Methods for treating neuropsychiatric disorders

• US 6,228,875 B1
• Filed: 04/14/1999
• Issued: 05/08/2001
• 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:
  US09/291,296
• Time in Patent Office: 755 Days
• Field of Search: 514/561, 514/380
• US Class Current: 514/380
• 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 pharmaceutical composition comprising (i) at least one agonist of the glycine site of an NMDA receptor and (ii) a second therapeutic agent selected from the group consisting of antipsychotics, antidepressants, psychostimulants, and Alzheimer'"'"'s disease therapeutics, wherein:

the agonist is selected from the group consisting of D-alanine, a salt of D-alanine, an ester of D-alanine, alkylated D-alanine, a precursor of D-alanine, D-serine, a salt of D-serine, an ester of D-serine, 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, and alkylated D-cycloserine; and

the pharmaceutical composition is substantially free of D-cycloserine when the agonist is D-alanine, a salt of D-alanine, an ester of D-alanine, an alkylated D-alanine, or a precursor of D-alanine; and

when the agonist is D-cycloserine, a salt of D-cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, or alkylated D-cycloserine, the pharmaceutical composition comprises an amount of the agonist equivalent to 105-500 mg of D-cycloserine.

2. The pharmaceutical composition of claim 1, wherein the therapeutic agent is an antipsychotic selected from the group consisting of typical antipsychotics, atypical antipsychotics, and depot antipsychotics.

3. The pharmaceutical composition of claim 1, wherein the therapeutic agent is 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, Velafaxine XR, Dextroamphetamine, Methamphetamine, Methylphenidate, Pemoline, Donepezil, Tacrine, Acetophenazine, Chlorprothixene, Droperidol, Pimozide, Butaperazine, Carphenazine, Remoxipride, Piperacetazine, Sulpiride, and Ziprasidone.

9. The method of claim 1, wherein the neuropsychiatric disorder is Alzheimer'"'"'s disease.

4. A pharmaceutical composition comprising (i) at least one glycine uptake inhibitor selected from the group consisting of N-methylglycine, a salt of N-methylglycine, an ester of N-methylglycine, alkylated N-methylglycine, and a precursor of N-methylglycine and (ii) a second therapeutic agent selected from the group consisting of antipsychotics, antidepressants, phychostimulants, and Alzheimer'"'"'s disease therapeutics.

5. The pharmaceutical composition of claim 4, wherein the second therapeutic agent is an antipsychotic selected from the group consisting of typical antipsychotics, atypical antipsychotics, and depot antipsychotics.

6. The pharmaceutical composition of claim 4, wherein the second therapeutic agent is 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, Velafaxine XR, Dextroamphetamine, Methamphetamine, Methylphenidate, Pemoline, Donepezil, Tacrine, Acetophenazine, Chlorprothixene, Droperidol, Pimozide, Butaperazine, Carphenazine, Remoxipride, Piperacetazine, Sulpiride, and Ziprasidone.

7. A method for treating a neuropsychiatric disorder characterized by attenuated NMDA neurotransmission in a patient, the method comprising administering to a patient diagnosed as suffering from the neuropsychiatric disorder a pharmaceutical composition comprising a therapeutically effective amount of an agonist of the glycine site of an NMDA receptor, wherein:

the agonist is selected from the group consisting of D-alanine, a salt of D-alanine, an ester of D-alanine, alkylated D-alanine, a precursor of D-alanine, D-serine, a salt of D-serine, an ester of D-serine, 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, and alkylated D-cycloserine;

the pharmaceutical composition is substantially free of D-cycloserine when the agonist is D-alanine, a salt of D-alanine, an ester of D-alanine, an alkylated D-alanine, or a precursor of D-alanine; and

when the agonist is D-cycloserine, a salt of D-cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, or alkylated D-cycloserine, the pharmaceutical composition comprises an amount of the agonist equivalent to 105-500 mg of D-cycloserine.

8. The method of claim 7, wherein the neuropsychiatric disorder is schizophrenia.

10. The method of claim 7, wherein the neuropsychiatric disorder is autism.

11. The method of claim 7, wherein the neuropsychiatric disorder is depression.

12. The method of claim 7, wherein the neuropsychiatric disorder is benign forgetfulness.

13. The method of claim 7, wherein the neurpsychiatric disorder is a childhood learning disorder.

14. The method of claim 7, wherein the neuropsychiatric disorder is attention deficit disorder.

15. The method of claim 7, wherein the neuropsychiatric disorder is close head injury.

16. The method of claim 7, wherein the agonist is selected from the group consisting of D-alanine, a salt of D-alanine, an ester of D-alanine, alkylated D-alanine, and a precursor of D-alanine.

