Compositions and methods for the treatment of addiction and other neuropsychiatric disorders

Abstract

The present invention is based, in part, on our discovery that certain types of therapeutic agents can be used in combination to treat a variety of neuropsychiatric and related disorders, including addiction (e.g., to a substance or to an activity) as well as to alleviate some of the symptoms experienced during menopause or associated with the menstrual cycle. Regardless of the precise formulation, the compositions of the invention can include at least one active ingredient that targets the hypothalamo-pituitary-adrenal (HPA) axis and at least one active ingredient that targets the prefrontal cortex. Either or both of these types of agents can be combined with an agent that inhibits activity in the sympathetic nervous system. Thus, the compositions or combination pharmacotherapies can also include an agent that inhibits a beta-adrenergic receptor or that otherwise acts as an anti-hypertensive or anxiolytic agent.

What is claimed is: 
     
         1 - 38 . (canceled) 
     
     
         39 . A pharmaceutical composition for the treatment of addiction comprising a first agent that targets the hypothalamo-pituitary-adrenal (HPA) axis and down-regulates the effect of cortisol in a subject to whom the composition is administered, and a second agent selected from the group consisting of: a benzodiazepine, mirtazapine, gabapentin, muscimol, baclofen, progabide, riluzole, vigabatrin, tiagabine, lamotrigine, carbamazepine, and topiramate, or pharmaceutically acceptable salts, solvates, hydrates, prodrugs, structural analogs or polymorphs thereof. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the first agent is a chemical compound or a pharmaceutically acceptable salt thereof. 
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein the first agent is metyrapone or a salt, solvate, hydrate, prodrug, structural analog, or polymorph thereof. 
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein the second agent is a benzodiazepine. 
     
     
         43 . The pharmaceutical composition of  claim 42 , wherein the benzodiazepine is oxazepam or chlordiazepoxide. 
     
     
         44 . The pharmaceutical composition of  claim 39 , wherein the second agent is benzodiazepine or a salt thereof. 
     
     
         45 . The pharmaceutical composition of  claim 44 , wherein the benzodiazepine is oxazepam or chlordiazepoxide. 
     
     
         46 . The pharmaceutical composition of  claim 39 , wherein the second agent is mirtazapine or a salt thereof. 
     
     
         47 . The pharmaceutical composition of  claim 39 , wherein the second agent is gabapentin or a salt thereof. 
     
     
         48 . The pharmaceutical composition of  claim 39 , wherein the second agent is muscimol progabide, riluzole, baclofen, vigabatrin, tiagabine, lamotrigine, carbamazepine, topiramate or baclofen or pharmaceutically acceptable salts thereof. 
     
     
         49 . The pharmaceutical composition of  claim 39 , comprising about 150-1000 mg of said first agent and about 5-100 mg of said second agent. 
     
     
         50 . The pharmaceutical composition of  claim 49 , wherein said composition comprises:
 (i) about 90 mg of said first agent and about 4 mg of said second agent;   (ii) about 180 mg of said first agent and about 8 mg of said second agent; or   (iii) about 360 mg of said first agent and about 16 mg of said second agent.   
     
     
         51 . The pharmaceutical composition of  claim 50 , wherein said first agent comprises metyrapone and said second agent comprises a benzodiazepine. 
     
     
         52 . The pharmaceutical composition of  claim 51 , wherein said second agent is oxazepam. 
     
     
         53 . The pharmaceutical composition of  claim 52 , wherein said composition is in unit dosage form. 
     
     
         54 . The pharmaceutical composition of  claim 49 , comprising about 250-1000 mg of said first agent and about 5-60 mg of said second agent. 
     
     
         55 . The pharmaceutical composition of  claim 39 , further comprising a third agent that inhibits activity in the sympathetic nervous system. 
     
     
         56 . The pharmaceutical composition of  claim 39 , wherein the ratio of the first agent to the second agent is about 100:1, 90:1, 80:1, 75:1, 70:1, 65:1, 60:1, 55:1, 50:1, 45:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or about 1:1. 
     
     
         57 . The pharmaceutical composition of  claim 48 , wherein the ratio of the first agent to the second agent is about 100:1, 90:1, 80:1, 75:1, 70:1, 65:1, 60:1, 55:1, 50:1, 45:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or about 1:1. 
     
     
         58 . The pharmaceutical composition of  claim 51 , wherein the dosage of metyrapone is about 25-1500 mg, 50-1250 mg, 100-1250 mg, 100-1000 mg, 250-1000 mg, 500-1000 mg or 750-1000 mg; and wherein dosage of said second agent is about 5-50 mg, about 5-40 mg, about 5-30 mg, about 5-20 mg, about 5-10 mg, about 10-50 mg, about 10-40 mg, about 10-30 mg, about 20-50 mg, about 20-40 mg, about 20-30 mg, about 30-50 mg or about 30-40 mg. 
     
     
         59 . The pharmaceutical composition of  claim 58 ,
 wherein the dosage of metyrapone is about 5, 10, 16, 25, 50, 90, 100, 180, 200, 250, 300, 360, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1250, or 1500 mg; and   wherein dosage of said second agent is about 1, 4, 5, 8, 10, 16, 20, 25, 30, 35, 40, 45, 50 mg.   
     
     
         60 . The pharmaceutical composition of  claim 57 ,
 wherein the dosage of metyrapone is about 5, 10, 16, 25, 50, 90, 100, 180, 200, 250, 300, 360, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1250, or 1500 mg; and   wherein dosage of oxazepam is about 1, 4, 5, 8, 10, 16, 20, 25, 30, 35, 40, 45, 50 mg.   
     
     
         61 . The pharmaceutical composition of  claim 53 , wherein the composition consists essentially of:
 (i) about 90 mg of metyrapone and about 4 mg of oxazepam;   (ii) about 180 mg of metyrapone and about 8 mg of oxazepam; or   (iii) about 360 mg of metyrapone and about 16 mg of oxazepam.   
     
     
         62 . The pharmaceutical composition of  claim 61 , wherein said composition is in unit dosage form. 
     
     
         63 . The pharmaceutical composition of  claim 53 , wherein the composition consists of:
 (i) about 90 mg of metyrapone and about 4 mg of oxazepam;   (ii) about 180 mg of metyrapone and about 8 mg of oxazepam; or   (iii) about 360 mg of metyrapone and about 16 mg of oxazepam.   
     
     
         64 . The pharmaceutical composition of  claim 63 , wherein said composition is in unit dosage form.