted using a mixed effects model for the intention to treat population. This model includes treatment as a fixed effect with other clinical and demographic factors as potential covariates. A two sided p-value of 0.05 is considered statistically significant. EXAMPLE 8
  • the anti-depressants are selected from an SSRI, SSNRI, a tri-cyclic anti-depressant and a tetra-cyclic anti-depressant.
  • SSRI include escitalopram, sertraline, citalopram, fluoxetine and agomelatine.
  • SSNRI include esmertazapine, venlafaxine, desvenlafaxine and duloxetine.
  • a tri-cyclic anti-depressant include amitriptyline and imipramine.
  • Examples of a tetracyclic anti-depressant include amoxapine and mirtazapine.
  • Candidates have symptoms of depression. Some have treatment resistant depression. The drugs are given separately or as part of a single or multiple formulation. In preparation for the treatment of human patients, an animal model may be used. An example of a suitable animal model is the Forced Swim Test (or Porsolt Test). Such an animal model is particularly useful in testing drugs in acute and chronic treatments.

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Abstract

La présente invention a pour objet des régimes de traitement neuropsychopharmacologiques pour le traitement d'un grand choix de troubles psychologiques comprenant la dépression et ses formes infraliminaires. La présente invention concerne un certain nombre de protocoles de traitement, comprenant une association synergique d'ocytocine et d'œstrogène qui cible l'axe hypothalamo-pituitaire-surrénal, en association avec des agents antidépresseurs. Ces protocoles de traitement peuvent être utilisés seuls ou en association avec d'autres thérapies de modification comportementale, pour le traitement de troubles psychologiques tels que la dépression et les symptômes de la dépression. La présente invention concerne également des compositions, des médicaments et des agents comprenant des associations d'ocytocine, d'œstrogène et d'antidépresseurs.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2879680A4 (fr) * 2012-08-06 2016-06-01 S1 Biopharma Inc Régimes de traitement
WO2021042029A1 (fr) * 2019-08-29 2021-03-04 New York University Compositions d'oxytocine pour le traitement de l'acouphène
CN114404544A (zh) * 2022-03-02 2022-04-29 李建军 一种治疗心理疾病的中药沙盘及其制备和应用
WO2023028086A1 (fr) * 2021-08-23 2023-03-02 Gilgamesh Pharmaceuticals, Inc. Combinaisons d'antagonistes du récepteur 5-ht2a périphérique et d'agonistes du récepteur 5-ht2a central
US11724985B2 (en) 2020-05-19 2023-08-15 Cybin Irl Limited Deuterated tryptamine derivatives and methods of use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043661A1 (fr) * 1997-03-27 1998-10-08 Thomas Lundeberg Utilisation de substances ayant une activite d'oxytocine dans la preparation de medicaments pour la suberification d'une blessure
WO2004067022A2 (fr) * 2003-01-24 2004-08-12 Beier Klaus M Utilisation d'un melange contenant des neuropeptides et des steroides pour traiter des troubles de la vie et du comportement psychosociaux
US20040235956A1 (en) * 2000-01-11 2004-11-25 Atossa Healthcare, Inc. Long-acting oxytocin analogues for the treatment and prevention of breast cancer and psychiatric disorders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043661A1 (fr) * 1997-03-27 1998-10-08 Thomas Lundeberg Utilisation de substances ayant une activite d'oxytocine dans la preparation de medicaments pour la suberification d'une blessure
US20040235956A1 (en) * 2000-01-11 2004-11-25 Atossa Healthcare, Inc. Long-acting oxytocin analogues for the treatment and prevention of breast cancer and psychiatric disorders
WO2004067022A2 (fr) * 2003-01-24 2004-08-12 Beier Klaus M Utilisation d'un melange contenant des neuropeptides et des steroides pour traiter des troubles de la vie et du comportement psychosociaux

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
GRAZIOTTIN A. ET AL.: "Depression and the menopause: why antidepressants are not enough", MENOPAUSE INTERNATIONAL, vol. 15, 2009, pages 76 - 81 *
MCCARTHY M. M. ET AL.: "An Anxiolytic Action of Oxytocin is Enhanced by Estrogen in the Mouse", PHYSIOLOGY & BEHAVIOR, vol. 60, no. 5, 1996, pages 1209 - 1215 *
OCHEDALSKI T. ET AL.: "Interaction Between Oestrogen and Oxytocin on Hypothalamic- Pituitary-Adrenal Axis Activity", JOURNAL OF NEUROENDOCRINOLOGY, vol. 19, no. 3, 2007, pages 189 - 197 *
THE ALFRED: "Oxytocin and Tibolone Adjuncts in Treatment Resistant Depression - A Pilot Study.", CLINICALTRIALS.GOV IDENTIFIER NCT01239888. CLINICALTRIALS.GOV: A SERVICE OF THE U.S. NATIONAL INSTITUTES OF HEALTH, 9 November 2010 (2010-11-09), Retrieved from the Internet <URL:http://clinicaltrials.gov/ct2/show/NCT01239888> [retrieved on 20110628] *
UVNAS-MOBERG K. ET AL.: "Oxytocin as a possible mediator of SSRI-induced antidepressant effects", PSYCHOPHARMACOLOGY, vol. 142, 1999, pages 95 - 101, XP002921911, DOI: doi:10.1007/s002130050867 *
WINDLE R.J. ET AL.: "Central Oxytocin Administration Reduces Stress-Induced Corticosterone Release and Anxiety Behaviour in Rats", ENDOCRINOLOGY, vol. 138, no. 7, 1997, pages 2829 - 2834 *

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