Combined therapy for nmdar antagonist-responsive neuropsychiatric disorders

Abstract

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.

I claim: 
     
         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.