Glutamate agents in the treatment of mental disorders

• US 20060270647A1
• Filed: 04/05/2006
• Published: 11/30/2006
• Est. Priority Date: 04/05/2005
• Status: Active Grant

• Current Assignee: Yale University
• Original Assignee: Yale University
• Inventors: Sanacora, Gerard, Krystal, John H., Coric, Vladimir
• Granted Patent: US 8,778,979 B2
• Time in Patent Office: Days
• US Class Current: 514/192
• 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 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/43 Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula , e.g. penicillins, penems
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/545 Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: , e.g. cephalosporins, cefaclor, or cephalexine
• 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: G02B 1/10 Optical coatings produced by application to, or surface treatment of, optical elements G02B1/08 takes precedence
• CPC Class Codes: G02B 5/281 designed for the infrared light
• CPC Class Codes: G02B 5/283 designed for the ultraviolet
• CPC Class Codes: G02B 5/285 comprising deposited thin solid films G02B5/281 - G02B5/289 take precedence; multilayered film filters for fibre optic multiplexing G02B6/29361
• CPC Class Codes: H01L 27/14621 Colour filter arrangements
• CPC Class Codes: H01L 27/14685 Process for coatings or optical elements

Abstract

Methods of treating mental disorders, including anxiety disorders such as obsessive-compulsive disorder, are provided. The methods comprise administering an effective amount of a glutamate modulator to an individual in need thereof. Also provided are methods of enhancing the activity of a serotonin reuptake inhibitor (SRI) comprising co-administering a glutamate modulator and a serotonin reuptake inhibitor. Pharmaceutical composition comprising a serotonin reuptake inhibitor and a glutamate modulator are also provided.

Claims

1. A method of treating a mental disorder in an individual in need thereof, comprising administering to the individual an effective amount of a glutamate modulator, wherein the individual does not have major depressive disorder.

4. The method of claim 1 or 2, wherein the disorder is an anxiety disorder.

5. The method of claim 4, wherein the anxiety disorder is obsessive-compulsive disorder.

6. The method of claims 1, 2, or 3, wherein the glutamate modulator attenuates presynaptic glutamate release or normalizes, enhances, or potentiates the uptake of glutamate by glia.

7. The method of claims 1 or 3, wherein the glutamate modulator is riluzole, N-acetylcysteine, a β

-lactam, amantadine, lamictal, acamprosate, memantine, neramexane, remacemide, ifenprodil, or dextromethorphan.

8. The method of claim 7, wherein the β

-lactam is penicillin, amoxicillin, ceftriaxone, cephapirin, cefoperazole, cefadroxil, bacampicillin, ampicillin, cephalothin, or nafcillin.

2. A method of treating a mental disorder in an individual in need thereof, comprising administering to the individual an effective amount of a glutamate modulator, wherein the glutamate modulator is not riluzole.

9. The method of claim 2, wherein the glutamate modulator is N-acetylcysteine, a β

-lactam, amantadine, lamictal, acamprosate, memantine, neramexane, remacemide, ifenprodil, or dextromethorphan.

10. The method of claim 9, wherein the β

-lactam is penicillin, amoxicillin, ceftriaxone, cephapirin, cefoperazole, cefadroxil, bacampicillin, ampicillin, cephalothin, or nafcillin.

3. A method of treating a mental disorder in an individual in need thereof, comprising administering to the individual an effective amount of a glutamate modulator, wherein the individual displays a Yale Brown Obsessive Compulsive Scale score of at least 20.

11. A method of treating a mental disorder in an individual in need thereof, comprising administering to the individual an effective amount of an agent that normalizes, enhances, or potentiates glutamate uptake by glia.

12. The method of claim 11, wherein the mental disorder is a disorder usually first diagnosed in infancy, childhood, or adolescence;

delirium, dementia, or an amnestic or other cognitive disorder;

a mental disorder due to a general medical condition;

a substance-related disorder;

schizophrenia or another psychotic disorder;

a mood disorder;

an anxiety disorder;

a somatoform disorder;

a factitious disorder;

a dissociative disorder;

a sexual or gender identity disorder;

an eating disorder;

a sleep disorder;

an impulse-control disorder;

or an adjustment disorder.

13. The method of claim 12, wherein the agent increases the expression, activity, or function of at least one glutamate transporter in glia.

14. The method of claim 13, wherein the mental disorder is an anxiety disorder.

15. The method of claim 14, wherein the anxiety disorder is obsessive-compulsive disorder.

16. The method of claim 13, wherein the agent is a glutamate modulating agent.

17. The method of claim 13, wherein the agent is β

-lactam.

