Methods and compositions for treating schizophrenia

• US 10,154,988 B2
• Filed: 11/14/2013
• Issued: 12/18/2018
• Est. Priority Date: 11/14/2012
• Status: Active Grant

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Gallagher, Michela
• Primary Examiner(s): Bakshi, Pancham
• Application Number:
  US14/442,996
• Publication Number:
  US 20150313876A1
• Time in Patent Office: 1,860 Days
• Field of Search: 51421113, 514282, 514424
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention relates to methods and compositions for treating schizophrenia or bipolar disorder (in particular, mania) by using a combination of a synaptic vesicle protein 2A (SV2A) inhibitor and an antipsychotic or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, and prodrugs thereof. The methods and the compositions can be used for treating one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia or bipolar disorder (in particular, mania).

Claims

1. A method for treating cognitive impairment associated with schizophrenia or bipolar disorder in a subject in need or at risk thereof, the method comprising the step of administering to said subject a therapeutically effective amount of a synaptic vesicle protein 2A (SV2A) inhibitor or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an antipsychotic or a pharmaceutically acceptable salt thereof,

wherein the SV2A inhibitor is selected from the group consisting of levetiracetam, seletracetam, and brivaracetam and pharmaceutically acceptable salts thereof;

wherein the antipsychotic is

a) selected from the group consisting of aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone and ziprasidone, and pharmaceutically acceptable salts thereof;

or

b) selected from the group consisting of aripiprazole, olanzapine and ziprasidone, and pharmaceutically acceptable salts thereof, or

c) selected from the group consisting of acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine, chlorprothixene, clotiapine, cyamemazine, diazepam, dixyrazine, droperidol, flupentixol, fluphenazine, fluspirilene, haloperidol, heptaminol, isopropamide iodide, levomepromazine, levosulpiride, loxapine, melperone, mesoridazine, molindone, oxypertine, oxyprothepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, pyridoxine, sulpiride, sultopride, tetrabenazine, thioproperazine, thioridazine, tiapride, tiotixene, trifluoperazine, triflupromazine, trihexyphenidyl, and zuclopenthixol, and pharmaceutically acceptable salts thereof;

and

wherein the SV2A inhibitor or the pharmaceutically acceptable salt thereof is administered at a daily dose of 0.07 mg to 350 mg.

2. The method of claim 1, wherein the antipsychotic or a pharmaceutically acceptable salt thereof is administered at a dose that is subtherapeutic as compared to the dose at which it is therapeutically effective when administered in the absence of the SV2A inhibitor or a pharmaceutically acceptable salt thereof.

3. The method of claim 1, wherein the SV2A inhibitor is levetiracetam or a pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein the SV2A inhibitor or the pharmaceutically acceptable salt thereof is administered:

a) at a daily dose of 7 mg to 350 mg, 35 mg to 350 mg, or 0.07 mg to 35 mg;

or

b) at a daily dose that is subtherapeutic as compared to the dose at which it is therapeutically effective when administered in the absence of the antipsychotic or a pharmaceutically acceptable salt thereof, wherein the subtherapeutic daily doses are selected from the group consisting of less than 7 mg/kg, less than 6 mg/kg, less than 5 mg/kg, less than 4 mg/kg, less than 3.6 mg/kg, less than 3 mg/kg, less than 2 mg/kg, less than 1.5 mg/kg, less than 1.5 mg/kg, less than 1 mg/kg, less than 0.1 mg/kg, less than 0.05 mg/kg, less than 0.01 mg/kg, or less than 0.0015 mg/kg.

5. The method of claim 1, wherein the SV2A inhibitor or the pharmaceutically acceptable salt thereof, and the antipsychotic, or the pharmaceutically acceptable salt thereof are administered simultaneously, or sequentially, or in a single formulation, or in separate formulations.

6. The method of claim 1,

a) wherein the SV2A inhibitor is levetiracetam or a pharmaceutically acceptable salt thereof and the antipsychotic is selected from the group consisting of aripiprazole, olanzapine, risperidone and ziprasidone, and pharmaceutically acceptable salts thereof;

or

b) wherein the SV2A inhibitor is brivaracetam or a pharmaceutically acceptable salt thereof and the antipsychotic is selected from the group consisting of aripiprazole, olanzapine, risperidone and ziprasidone, and pharmaceutically acceptable salts thereof;

or

c) wherein the SV2A inhibitor is seletracetam or a pharmaceutically acceptable salt thereof and the antipsychotic is selected from the group consisting of aripiprazole, olanzapine, risperidone and ziprasidone, and pharmaceutically acceptable salts thereof.

7. The method of claim 1,

a) wherein the treatment has a longer therapeutic effect in the subject than is attained by administering the antipsychotic or a pharmaceutically acceptable salt thereof in the absence of the SV2A inhibitor or a pharmaceutically acceptable salt thereof by at least about 1.5x, or 2.0x, or 2.5x, or 3.0x, or 3.5x, or 4.0x, or 4.5x, or 5.0x, or 5.5x, or 6.0x, or 6.5x, or 7.0x, or 7.5x, or 8.0x, or 8.5x, or 9.0x, or 9.5x, or 10x, or greater than about 10x;

or

b) wherein the treatment has a longer therapeutic effect in the subject than is attained by administering the SV2A inhibitor or a pharmaceutically acceptable salt thereof in the absence of the antipsychotic or a pharmaceutically acceptable salt thereof by at least about 1.5x, or 2.0x, or 2.5x, or 3.0x, or 3.5x, or 4.0x, or 4.5x, or 5.0x, or 5.5x, or 6.0x, or 6.5x, or 7.0x, or 7.5x, or 8.0x, or 8.5x, or 9.0x, or 9.5x, or 10x, or greater than about 10x.