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WO2012109565A1 - Identification génétique de réponse à des médicaments antidépresseurs - Google Patents

Identification génétique de réponse à des médicaments antidépresseurs Download PDF

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WO2012109565A1
WO2012109565A1 PCT/US2012/024694 US2012024694W WO2012109565A1 WO 2012109565 A1 WO2012109565 A1 WO 2012109565A1 US 2012024694 W US2012024694 W US 2012024694W WO 2012109565 A1 WO2012109565 A1 WO 2012109565A1
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gene
seq
outcome
homozygote
genotype
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Marc K. Samet
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NEUROTHERICS LLC
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NEUROTHERICS LLC
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention identifies genes, single nucleotide polymorphisms and haplotypes which predict a high probability of failure of first line antidepressant therapy targeting increases in serotonergic neurotransmission with or without concomitant changes in adrenergic neurotransmission for major depressive disorder.
  • the present invention also discloses genes, single nucleotide polymorphisms and haplotypes which predict a high probability of response to first line antidepressant therapy targeting increases in
  • antidepressants modulate both adrenergic and serotonergic neurotransmission stimulated the search for compounds that would selectively inhibit the reuptake of either
  • nucleic acid sequences listed in the accompanying sequence listing are shown using standard letter abbreviations for nucleotide bases, as defined in 37 C.F.R. 1 .822. Only one strand of each nucleic acid sequence is shown, but the complementary strand is understood as included by any reference to the displayed strand.
  • SEQ ID NO: 1 is a nucleic acid sequence context of a Single Nucleotide Polymorphism (SNP) assigned RefSNP accession ID (rs number), rs666693, in the Single Nucleotide Polymorphism (SNP) database (dbSNP) at the National Center for SNP.
  • SNP Single Nucleotide Polymorphism
  • dbSNP Single Nucleotide Polymorphism
  • NBI Biotechnology Information
  • HTR2A 5-hydroxytryptamine receptor 2A
  • SEQ ID NO: 2 is a nucleic acid sequence context of a SNP assigned rs number rs582385 in the dbSNP at NCBI and comprising human SNP alleles -C/T
  • SEQ ID NO: 3 is a nucleic acid sequence context of a SNP assigned rs number rs9316232 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs9316232-A and rs9316232-G, within the HTR2A gene:
  • SEQ ID NO: 4 is a nucleic acid sequence context of a SNP assigned rs number rs17275521 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs17275521 -A and rs17275521 -G, within the mu-opiod receptor (OPRM1 ) gene:
  • SEQ ID NO: 5 is a nucleic acid sequence context of a SNP assigned rs number rs1720971 1 in the dbSNP at NCBI and comprising human SNP alleles A/T (single nucleotide variation), or rs1720971 1 -A and rs1720971 1 -T, within the OPRM1 gene:
  • SEQ ID NO: 6 is a nucleic acid sequence context of a SNP assigned rs number rs3778149 in the dbSNP at NCBI and comprising human SNP alleles C/G (single nucleotide variation), or rs3778149-C and rs3778149-G, within the OPRM1 gene:
  • SEQ ID NO: 7 is a nucleic acid sequence context of a SNP assigned rs number rs3778146 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs3778146-C and rs3778146-T, within the OPRM1 gene:
  • SEQ ID NO: 8 is a nucleic acid sequence context of a SNP assigned rs number rs7773995 in the dbSNP at NCBI and comprising human SNP alleles C/T (single
  • SEQ ID NO: 9 is a nucleic acid sequence context of a SNP assigned rs number rs3778145 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs3778145-A and rs3778145-C, within the OPRM1 gene: CCCGCCCACATTGTGACCGTCTCAAA[A/C]ACATGCCTCGTTTTCCTCTTCCCTG
  • SEQ ID NO: 10 is a nucleic acid sequence context of a SNP assigned rs number rs885345 in the dbSNP at NCBI and comprising human SNP alleles C/T (single nucleotide variation), or rs885345-C and rs885345-T, within the neuronal calcium sensor 1 (FREQ) gene, which is also known as NCS1 : CTCCAGTGCCGGTCAGGTCCCAAGTC[C/T]CCAGGAGAGCACAGGCCAGGGCACG [00014] SEQ ID NO: 1 1 is a nucleic acid sequence context of a SNP assigned rs number rs10052016 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs10052016-A and rs10052016-G, within the solute carrier family 6 (neurotransmitter transporter, dopamine), member 3 (SLC
  • SEQ ID NO: 12 is a nucleic acid sequence context of a SNP assigned rs number rs1861646 in the dbSNP at NCBI and comprising human SNP alleles G/T (single nucleotide variation), or rs1861646-G and rs1861646-T, within the norepinephrine transporter (SLC6A2) gene: TCTCTCTGATACTCTTAGAGTTCTTG[G/T]TCATGCCATTGAGAGCAAAGAAAGT
  • SEQ ID NO: 13 is a nucleic acid sequence context of a SNP assigned rs number rs6495308 in the dbSNP at NCBI and comprising human SNP alleles C/T (single nucleotide variation), or rs6495308-C and rs6495308-T, within the cholinergic receptor, nicotinic alpha-3 (CHRNA3) gene: GTAACTGTCTGATGGCAGGTTTGCTG[C/T]TGGGAGAGTAGAGAAGAGGTTTGGG
  • SEQ ID NO: 14 is a nucleic acid sequence context of a SNP assigned rs number rs 0053602 in the dbSNP at NCBI and comprising human SNP alleles C T (single nucleotide variation), or rs10053602-C and rs10053602-T, within the solute carrier family 6 (neurotransmitter transporter, dopamine) SLC6A3, gene: ATAACCTCTCTGACATTTATGCAACT[C/T]TCCAACCAAAGACAGCAGAATACAT
  • SEQ ID NO: 15 is a nucleic acid sequence context of a SNP assigned rs number rs2350786 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs2350786-A and rs2350786-G, within the cholinergic receptor, muscarinic 2 (CHRM2) gene: TACTCTTTGTC ATG G AG G C AA ACTAC [A/G] GTAG CTG ATTAC C ATTTTTTAATG A
  • SEQ ID NO: 16 is a nucleic acid sequence context of a SNP assigned rs number rs6960707 in the dbSNP at NCBI and comprising human SNP alleles C/T (single nucleotide variation), or rs6960707-C and rs6960707-T, within the cholinergic receptor; muscarinic 2 (CHRM2) gene:
  • SEQ ID NO: 17 is a nucleic acid sequence context of a SNP assigned rs number rs929492 in the dbSNP at NCBI and comprising human SNP alleles C/T (single nucleotide variation), or rs929492-C and rs929492-T, within the calcium channel voltage- dependent, L type, alpha 1C subunit (CACNA1 C) gene:
  • SEQ ID NO: 18 is a nucleic acid sequence context of a SNP assigned rs number rs6678672 in the dbSNP at NCBI and comprising human SNP alleles C/T (single nucleotide variation), or rs6678672-C and rs6678672-T, within the S100 calcium binding protein A10 (S100A10) gene:
  • SEQ ID NO: 19 is a nucleic acid sequence context of a SNP assigned rs number rs6587640 in the dbSNP at NCBI and comprising human SNP alleles C/T (single nucleotide variation), or rs6587640-C and rs6587640-T, within the S100A10 gene:
  • SEQ ID NO: 20 is a nucleic acid sequence context of a SNP assigned rs number rs17047279 in the dbSNP at NCBI and comprising human SNP alleles G/T (single nucleotide variation), or rs17047279-G and rs17047279-T, within the glutamate receptor metabotropic 7 receptor (GRM7) gene:
  • SEQ ID NO: 21 is a nucleic acid sequence context of a SNP assigned rs number rs17047286 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs17047286-A and rs17047286-G, within the GRM7 gene:
  • SEQ ID NO: 22 is a nucleic acid sequence context of a SNP assigned rs number rs9368881 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs9368881 -A and rs9368881 -G, within the FK506 binding protein (FKBP5) gene: AAAAATAAAGACACAGTTACAAACGA[A/C/G/T]TTGATATGGAAAGTTTAAGAATGCC
  • SEQ ID NO: 23 is a nucleic acid sequence context of a SNP assigned rs number rs4765933 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs4765933-A and rs4765933-G, within the CACNA1 C gene:
  • SEQ ID NO: 24 is a nucleic acid sequence context of a SNP assigned rs number rs7782904 in the dbSNP at NCBI and comprising human SNP alleles A/T (single nucleotide variation), or rs7782904-A and rs7782904-T, within the CHR 2 gene:
  • SEQ ID NO: 25 is a nucleic acid sequence context of a SNP assigned rs number rs1455857 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs1455857-A and rs1455857-G, within the CHRM2 gene:
  • SEQ ID NO: 26 is a nucleic acid sequence context of a SNP assigned rs number rs11862589 in the dbSNP at NCBI and comprising human SNP alleles C/T (single nucleotide variation), or rs1 1862589-C and rs1 1862589-T, within the SLC6A2 gene:
