Methods of treating mental disorders

Abstract

This invention provides methods for preventing, mitigating, ameliorating and/or controlling psychiatric disorders, including depression, major depression, bipolar disorder, schizophrenia and substance abuse (including addiction and dependence) by administration of an agent that increases epoxy-fatty acids (e.g., an inhibitor of soluble epoxide hydrolase), as sole active agent or in combination with another agent (e.g., an antidepressant, an antipsychotic, an anxiolytic). When co-administered in combination with another agent, one or both agent may be administered at a subtherapeutic dose.

1 . A method of preventing, reducing, ameliorating, mitigating, inhibiting and/or reversing one or more symptoms associated with a neuropsychiatric disorder having or characterized by depressive symptoms in a subject in need thereof, comprising administering to the subject an agent that increases the level of epoxy-fatty acids, or a functional derivative or mimic thereof. 
     
     
         2 . A method of accelerating responsiveness to pharmacological treatment and/or preventing, reducing, ameliorating, mitigating, inhibiting, delaying and/or reversing recurrence and/or relapse of one or more symptoms associated with a neuropsychiatric disorder of a neuropsychiatric disorder having or characterized by depressive symptoms in a subject in need thereof, comprising administering to the subject an agent that increases the level of epoxy-fatty acids, or a functional derivative or mimic thereof, as sole active agent or co-administered with a second agent. 
     
     
         3 . The method of  claim 2  wherein the second agent is an antidepressant, a mood stabilizer, an antipsychotic drug or an anxiolytic. 
     
     
         4 .- 13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the neuropsychiatric disorder is selected from the group consisting of depression, major depression, schizophrenia, bipolar disorder, post-traumatic disorder (PTSD), eating disorder, substance abuse, drug addiction, drug dependency, social anxiety, Alzheimer's disease, dementia, and attention-deficit hyperactivity disorder (ADHD). 
     
     
         15 . The method of  claim 2 , wherein one or both of the agent that increases the level of epoxy-fatty acids and the second agent are administered at a subtherapeutic or therapeutically ineffective dose. 
     
     
         16 .- 19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the agent that increases the level of epoxy-fatty acids comprises one or more epoxy-fatty acids. 
     
     
         21 . The method of  claim 1 , wherein the epoxy-fatty acids are selected from the group consisting of cis-epoxyeicosantrienoic acids (“EETs”), epoxides of linoleic acid, epoxides of eicosapentaenoic acid (“EPA”), epoxides of docosahexaenoic acid (“DHA”), epoxides of the arachidonic acid (“AA”), epoxides of cis-7,10,13,16,19-docosapentaenoic acid, and mixtures thereof. 
     
     
         22 . The method of  claim 1 , wherein the agent that increases the level of epoxy-fatty acids increases the levels of cis-epoxyeicosantrienoic acids (“EETs”). 
     
     
         23 . The method of  claim 22 , wherein the agent that increases the level of EETs is an inhibitor of soluble epoxide hydrolase (“sEH”). 
     
     
         24 . The method of  claim 23 , wherein the inhibitor of sEH comprises an inhibitory nucleic acid that specifically targets soluble epoxide hydrolase (“sEH”). 
     
     
         25 . The method of  claim 24 , wherein the inhibitory nucleic acid is selected from the group consisting of short interfering RNA (siRNA), short hairpin RNA (shRNA), small temporal RNA (stRNA), and micro-RNA (miRNA). 
     
     
         26 . The method of  claim 23 , wherein the inhibitor of sEH comprises a primary pharmacophore selected from the group consisting of a urea, a carbamate, and an amide. 
     
     
         27 . The method of  claim 26 , wherein the inhibitor of sEH comprises a cyclohexyl moiety, aromatic moiety, substituted aromatic moiety or alkyl moiety attached to the pharmacophore. 
     
     
         28 . The method of  claim 26 , wherein the inhibitor of sEH comprises a cyclohexyl ether moiety attached to the pharmacophore. 
     
     
         29 . The method of  claim 26 , wherein the inhibitor of sEH comprises a phenyl ether or piperidine moiety attached to the pharmacophore. 
     
     
         30 . The method of  claim 26 , wherein the inhibitor of sEH comprises a polyether secondary pharmacophore. 
     
     
         31 . The method of  claim 26 , wherein the inhibitor of sEH has an IC50 of less than about 100 μM. 
     
     
         32 . The method of  claim 26 , wherein the inhibitor of sEH is selected from the group consisting of:
 a) 3-(4-chlorophenyl)-1-(3,4-dichlorphenyl)urea or 3,4,4′-trichlorocarbanilide (TCC; compound 295);   b) 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA; compound 700);   c) 1-adamantanyl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl]}urea (AEPU; compound 950);   d) 1-(1-acetypiperidin-4-yl)-3-adamantanylurea (APAU; compound 1153);   e) trans-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB; compound 1471);   f) cis-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (cAUCB; compound 1686);   g) 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS; compound 1709);   h) trans-4-{4-[3-(4-Trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (tTUCB; compound 1728);   i) 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU; compound 1770);   j) 1-(1-ethylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPSE; compound 2213);   k) 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (CPTU; compound 2214);   l) trans-N-methyl-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzamide (tMAUCB; compound 2225);   m) trans-N-methyl-4-[4-((3-trifluoromethyl-4-chlorophenyl)-ureido)-cyclohexyloxy]-benzamide (tMTCUCB; compound 2226);   n) cis-N-methyl-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzamide (cMTUCB; compound 2228);   o) 1-cycloheptyl-3-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)urea (HDP 3 U; compound 2247);   p) trans-2-(4-(4-(3-(4-trifluoromethoxy-phenyl)-ureido)-cyclohexyloxy)-benzamido)-acetic acid (compound 2283);   q) N-(methylsulfonyl)-4-(trans-4-(3-(4-trifluoromethoxy-phenyl)-ureido)-cyclohexyloxy)-benzamide (compound 2728);   r) 1-(trans-4-(4-(1H-tetrazol-5-yl)-phenoxy)-cyclohexyl)-3-(4-(trifluoromethoxy)-phenyl)-urea (compound 2806);   s) 4-(trans-4-(3-(2-fluorophenyl)-ureido)-cyclohexyloxy)-benzoic acid (compound 2736);   t) 4-(4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-phenoxy)-benzoic acid (compound 2803);   u) 4-(3-fluoro-4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-phenoxy)-benzoic acid (compound 2807);   v) N-hydroxy-4-(trans-4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-cyclohexyloxy)-benzamide (compound 2761);   w) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-((1r,4r)-4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-cyclohexyloxy)-benzoate (compound 2796);   x) 1-(4-oxocyclohexyl)-3-(4-(trifluoromethoxy)-phenyl)-urea (compound 2809);   y) methyl 4-(4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-cyclohexylamino)-benzoate (compound 2804);   z) 1-(4-(pyrimidin-2-yloxy)-cyclohexyl)-3-(4-(trifluoromethoxy)-phenyl)-urea (compound 2810);   aa) 4-(trans-4-(3-(4-(difluoromethoxy)-phenyl)-ureido)-cyclohexyloxy)-benzoic acid (compound 2805); and   bb) (1R,3 S)—N-(4-cyano-2-(trifluoromethyl)benzyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)cyclohexane-1-carboxamide (GSK2256294A).   
     
     
         33 . A kit comprising (i) one or more first agents that increase the level of epoxy-fatty acids; and (ii) one or more second agents comprising an antidepressant, a mood stabilizer, a antipsychotic drug and/or an anxiolytic. 
     
     
         34 .- 50 . (canceled)