Compositions and methods for alleviating depression or improving cognition

Abstract

This application describes compositions of receptor inhibitors, including antipsychotic agents, for example haloperidol, and methods of use for alleviating clinical depression, improving cognition and/or treating other syndromes, conditions or diseases for which anti-depressant agents are prescribed. Furthermore, this application describes compositions and methods to induce supersensitivity in dopamine D2 and other receptors involved in depression and/or cognition as a means of alleviating clinical depression or improving cognition.

1 . A method of treating depression, of improving cognition and/or treating other syndromes, conditions or diseases for which anti-depressant agents are prescribed, comprising administering, to a subject in need thereof, an amount of a receptor inhibitor that is effective to elevate amounts of the high affinity state of the receptor, inducing receptor supersensitivity, wherein the receptor state is associated with depression, cognition and/or other conditions, syndromes or diseases for which antidepressants are prescribed. 
     
     
         2 . The method according to  claim 1 , further comprising stopping administration of the receptor inhibitor after receptor supersensitivity is induced, followed by restarting administration of the receptor inhibitor after a time sufficient for receptor supersensitivity to decrease and, optionally, repeating the stopping and restarting administration cycle for a period of time effective to treat the depression, to improve cognition and/or to treat other syndromes, conditions or diseases for which anti-depressant agents are prescribed. 
     
     
         3 . The method according to claim I, wherein the receptor is the dopamine D2 receptor. 
     
     
         4 . The method according to  claim 3 , wherein the dopamine D2 receptor inhibitor used to stimulate supersensitivity in the dopamine D2 receptor is an antipsychotic agent. 
     
     
         5 . The method according to  claim 4 , wherein the antipsychotic agent is selected from typical antipsyhotic agents selected from haloperidol, chlorpromazine, fluphenazine, molindone, thiothixene, thioridazine, trifluoperazine, loxapine, perphenazine, prochlorperazine, pimozide, and zuclopenthixol and atypical anti psychotics selected from aripiprazole, clozapine, olanzapine, olanzapine/fluoxetine, quetiapine, risperidone and ziprasidone. 
     
     
         6 . The method according to  claim 5 , wherein the typical antipsychotic agent is haloperidol. 
     
     
         7 . The method according to  claim 3 , wherein the amount of a dopamine D2 receptor inhibitor that is effective to elevate dopamine D2 High  receptor amounts, inducing dopamine supersensitivity, are those doses which result in dopamine D2 supersensitivity and/or increased antidepressant and/or pro-cognitive effect as shown in an animal model of depression or in humans using depression score systems and tests of memory. 
     
     
         8 . The method according to  claim 7 , wherein the amount of a dopamine D2 receptor inhibitor that is effective to elevate dopamine D2 High  receptor amounts, inducing dopamine supersensitivity is approximately 1-10% or 11-30% of a typical daily antipsychotic dose of the inhibitor. 
     
     
         9 . The method according to  claim 8 , wherein the dopamine D2 receptor inhibitor is haloperidol and oral preparations of low-dose haloperidol are formulated as tablets, capsules, or drops, containing 0.05-2 milligrams, 0.1-0.5 milligrams, or 0.2, 0.3 or 0.4 milligrams of haloperidol, per dosage unit. 
     
     
         10 . The method according to  claim 3 , comprising
 (a) 1-10 days dosing with the dopamine D2 receptor inhibitor followed by 1-10 days of dosing with placebo;   (b) 6-10 days dosing with the dopamine D2 receptor inhibitor, followed 6-10 days of dosing with placebo; or   (c) 7, 8 or 9 days dosing with the dopamine D2 receptor inhibitor followed by 7, 8 and 9 days of dosing with placebo; and   (d) optionally repeating (a), (b) or (c) for a period of time effective to treat the depression, to improve cognition and/or to treat other conditions, syndromes or diseases for which antidepressants are prescribed.   
     
     
         11 . The method according to  claim 3  wherein receptor occupancy after administering the amount of a dopamine D2 receptor inhibitor that is effective to elevate dopamine D2 High  receptor amounts, inducing dopamine supersensitivity, is about 2%-10%, 11%-15%, 16%-20% or 20%-25%. 
     
     
         12 . The method according to  claim 6 , wherein the haloperidol is administered for 7 days as follows: 0.2 mg on day 1, 0.2 mg on day 2, 0.25 mg on day 3, 0.25 mg on day 4, 0.25 mg on day 5, 0.3 mg on day 6 and 0.3 mg on day 7, followed by a complete cessation of the medication until a repeat treatment is clinically indicated. 
     
     
         13 . The method according to  claim 1 , wherein the other syndromes, conditions or diseases for which anti-depressant agents are prescribed are selected from anxiety disorders, post-traumatic stress, phobias, sleep disorders, movement disorders, fibromyalgia and other pain syndromes, chronic fatigue syndrome, migraine, enuresis, overactive bladder, anorexia and/or bulimia, obsessive-compulsive disorder, hair pulling, nail biting and teeth grinding. 
     
     
         14 . The method according to  claim 13 , wherein depressive symptoms of the other syndromes, conditions or diseases are treated. 
     
     
         15 . The method according to  claim 1  for treating depression and/or improving cognition.