VAL66MET (SNP rs6265) GENOTYPE SPECIFIC DOSING REGIMENS AND METHODS FOR THE TREATMENT OF DEPRESSION

Abstract

The present invention is directed to methods and dosing regimens for the treatment of depression (preferably, treatment resistant depression), for the treatment of depression in a suicidal patient, and/or for the treatment and/or prevention of suicidality (e.g. suicidal ideations) comprising genotyping a patient to determine their Val66Met rs6265 polymorphism in BDNF and administering a ketamine, preferably esketamine, preferably intranasal esketamine, according to a dosing regimen matched to the patient's genotype.

We claim: 
     
         1 . A method for the treatment of depression, for the treatment of depression in a suicidal patient, for the treatment of suicidality or for the prevention of suicidality, comprising
 Step A: genetically testing a patient suffering from depression to determine their Val66Met rs6265 polymorphism in the BDNF gene; and   Step B: administering esketamine according to an induction phase regimen;
 wherein the induction phase comprises a treatment period of between 2 and 8 weeks; 
 wherein the esketamine is administered at a dosing frequency of one to five times per week; 
 wherein, if the patient is a Val/Val homozygote, then the esketamine is administered at a dosage in an amount in the range of from about 28 mg to about 56 mg; 
 wherein, if the patient is a Val/Met heterozygote or a Met/Met homozygote, then the esketamine is administered at a dosage in an amount in the range of from about 56 mg to about 84 mg; 
 and wherein, during the induction phase, the dosage amount or the dosing frequency for the patient who is a Val/Val homozygote and the dosage amount or the dosing frequency for the patient who is a Val/Met heterozygote or Met/Met homozygote is different. 
   
     
     
         2 . A method as in  claim 1 , for the treatment of depression. 
     
     
         3 . A method as in  claim 1 , for the treatment of depression, wherein the depression is treatment resistant depression. 
     
     
         4 . A method as in  claim 1 , for the treatment of depression in a suicidal patient. 
     
     
         5 . A method as in  claim 1 , for the treatment of depression in a suicidal patient, wherein the depression is treatment resistant depression. 
     
     
         6 . A method as in  claim 1  for the treatment or prevention of suicidality. 
     
     
         7 . A method as in  claim 1 , wherein the esketamine is administered intranasally. 
     
     
         8 . A method as in  claim 1 , wherein the induction phase comprises a treatment period of between 2 and 6 weeks. 
     
     
         9 . A method as in  claim 1 , wherein the induction phase comprises a treatment period of 4 weeks. 
     
     
         10 . A method as in  claim 1 , wherein the esketamine is administered at a dosing frequency of one to three times per week. 
     
     
         11 . A method as in  claim 1 , wherein the esketamine is administered at a dosing frequency of one to two times per week. 
     
     
         12 . A method as in  claim 1 , wherein, if the patient is a Val/Val homozygote, then the esketamine is administered at a dosage of about 28 mg; and wherein the esketamine is administered at a dosing frequency of twice per week. 
     
     
         13 . A method as in  claim 1 , wherein, if the patient is a Val/Met heterozygote or a Met/Met homozygote, then the esketamine is administered at a dosage of about 56 mg; and wherein the esketamine is administered at a dosing frequency of twice per week. 
     
     
         14 . A method as in  claim 1 , wherein the esketamine is administered intranasally, wherein the induction phase comprises a treatment period of 4 weeks and wherein the esketamine is administered at a dosing frequency of one to two times per week. 
     
     
         15 . A method for the treatment of depression, for the treatment of depression in a suicidal patient, for the treatment of suicidality or for the prevention of suicidality, comprising
 Step A: genetically testing a patient suffering from depression to determine their Val66Met rs6265 polymorphism in the BDNF gene; and   Step B: administering esketamine according to a maintenance phase regimen;
 wherein the maintenance phase comprises a treatment period of at least 6 weeks; 
 wherein, if the patient is a Val/Val homozygote, then the esketamine is administered at a dosage in an amount in the range of from about 28 mg to about 56 mg; and at a dosing frequency in the range of once every two weeks to once every four weeks; 
 wherein, if the patient is a Val/Met heterozygote or a Mate/Met homozygote, then the esketamine is administered at a dosage in an amount in the range of from about 56 mg to about 84 mg; and at a dosing frequency in the range of once per week to once every two weeks; 
 wherein, during the maintenance phase, the dosage amount or the dosing frequency for the patient who is a Val/Val homozygote and the dosage amount or the dosing frequency for the patient who is a Val/Met heterozygote or Met/Met homozygote is different; 
 and wherein the maintenance phase continues until further treatment is not required. 
   
