Treatment of Depressive Disorders

Abstract

The invention provides for the use of carbonic anhydrase activators; protein kinase C activators and FGF-18 to treat depressive disorders. The invention also relates to improved animal models and methods for screening and identifying compounds the treatment of depressive disorders.

1 . A method comprising the steps of:
 a) identifying a subject with a depressive disorder; and   b) administering an effective amount of a composition comprising a carbonic anhydrase activator and a pharmaceutically acceptable carrier to said subject, wherein the activator is selected from the group consisting of:   
     
       
         
         
             
             
         
       
       
         wherein R 1  is H or OH; R 2  and R 3  are independent H, COOH or lower alkyl, for example linear, branched or cyclic C 1 -C 6  alkyl or C 1 -C 4  alkyl; and Ar is phenyl, imidizolyl or phenyl or imidizolyl substituted with one or more halo, hydroxy, amino or lower alkyl groups for example linear, branched or cyclic C 1 -C 6  group or C 1 -C 4  alkyl group; 
       
     
     
       
         
         
             
             
         
       
       
         wherein R1 and R 2  are independently H or lower alkyl, for example linear, branched or cyclic C 1 -C 6  alkyl or C 1 -C 4  alkyl; 
       
     
     
       
         
         
             
             
         
       
       
         wherein n is 1 or 2 and R 2  is H or lower alkyl, for example linear, branched or cyclic C 1 -C 6  alkyl or C 1 -C 4  alkyl; and 
         pharmaceutically acceptable salts of I, II, or III. 
       
     
   
   
       2 . The method of  claim 1 , wherein the activator has structure I wherein R 1  is H or OH; R 2  is H, CH 3  or COOH; R 3  is H or CH 3 ; and Ar is phenyl, or a substituted phenyl. 
   
   
       3 . The method of  claim 2 , wherein the substituted phenyl is 4-hydroxyphenyl, 4-fluorophenyl, 4-aminophenyl, 3-amino-4-hydroxyphenyl, or 3,4-dihydroxyphenyl. 
   
   
       4 . The method of  claim 1 , wherein the activator has structure I wherein R 1  is H or OH; R 2  is H, CH 3  or COOH; R 3  is H or CH 3 ; and Ar is imidazole or a substituted imidazole. 
   
   
       5 . The method of  claim 4 , wherein the substituted imidazole is imadazol-4-yl-, or 5-methylimidazole-4-yl-. 
   
   
       6 . The method of  claim 1 , wherein the activator has structure II wherein R 1  is H, methyl, ethyl or propyl; and R 2  is H or methyl. 
   
   
       7 . The method of  claim 1 , wherein the activator is structure III wherein n is 1 or 2; and R 2  is H or methyl. 
   
   
       8 . The method of  claim 1 , wherein the activator is selected from the group consisting of: imidazole, phenylalanine, a substituted ethylamine, phenethylamine, histamine, histidine, a linked di-imidazole, a triazole, and pharmaceutically acceptable salts thereof. 
   
   
       9 . The method of  claim 8 , wherein the activator is histidine. 
   
   
       10 . The method of  claim 8 , wherein the activator is histamine. 
   
   
       11 . The method of  claim 8 , wherein the activator is phenylalanine. 
   
   
       12 . The method of  claim 8 , wherein the activator is 4-hydroxy phenylalanine. 
   
   
       13 . The method of  claim 8 , wherein the activator is 4-fluoro phenylalanine. 
   
   
       14 . The method of  claim 8 , wherein the activator is 3,4-dihydroxy phenylalanine. 
   
   
       15 . The method of  claim 8 , wherein the activator is 3-amino-4-hydroxyphenylalanine. 
   
   
       16 . The method of  claim 8 , wherein the activator is 4-amino phenylalanine. 
   
   
       17 . The method of  claim 8 , wherein the activator is tyrosine. 
   
   
       18 . The method of  claim 8 , wherein the activator is dopamine. 
   
   
       19 . The method of  claim 8 , wherein the activator is noradrenaline. 
   
   
       20 . The method of  claim 8 , wherein the activator is adrenaline. 
   