  • SEQ ID NO: 27 is a nucleic acid sequence context of a SNP assigned rs number rs879522 in the dbSNP at NCBI and comprising human SNP alleles C/T (single nucleotide variation), or rs879522-C and rs879522-T, within the SLC6A2 gene: CTG AAAC ATG AG AAG G C CT ATA AC [C/TjTA AATG C C AG ATG GTTC C AC C C CTC [00031] SEQ ID NO: 28 is a nucleic acid sequence context of a SNP assigned rs number rs4564560 in the dbSNP at NCBI and comprising human SNP alleles C/T (single nucleotide variation), or rs4564560-C and rs4564560-T, within the SLC6A2 gene:
  • SEQ ID NO: 29 is a nucleic acid sequence context of a SNP assigned rs number rs1002513 in the dbSNP at NCBI and comprising human SNP alleles C/T (single nucleotide variation), or rs1002513-C and rs1002513-T, within the HTR2A gene:
  • SEQ ID NO: 30 is a nucleic acid sequence context of a SNP assigned rs number rs1378646 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs1378646-A and rs1378646-G, within the CHRM2 gene:
  • SEQ ID NO: 31 is a nucleic acid sequence context of a SNP assigned rs number rs11 198986 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs1 1198986-A and rs11 198986-G within the gene RGS10:
  • SEQ ID NO: 32 is a nucleic acid sequence context of a SNP assigned rs number rs16965623 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs 6965623-A and rs16965623-G within the gene SLC6A4; TATAGCCAGGAGCAACCCGTACCTGA[A/G]CAAGCATGTAATTATCCCGATTGGT
  • SEQ ID NO: 33 is a nucleic acid sequence context of a SNP assigned rs number rs6916787 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs6916787-A and rs6916787-G within the gene OPRM1 :
  • SEQ ID NO: 34 is a nucleic acid sequence context of a SNP assigned rs number rs17047321 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs17047321-A and rs17047321-G within the gene GRM7:
  • SEQ ID NO: 35 is a nucleic acid sequence context of a SNP assigned rs number rs21 13545 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs21 13545-A and rs21 13545-G within the gene CHRM2:
  • SEQ ID NO: 36 is a nucleic acid sequence context of a SNP assigned rs number rs985934 in the dbSNP at NCBI and comprising human SNP alleles C/T (single nucleotide variation), or rs985934-C and rs985934-T within the gene OPRM1 :
  • SEQ ID NO: 37 is a nucleic acid sequence context of a SNP assigned rs number rs1814270 in the dbSNP at NCBI and comprising human SNP alleles C/T (single nucleotide variation), or rs1814270-C and rs1814270-T within the SLC6A2 gene:
  • SEQ ID NO: 38 is a nucleic acid sequence context of a SNP assigned rs number rs9462104 in the dbSNP at NCBI and comprising human SNP alleles C/T (single nucleotide variation), or rs9462104-C and rs9462104-T within the FKBP5 gene:
  • SEQ ID NO: 39 is a nucleic acid sequence context of a SNP assigned rs number rs6900677 in the dbSNP at NCBI and comprising human SNP alleles C/G (single nucleotide variation), or rs6900677-C and rs6900677-G within the OPRM1 gene; TAATCAAATGACTTTGGTAGACAACT[C/G]TTCAAGATATGTCTTGTTAAGATTA
  • SEQ ID NO: 40 is a nucleic acid sequence complement of the nucleic acid sequence (rs666693) of SEQ ID NO: 1 : AGACTCTTCGTGACGGATGTGATAGT[T/C]AAATCCTAACCTCGTCTGAAAATTG
  • SEQ ID NO: 41 is a nucleic acid sequence complement of the nucleic acid sequence (rs582385) of SEQ ID NO: 2:
  • SEQ ID NO: 42 is a nucleic acid sequence complement of the nucleic acid sequence (rs9316232) of SEQ ID NO: 3:
  • SEQ ID NO: 43 is a nucleic acid sequence complement of the nucleic acid sequence (rs17275521 ) of SEQ ID NO: 4:
  • SEQ ID NO: 44 is a nucleic acid sequence complement of the nucleic acid sequence (rs1720971 1 ) of SEQ ID NO: 5:
  • SEQ ID NO: 45 is a nucleic acid sequence complement of the nucleic acid sequence (rs3778149) of SEQ ID NO: 6:
  • SEQ ID NO: 46 is a nucleic acid sequence complement of the nucleic acid sequence (rs3778146) of SEQ ID NO: 7:
  • SEQ ID NO: 47 is a nucleic acid sequence complement of the nucleic acid sequence (rs7773995) of SEQ ID NO: 8:
  • SEQ ID NO: 48 is a nucleic acid sequence complement of the nucleic acid sequence (rs3778145) of SEQ ID NO: 9: GGGCGGGTGTAACACTGGCAGAGTTT[T/G]TGTACGGAGCAAAAGGAGAAGGGAC
  • SEQ ID NO: 49 is a nucleic acid sequence complement of the nucleic acid sequence (rs885345) of SEQ ID NO: 10:
  • SEQ ID NO: 50 is a nucleic acid sequence complement of the nucleic acid sequence (rs10052016) of SEQ ID NO: 1 1 :
  • SEQ ID NO: 51 is a nucleic acid sequence complement of the nucleic acid sequence (rs186 646) of SEQ ID NO: 2:
  • SEQ ID NO: 52 is a nucleic acid sequence complement of the nucleic acid sequence (rs6495308 ) of SEQ ID NO: 13:
  • SEQ ID NO: 53 is a nucleic acid sequence complement of the nucleic acid sequence (rs10053602) of SEQ ID NO: 14:
  • SEQ ID NO: 54 is a nucleic acid sequence complement of the nucleic acid sequence (rs2350786) of SEQ ID NO: 15:
  • SEQ ID NO: 55 is a nucleic acid sequence complement of the nucleic acid sequence (rs6960707) of SEQ ID NO: 16:
  • SEQ ID NO: 56 is a nucleic acid sequence complement of the nucleic acid sequence (rs929492) of SEQ ID NO: 17: AAAATGCGTCTCCTCCGGACACTCGC[G/A]ACACGATCGATGACTCATAGACCAC
  • SEQ ID NO: 57 is a nucleic acid sequence complement of the nucleic acid sequence (rs6678672) of SEQ ID NO: 18:
  • SEQ ID NO: 58 is a nucleic acid sequence complement of the nucleic acid sequence (rs6587640) of SEQ ID NO: 19:
  • SEQ ID NO: 59 is a nucleic acid sequence complement of the nucleic acid sequence (rs17047279) of SEQ ID NO: 20:
  • SEQ ID NO: 60 is a nucleic acid sequence complement of the nucleic acid sequence (rs17047286) of SEQ ID NO: 21 :
  • SEQ ID NO: 61 is a nucleic acid sequence complement of the nucleic acid sequence (rs9368881 ) of SEQ ID NO: 22:
  • SEQ ID NO: 62 is a nucleic acid sequence complement of the nucleic acid sequence (rs4765933) of SEQ ID NO: 23:
  • SEQ ID NO: 63 is a nucleic acid sequence complement of the nucleic acid sequence (rs7782904) of SEQ ID NO: 24:
  • SEQ ID NO: 64 is a nucleic acid sequence complement of the nucleic acid sequence (rs1455857) of SEQ ID NO: 25: TTTCCTTCGTCAGTCCTACGTAAAGT[T/C]TTAGTACTCTTTCTTCCTCCTCTCC
  • SEQ ID NO: 65 is a nucleic acid sequence complement of the nucleic acid sequence (rs1 1862589) of SEQ ID NO: 26:
  • SEQ ID NO: 66 is a nucleic acid sequence complement of the nucleic acid sequence (rs879522) of SEQ ID NO: 27:
  • SEQ ID NO: 67 is a nucleic acid sequence complement of the nucleic acid sequence (rs4564560) of SEQ ID NO: 28:
  • SEQ ID NO: 68 is a nucleic acid sequence complement of the nucleic acid sequence (rs1002513) of SEQ ID NO: 29:
  • SEQ ID NO: 69 is a nucleic acid sequence complement of the nucleic acid sequence (rs1378646) of SEQ ID NO: 30:
  • SEQ ID NO: 70 is a nucleic acid sequence complement of the nucleic acid sequence (rs1 1 198986) of SEQ ID NO: 31 :
  • SEQ ID NO: 71 is a nucleic acid sequence complement of the nucleic acid sequence (rs16965623) of SEQ ID NO: 32:
  • SEQ ID NO: 72 is a nucleic acid sequence complement of the nucleic acid sequence (rs6916787) of SEQ ID NO: 33: TTTATACAGAAGTGCTTTTCGGTTTC[T/C]TTTCGTAAGTTTCGATAAGTGTTTG
  • SEQ ID NO: 73 is a nucleic acid sequence complement of the nucleic acid sequence (rs17047321 ) of SEQ ID NO: 34:
  • SEQ ID NO: 74 is a nucleic acid sequence complement of the nucleic acid sequence (rs21 13545) of SEQ ID NO: 35:
  • SEQ ID NO: 75 is a nucleic acid sequence complement of the nucleic acid sequence (rs985934) of SEQ ID NO: 36: ATTCAATCGTAGATGGTCTTATGTTT[G/A]CCTTTGAACTTAATCAGGTTCAGAG
  • SEQ ID NO: 76 is a nucleic acid sequence complement of the nucleic acid sequence (rs1814270) of SEQ ID NO: 37:
  • SEQ ID NO: 77 is a nucleic acid sequence complement of the nucleic acid sequence (rs9462104) of SEQ ID NO: 38:
  • SEQ ID NO: 78 is a nucleic acid sequence complement of the nucleic acid sequence (rs6900677) of SEQ ID NO: 39:
  • SEQ ID NO: 79 is a nucleic acid sequence context of a SNP assigned rs number rs1814270 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs1814270-C and rs1814270-T, withing the SLC6A2 gene:
  • SEQ ID NO: 80 is a nucleic acid sequence context of a SNP assigned rs number rs9567739 in the dbSNP at NCBI and comprising human SNP alleles A/G (single nucleotide variation), or rs9567739-C and rs9567739-G, withing the HTR2A gene:
  • SEQ ID NO: 81 is a nucleic acid sequence complement of the nucleic acid sequence (rs1814270) of SEQ ID NO: 79:
  • SEQ ID NO: 82 is a nucleic acid sequence complement of the nucleic acid sequence (rs9567739) of SEQ ID NO: 80:
  • the present invention addresses the significant fraction of patients exposed to elevations in serotonergic neurotransmission, with or without concomitant changes in adrenergic neurotransmission, who do now and/or will in the future suffer degradation of treatment response with antidepressants. Along with decreased dopaminergic
  • neurotransmission efficiency the identification of certain psychiatric symptoms correlated with mood, reward and attentional dysfunctions may occur.