     
     
         16 . A method as in  claim 15  for the treatment of depression. 
     
     
         17 . A method as in  claim 15  for the treatment of depression, wherein the depression is treatment resistant depression. 
     
     
         18 . A method as in  claim 15  for the treatment of depression in a suicidal patient. 
     
     
         19 . A method as in  claim 15  for the treatment of depression in a suicidal patient, wherein the depression is treatment resistant depression. 
     
     
         20 . A method as in  claim 15  for the treatment or prevention of suicidality. 
     
     
         21 . A method as in  claim 15 , wherein the esketamine is administered intranasally. 
     
     
         22 . A method as in  claim 15 , wherein the maintenance phase comprises a treatment period of at least 8 weeks. 
     
     
         23 . A method as in  claim 15 , wherein the maintenance phase comprises a treatment period of at least 12 weeks. 
     
     
         24 . A method as in  claim 15 , wherein if the patient is a Val/Val homozygote, then the esketamine is administered at a dosage of 28 mg; and wherein the esketamine is administered at a dosing frequency of once every two weeks. 
     
     
         25 . A method as in  claim 15 , wherein if the patient is a Val/Met heterozygote or a Met/Met homozygote, then the esketamine is administered at a dosage of 56 mg; and wherein the esketamine is administered at a dosing frequency of once per week. 
     
     
         26 . A method as in  claim 15 , wherein the esketamine is administered at the lowest dosing frequency at which an antidepressant response is maintained. 
     
     
         27 . A method as in  claim 15 , wherein the esketamine is administered at the lowest dosage amount at which an antidepressant response is maintained. 
     
     
         28 . A method as in  claim 15 , wherein the esketamine is administered intranasally; wherein if the patient is a Val/Val homozygote, then the esketamine is administered at a dosage of 28 mg and at a dosing frequency of once every two weeks; and wherein if the patient is a Val/Met heterozygote or a Met/Met homozygote, then the esketamine is administered at a dosage of 56 mg and at a dosing frequency of once per week. 
     
     
         29 . A method for the treatment of depression, for the treatment of depression in a suicidal patient, for the treatment of suicidality or for the prevention of suicidality, comprising
 Step A: genetically testing a patient suffering from depression to determine their Val66Met rs6265 polymorphism in the BDNF gene; and   Step B: administering an esketamine dosing regimen; wherein the esketamine dosing regimen comprises
 (i) an induction dosing phase; 
 wherein the induction phase comprises a treatment period of between 2 and 8 weeks; 
 wherein the esketamine is administered at a dosing frequency of one to five times a week; 
 wherein, if the patient is a Val/Val homozygote, then the esketamine is administered at a dosage in an amount in the range of from about 28 mg to about 56 mg; 
 wherein, if the patient is a Val/Met heterozygote or a Met/Met homozygote, then the esketamine is administered at a dosage in an amount in the range of from about 56 mg to about 84 mg; 
 and wherein, during the induction phase, the dosage amount or the dosing frequency for the patient who is a Val/Val homozygote and the dosage amount or the dosing frequency for the patient who is a Val/Met heterozygote or Met/Met homozygote is different; 
 and (b) a maintenance phase; 
 wherein the maintenance phase comprises a treatment period of at least 6 weeks; 
 wherein, if the patient is a Val/Val homozygote, then the esketamine is administered at a dosage in an amount in the range of from about 28 mg to about 56 mg; and at a frequency in the range of once every two weeks to once every four weeks; 
 wherein, if the patient is a Val/Met heterozygote or a Mate/Met homozygote, then the esketamine is administered at a dosage in an amount in the range of from about 56 mg to about 84 mg; and at a frequency in the range of once per week to once every two weeks; 
 and wherein, during the maintenance phase, the dosage amount or the dosing frequency for the patient who is a Val/Val homozygote and the dosage amount or the dosing frequency for the patient who is a Val/Met heterozygote or Met/Met homozygote is different; 
 and wherein the maintenance phase continues until further treatment is not required. 
   
     
     
         30 . A method as in  claim 29  for the treatment of depression. 
     
     
         31 . A method as in  claim 29  for the treatment of depression, wherein the depression is treatment resistant depression. 
     
