Composition and method for treatment of depression and psychosis in humans

Abstract

This application relates to combination compositions for use in treatment of depression, and which can alleviate the anxiogenic side effects of certain antidepressant and antipsychotic medications. Methods for treatment of depression and medicament side effects, particular anxiety, akathisia, and associated suicidality are also described herein.

I claim: 
     
         1 . A pharmaceutical composition for treatment of depression and associated suicidality comprising:
 an NMDAR-antagonist selected from the group consisting of an NMDAR-antagonist effective amount of D-cycloserine, dextromethorphan, and dextromethadone; and   an effective amount of an atypical antipsychotic that is a combined dopamine D2/5-HT2A receptor antagonist,   wherein the NMDAR-antagonist effective amount of D-cycloserine is sufficient to produce a sustained blood plasma concentration in excess of 25 microgram/mL but lower than 125 microgram/mL.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the NMDAR-antagonist effective amount of D-cycloserine is in excess of 500 mg/day and less than 1000 mg. 
     
     
         3 . The pharmaceutical composition of  claim 1  wherein the NMDAR antagonist effective amount of D-cycloserine is in excess of 10 mg/kg/day, and is less than 25 mg/kg/d. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the atypical antipsychotic that is a combined dopamine D2/5-HT2A receptor antagonist is selected from the group consisting quetiapine, quetiapine XR, risperidone, cariprazine, ITI-007, MIN-101, aripiprazole and brexpiprazole. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the atypical antipsychotic is lurasidone, and wherein the effective amount of the lurasidone is between 20 mg-200 mg per day. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the atypical antipsychotic is quetiapine, and wherein the effective amount of the quetiapine is between 50 mg-500 mg. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is formulated for sustained release. 
     
     
         8 . The pharmaceutical composition of  claim 1 , further comprising an enteric coating. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the NMDAR-antagonist effective amount of D-cycloserine is provided as a prodrug. 
     
     
         10 . A method for treating a subject with depression or suicidality and in need of treatment with an atypical antipsychotic, but in need of reduced side effects thereof, the method comprising,
 administering to the subject an atypical antipsychotic that is a combined dopamine D2/5-HT2A receptor antagonist in a composition comprising the pharmaceutical composition of  claim 1 ,   thereby treating the subject with the atypical antipsychotic, but with reduced side effects.   
     
     
         11 . The method of  claim 10 , wherein the side effects are at least one anxiogenic side effect. 
     
     
         12 . The method of  claim 10 , wherein the at least one anxiogenic side effect is selected from the group consisting of akathisia, agitation, anxiety, and suicidality. 
     
     
         13 . The method of  claim 10 , wherein the depression is major depression or bipolar depression. 
     
     
         14 . A pharmaceutical composition comprising:
 an NMDAR-antagonist effective amount of gavestinel, D-CPPene or CGS19755; and   an effective amount of an atypical antipsychotic that is a combined dopamine D2/5-HT2A receptor antagonist.   
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the atypical antipsychotic that is a combined dopamine D2/5-HT2A receptor antagonist is selected from the group consisting quetiapine, quetiapine XR, risperidone, cariprazine, ITI-007. aripiprazole and brexpiprazole. 
     
     
         16 . A pharmaceutical composition comprising:
 an NMDAR-antagonist wherein the NMDAR antagonist is gavestinel, D-CPPene or CGS19755; and   an effective amount of a selective 5-HT2AR antagonist.   
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the selective 5-HT2A receptor antagonist is selected from the group consisting of SR46349B, EMD281014, or pimavanserin. 
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein the NMDAR antagonist and/or the selective 5-HT2AR antagonist formulated as a prodrug.