Methods for treating neuropsychiatric disorders

• US 6,667,297 B2
• Filed: 07/15/2002
• Issued: 12/23/2003
• Est. Priority Date: 04/14/1998
• Status: Expired due to Term

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Coyle, Joseph, Tsai, Guochuan
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US10/196,686
• Publication Number:
  US 20020193429A1
• Time in Patent Office: 526 Days
• Field of Search: 514/119, 514/380, 514/561
• US Class Current: 514/119
• 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 31/198 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 31/315 Zinc compounds
• CPC Class Codes: A61K 31/42 Oxazoles
• 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 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• 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

Abstract

The invention provides methods for treating neuropsychiatric disorders such as schizophrenia, Alzheimer'"'"'s Disease, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder. The methods entail administering to a patient diagnosed as having a neuropsychiatric disorder a pharmaceutical composition containing (i) a therapeutically effective amount of D-alanine (or a modified form thereof), provided that the composition is substantially free of D-cycloserine, and/or (ii) D-serine (or a modified form thereof), and/or (iii) 105 to 500 mg of D-cycloserine (or a modified form thereof), and/or (iv) N-methylglycine (or a modified form thereof).

Claims

1. A method for treating autism, the method comprising administering to a patient diagnosed as suffering from autism a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of D-alanine, a salt of D-alanine, an ester of D-alanine, an alkylated D-alanine, a precursor of D-alanine, D-serine, a salt of D-serine, an alkylated D-serine, a precursor of D-serine, D-cycloserine, a salt of D-cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, an alkylated D-cycloserine, N-methylglycine, a salt of N-methylglycine, an ester of N-methylglycine, an alkylated N-methylglycine, and N,N,N-trimethylglycine.

2. The method of claim 1, wherein the compound is selected from the group consisting of D-alanine, a salt of D-alanine, an ester of D-alanine, an alkylated D-alanine, and a precursor of D-alanine.

3. The method of claim 2, wherein the D-alanine, salt of D-alanine, ester of D-alanine, alkylated D-alanine, or precursor of D-alanine is administered at a dosage equivalent to 10 mg to 100 g of D-alanine.

4. The method of claim 2, wherein the compound is a D-alanine salt selected from the group consisting of a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a zinc salt, and an ammonium salt of D-alanine.

5. The method of claim 2, wherein the compound is an ester of D-alanine having an ester group with 1-20 carbon atoms.

6. The method of claim 2, wherein the compound is an alkylated D-alanine having an alkyl group with 1-20 carbon atoms.

7. The method of claim 2, wherein the pharmaceutical composition further comprises D-serine.

8. The method of claim 1, wherein the compound is selected from the group consisting of D-serine, a salt of D-serine, alkylated D-serine, and a precursor of D-serine.

9. The method of claim 8, wherein the D-serine, salt of D-serine, precursor of D-serine, or alkylated D-serine is administered at a dosage equivalent to 10 mg to 100 g of D-serine.

10. The method of claim 8, wherein the compound is a D-serine salt selected from the group consisting of a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a zinc salt, and an ammonium salt of D-serine.

11. The method of claim 8, wherein the compound is an alkylated D-serine having an alkyl group with 1-20 carbon atoms.

12. The method of claim 1, wherein the compound is selected from the group consisting of D-cycloserine, a salt of D-cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, and an alkylated D-cyclosenne.

13. The method of claim 12, wherein the D-cycloserine, salt of D-cycloserine, ester of D-cycloserine, alkylated D-cycloserine, or precursor of D-cycloserine is administered in a dose equivalent to 125-400 mg of D-cycloserine.

14. The method of claim 13, wherein the D-cycloserine, D-cycloserine salt, ester of D-cycloserine, alkylated D-cycloserine, or precursor of D-cycloserine is administered in a dose equivalent to 150-300 mg of D-cycloserine.

15. The method of claim 12, wherein the compound is a salt of D-cycloserine selected from the group consisting of a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a zinc salt, and an animonium salt of D-cyclosenne.

16. The method of claim 12, wherein the compound is an ester of D-cycloserine having an ester group with 1-20 carbon atoms.

17. The method of claim 12, wherein the compound is an alkylated D-cycloserine having an alkyl group with 1-20 carbon atoms.