  • a genetic profile can be identified in patients who are not responsive to first line antidepressant medications targeting changes in serotonergic neurotransmission with or without concomitant changes in adrenergic neurotransmission for major depressive disorder.
  • One aspect of the invention provides a method of predicting the outcome of treatment with antidepressant medication in a patient receiving antidepressant therapy targeting increases in serotonergic neurotransmission with or without concomitant changes in adrenergic neurotransmission, the method comprising (a) obtaining a sample of genetic material from the patient; (b) assaying the sample for the presence of a genotype in the patient which is associated with the outcome of treatment with antidepressant medication; and (c) predicting the outcome of treatment with antidepressant medication in the patient based on the presence of the genotype in the sample, wherein the genotype is
  • 5-hydroxytryptamine (serotonin) receptor 2A HTR2A
  • OPRM1 neuronal calcium sensor 1
  • FREQ neuronal calcium sensor 1
  • SLC6A3 neurotransmitter transporter, dopamine member 3 gene
  • SLC6A2 norepinephrine transporter gene
  • CHRNA3 nicotinic alpha-3 gene
  • CHRM2 cholinergic receptor, muscarinic 2 gene
  • CACNA1 C calcium channel voltage-dependent, L type, alpha 1 C subunit
  • Another aspect of the present invention is to provide a method of screening patients to identify those patients with an increased risk of non-response to treatment with an antidepressant medication.
  • the method comprises (a) obtaining a sample of genetic material from the patient; (b) assaying the sample for the presence of a genotype in the patient which is associated with the outcome of treatment with antidepressant medication; and (c) predicting the outcome of treatment with antidepressant medication in the patient based on the presence of the genotype in the sample, wherein the genotype is
  • HTR2A mu-opiod receptor gene
  • FREQ neuronal calcium sensor 1
  • SI_C6A3 solute carrier family 6 (neurotransmitter transporter, dopamine) member 3 gene
  • CHRNA3 nicotinic alpha-3 gene
  • CACNA1 C calcium channel voltage-dependent, L type, alpha 1 C subunit
  • the present invention provides a method comprising assaying for the presence of a genotype in patients receiving antidepressant therapy targeting increases in serotonergic neurotransmission with or without concomitant changes in adrenergic neurotransmission which is associated with a increased probability of response to treatment with antidepressant medication, wherein the genotype is
  • Elevations in serotonergic neurotransmission refers to any compound that increases, directly or indirectly, the availability of serotonin in the central nervous system for binding to serotonin receptors at the post-synaptic membrane, including but not limited to serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, serotonin agonists, amphetamines, serotonin precursors, serotonin prodrugs, intermediates in the biosynthesis of serotonin, co-factors and pharmaceutically acceptable salts thereof. Such compounds may be given alone or in combination with other serotonin enhancers and/or agents which modulate dopaminergic neurotransmission.
  • “Alterations in dopaminergic neurotransmission” refers to the induction, directly or indirectly, of changes in the ability of dopamine to interact with dopamine receptors leading to alterations in dopaminergic neurotransmission.
  • the alterations in dopaminergic neurotransmission can occur by the administration of drugs which, directly or indirectly, act upon the ability of dopamine to interact with postsynaptic receptors involved in neurotransmission and/or modulate receptor signal transduction.
  • Such compounds include, but are not limited to, bupropion, monoamine oxidase inhibitors, tricyclic antidepressants,
  • first line antidepressant therapies can be associated with specific genes, single nucleotide polymorphisms and haplotypes.
  • the genetic biomarkers for high probability of failing first line antidepressant therapies include genes associated with dopaminergic, serotonergic, cholinergic and adrenergic neurotransmission.
  • Additional biomarkers for prediction of high probability of first line antidepressant failure include genes, single nucleotide polymorphisms and haplotypes associated with voltage gated calcium channels and proteins associated with dopaminergic
  • neurotransmission which may or may not be associated with voltage gated calcium channels but do result in alterations in dopaminergic neurotransmission.
  • Further definition of those patients who are likely to fail first line antidepressant therapy can be identified by specific genes, single nucleotide polymorphisms and haplotypes. Genetic markers associated with a high probability of failing first line
  • antidepressant therapies which target serotonergic neurotransmission, with or without concomitant changes in adrenergic neurotransmission, can be found in the norepinephrine transporter gene.
  • DAT Dopamine transporter
  • FKBP5 FK506 binding protein
  • GAM7 metabotropic 7 associated with a high probability of failing or responding to antidepressant therapy targeting serotonin transmission efficiency with or without concomitant changes in adrenergic neurotransmission.
  • CACNA1 C are associated with either failing or responding to antidepressant therapy targeting serotonin transmission efficiency with or without concomitant changes in adrenergic neurotransmission.
  • HTRA2 Serotonin 2A receptor
  • FREQ/NCS1 Genetic markers associated with dopamine signaling proteins are associated with failing to respond to antidepressant therapy targeting serotonin transmission efficiency with or without concomitant changes in adrenergic
  • individuals who are likely to fail first line antidepressant therapy can be associated with genes, single nucleotide polymorphisms and haplotypes within the norepinephrine transporter.
  • specific polymorphisms in particular genes can be used to identify individuals that are at an increased risk of non-response to antidepressant treatment, where such treatment targets elevations in serotonergic neurotransmission with or without concomitant changes in adrenergic neurotransmission.
  • Individuals with the identified polymorphisms can benefit from closer monitoring, earlier institution of alternative and/or adjunctive treatments, and/or more rapid exposure to specialty care.
  • SNPs and haplotypes which can predict a high probability of responding to first line antidepressant medications.
  • Genes, SNPs and haplotypes associated with a high probability of responding to first line antidepressant medications include one or any combination of the following, CHRM2, SLC6A3,HTR2A, CACNA1 C, S100A10, and GRM7.
  • Other genetic polymorphic markers can indicate a high probability for an inidivdual not to respond to antidepressant medications.
  • Haplotypes within specified genes can predict a high probability of not responding to first line antidepressant medications.
  • SNPs and haplotypes include one or any combination of FREQ/NCS1 , CHRM2, SLC6A3, OPRM1 , SLC6A2, CHRNA3, HTR2A, FKBP5, CACNA1 C, S100A10, RGS10, SLC6A4 and GRM7.
  • Genes, SNPs and haplotypes associated with a high probability of failing first line antidepressant medications include one or any combination of the following: FREQ, CHRM2, SLC6A3, OPRM1 , SLC6A2, CHRNA3, HTR2A, FKBP5, CACNA1 C, S100A10, RGS10, SLC6A4 and GRM7.
  • Treatment resistant depressed patients may also be identified from among those persons having undergone treatment for Major Depressive Illness with medications that modulate serotonergic neurotransmission with or without concomitant changes in adrenergic neurotransmission.
