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 hypothalamopituitary-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 . A pharmaceutical composition comprising a first agent that targets the hypothalamo-pituitary-adrenal (HPA) axis and a second agent that targets the prefrontal cortex. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the first agent is an agent that inhibits corticotropin-releasing hormone (CRH), inhibits adrenocorticotropic hormone (ACTH), or inhibits cortisol. 
     
     
         3 . The pharmaceutical composition of  claim 1  or  claim 2 , wherein the second agent increases the expression or activity of gamma-aminobutyric acid (GABA), is a GABA mimic, or inhibits GABA metabolism. 
     
     
         4 . The pharmaceutical composition of any of  claims 1 - 3 , wherein the first agent or the second agent is a chemical compound. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the first agent is metyrapone (Metopirone®) or ketoconazole (Nizoral®) or a salt, solvate, hydrate, prodrug, structural analog, or polymorph thereof. 
     
     
         6 . The pharmaceutical composition of any of  claims 1 - 4 , wherein the second agent is a benzodiazepine or a salt, solvate, hydrate, prodrug, structural analog, or polymorph thereof. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the benzodiazepine is oxazepam or chlordiazepoxide. 
     
     
         8 . The pharmaceutical composition of any of  claims 1 - 5 , wherein the second agent is mirtazapine or atomoxetine or a salt, solvate, hydrate, prodrug, structural analog, or polymorph thereof. 
     
     
         9 . The pharmaceutical composition of any of  claims 1 - 5 , wherein the second agent is gabapentin (Neurontin™) or a salt, solvate, hydrate, prodrug, structural analog, or polymorph thereof. 
     
     
         10 . The pharmaceutical composition of any of  claims 1 - 5 , wherein the second agent is muscimol or baclofen or a salt, solvate, hydrate, prodrug, structural analog, or polymorph thereof. 
     
     
         11 . The pharmaceutical composition of any of  claims 1 - 5 , wherein the second agent is progabide, riluzole, baclofen, vigabatrin, valproic acid (Depakote™), tiagabine (Gabitril™), lamotrigine (Lamictal™), phenytoin (Dilantin™), carbamazepine (Tegretol™); or topiramate (Topamax™) or a salt, solvate, hydrate, prodrug, structural analog, or polymorph thereof. 
     
     
         12 . The pharmaceutical composition of any of  claims 1 - 11 , wherein the composition is formulated for oral administration. 
     
     
         13 . The pharmaceutical composition of any of  claims 1 - 11 , wherein the composition is formulated for intravenous administration. 
     
     
         14 . The pharmaceutical composition of any of  claims 1 - 13 , wherein the amount of the first agent or the amount of the second agent in a unit dosage is less than the amount of the first agent or the second agent currently or typically prescribed for a patient requiring the same unit dosage. 
     
     
         15 . A pharmaceutical composition comprising about 5-60 mg of oxazepam and about 250-1000 mg of metyrapone (Metopirone®) in unit dosage form. 
     
     
         16 . The pharmaceutical composition of any of  claims 1 - 15 , further comprising a third agent that inhibits activity in the sympathetic nervous system. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the third agent is a beta blocker or other anxiolytic compound. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the beta blocker is sotalol (Betapace®), imolol (Blocadren®), carteolol (Cartrol®), carvedilol (Coreg®), nadolol (Corgard®), nadol/bendroflunetazide (Corzide®), propranolol (Inderal®), propranolol/HCTZ (Inderide®), betaxolol (Kerlone®), penbutolol (Levatol®), metoprolol (Lopressor®), labetalol (Normodyne®), acebutolol (Sectral®), atenolol/HCTZ (Tenoretic®), atenolol (Tenorrnin®), timolol/HCTZ (Timolide®), metoprolol (Toprol®), labetalol (Trandate®), pindolol (Visken®), bisoprolol (Zebeta®), bisoprolol/HCTZ (Ziac®), or esmolol (Brevibloc®). 
     
     
         19 . The pharmaceutical composition of  claim 16 , wherein the other anxiolytic compound is a selective serotonin reuptake inhibitor (SSRI). 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the SSRI is citalopram (Celexa®), escitalopram oxalate (Lexapro®), fluvoxamine (Luvox®), paroxetine (Paxil®), fluoxetine (Prozac®), or sertraline (Zoloft®). 
     
     
         21 . The pharmaceutical composition of  claim 16 , wherein the other anxiolytic compound is an angiotensin II inhibitor. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the angiotensin II inhibitor is candasartan (Atacand®), eprosartan (Teveten®), irbesartan (Avapro®), losartan (Cozaar®), telmisartan (Micardis®), or valsartan (Diovan®). 
     
     
         23 . A method of treating a patient who is suffering from a disorder associated with aberrant activity in the HPA axis, the method comprising:
 (a) identifying a patient in need of treatment; and   (b) administering to the patient a therapeutically effective amount of a composition of any of  claims 1 - 22 .   
     
     
         24 . The method of  claim 23 , wherein the disorder comprises addiction, anxiety, schizophrenia, or depression. 
     
     
         25 . The method of  claim 23  or  24 , wherein the disorder is addiction to a substance. 
     
     
         26 . The method of  claim 25 , wherein the substance is a chemical stimulant, opiate, nicotine, alcohol, prescription pain reliever, or naturally-occurring plant-derived drug. 
     
     
         27 . The method of  claim 26 , wherein the chemical stimulant is cocaine, an amphetamine, a methamphetamine, methylphenidate, or an analog thereof. 
     
     
         28 . The method of  claim 26 , wherein the opiate is heroin, codeine, hydrocodone, or an analog thereof. 
     
     
         29 . The method of  claim 26 , wherein the naturally-occurring plant-derived drug is marijuana. 
     
     
         30 . The method of  claim 23  or  24 , wherein the disorder is an addiction to an activity. 
     
     
         31 . The method of  claim 30 , wherein the activity is gambling or engaging in a sexual activity. 
     
     
         32 . The method of  claim 30 , wherein the activity is excessive eating. 
     
     
         33 . The method of  claim 23  or  24 , wherein the anxiety is associated with panic disorder, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), social anxiety disorder, or a generalized anxiety disorder. 
     
     
         34 . The method of  claim 24 , wherein the depression is associated with major, depressive disorder or dysthymia, is a bipolar depression, or is associated with a medical condition or substance abuse. 
     
     
         35 . The method of  claim 23 , wherein the disorder is an eating disorder or a sleep disorder. 
     
     
         36 . The method of  claim 23 , wherein the disorder is an attention deficit disorder. 
     
     
         37 . A method of treating a patient who is suffering from an unwanted symptom of menopause or the menstrual cycle that is associated with activity in the HPA axis, the method comprising:
 (a) identifying a patient in need of treatment; and   (b) administering to the patient a therapeutically effective amount of a composition of any of  claims 1 - 22 .   
     
     
         38 . The method of  claim 37 , wherein the symptom is anxiety, depression, or difficulty sleeping.