18. The method of claim 12, wherein the compound is a precursor of D-cycloserine.

19. The method of claim 1, wherein the N-methylglycine, salt of N-methylglycine, ester of N-methylglycine, alkylated N-methylglycine, or N,N,N-trimethylglycine is administered at a dosage equivalent to 10 mg to 100 g of N-methylglycine.

20. The method of claim 1, wherein the compound is an ester of N-methylglycine having an ester group with 1-20 carbon atoms.

21. The method of claim 1, wherein the compound is an alkylated N-methylglycine having an alkyl group with 1-20 carbon atoms.

22. The method of claim 1, wherein the pharmaceutical composition is administered to the patient at least once daily for at least one week.

23. The method of claim 1, further comprising administering to the patient at least one therapeutic agent selected from the group consisting of antipsychotics, antidepressants, psychostimulants, and Alzheimer'"'"'s disease therapeutics.

24. The method of claim 1, wherein the compound is a precursor of D-serine, and the precursor is D-phosphoserine or L-phosphoserine.

25. The method of claim 1, further comprising administering to the patient at least one therapeutic agent selected from the group consisting of Chlorpromazine, Thioridazine, Mesoridazine, Fluphenazine, Perphenazine, Trifluoperazine, Thiothixene, Haloperidol, Loxapine, Molindone, Clozapine, Risperidone, Olanzapine, Quetiapine, Haloperidol decanoate, Fluphenazine decanoate, Fluphenazine enanthate, Amitriptyline, Amoxapine, Bupropion, Bupropion SR, Clomipramine, Desipramine, Doxepin, Fluoxetine, Fluvoxamine, Imipramine, Maprotiline, Mirtazapine, Nefazodone, Nortriptyline, Paroxetine, Pheneizine, Protriptyline, Sertraline, Tranylcypromine, Trazodone, Trimipramine, Venlafaxine, Venlafaxine XR, Dextroamphetamine, Methamphetamine, Methylphenidate, Pemoline, Donepezil, Tacrine, Acetophenazine, Chlorprothixene, Droperidol, Pimozide, Butaperazine, Carphenazine, Remoxipride, Piperacetazine, Sulpiride, and Ziprasidone.

26. The method of claim 1, wherein the pharmaceutical composition is administered for at least six weeks.

27. The method of claim 1, wherein the pharmaceutical composition is administered for at least eight weeks.

28. The method of claim 1, wherein the pharmaceutical composition is administered for at least four months.

29. The method of claim 1, wherein the pharmaceutical composition is administered for at least eight months.

30. The method of claim 1, wherein the pharmaceutical composition is administered for at least twelve months.

31. A method for treating schizophrenia, the method comprising administering to a patient diagnosed as suffering from schizophrenia a pharmaceutical composition comprising a compound selected from the group consisting of D-serine, a salt of D-serine, an ester of D-serine, an alkylated D-serine, and a precursor of D-serine, wherein the pharmaceutical composition is administered at a dose equivalent to 100 mg to 10 g D-serine per day.

32. The method of claim 31, wherein the compound is D-serine.

33. The method of claim 31, wherein the compound is a salt of D-serine selected from the group consisting of a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a zinc salt, and an ammonium salt of D-serine.

34. The method of claim 31, wherein the compound is an ester of D-serine having an ester group with 7, 8, 10, 12, 14, 16, or 18 carbon atoms.

35. The method of claim 31, wherein the compound is an alkylated D-serine having an alkyl group with 1-20 carbon atoms.

36. The method of claim 31, wherein the compound is a precursor of D-serine, and the precursor is D-phosphoserine or L-phosphoserine.

37. The method of claim 31, further comprising administering to the patient at least one therapeutic agent selected from the group consisting of antipsychotics, antidepressants, psychostimulants, and Alzheimer'"'"'s disease therapeutics.