  • Treatment resistant depression may be induced by such medications when chosen for therapeutic reasons by one practiced in the art of psychopharmacology to produce chronic increases in serotonergic transmission efficiency.
  • the increase may result in alterations of dopaminergic transmission efficiency in conditions other than Major Depressive Illness such as but not limited to: depressive disorder, anxiety disorder, social anxiety disorder, generalized anxiety disorder, bipolar disorder, schizophrenia, autism, epilepsy, mood disorders, cigarette smoking, alcohol or substance abuse and associated disorders, panic disorder, migraine, obesity, bulimia, anorexia, premenstrual syndrome, menopause, sleep disorders, attention-deficit/hyperactivity disorder (ADHD), Tourette syndrome, aggression, obsessive compulsive disorder, pathological gambling, novelty seeking, borderline personality disorders, antisocial personality disorder, suicidility, eating disorders, sexual dysfunction, dementia, social phobia, fibromyalgia, overactive bladder, chronic fatigue syndrome, chronic pain, sudden infant death syndrome, post-traumatic stress syndrome, and Alzheimer's disease.
  • Treatment resistant depression may be produced by conditions that are now or may in the future be treated by chronic blockade of SERT, by SSRI or SNRI therapy, or by any future therapies that produce chronic up regulation of serotonergic transmission efficiency or increased synthesis and/or release of serotonin with or without concomitant changes in adrenergic neurotransmission.
  • Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial which is a large prospective treatment trial for major depression, can be used as test for whether specific genetic markers could predict the outcome of antidepressant treatment in patients treated with selective serotonin reuptake inhibitor (SSRI), e.g., citalopram.
  • SSRI serotonin reuptake inhibitor
  • HTR2A encodes the serotonin 2A receptor.
  • HTR2A also is known as HTR2 and 5-HT2A receptor.
  • HTR2A is located on chromosome 13q14-q21 .
  • HTR2A is identified by GenBank Accession Number NM000621 .
  • the 5HT2A, B, and C subtypes are positively coupled with the enzyme phospholipase C (PLC).
  • PLC phospholipase C
  • the 5-HT2A receptors are postsynaptic receptors that are highly enriched in neocortex and regulate the function of prefrontal-subcortical circuits.
  • the 5-HT2A receptors interact with Gq/G1 1 guanine nucleotide binding proteins (G proteins) and thereby stimulate PLC to produce the intracellular second messengers sn-1 ,2-DAG (an endogenous activator of protein kinase C) and inositol-1 ,4,5-triphosphate (IP3), which stimulates the release of Ca2+ ions from intracellular stores.
  • G proteins Gq/G1 1 guanine nucleotide binding proteins
  • IP3 inositol-1 ,4,5-triphosphate
  • the mu-opiod receptor (OPRM1) gene encodes the opioid receptor, mu1 , which is a member of the G protein coupled receptor superfamily and the primary site of action for the most commonly used opioids, including morphine, heroin, fentanyl, and methadone as well as the primary receptor for endogenous opioid peptides.
  • the neuronal calcium sensor 1 (NCS-1) gene also called FREQ, is a member of the neuronal calcium sensor gene family, which encodes calcium-binding proteins expressed predominantly in neurons.
  • the protein encoded by FREQ regulates G protein- coupled receptor phosphorylation in a calcium-dependent manner and can substitute for calmodulin.
  • the protein is associated with secretory granules and modulates synaptic transmission and synaptic plasticity.
  • the solute carrier family 6 neurotransmitter transporter, dopamine member 3 gene (SLC6A3), also called DAT gene and DAT1 gene, encodes a dopamine transporter, which is a member of the sodium- and chloride-dependent neurotransmitter transporter family.
  • the 3' UTR of this gene contains a 40 bp tandem repeat, referred to as a variable number tandem repeat or VNTR, which can be present in 3 to 1 1 copies.
  • the solute carrier family 6 neurotransmitter transporter, noradrenalin
  • member 2 gene SLC6A2
  • NET norepinephrine transporter
  • SLC6A2 encodes a member of the sodium- and chloride neurotransmitter symporter family. This member is a multi-pass membrane protein, which is responsible for reuptake of
  • norepinephrine into presynaptic nerve terminals and is a regulator of norepinephrine homeostasis.
  • the cholinergic receptor, nicotinic alpha-3 (CHRNA3) gene encodes a member of the nicotinic acetylcholine receptor family of proteins. Members of this family of proteins form pentameric complexes comprised of both alpha and beta subunits.
  • the CHRNA3 gene encodes an alpha-type subunit, as it contains characteristic adjacent cysteine residues.
  • the encoded protein is a ligand-gated ion channel that likely plays a role in neurotransmission.
  • CHRM2 cholinergic receptor 2
  • muscarinic 2 The cholinergic receptor, muscarinic 2 (CHRM2) gene encodes muscarinic acetylcholine receptor M2, also known as the cholinergic receptor, muscarinic 2.
  • Muscarinic cholinergic receptors including cholinergic receptor, muscarinic 2, belong to a large family of G protein-coupled receptors whose functional diversities are defined by the binding of acetylcholine and include cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation.
  • the muscarinic cholinergic receptor 2 is involved in mediation of bradycardia and a decrease in cardiac contractility.
  • the calcium channel voltage-dependent, L type, alpha 1 C subunit (CACNA1 C) gene also known as voltage-gated calcium channel subunit alpha Cav1 gene, encodes an alpha-1 subunit of a voltage-dependent calcium channel.
  • Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death.
  • the isoform alpha-1 C gives rise to L-type calcium currents.
  • Long-lasting (L-type) calcium channels belong to the "high-voltage activated" (HVA) group.
  • the S100 calcium binding protein A10 (S100A10) gene encodes a protein that is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and are involved in the regulation of a number of cellular processes including cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1 q21.
  • the glutamate receptor metabotropic 7 receptor is an L-glutamate group III receptor protein which is linked to the inhibition of the cAMP cascade and appears to modulate other neurotransmitters involved in mood disorders, attentional dysfunctions and reward.
  • the solute carrier family 6 (neurotransmitter transporter, serotonin) member 3 gene (SLC6A4), also called SERT gene, encodes a serotonin transporter. This member is a multi-pass membrane protein, which is responsible for reuptake of serotonin into presynaptic nerve terminals and is a regulator of serotonin homeostasis.
  • Regulator of G protein signaling (RGS10) family members are regulatory proteins that act as GTPase activating proteins (GAPs) for G-alpha subunits of
  • RGS proteins are able to deactivate G-protein subunits of the Gi alpha, Go alpha and Gq alpha subtypes. They drive G-proteins into their inactive GDP- bound forms.
  • Regulator of G-protein signaling 10 belongs to this family. All RGS proteins share a conserved 120-amino acid sequence termed the RGS domain. This protein associates specifically with the activated forms of the two related G-protein subunits, G- alphai3 and G-alphaz but fails to interact with the structurally and functionally distinct G- alpha subunits. Regulator of G protein signaling 10 proteins are localized in the nucleus. Two transcript variants encoding different isoforms have been found for this gene. [000132] The FK506 binding protein (FKBP5) is encoded by a member of the
  • immunophilin protein family which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking.
  • This encoded protein is a cis-trans prolyl isomerase that binds to the immunosuppressants FK506 and rapamycin. It is thought to mediate calcineurin inhibition. It also interacts functionally with mature hetero-oligomeric progesterone receptor complexes along with the 90 kDa heat shock protein and P23 protein. This gene has been found to have multiple polyadenylation sites. Alternative splicing results in multiple transcript variants. Recent analysis of subjects in STAR*D suggest that FKBP5 is associated with depression.
