V1b receptor antagonist for use in the treatment of patients having an elevated avp level and/or an elevated copeptin level

Abstract

The present invention relates to a vasopressin receptor 1B (V 1B ) antagonist for use in the treatment of depressive symptoms and/or anxiety symptoms in patients showing an elevated arginine vasopressin (AVP) level and/or an elevated copeptin level. The present invention further relates to a method for predicting the treatment response to a V 1B antagonist in patients with depressive symptoms and/or anxiety symptoms.

1 . A method of treating depressive symptoms and/or anxiety symptoms comprising administering an effective amount of a vasopressin receptor 1B (V 1B ) antagonist to a patient having depressive symptoms and/or anxiety symptoms and having an elevated arginine vasopressin (AVP) level and/or an elevated copeptin level, thereby treating the depressive symptoms and/or anxiety symptoms in the patient. 
     
     
         2 .- 3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the patient has been pre-treated with dexamethasone. 
     
     
         5 . The method of  claim 1 , wherein the elevated AVP level is indicated by a copeptin blood concentration of at least 5 pmol/L. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the elevated AVP level is an AVP concentration of at least 4 pg/ml AVP. 
     
     
         8 . The method of  claim 1 , wherein the elevated AVP level and/or the elevated copeptin level is detected by determining the presence or absence of at least one polymorphic variant in the AVPR1B gene in combination with the presence or absence of at least one polymorphic variant in the patient's genome excluding the AVPR1B gene. 
     
     
         9 . The method of  claim 8 , wherein the polymorphic variant in the AVPR1B gene and/or in the patient's genome excluding the AVPR1B gene is a single nucleotide polymorphism (SNP). 
     
     
         10 . The method of  claim 9 , wherein the SNP in the AVPR1B gene is SNP rs28373064 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 2, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide G. 
     
     
         11 . The method of  claim 8 , wherein the at least one polymorphic variant in the patient's genome excluding the AVPR1B gene is selected from the group of biomarkers consisting of:
 SNP rs9880583 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 3, wherein in one or two alleles the wild-type nucleotide C is replaced by indicator nucleotide G,   SNP rs13099050 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 4, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide C,   SNP rs7441352 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 5, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G,   SNP rs730258 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 6, wherein in one or two alleles the wild-type nucleotide C is replaced by indicator nucleotide T,   SNP rs12654236 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 7, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G,   SNP rs17091872 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 8, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G,   SNP rs12254219 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 9, wherein in one or two alleles the wild-type nucleotide C is replaced by indicator nucleotide T,   SNP rs11575663 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 10, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G,   SNP rs7080276 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 11, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G,   SNP rs7416 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 12, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G,   SNP rs12424513 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 13, wherein in one or two alleles the wild-type nucleotide C is replaced by indicator nucleotide T,   SNP rs1035050 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 14, wherein in one or two alleles the wild-type nucleotide C is replaced by indicator nucleotide T,   SNP rs9959162 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 15, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide C, and/or   SNP rs8088242 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 16, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G.   
     
     
         12 . The method of  claim 11 , wherein the at least one polymorphic variant in the patient's genome excluding the AVPR1B gene is at least 2 biomarkers of the group of biomarkers. 
     
     
         13 . The method of  claim 12 , wherein the at least one polymorphic variant in the patient's genome excluding the AVPR1B gene consists of all of the biomarkers of the group of biomarkers. 
     
     
         14 . The method of  claim 11 , wherein the combination of the presence or absence of SNP rs28373064 with the presence or absence of at least 1 of the biomarkers of the group of biomarkers is determined. 
     
     
         15 . The method of  claim 14 , wherein the presence of SNP rs28373064 in combination with the presence of SNP rs9880583, SNP rs730258, SNP rs12654236, SNP rs17091872, SNP rs12254219, SNP rs11575663, SNP rs7080276, SNP rs7416, SNP rs1035050, SNP rs9959162 and SNP rs8088242 and the absence of SNP rs28373064 in combination with the absence of SNP rs13099050, SNP rs7441352 and SNP rs12424153 is determined. 
     
     
         16 . The method of  claim 1 , wherein the V 1B  receptor antagonist is selected from the group consisting of SSR149415, Org 52186, ABT-436 and/or ABT-558. 
     
     
         17 . The method of  claim 1 , wherein the V 1B  receptor antagonist is administered in combination with at least one further pharmaceutically active compound suitable for the treatment of depressive symptoms and/or anxiety symptoms. 
     
