Slow-release formulations of 5-hydroxytryptophan as an adjunct to pro-serotonergic therapies

Abstract

The present invention concerns the treatment of serotonergic dysregulation disordersand/or augmentation of serotonin levels in the brain by add-on treatments to serotonin enhancers, and slow-release formulations of 5-hydroxytryptophan (5-HTP) therefor.

1 . A method of treating a subject for a serotonergic neurotransmission dysregulation disorder, wherein said subject in being treated with a serotonin enhancer, comprising administering to said subject 5-hydroxytryptophan (5-HTP) at a slow rate in combination with said serotonin enhancer, said 5-HTP administered in an amount effective to enhance the effects of the serotonin enhancer, to thereby treat the serotonergic neurotransmission dysregulation disorder. 
     
     
         2 . The method of  claim 1 , wherein said 5-HTP is provided in an amount effective to increase extracellular levels of serotonin in the brain as compared to the levels upon serotonin enhancer treatment without the 5-HTP administration. 
     
     
         3 . The method of  claim 1 , wherein said serotonin enhancer is selected from the group consisting of serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, serotonin agonists, amphetamines, serotonin precursors, serotonin prodrugs, intermediates in the biosynthesis of serotonin, and pharmaceutically acceptable salts thereof. 
     
     
         4 . The method of  claim 1 , wherein said serotonin enhancer is a selective serotonin reuptake inhibitor (SSRI). 
     
     
         5 . The method of  claim 1 , wherein said serotonin enhancer is selected from the group consisting of: citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, vilazodone, zimelidine and combinations thereof. 
     
     
         6 . The method of  claim 1 , wherein said serotonin enhancer comprises fluoxetine. 
     
     
         7 . The method of  claim 1 , wherein said subject has been treated with the serotonin enhancer for at least 2 weeks. 
     
     
         8 . The method of  claim 1 , wherein said 5-HTP is administered as a slow-release formulation. 
     
     
         9 . The method of  claim 1 , wherein said 5-HTP is administered as a sustained release formulation. 
     
     
         10 . The method of  claim 1  in which said 5-HTP is administered such that the Tmax of said 5-HTP occurs between 2 hours and 8 hours after said administering step. 
     
     
         11 . The method of  claim 1  in which said 5-HTP comprises a half-life of between 4 to 24 hours after administration. 
     
     
         12 . The method according to  claim 11 , wherein the half-life of said 5-HTP is between 8 and 24 hours. 
     
     
         13 . The method of  claim 1 , wherein said disorder is depression, anxiety, suicidality, obsessive compulsive disorder, or ADHD. 
     
     
         14 . The method of  claim 13 , wherein said disorder is depression. 
     
     
         15 . The method of  claim 13 , wherein said disorder is major depressive disorder. 
     
     
         16 . The method of  claim 13 , wherein said disorder is treatment-resistant depression. 
     
     
         17 . The method of  claim 1 , wherein said subject has a tryptophan hydroxylase 2 (Tph2) variant and/or low endogenous serotonin in the brain. 
     
     
         18 . The method of  claim 1 , wherein said subject has not been determined to have low endogenous serotonin in the brain. 
     
     
         19 . The method of  claim 1 , wherein said administering is subject to the proviso that the subject is not concurrently administered a peripheral decarboxylase inhibitor in an amount effective to reduce peripheral degradation of said 5-HTP. 
     
     
         20 . The method of  claim 1 , wherein said 5-HTP is provided at a rate of from 0.1 to 8 grams per day. 
     
     
         21 . The method of  claim 1 , wherein said administering step is carried out by transdermal administration. 
     
     
         22 . A patch comprising:
 a) a backing; and   b) a drug layer comprising 5-hydroxytryptophan (5-HTP), or a pharmaceutically acceptable salt or prodrug thereof;   said patch configured to administer said 5-HTP transdermally.   
     
     
         23 . The patch of  claim 22 , wherein said patch is a single-layer drug-in-adhesive patch, a multi-layer drug-in-adhesive patch, a reservoir-type patch, a matrix-type patch or a monolithic patch. 
     
     
         24 . The patch of  claim 22 , wherein said patch further comprises a release liner. 
     
     
         25 . The patch of  claim 22 , wherein said patch is configured to administer 5-HTP transdermally at a rate of from 0.01 to 5 grams per day.