  • suitable genetic markers and/or polymorphisms are associated with a nucleic acid sequence having at least about 98% sequence identity to the sequence of sequence identity number (SEQ ID NO) selected from the group consisting of SEQ ID NO: 1 (rs666693-A and/or rs666693-G); SEQ ID NO: 2 (rs5852385-[- /AT]); SEQ ID NO: 3 or namely (rs9316232-A and/or rs9316232-G); SEQ ID NO: 4
  • suitable genetic markers and/or polymorphisms are associated with a nucleic acid sequence having from about 98% to about 99% sequence identity to the sequence of SEQ ID NO selected from the group consisting of SEQ ID NO: 1 (rs666693-A and/or rs666693-G); SEQ ID NO: 2 (rs5852385-[-/AT]); SEQ ID NO: 3 or namely (rs9316232-A and/or rs9316232-G); SEQ ID NO: 4 (rs17275521-A and/or rs17275521 -G); SEQ ID NO: 5 (rs1720971 1 -A and/or rs1720971 1-T); SEQ ID NO: 6 (rs3778149-C and/or rs3778149-G); SEQ ID NO: 7 (rs3778146-C and/or rs3778146-T); SEQ ID NO: 8 (rs7773995-C and
  • suitable genetic markers and/or polymorphisms are associated with a nucleic sequence having from about 98% to about 99.9% sequence identity to the sequence of SEQ ID NO selected from the group consisting of SEQ ID NO: 1 (rs666693-A and/or rs666693-G); SEQ ID NO: 2 (rs582385-[-/AT]); SEQ ID NO: 3
  • suitable genetic markers and/or polymorphisms are associated with a nucleic sequence having at least about 98% sequence identity to the sequence of SEQ ID NO selected from the group consisting of SEQ ID NO: 40 (rs666693-T and/or rs666693-C); SEQ ID NO: 41 (rs5852385-[-/TA]); SEQ ID NO: 42 (rs9316232-T and/or rs9316232 -C); SEQ ID NO: 43 (rs17275521-T and/or rs17275521 -C); SEQ ID NO: 44 (rs1720971 1 -T and/or rs1720971 1 -A); SEQ ID NO: 45 (rs3778149-G and/or rs37
  • rs6587640-G and/or rs6587640-A SEQ ID NO: 59 (rs17047279-C and/or rs17047279-A); SEQ ID NO: 60 (rs17047286-T and/or rs17047286-C); SEQ ID NO: 61 (rs9368881 -T and/or rs9368881 -G and/or rs9368881 -C and/or rs9368881 -A); SEQ ID NO: 62
  • rs4765933-T and/or rs4765933-C SEQ ID NO: 63 (rs7782904-T and/or rs7782904-A); SEQ ID NO: 64 (rs1455857-T and/or rs1455857-C); SEQ ID NO: 65 (rs1 1862589-G and/or rs1 1862589-A); SEQ ID NO: 66 (rs879522-G and/or rs879522-A); SEQ ID NO: 67
  • rs9462104-G and/or rs9462104-A SEQ ID NO: 78 (rs6900677-G and/or rs6900677-C); SEQ ID NO: 81 (rs1814270-G and/or rs1814270-A; SEQ ID NO: 82 (rs9567739-G and/or rs9567739-C); and combinations thereof.
  • suitable genetic markers and/or polymorphisms are associated with a nucleic sequence having from about 98% to about 99.9% sequence identity to the sequence of SEQ ID NO selected from the group consisting of SEQ ID NO: 40 (rs666693-T and/or rs666693-C); SEQ ID NO: 41 (rs5852385-[-/TA]); SEQ ID NO: 42 (rs9316232-T and/or rs9316232 -C); SEQ ID NO: 43 (rs17275521-T and/or rs17275521 - C); SEQ ID NO: 44 (rs1720971 1 -T and/or rs1720971 1 -A); SEQ ID NO: 45 (rs3778149-G and/or rs3778149 -C); SEQ ID NO: 46 (rs3778146-T and/or rs3778146-G and/or rs3778146 -C and/or
  • a method is identified which can predict a high probability of first line antidepressant treatment failure using specific genes, single nucleotide
  • a method is identified which can predict the outcome (e.g., failure or success) of treatment with antidepressant medication in a patient receiving
  • the method comprises: (a) obtaining a sample of genetic material from the patient; (b) assaying the sample for the presence of a genotype in the patient which is associated with a high probability of first line antidepressant treatment failure with the antidepressant therapy targeting increases in serotonergic neurotransmission with or without concomitant changes in adrenergic neurotransmission; and (c) predicting the outcome of treatment with antidepressant medication in the patient based on the presence of the genotype in the sample, wherein the genotype is characterized by specific polymorphisms in a gene, wherein the gene and the polymorphisms are selected from the group consisting of: HTR2A and single nucleotide polymorphisms (SNPs) having reference sequence numbers SEQ ID NO: 1 (rs666693-A and/or rs666693-G), SEQ ID NO: 2 (
  • the target polymorphisms provided in the sample would be complementary to that specified by the corresponding sense nucleic acid sequence. Therefore, the complements of all of the nucleic acid sequences disclosed herein are suitable for use in all aspects of the present invention.
  • single nucleotide polymorphisms SNPs having reference sequences of SEQ ID NO 40 through SEQ ID NO 78, and SEQ ID NOs 81 and 82 and combinations thereof are suitable for use in all aspects of the present invention.
  • the polymorphism can occur anywhere in a gene. Typically, the polymorphism is a single nucleotide polymorphism. In certain embodiments, the polymorphism is the same as that discussed herein. In other embodiments, it is a different polymorphism.
  • a method is identified which can predict a high probability of responding to first line antidepressant treatment using specific genes, single nucleotide polymorphims and haplotypes.
  • a method which can predict the outcome of treatment with antidepressant medication in a patient receiving antidepressant therapy targeting increases in serotonergic neurotransmission with or without concomitant changes in adrenergic neurotransmission, the method comprising (a) obtaining a sample of genetic material from the patient; (b) assaying the sample for the presence of a genotype in the patient which is associated with a high probability of not responding to first line antidepressant treatment with the antidepressant therapy targeting increases in
  • genotype is characterized by a polymorphism in a gene having at least one marker, wherein the gene is selected from the group consisting of HTR2A, OPRM1 , FREQ, SLC6A3, SLC6A4, SLC6A2, CHRNA3, CHRM2, CACNA1 C, S100A10, FKBP5; GRM7, RGS10, , and combinations thereof.
  • Another aspect of the present invention is to provide a method of screening patients to identify those patients with a increased risk of non-response to treatment with antidepressant medication, the method comprising (a) obtaining a sample of genetic material from the patient; (b) assaying the sample for the presence of a genotype in the patient which is associated with a decreased risk of non-response to treatment with antidepressant medication, wherein the genotype is characterized by a polymorphism in a gene selected from the group consisting of HTR2A, , SLC6A3,, CHRM2, CACNA1 C, S100A10, GRM7;and combinations thereof.
  • a patient refers to an individual awaiting or under medical care and treatment, such as treatment for depression. While the inventive methods are designed for human patients, such methods are applicable to any suitable individual, which includes, but is not limited to, a mammal, such as a mouse, rat, rabbit, hamster, guinea pig, cat, dog, goat, cow, horse, pig, and simian. Human patients include male and female patients of any ethnicity (e.g., Caucasian, Asian, Hispanic, Native American, and Black).
  • the sample of genetic material can be obtained from the patient by any suitable manner.
  • the sample can be isolated from a source including saliva, buccal cells, hair roots, blood, cord blood, amniotic fluid, interstitial fluid, peritoneal fluid, chorionic villus, semen, or other suitable cell or tissue sample. Methods for isolating genomic DNA from various sources are well-known in the art.
  • a polymorphism refers to one of multiple alleles of a gene.
  • the polymorphism is a single nucleotide polymorphism (SNP).
  • SNP single nucleotide polymorphism
  • the polymorphism that is associated with treatment outcome to an antidepressant medication can be any suitable polymorphism.
  • the polymorphism can correlate with an increased or decreased risk of non-response to treatment with antidepressant medication.
  • the polymorphism included in a marker of a gene can be detected by any suitable manner known in the art.
  • the polymorphism can be detected by techniques, such as allele specific hybridization, allele specific oligonucleotide ligation, primer extension, minisequencing, mass spectroscopy, heteroduplex analysis, single strand conformational polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE), oligonucleotide microarray analysis, temperature gradient gel electrophoresis (TGGE), and combinations thereof.
  • SSCP single strand conformational polymorphism
  • DGGE denaturing gradient gel electrophoresis
  • TGGE temperature gradient gel electrophoresis
  • antidepressant medication e.g., that correlates an increased risk of non-response to treatment with antidepressant medication or a high probability of not achieving remission
  • markers rs666693 SEQ ID NO: 1
  • rs9316232 SEQ ID NO: 3
  • rs582385 SEQ ID NO: 2
  • the markers in the OPRM1 gene that are associated with the outcome of treatment with antidepressant medication include rs1720971 1 (which identifies a SNP in OPRM1 , e.g., SEQ ID NO: 5), rs3778149 (which identifies a SNP in the OPRM1 , e.g.
  • rs3778146 which identifies a SNP in the OPRM1 , e.g., SEQ ID NO: 7
  • rs7773995 which identifies a SNP in the OPRM1 , e.g., SEQ ID NO: 8
  • rs6900677 which identifies SEQ ID NO: 39
  • rs3778145 which identifies a SNP in the OPRM 1 , e.g., SEQ ID NO: 9).
  • antidepressant medication is rs885345 (which identifies a SNP in FREQ, e.g., SEQ ID NO: 10).
  • antidepressant medication is rs10052016 (which identifies a SNP in SLC6A3, e.g., SEQ ID NO: 1 1 ), rs10053602 (e.g. SEQ ID NO: 14) [000154]
  • the marker in SLC6A2 associated with the outcome of treatment with rs10052016 which identifies a SNP in SLC6A3, e.g., SEQ ID NO: 1 1
  • rs10053602 e.g. SEQ ID NO: 14
  • antidepressant medication is rs1814270 (which identifies a SNP in SLC6A2, e.g., SEQ ID NO: 79), rs11862589 (SEQ ID NO: 26); rs879522 (SEQ ID NO: 27), rs4564560 (SEQ ID NO: 28);); and rs1861646 (SEQ ID NO: 12).
