COMBINED THERAPY FOR NMDAR ANTAGONIST-RESPONSIVE NEUROPSYCHIATRIC DISORDERS
Described herein are compositions, including an oral dosage regimen, for the treatment of NMDAR-related neuropsychiatric disorders such as depression and obsessive-compulsive disorder and that includes an NMDAR antagonist, such as D-cycloserine formulated to produce plasma levels in excess of 25 microgram/mL, combined with more recently developed antidepressants.
1 . A method for treatment of a NMDA receptor-responsive neuropsychiatric disorder selected from the group consisting of depression, obsessive compulsive disorder, and anxiety disorders, the method comprising administering to a subject in need thereof a composition comprising:
a first agent consisting of a NMDA receptor antagonist; and
an anti-depressant selected from the group consisting of levomilnacipran, milnacipran, vilazadone, vortioxetine, S-mirtazapine and R-mirtazapine,
thereby treating the NMDA receptor-responsive neuropsychiatric disorder.
2 . The method of claim 1 wherein, the first agent is D-cycloserine provided at a net antagonistic dose.
3 . The method of claim 2 , wherein the D-cycloserine is administered at a dose of ≥500 mg/day to ≤1000 mg/day and is formulated to produce an average plasma level in the subject of greater than 25 μg/mL.
4 . The method of claim 2 , wherein the D-cycloserine is administered at a dose of 7.5-12.5 mg/kg/day.
5 . The method of claim 1 , wherein the first agent is selected from the group consisting of ketamine, S-Ketamine, R-ketamine, GlyX-13, NRX-1074, NYX-2925, AGN-241751, CERC-301, AZD6765, AV101 and Gavestinel.
6 . The method of claim 1 , wherein the NMDA receptor antagonist-responsive neuropsychiatric disorder is depression.
7 . The method of claim 6 , wherein the depression is major depression, major depressive disorder, atypical, agitated, melancholic depression or dysthymic disorder.
8 . The method of claim 1 , wherein the depression is bipolar disorder.
9 . The method of claim 8 , wherein the bipolar disorder is bipolar type I or bipolar type 2 depressive disorder.
10 . The method of claim 8 , wherein the bipolar disorder is depressive or mixed episodes associated with bipolar depression.
11 . The method of claim 1 , wherein the composition reduces symptoms of depression, reduces suicide incidence or treats suicide ideation in the subject.
12 . The method of claim 1 , wherein the NMDAR antagonist-responsive neuropsychiatric disorder is associated with suicidality.
14 . The method of claim 1 , wherein the first and second agents are provided in a single pharmaceutical composition.
15 . The method of claim 1 , wherein the composition is formulated for sustained release delivery.