18. The method of claim 17, wherein the β

-lactam is a β

-lactam antibiotic.

19. The method of claim 18, wherein the β

-lactam antibiotic is penicillin, amoxicillin, ceftriaxone, cephapirin, cefoperazole, cefadroxil, bacampicillin, ampicillin, cephalothin, or nafcillin.

20. The method of claim 12, wherein the agent protects glial cells against glutamate toxicity, repletes levels of glutathione, or attenuates toxic levels of glutamate.

21. The method of claim 20, wherein the agent is N-acetylcysteine.

22. A method of enhancing the activity of a serotonin reuptake inhibitor (SRI) in an individual in need thereof, comprising co-administering to the individual a glutamate modulator and a SRI, wherein the glutamate modulator is administered in an amount sufficient to normalize synaptic glutamate levels in the individual, thereby resulting in greater activity of the SRI in the individual than would occur in the absence of co-administration of the glutamate modulator.

24. The method of claim 22, wherein the individual has an anxiety disorder.

26. The method of claims 22 or 23, wherein the individual does not have a mood disorder.

27. The method of claim 22 or 23, wherein the individual is resistant to treatment with a serotonin reuptake inhibitor.

28. The method of claim 22 or 23, wherein the glutamate modulator is riluzole, N-acetylcysteine, a β

-lactam, amantadine, lamictal, acamprosate, memantine, neramexane, remacemide, ifenprodil, or dextromethorphan.

29. The method of claim 22 or 23, wherein the glutamate modulator is N-acetylcysteine, a β

-lactam, amantadine, lamictal, acamprosate, memantine, neramexane, remacemide, ifenprodil, or dextromethorphan.

30. The method of claim 22 or 23, wherein the serotonin reuptake inhibitor is citalopram, escitalopram, flouxetine, fluvoxamine, paroxetine, sertraline, trazodone, venlafaxine, mirtazepine, clomipramine, or combinations with other psychotropic medications including an anti-psychotic, an anti-convulsant, a tricyclic antidepressant, a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor, a selective serotonin-norepinephrine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, a serotonin-2 antagonist reuptake inhibitor, a benzodiazepine, a wakefulness promoting agent, anti-manic agent, or a combination of one or more of the foregoing.

23. A method of enhancing the activity of a serotonin reuptake inhibitor (SRI) in an individual in need thereof, comprising co-administering to the individual a glutamate modulator and a SRI, wherein the glutamate modulator is administered in an amount sufficient to normalize synaptic glutamate levels in the individual, thereby resulting in greater activity of the SRI in the individual than would occur in the absence of co-administration of the glutamate modulator, and wherein the individual displays a Yale Brown Obsessive Compulsive Scale score of at least 20.

25. The method of claim 23, wherein the anxiety disorder is obsessive-compulsive disorder.

31. A pharmaceutical composition comprising a serotonin reuptake inhibitor and a glutamate modulator.

32. The pharmaceutical composition of claim 31, wherein (a) the serotonin reuptake inhibitor is at least one of the following:

citalopram, escitalopram, flouxetine, fluvoxamine, paroxetine, sertraline, trazodone, venlafaxine, mirtazepine, clomipramine, or combinations with other psychotropic medications including an anti-psychotic, an anti-convulsant, a tricyclic antidepressant, a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor, a selective serotonin-norepinephrine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, a serotonin-2 antagonist reuptake inhibitor, a benzodiazepine, a wakefulness promoting agent, anti-manic agent, or a combination of one or more of the foregoing; and

(b) the glutamate modulator is at least one of the following;

riluzole, N-acetylcysteine, a β

-lactam, amantadine, lamictal, acamprosate, memantine, neramexane, remacemide, ifenprodil, and dextromethorphan.

33. The pharmaceutical composition of claim 32, wherein (a) the serotonin reuptake inhibitor is at least one of the following:

citalopram, escitalopram, flouxetine, fluvoxamine, paroxetine, sertraline, trazodone, venlafaxine, mirtazepine, clomipramine, or combinations with other psychotropic medications including an anti-psychotic, an anti-convulsant, a tricyclic antidepressant, a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor, a selective serotonin-norepinephrine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, a serotonin-2 antagonist reuptake inhibitor, a benzodiazepine, a wakefulness promoting agent, anti-manic agent, or a combination of one or more of the foregoing; and

(b) the glutamate modulator is at least one of the following;

N-acetylcysteine, a β

-lactam, amantadine, lamictal, acamprosate, memantine, neramexane, remacemide, ifenprodil, and dextromethorphan.

34. The pharmaceutical composition of claims 32 or 33, additionally comprising a pharmaceutically acceptable carrier.