38. The method of claim 31, further comprising administering to the patient at least one therapeutic agent selected from the group consisting of Chlorpromazine, Thioridazine, Mesoridazine, Fluphenazine, Perphenazine, Trifluoperazine, Thiothixene, Haloperidol, Loxapine, Molindone, Clozapine, Risperidone, Olanzapine, Quetiapine, Haloperidol decanoate, Fluphenazine decanoate, Fluphenazine enanthate, Amitriptyline, Amoxapine, Bupropion, Bupropion SR, Clomipramine, Desipramine, Doxepin, Fluoxetine, Fluvoxamine, Imipramine, Maprotiline, Mirtazapine, Nefazodone, Nortriptyline, Paroxetine, Phenelzine, Protriptyline, Sertraline, Tranylcypromine, Trazodone, Trimipramine, Venlafaxine, Venlafaxine XR, Dextroamphetamine, Methamphetamine, Methylphenidate, Pemoline, Donepezil, Tacrine, Acetophenazine, Chlorprothixene, Droperidol, Pimozide, Butaperazine, Carphenazine, Remoxipride, Piperacetazine, Sulpiride, and Ziprasidone.

39. The method of claim 31, wherein the pharmaceutical composition is administered to the patient at least once daily for at least one week.

40. The method of claim 31, wherein the pharmaceutical composition is administered for at least six weeks.

41. The method of claim 31, wherein the pharmaceutical composition is administered for at least eight weeks.

42. The method of claim 31, wherein the pharmaceutical composition is administered for at least four months.

43. The method of claim 31, wherein the pharmaceutical composition is administered for at least eight months.

44. The method of claim 31, wherein the pharmaceutical composition is administered for at least twelve months.

45. A method for treating a positive symptom of schizophrenia, the method comprising administering to a patient diagnosed as suffering from a positive symptom of schizophrenia a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of D-serine, a salt of D-serine, an ester of D-serine, an alkylated D-serine, and a precursor of D-serine.

46. The method of claim 45, further comprising observing an improvement in the patient'"'"'s positive symptom following administration of the pharmaceutical composition.

47. The method of claim 46, wherein the compound is D-serine.

48. The method of claim 46, wherein the compound is a salt of D-serine selected from the group consisting of a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a zinc salt, and an ammonium salt of D-serine.

49. The method of claim 46, wherein the compound is an ester of D-serine having an ester group with 1-20 carbon atoms.

50. The method of claim 46, wherein the compound is an alkylated D-serine having an alkyl group with 1-20 carbon atoms.

51. The method of claim 46, wherein the compound is a precursor of D-serine, and the precursor is D-phosphoserine or L-phosphoserine.

52. The method of claim 46, further comprising administering to the patient at least one therapeutic agent selected from the group consisting of antipsychotics, antidepressants, psychostimulants, and Alzheimer'"'"'s disease therapeutics.

53. The method of claim 46, further comprising administering to the patient at least one therapeutic agent selected from the group consisting of Chlorpromazine, Thioridazine, Mesoridazine, Fluphenazine, Perphenazine, Trifluoperazine, Thiothixene, Haloperidol, Loxapine, Molindone, Clozapine, Risperidone, Olanzapine, Quetiapine, Haloperidol decanoate, Fluphenazine decanoate, Fluphenazine enanthate, Amitriptyline, Amoxapine, Bupropion, Bupropion SR, Clomipramine, Desipramine, Doxepin, Fluoxetine, Fluvoxamine, Imipramine, Maprotiline, Mirtazapine, Nefazodone, Nortriptyline, Paroxetine, Pheneizine, Protriptyline, Sertraline, Tranylcypromine, Trazodone, Trimipramine, Venlafaxine, Venlafaxine XR, Dextroamphetamine, Methamphetamine, Methylphenidate, Pemoline, Donepezil, Tacrine, Acetophenazine, Chiorprothixene, Droperidol, Pimozide, Butaperazine, Carphenazine, Remoxipride, Piperacetazine, Sulpiride, and Ziprasidone.

54. The method of claim 46, wherein the pharmaceutical composition is administered to the patient at least once daily for at least one week.

55. The method of claim 46, wherein the pharmaceutical composition is administered for at least six weeks.

56. The method of claim 46, wherein the pharmaceutical composition is administered for at least eight weeks.

57. The method of claim 46, wherein the pharmaceutical composition is administered for at least four months.

58. The method of claim 46, wherein the pharmaceutical composition is administered for at least eight months.

59. The method of claim 46, wherein the pharmaceutical composition is administered for at least twelve months.