  • the SLC6A2 transporter is associated with modulating adrenergic neurotransmission.
  • the marker in SLC6A4 associated with the outcome of treatment with with antidepressant medication is rs16965623 (which identifies a SNP in SLC6A4, e.g. SEQ ID NO 32).
  • the SLC6A4 transporter is associated with modulating serotonin
  • antidepressant medication is rs1 1 198986 (which identifies a SNP in RGS10, e.g. SEQ ID NO 31 ).
  • the RGS10 gene is associated with regulating G-protein signaling.
  • the marker in OPRM1 assocaited with the outcome of treatment with antidepressant medication is rs6916787 (which identifies a SNP in OPRM1 , e.g. SEQ ID NO 33).
  • the OPRM1 gene is associated withthe mu opiod receptor .
  • CHRNA3 typically comprises SEQ ID NO: 13.
  • the CHRNA3 gene is involved in modulating cholinergic neurotransmission through nicotinic receptors. Since some adjunctive antidepressant therapies include agents which can act upon cholinergic neurotransmission (e.g. bupropion), this gene can be involved in treatment outcomes for drug therapies directed towards modulating serotonergic neurotransmission with or without changes in adrenergic transmission.
  • the marker in the CHRM2 gene associated with the outcome of treatment with antidepressant medication is rs21 13545 (which identifies a SNP in CHRM2, e.g., SEQ ID NO: 35).
  • Other markers in the CHRM2 gene that correlate with treatment outcomes include: rs2350786 (which identifies a SNP in CHRM2, e.g., SEQ ID NO: 15) and rs1455857 (which identifies a SNP in CHRM2, e.g., SEQ ID NO: 25 ), rs7782904 SEQ ID NO: 24 ), rs2350786 (SEQ ID NO: 15), and rs1378646 (SEQ ID NO: 30); rs 21 13545 (SEQ ID NO: 35 ).
  • the CHRM2 gene is involved in modulating cholinergic
  • adjunctive antidepressant therapies include agents which can act upon cholinergic neurotransmission (e.g.
  • this gene can be involved in treatment outcomes for drug therapies directed towards modulating serotonergic neurotransmission with or without changes in adrenergic transmission.
  • the marker in CACNA C associated with the outcome of treatment with antidepressant medication is rs929492 (which identifies a SNP in CACNA C, e.g., SEQ ID NO: 17), and rs4765933 (SEQ ID NO: 24).
  • the CACNA1 C gene is involved in voltage- dependent L-type, alpha-1 -C calcium channel subunits which are involved in
  • the marker in S100A10 associated with the outcome of treatment with antidepressant medication is rs6678672 (which identifies SNPs in S100A10, e.g., SEQ ID NO: 18) or rs6587640 (SEQ ID NO: 19) and rs929492 (SEQ ID NO: 17).
  • the S100A10 gene is involved in calcium binding. Calcium is intimately involved in neurotransmission. Any therapies directed towards modulating serotonergic neurotransmission with or without modulating adrenergic neurotransmission will involve calcium binding.
  • the invention also comprises assaying for the presence of a genotype that is associated with an increased risk of non-response to treatment with antidepressant medication, wherein the genotype is characterized by a polymorphism in a gene selected from the group consisting of HTR2A, OPRM1 , FREQ, SLC6A3, SLC6A2, SLC6A4, RGS10,and CHRNA3, CHRM2, CACNA1 C, S100A10, FKBP5, GRM7 and combinations thereof.
  • the outcome of treatment with an antidepressant medication refers to whether or not a patient will remit and/or respond to treatment with the antidepressant medication (e.g., an SSRI, such as citalopram).
  • the antidepressant medication e.g., an SSRI, such as citalopram.
  • the ability to remit and/or not respond to treatment is dependent upon the tolerability of an individual to the medication.
  • non-response refers to a treatment response that does not improve the symptoms associated with depression to a clinically meaningful extent.
  • non-response to treatment with antidepressant medication refers to patients that achieved less than 50% reduction in baseline 16-item Quick Inventory of Depressive Symptomatology-Clinician-rated (QIDS-C16 ) score at the last treatment visit (Trivedi et al., Am. J.
  • non-response is defined as those subjects who's Quick Inventory of Depressive Symptomatology-Clinican-rate (QIDS-Cie) score was greater on study exit than on study entry.
  • QIDS-Cie Quick Inventory of Depressive Symptomatology-Clinican-rate
  • non-responders patients with a non-response to treatment
  • patients with a non-response to treatment refers to patients that achieve less than 50% (e.g., less than 45%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, than 10%or less than 5%) reduction in symptoms of depression following treatment with the antidepressant medication as measured by QIDS-C-
  • non-responders refers to patients whose reduction in symptoms of depression following treatment is from about 0% to about 5%, from about 0% to about 10%, from about 0% to about 15%, from about 0% to about 20%, from about 0% to about 25%, from about 0% to about 30%, from about 0% to about 35%, from about 0% to about 45%, from about 0% to about 50%, from about 10% to about 15%, from 10% to about 20%, from 10% to about 25%, from about 10% to about 30%, from about 10% to about 35%, from about 10% to about 45%, from about 10% to about 50%, from about 15% to about 20%, from about 15% to about 25%, from about 15% to about 30%, from about 15% to about 35%, from about 15% to about 45%, from about 15% to about 50%, from about 20% to about 25%, from about 20% to about 30%, from about 20% to about 35%, from about 20% to about 45%, from about 20% to about 50%, from about 25% to about 30%, from about 25% to about 35%, from about 25% to about 45%, from about 25% to
  • Positive response to treatment also can be measured by an improvement in one or more symptoms of depression.
  • symptoms include emotional and physical symptoms.
  • emotional symptoms of depression include feelings of guilt, worthlessness, sadness, emptiness, hopelessness, numbness, helplessness, irritability, anxiety, indecisiveness, pessimism, and thoughts of death and suicide.
  • physical symptoms of depression include headaches, back pain, muscle aches and joint pain, chest pain, digestive problems, exhaustion, fatigue, insomnia, a change in appetite or weight, and dizziness or lightheadedness.
  • patients in remission following antidepressant medication identified by a QIDS-Ci 6 score of less than or equal to 5 following administration of the antidepressant medication on exit of the study protocol. Therefore, patients that remit following treatment refers to patients that have a QIDS-C16 score of less than or equal to 5 (e.g., 5, 4, 3, 2, , or 0) following treatment with the antidepressant medication. Furthermore, remission was defined as having a CIRS score ⁇ 6 on study entry and a QIDS-C16 score > 18 on study entry to be genotyped and classified as in remission upon study exit.
  • the present invention also provides a method of identifying patients with an increased likelihood of experiencing remission following treatment with an antidepressant medication targeting increases in serotonergic neurotransmission with or without concomitant changes in adrenergic neurotransmission, the method comprising (a) obtaining a sample of genetic material from the patients, and (b) assaying the sample for the presence of a genotype in the patients that is associated with an increased likelihood of experiencing remission following treatment with antidepressant medication, wherein the genotype is characterized by a polymorphism in a gene selected from the group consisting of HTR2A, SLC6A3, , CHRM2, CACNA1 C, S100A10, GRM7, and combinations thereof
  • the antidepressant medication can be any suitable antidepressant medication known in the art.
  • the antidepressant medication can be a SSRI, a tricyclic antidepressant (TCA), a tetracyclic antidepressant, a MAOI, a reversible inhibitor of monoamine oxidase A (RIMA), a dopamine reuptake inhibitor (DARI), a norepinephrine- dopamine reuptake inhibitor, a norepinephrine reuptake inhibitor (NRI) or (NARI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a selective serotonin reuptake enhancer (SSRE), a noradrenergic and specific serotonergic antidepressant (NaSSA), or another suitable antidepressant medication.
  • TCA tricyclic antidepressant
  • MAOI a reversible inhibitor of monoamine oxidase A
  • RIMA dop
  • the antidepressant medication is a SSRI, such as citalopram, alaproclate, escitalopram, etoperidone, fluoxetine, fluvoxamine, paroxetine, sertraline, zimelidine, or combinations thereof.
  • SSRI such as citalopram, alaproclate, escitalopram, etoperidone, fluoxetine, fluvoxamine, paroxetine, sertraline, zimelidine, or combinations thereof.
  • the present invention provides a kit comprising reagents suitable for applying the methods of the invention.
  • the kit provides the necessary materials for identifying a polymorphism packaged into a suitable container.
  • the kit contains a reagent that identifies a polymorphism in the selected gene that is associated with a selected trait, such as treatment outcome.