17. The method of claim 16, 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.

18. The method of claim 16, wherein the agonist 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.

19. The method of claim 16, wherein the agonist is an ester of D-alanine having an ester group with 1-20 carbon atoms.

20. The method of claim 16, wherein the agonist is an alkylated D-alanine having an alkyl group with 1-20 carbon atoms.

21. The method of claim 16, wherein the pharmaceutical composition further comprises D-serine.

22. The method of claim 7, wherein the agonist is selected from the group consisting of D-serine and a salt of D-serine.

23. The method of claim 22, wherein the D-serine or salt of D-serine is administered at a dosage equivalent to 10 mg to 100 g of D-serine.

24. The method of claim 22, wherein the agonist 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.

25. The method of claim 7, wherein the agonist 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-cycloserine.

26. The method of claim 25, 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.

27. The method of claim 26, 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.

28. The method of claim 25, wherein the pharmaceutical composition comprises 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 ammonium salt of D-cycloserine.

29. The method of claim 25, wherein the pharmaceutical composition comprises an ester of D-cycloserine having an ester group with 1-20 carbon atoms.

30. The method of claim 25, wherein the pharmaceutical composition comprises an alkylated D-cycloserine having an alkyl group with 1-20 carbon atoms.

31. The method of claim 25, wherein the pharmaceutical composition comprises a precursor of D-cycloserine.

32. The method of claim 7, wherein the pharmaceutical composition is administered to the patient at least once daily for at least one week.

33. The method of claim 7, further comprising administering to the patient a second therapeutic agent selected from the group consisting of antipsychotics, antidepressants, phsychostimulants, and Alzheimer'"'"'s disease therapeutics.

34. The method of claim 7, wherein the agonist is D-serine.

35. The method of claim 34, wherein the D-serine is administered at a dosage of 100 μ

g-100g.

36. The method of claim 34, wherein the D-serine is administered at a dosage of 1 mg-100 mg.

37. The method of claim 34, wherein the D-serine is administered at a dosage of 10 mg-10 g.

38. The method of claim 34, wherein the D-serine is administered at a dosage of 10-500 mg.

39. The method of claim 7, wherein the agonist is selected from the group consisting of an ester of D-serine, alkylated D-serine, and a precursor of D-serine.

40. The method of claim 39, wherein the ester 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.

41. A method of treating schizophrenia, the method comprising treating a patient diagnosed as having schizophrenia with a therapeutically effective amount of D-serine.

42. The method of claim 41, wherein the D-serine is administered at a dosage of 100 μ

g-100 g.

43. The method of claim 41, wherein the D-serine is administered at a dosage of 1 mg-100 mg.

44. The method of claim 41, wherein the D-serine is administered at a dosage of 10 mg-100 g.

45. The method of claim 41, wherein the D-serine is administered at a dosage of 10 mg-10 g.

46. The method of claim 41, wherein the D-serine is administered at a dosage of 10 mg-500 mg.

47. A method for treating a neuropsychiatric disorder, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a glycine uptake inhibitor to a patient diagnosed as suffering from a neuropsychiatric disorder selected from the group consisting of benign forgetfulness, childhood learning disorder, attention deficit disorder, and closed head injury.

48. The method of claim 47, wherein the glycine uptake inhibitor is selected from the group consisting of N-methylglycine, a salt of N-methylglycine, an ester of N-methylglycine, and a precursor of N-methylglycine.

49. A method for treating a neuropsychiatric disorder characterized by attenuated NMDA neurotransmission in a patient, the method comprising administering to a patient diagnosed as suffering from the neuropsychiatric disorder a pharmaceutical composition comprising a therapeutically effective amount of a glycine uptake inhibitor selected from the group consisting of N-methylglycine, a salt of N-methylglycine, an ester of N-methylglycine, alkylated N-methylglycine, and a precursor of N-methylglycine.

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

51. The method of claim 49, wherein the agonist is an alkylated D-serine having an alkyl group with 1-20 carbon atoms.

52. The method of claim 49, wherein the N-methylglycine, salt of N-methylglycine, ester of N-methylglycine, alkylated N-methylglycine, or precursor of N-methylglycine is administered at a dosage equivalent to 10 mg to 100 g of N-methylglycine.

53. The method of claim 49, wherein the glycine uptake inhibitor is an ester of N-methylglycine having an ester group with 1-20 carbon atoms.

54. The method of claim 49, wherein glycine uptake inhibitor is an alkylated N-methylglycine having an alkyl group with 1-20 carbon atoms.

55. The method of claim 49, wherein the precursor is selected from the group consisting of N,N,N-trimethylglycine and N,N-dimethylglycine.

56. 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 glycine uptake inhibitor, wherein the glycine uptake inhibitor is selected from the group consisting of N-methylglycine, a salt of N-methylglycine, and an ester of N-methylglycine.