     
         32 . A method as in  claim 29  for the treatment of depression in a suicidal patient. 
     
     
         33 . A method as in  claim 29  for the treatment of depression in a suicidal patient, wherein the depression is treatment resistant depression. 
     
     
         34 . A method as in  claim 29  for the treatment or prevention of suicidality. 
     
     
         35 . A method as in  claim 29 , wherein the esketamine is administered intranasally. 
     
     
         36 . A method as in  claim 29 , wherein the induction phase comprises a treatment period of between 2 and 6 weeks. 
     
     
         37 . A method as in  claim 29 , wherein the induction phase comprises a treatment period of 4 weeks. 
     
     
         38 . A method as in  claim 29 , wherein during the induction phase, the esketamine is administered at a dosing frequency of one to three times per week. 
     
     
         39 . A method as in  claim 29 , wherein during the induction phase the esketamine is administered at a dosing frequency of one to two times per week. 
     
     
         40 . A method as in  claim 29 , wherein during the induction phase, if the patient is a Val/Val homozygote, then the esketamine is administered at a dosage of about 28 mg and at a dosing frequency of twice per week. 
     
     
         41 . A method as in  claim 29 , wherein during the induction phase, if the patient is a Val/Met heterozygote or a Met/Met homozygote, then the esketamine is administered at a dosage of about 56 mg and at a dosing frequency of twice per week. 
     
     
         42 . A method as in  claim 29 , wherein the maintenance phase comprises a treatment period of at least 8 weeks. 
     
     
         43 . A method as in  claim 29 , wherein the maintenance phase comprises a treatment period of at least 12 weeks. 
     
     
         44 . A method as in  claim 29 , wherein during the maintenance phase, if the patient is a Val/Val homozygote, then the esketamine is administered at a dosage of 28 mg and at a dosing frequency of once every two weeks. 
     
     
         45 . A method as in  claim 29 , wherein during the maintenance phase, if the patient is a Val/Met heterozygote or a Met/Met homozygote, then the esketamine is administered at a dosage of 56 mg and at a dosing frequency of once per week. 
     
     
         46 . A method as in  claim 29 , wherein during the maintenance phase, the esketamine is administered at the lowest dosing frequency at which an antidepressant response is maintained. 
     
     
         47 . A method as in  claim 29 , wherein during the maintenance phase, the esketamine is administered at the lowest dosage amount at which an antidepressant response is maintained. 
     
     
         48 . A method for the treatment of treatment resistant depression or for the treatment of depression in a suicidal patient, comprising
 Step A: genetically testing a patient suffering from depression to determine their Val66Met rs6265 polymorphism in the BDNF gene; and   Step B: administering an esketamine dosing regimen; wherein the esketamine is administered intranasally; and wherein the dosing regimen comprises
 (i) an induction dosing phase; 
 wherein the induction phase comprises a treatment period of 4 weeks; 
 wherein the esketamine is administered at a dosing frequency of one to two times per week; 
 wherein, if the patient is a Val/Val homozygote, then the esketamine is administered at a dosage of about 28 mg; 
 wherein, if the patient is a Val/Met heterozygote or a Met/Met homozygote, then the esketamine is administered at a dosage of about 56 mg; 
 and wherein, during the induction phase, the dosage amount or the dosing frequency for the patient who is a Val/Val homozygote and the dosage amount or dosing frequency for the patient who is a Val/Met heterozygote or Met/Met homozygote is different; 
 and (b) a maintenance phase; 
 wherein the maintenance phase comprises a treatment period of at least 12 weeks; 
 wherein, if the patient is a Val/Val homozygote, then the esketamine is administered at a dosage in an amount of about 28 mg and at a dosing frequency of once every two weeks; 
 wherein, if the patient is a Val/Met heterozygote or a Met/Met homozygote, then the esketamine is administered at a dosage in an amount of about 56 mg and at a dosing frequency of once per week; 
 wherein during the maintenance phase, the dosage amount or the dosing frequency for the patient who is a Val/Val homozygote and the dosage amount or the dosing frequency for the patient who is a Val/Met heterozygote or Met/Met homozygote is different. 
   
     
     
         49 . A method for the treatment of depression, for the treatment of depression in a suicidal patient, for the treatment of suicidality or for the prevention of suicidality, as herein described. 
     
     
         50 . A dosing regimen for the treatment of depression, for the treatment of depression in a suicidal patient, for the treatment of suicidality or for the prevention of suicidality, as herein described.