  • the reagent is a set of primers or a PCR set (a set of primers, DNA polymerase, and 4 nucleoside triphosphates) that hybridizes with the gene or a fragment thereof.
  • the kit also can include other reagents for detecting or measuring the detectable entity and/or a control. Other reagents used for hybridization, prehybridization, DNA extraction, visualization, and the like also can be included.
  • the kit may also utilize methodologies for analysis of single stranded and/or double stranded DNA segments by whatever technology permits the anlaysis of a biological sample from patients (blood, stool, saliva, etc) to identify the disclosed genetic markers associated with treatment outcome which include genes, SNPs and haplotypes disclosed herein.
  • Sensitivity is the probability that a symptom is present (or the screening test is positive) when a patient has a disorder.
  • the sensitivity of the polymorphism associated with the outcome of treatment with antidepressant medication in the inventive method can be any suitable sensitivity.
  • the sensitivity is about 0.5 or higher (e.g., about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, or about 0.95).
  • the sensivity is from about 0.5 to about 0.95, from about 0.5 to about 0.9, from about 0.5 to about 0.85, from about 0.5 to about 0.8, from about 0.5 to about 0.75, from about 0.5 to about 0.7, from about 0.5 to about 0.65, from about 0.5 to about 0.6, from about 0.5 to about 0.55, from about 0.55 to about 0.95, from about 0.55 to about 0.9, from about 0.55 to about 0.85, from about 0.55 to 0.8, from about 0.55 to about 0.75, from about 0.55 to about 0.7, from about 0.55 to about 0.65, from about 0.55 to about 0.6, from about 0.6 to about 0.95, from about 0.6 to about 0.9, from about 0.6 to about 0.85, from about 0.6 to 0.8, from about 0.6 to about 0.75, from about 0.6 to about 0.7, from about 0.6 to about 0.65, from about 0.65 to about 0.95, from about 0.65 to about 0.9, from about 0.65 to about 0.85, from about 0.65 to about 0.75,
  • Specificity is the probability that a symptom is not present (or the screening test is negative) when a patient does not have a disorder.
  • the specificity of the polymorphism associated with the outcome of treatment with antidepressant medication in the inventive method can be any suitable specificity. Preferably, the specificity is about 0.5 or higher
  • the specificity is from about 0.5 to about 0.95, from about 0.5 to about 0.9, from about 0.5 to about 0.85, from about 0.5 to 0.8, from about 0.5 to about 0.75, from about 0.5 to about 0.7, from about 0.5 to about 0.65, from about 0.5 to about 0.6, from about 0.5 to about 0.55, from about 0.55 to about 0.95, from about 0.55 to about 0.9, from about 0.55 to about 0.85, from about 0.55 to 0.8, from about 0.55 to about 0.75, from about 0.55 to about 0.7, from about 0.55 to about 0.65, from about 0.55 to about 0.6, from about 0.6 to about 0.95, from about 0.6 to about 0.9, from about 0.6 to about 0.85, from about 0.6 to about 0.75, from about 0.6 to about 0.7, from about 0.55 to about 0.65, from about 0.55 to about 0.6, from about 0.6 to about 0.95, from about 0.6 to about 0.9, from about 0.6 to about 0.85, from about 0.6 to about 0.75,
  • Positive predictive value is the probability that a patient has a disorder given a positive test result.
  • the positive predictive value of the polymorphism associated with the outcome of treatment with antidepressant medication in the inventive method can be any suitable value.
  • the positive predictive value is about 0.05 or higher (e.g., about 0.1 , about 0.2, about 0.25, about 0.3, about 0.4, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, or about 0.95).
  • the positive predictive value is from about 0.05 to about 0.95, from about 0.05 to about 0.9, from about 0.05 to about 0.85, from about 0.05 to about 0.8, from about 0.05 to about 0.75, from about 0.05 to about 0.7, from about 0.05 to about 0.65, from about 0.05 to about 0.65, from about 0.05 to about 0.6, from about 0.05 to about 0.55, from about 0.05 to about 0.5, from about 0.05 to about 0.4, from about 0.05 to about 0.3, from about 0.05 to about 0.25, from about 0.05 to about 0.2, from about 0.05 to about 0.1 , from about 0.1 to about 0.95, from about 0.1 to about 0.9, from about 0.1 to about 0.85, from about 0.1 to about 0.8, from about 0.1 to about 0.75, from about 0.1 to about 0.7, from about 0.1 to about 0.65, from about 0.1 to about 0.65, from about 0.1 to about 0.6, from about 0.1 to about 0.55, from about 0.1 to about 0.5, from about 0.05 to
  • Negative predictive value is the probability that a patient has the disorder given a negative test result.
  • the negative predictive value of the polymorphism associated with the outcome of treatment with antidepressant medication in the inventive method can be any suitable value.
  • the negative predictive value is about 0.5 or higher (e.g., about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, about 0.8, about 0.85, about 0.9, or about 0.95).
  • the negative predictive value is from about 0.5 to about 0.95, from about 0.5 to about 0.9, from about 0.5 to about 0.85, from about 0.5 to about 0.8, from about 0.5 to about 0.75, from about 0.5 to about 0.7, from about 0.5 to about 0.65, from about 0.5 to about 0.6, from about 0.5 to about 0.55, from about 0.55 to about 0.95, from about 0.55 to about 0.9, from about 0.55 to about 0.85, from about 0.55 to 0.8, from about 0.55 to about 0.75, from about 0.55 to about 0.7, from about 0.55 to about 0.65, from about 0.55 to about 0.6, from about 0.6 to about 0.95, from about 0.6 to about 0.9, from about 0.6 to about 0.85, from about 0.6 to 0.8, from about 0.6 to about 0.75, from about 0.6 to about 0.7, from about 0.6 to about 0.65, from about 0.65 to about 0.95, from about 0.65 to about 0.9, from about 0.65 to about 0.85, from about 0.6 to 0.8,
  • DSM non-psychotic major depressive disorder
  • Non-response was defined as an exit QIDS-C16 score greater than entry score, a CIRS index ⁇ 6, or a QIDS-C16 score less than 50% reduced when comparing entry and exit test scores (e.g. at least 45%; at least 40%, at least 35%, at least 30%, at least 25%, at least 20%, at least 15%, at least 0% or at least 5% and ranges included).
  • entry and exit test scores e.g. at least 45%; at least 40%, at least 35%, at least 30%, at least 25%, at least 20%, at least 15%, at least 0% or at least 5% and ranges included.
  • Outcome 1 is Sequenced Treatment Alternatives to Relieve Depression (STAR*D) remission which is defined as tolerant or probably tolerant to modulating serotonergic neurotransmission with or without concomitant changes in adrenergic neurotransmission and who have achieved full symptomatic relief from their presenting major depressive disorder symptoms. This set of subjects included those classified as in remission and those classified as responders. Outcome 1 corresponds to an entry Quick Inventory Depression scale (QIDS) >18, an exit QIDS of ⁇ 5, a CIRS total score ⁇ 6 and tolerant/probably tolerant of drug therapy.
  • QIDS Quick Inventory Depression scale
  • Outcome 0 is STAR*D non-responder which is defined as below.
  • Outcome 0 corresponds to an entry QIDS ⁇ 18 and a less than ⁇ 50% reduction in exit QIDS, a tolerance/probable tolerance of drug therapy with a Cumulative Illness Rating Scale (CIRS) total score ⁇ 6.
  • Outcome 0 also corresponds to an exit QIDS score ⁇ entry QIDS with a CIRS total score ⁇ 6 and tolerant/probably tolerant of drug therapy.
  • TABLE 2 exemplary embodiment 2
  • CACNA1 C calcium channel voltage-dependent, L type, alpha 1 C subunit
  • rs21 13545-T_T allele predicts a high probability of achieving remission in patients with this inheritance pattern.
  • OPRM1 mu-opiod receptor gene
  • nicotinic alpha-3 gene (CHRNA3) polymorphism rs6495308, those that are rs6495308-A_G heterozygous have a greater chance of outcome 0, namely 18/28 0.64. Therefore, rs6495308-A_G allele predicts a high probability of non-response in patients with this inheritance pattern.
  • rs3778149-C_C allele predicts a high probability of non-response to antidepressant therapy in patients with this inheritance pattern.
  • G_G homozygous at rs3778149 are 4 times as likely to fail antidepressant therapy although these numbers may not be significant with a larger rs3778149-G_G haplotype.
  • CHRM2 muscarinic 2 gene
  • exemplary embodiment 14
  • Genotyping patients for genes, SNPs and haplotype markers can help to determine the outcome of treatment with antidepressant medication.
  • genotyping and haplotype aniaysis of patients using HTR2A, OPRM1 , SLC6A2, CHRNA3, GRM7, FKBP5, SLC6A3 markers, among others identified in the teachings of this patent can identify patients with a high probability of non-response to treatment with
  • a haplotype of T_T indicates that outcome 1 (true remitter) has a statistically reliable probability (p ⁇ 0.001) of occurring when compared to outcome 0 (non- response).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of C_C indicates that outcome 1 (true remitter) has a statistically reliable probability (p ⁇ 0.001) of occurring when compared to outcome 0 (non- response).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • G_G 130 55 185 2.207 as.