     
         18 .- 19 . (canceled) 
     
     
         20 . A method for predicting a treatment response to a V 1B  receptor antagonist in a patient with depressive symptoms and/or anxiety symptoms comprising the following steps:
 (i) determining the presence or absence of at least one polymorphic variant in the AVPR1B gene in a nucleic acid sample of said patient and   (ii) determining the presence or absence of at least one polymorphic variant in the patient's genome excluding the AVPR1B gene in a nucleic acid sample of said patient,   
       wherein the presence or absence of at least one polymorphic variant in the AVPR1B gene in combination with the presence or absence of at least one polymorphic variant in the patient's genome excluding the AVPR1B gene is indicative for the treatment response. 
     
     
         21 . The method of  claim 20 , wherein the polymorphic variant in the AVPR1B and/or in the patient's genome excluding the AVPR1B gene is a single nucleotide polymorphism (SNP). 
     
     
         22 . The method of  claim 21 , wherein a polymorphic variant in the AVPR1B gene is SNP rs28373064 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 2, wherein in one or two alleles of the wild-type nucleotide A is replaced by indicator nucleotide G. 
     
     
         23 . The method of  claim 20 , wherein the at least one polymorphic variant in the patient's genome excluding the AVPR1B gene is selected from the group of biomarkers consisting of:
 SNP rs9880583 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 3, wherein in one or two alleles the wild-type nucleotide C is replaced by indicator nucleotide G,   SNP rs13099050 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 4, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide C,   SNP rs7441352 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 5, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G,   SNP rs730258 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 6, wherein in one or two alleles the wild-type nucleotide C is replaced by indicator nucleotide T,   SNP rs12654236 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 7, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G,   SNP rs17091872 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 8, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G,   SNP rs12254219 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 9, wherein in one or two alleles the wild-type nucleotide C is replaced by indicator nucleotide T,   SNP rs11575663 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 10, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G,   SNP rs7080276 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 11, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G,   SNP rs7416 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 12, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G,   SNP rs12424513 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 13, wherein in one or two alleles the wild-type nucleotide C is replaced by indicator nucleotide T,   SNP rs1035050 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 14, wherein in one or two alleles the wild-type nucleotide C is replaced by indicator nucleotide T,   SNP rs9959162 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 15, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide C, and/or   SNP rs8088242 which is represented by a single polymorphic change at position 27 of SEQ ID NO: 16, wherein in one or two alleles the wild-type nucleotide A is replaced by indicator nucleotide G.   
     
     
         24 . The method of  claim 23 , wherein the at least one polymorphic variant in the patient's genome excluding the AVPR1B gene is at least 2 biomarkers of the group of biomarkers. 
     
     
         25 . The method of  claim 24 , wherein the at least one polymorphic variant in the patient's genome excluding the AVPR1B gene consists of all of the biomarkers of the group of biomarkers. 
     
     
         26 . The method of  claim 23 , wherein the combination of the presence or absence of SNP rs28373064 with the presence or absence of at least 1 biomarker of the group of biomarkers is determined. 
     
     
         27 . The method of  claim 26 , wherein the presence of SNP rs28373064 in combination with the presence of SNP rs9880583, SNP rs730258, SNP rs12654236, SNP rs17091872, SNP rs12254219, SNP rs11575663, SNP rs7080276, SNP rs7416, SNP rs1035050, SNP rs9959162 and SNP rs8088242 and the absence of SNP rs28373064 in combination with the absence of SNP rs13099050, SNP rs7441352 and SNP rs12424153 is determined. 
     
     
         28 . A method for predicting a treatment response to a V 1B  receptor antagonist in a patient with depressive symptoms and/or anxiety symptoms, wherein the copeptin concentration in a blood sample of said patient is determined and/or the AVP concentration in a sample of cerebrospinal fluid of said patient is determined and wherein an elevated copeptin and/or an elevated AVP concentration is indicative for a patient responding to a treatment with a V 1B  receptor antagonist. 
     
     
         29 . The method of  claim 28 , further comprising a step of pre-treating the patient with dexamethasone and subsequently determining the copeptin concentration in the blood sample and/or the AVP concentration in the sample of cerebrospinal fluid. 
     
     
         30 . The method of  claim 29 , further comprising subjecting the patient to at least one combined dexamethasone/corticotropin test (dex/CRH test). 
     
     
         31 . The method of  claim 28 , wherein the elevated copeptin concentration indicative for a patient responding to a treatment with a vasopressin receptor antagonist is at least 5 pmol/L. 
     
     
         32 . The method of  claim 28 , wherein the elevated AVP concentration indicative for a patient responding to a treatment with a V 1B  receptor antagonist is at least 4 pg/ml AVP.