   
       21 . The method of  claim 8 , wherein the activator is histamine. 
   
   
       22 . The method of  claim 8 , wherein the activator is 5-methyl histamine. 
   
   
       23 . A method of treating depression in a subject in need thereof, comprising administering an effective amount of a composition comprising a carbonic anhydrase activator and a pharmaceutically acceptable carrier, wherein the activator is selected from the group consisting of: an aromatic amine or an aromatic amino acid wherein the aromatic amine or aromatic amino acid contains a single aromatic group. 
   
   
       24 . The method of  claim 23 , wherein the activator is selected from the group consisting of: phenylalanine, a substituted phenylalanine, histidine, a substituted histidine, a substituted phenylalanineimidazole, a substituted imidazole, a linked di-imidazole, and a linked substituted di-imidazole. 
   
   
       25 . The method of  claim 1 , wherein the activator is an aromatic amine or an aromatic amino acid wherein the aromatic amine or aromatic amino acid contains a single aromatic group. 
   
   
       26 . The method of  claim 25 , wherein the aromatic amine is selected from the group consisting of dopamine, noradrenaline, adrenaline, histamine, and 5-methyl histamine. 
   
   
       27 . The method of  claim 23 , wherein the aromatic amine is selected from the group consisting of dopamine, noradrenaline, adrenaline, histamine, and 5-methyl histamine. 
   
   
       28 . The method of  claim 1 , wherein the activator activates intraneuronal carbonic anhydrase. 
   
   
       29 . A method comprising the steps of:
 a) identifying a subject with a depressive disorder; and   b) administering an effective amount of a composition comprising a protein kinase C activator and a pharmaceutically acceptable carrier to said subject, wherein the PKC activator is selected from a group consisting of: FGF-18, a macrocyclic lactone, a benzolactam, a pyrrolidinone, or a combination thereof.   
   
   
       30 . The method of  claim 29 , wherein the macrocyclic lactone is a bryostatin or neristatin. 
   
   
       31 . The method of  claim 30 , wherein the bryostatin is selected from a group consisting of bryostatin-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18. 
   
   
       32 . The method of  claim 31 , wherein the bryostatin is bryostatin-1. 
   
   
       33 . The method of  claim 30 , wherein the neristatin is neristatin-1. 
   
   
       34 . A method of treating depression in a subject in need thereof, comprising administering an effective amount of a composition comprising a protein kinase C activator and a pharmaceutically acceptable carrier, wherein the activator is selected from the group consisting of: FGF-18, a macrocyclic lactone, a benzolactam, a pyrrolidinone, or a combination thereof. 
   
   
       35 . The method of  claim 34 , wherein the macrocyclic lactone is a bryostatin or neristatin. 
   
   
       36 . The method of  claim 35 , wherein the bryostatin is selected from a group consisting of bryostatin-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18. 
   
   
       37 . The method of  claim 36 , wherein the bryostatin is bryostatin-1. 
   
   
       38 . The method of  claim 35 , wherein the neristatin is neristatin-1. 
   
   
       39 . A method for screening an agent for antidepressant activity, comprising the steps of:
 a) administering an agent in a pharmaceutically acceptable carrier to a test subject and administering the pharmaceutically acceptable carrier to the control subject;   b) individually placing said test and control subject into a pool of water and measuring the distance and/or duration of swimming during a testing period; and   c) comparing the distance or duration of swimming of the test subject to a control subject, wherein increased distance or duration of swimming of the test subject compared to the control subject is indicative of antidepressant activity.   
   
   
       40 . The method of  claim 39 , wherein the pool is round. 
   
   
       41 . The method of  claim 40 , wherein the pool has a diameter of between 100 and 200 cm. 
   
   
       42 . The method of  claim 41 , wherein the pool has a diameter of 150 cm. 
   
   
       43 . The method of  claim 39 , wherein the pool provides no escape. 
   
   
       44 . The method of  claim 39 , wherein steps (a), (b), and (c) are repeated. 
   
   
       45 . The method of  claim 44 , wherein the steps are repeated three times. 
   
   
       46 . The method of  claim 39 , wherein the distance and/or duration of swimming is measured by video means.