  • a haplotype of A_A indicates that outcome 1 (true remitter) has a statistically reliable probability (p ⁇ 0.001 ) of occurring when compared to outcome 0 (non- response).
  • a haplotype of A_G indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.05) of occurring when compared with outcome 1 (true remitter).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01 ) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of A_G (p ⁇ 0.01 ) or G_G (p ⁇ 0.001) indicates that outcome 0 (non-response) has a statistically reliable probability of occurring when compared with outcome 1 (true remitter).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01 ) of outcome 0 (non- response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of T_T indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.001 ) of occurring when compared with outcome 1 (true remitter).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01 ) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • G_G 29 16 45 2.6745 n.s.
  • a haplotype of A_A indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.001 ) of occurring when compared with outcome 1 (true remitter).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01 ) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of A_G indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.001 ) of occurring when compared with outcome 1 (true remitter).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of C_T (p ⁇ 0.001 ) or T_T (p ⁇ 0.05) indicates that outcome 0 (non-response) has a statistically reliable probability of occurring when compared with outcome 1 (true remitter).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01 ) of outcome 0 (non- response) when compared to outcome 1 (true remitter) for this gene.
  • C_C For the SNP a haplotype of C_C indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.001 ) of occurring when compared with outcome 1 (true remitter).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01 ) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • T_T For the SNP a haplotype of T_T indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.05) of occurring when compared with outcome 1 (true remitter).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • C_C For the SNP a haplotype of C_C indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.001) of occurring when compared with outcome 1 (true remitter).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of A_A indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.001) of occurring when compared with outcome 1 (true remitter).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of G_G indicates that outcome 1 (true remitter) has a statistically reliable probability (p ⁇ 0.001) of occurring when compared with outcome 0 (non- responder).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of G_G indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.05) of occurring when compared with outcome 1 (true remitter).
  • a haplotype of A_A indicates a statistically reliable probability (p ⁇ 0.001) of outcome 1 (true remitter) when compared with outcome 0 (non-responder).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • a haplotype of T_T indicates that outcome 1 (true remitter) has a statistically reliable probability (p ⁇ 0.001 ) of occurring when compared with outcome 0 (non- responder).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of C_C indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.01 ) of occurring when compared with outcome 1 (true remitter).
  • a haplotype of T_T indicates a statistically reliable probability (p ⁇ 0.001 ) of outcome 1 (true remitter) of occurring when compared to outcome 0 (non-response).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • a haplotype of C_T (p ⁇ 0.001) or T_T (p ⁇ 0.01) indicates that outcome 0 (non-response) has a statistically reliable probability of occurring when compared with outcome 1 (true remitter).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non- response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of A_A indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.05) of occurring when compared with outcome 1 (true remitter).
  • a haplotype of G_G has a statistically reliable probability (p ⁇ 0.001) of outcome 1 (true remitter) of occurring when compared with outcome 0 (non-responder).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • a haplotype of A_A (p ⁇ 0.001) or G_G (p ⁇ 0.05) indicates that outcome 0 (non-response) has a statistically reliable probability of occurring when compared with outcome 1 (true remitter).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non- response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of A_A indicates that outcome 1 (true remitter) has a statistically reliable probability (p ⁇ 0.001) of occurring when compared with outcome 0 (non- response).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • T__T For the SNP a haplotype of T__T indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.01) of occurring when compared with outcome 1 (true remitter).
  • a haplotype of G_T indicates that outcome 1 (true remitter) has a statically reliable probability (p ⁇ 0.01) of occurring when compared with outcome 0 (non-response).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a
  • T_T For the SNP a haplotype of T_T indicates that outcome 1 (true remitter) has a statistically reliable probability (p ⁇ 0.001) of occurring when compared with outcome 0 (non- response).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of A_A indicates that outcome 1 (true remitter) has a statistically reliable probability (p ⁇ 0.001) of occurring when compared with outcome 0 (non- response).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of A_A indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.01) of occurring when compared with outcome 1 (true remitter).
  • a haplotype of G_G indicates that outcome 1 (true remitter) has a statistically reliable probability (p ⁇ 0.001) of occurring when compared with outcome 0 (non-response).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • C_C For the SNP a haplotype of C_C indicates that outcome 0 (non-response) has a statistically reliable probability (p ⁇ 0.001) of occurring when compared with outcome 1 (true remitter).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of A_A indicates that outcome 1 (true remitter) has a statistically reliable probability (p ⁇ 0.001) of occurring when compared with outcome 0 (non- response).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • a haplotype of C_C indicates that outcome 1 (true remitter) has a statistically reliable probability (p ⁇ 0.001) of occurring when compared with outcome 0 (non- responder).
  • the Chi square analysis compares outcome 0 (non-response) with outcome 1 (response) as defined in disclosures.
  • the Grand total Chi square value indicates that there is a statistically reliable probability (p ⁇ 0.01) of outcome 0 (non-response) when compared to outcome 1 (true remitter) for this gene.
  • Table 49 provides Fischer's exact p values for the identified SNPs and genes. A statistically significant association with non-response was found for all listed genes and SNPs (p ⁇ 0.04 or greater).
  • the minor allele frequency refers to the frequency at which the less common allele occurs in a given population. In most cases genes and SNPs in this table have a minor allele frequency greater than 0.15 (15%).
  • Hardy Weinberg equilibrium values indicate that both allele and genotype frequencies in a population remain constant. The Hardy Weinberg equilibrium value for each gene and SNP indicates that alleles from these genes are normally distributed between generations. That is, the frequency of each allele for the identified genes follows a normal distribution from generation to generation.

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Abstract

La présente invention vise la fraction importante de patients exposés à une augmentation de la neurotransmission sérotonergique, avec ou sans variations concomitantes de la neurotransmission adrénergique, qui souffrent actuellement et/ou souffriront à l'avenir d'une dégradation de la réponse à un traitement au moyen d'antidépresseurs. Avec la baisse d'efficacité de la neurotransmission dopaminergique, l'identification de certains symptômes psychiatriques liés à des dysfonctionnements de l'humeur, du système de récompense et de l'attention peut avoir lieu. L'invention permet d'identifier un profil génétique chez des patients qui soit ne sont pas sensibles à des médicaments antidépresseurs de première intention, soit peuvent présenter une rémission à des thérapies ciblant des variations de la neurotransmission sérotonergique avec ou sans variations concomitantes de la neurotransmission adrénergique pour un trouble dépressif majeur.
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US20090176878A1 (en) * 2007-10-05 2009-07-09 Washington University In St. Louis Genetic polymorphisms and substance dependence
US20090253585A1 (en) * 2005-11-30 2009-10-08 Luda Diatchenko Identification of Genetic Polymorphic Variants Associated With Somatosensory Disorders and Methods of Using the Same
WO2009155585A1 (fr) * 2008-06-21 2009-12-23 Blumy Kenneth Nutragenomique
US7795033B2 (en) * 2007-03-19 2010-09-14 The United States Of America As Represented By The Department Of Health And Human Services Methods to predict the outcome of treatment with antidepressant medication
WO2010111080A2 (fr) * 2009-03-27 2010-09-30 Eli Lilly And Company Traitement optimisé de la schizophrénie
US20100304391A1 (en) * 2009-05-29 2010-12-02 Lombard Jay L Methods for assessment and treatment of depression via utilization of single nucleotide polymorphisms analysis

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US20090253585A1 (en) * 2005-11-30 2009-10-08 Luda Diatchenko Identification of Genetic Polymorphic Variants Associated With Somatosensory Disorders and Methods of Using the Same
US7795033B2 (en) * 2007-03-19 2010-09-14 The United States Of America As Represented By The Department Of Health And Human Services Methods to predict the outcome of treatment with antidepressant medication
US20090176878A1 (en) * 2007-10-05 2009-07-09 Washington University In St. Louis Genetic polymorphisms and substance dependence
WO2009155585A1 (fr) * 2008-06-21 2009-12-23 Blumy Kenneth Nutragenomique
WO2010111080A2 (fr) * 2009-03-27 2010-09-30 Eli Lilly And Company Traitement optimisé de la schizophrénie
US20100304391A1 (en) * 2009-05-29 2010-12-02 Lombard Jay L Methods for assessment and treatment of depression via utilization of single nucleotide polymorphisms analysis

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106536751A (zh) * 2014-03-05 2017-03-22 武田药品工业株式会社 治疗抑郁症和重性抑郁障碍的方法
EP3114239A4 (fr) * 2014-03-05 2017-10-11 Takeda Pharmaceutical Company Limited Méthode de traitement de la dépression et du trouble dépressif majeur

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