Pharmacogenetics in Obsessive-compulsive Disorder Oğuz Tan, MD, Ass. Prof. Üsküdar University April 17th, 2015 7th International Congress on Psychopharmacology April 15th-19th, 2015, Antalya

OCD The 4th most common psychiatric disorder (1) Life-time prevalence of 2.3 % (1) 10th among all medical causes of disability (2) Despite medication and CBT: 40 % keep having obvious symptoms 10 % do not respond at all (3,4) 1) Karno et al. Molecular Psychiatry 2010; 15: 53–63. 2) Murray and Lopez. Science 1996; 274(5288): 740–3. 3) Pallanti and Quercioli . Progress in Neuro-Psychopharmacology & Biological Psychiatry 2006; 30: 400–12. 4) Simpson et al. Psychiatr Clin North Am 2006; 29: 553–84.

Pharmacogenetics in OCD Pharmacokinetics Pharmacodynamics Cytochrome P450 (CYP450) enzymes Serotonin system Serotonin transporter Serotonin receptors Glutamat transporter Norepinephrine transp. BDNF COMT Dopamin receptors

Hepatic metabolism of drugs for OCD CYP2D6 CYP2C19 Main Secondary Clomipramine Fluoxetine Fluvoxamine Paroxetine Sertraline Venlafaxine Citalopram Escitalopram

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60 different CYP genes (on different chromosomes) Different Phenotypes: Poor metabolizer Intermediate metabolizer Extensive (normal) metabolizer Ultrarapid metabolizer Brandl et al. Pharmacogenomics J. 2014 Apr;14(2):176-81 CYP2C19 and CYP2D6 genes: 10th and 22nd chromosomes More than 130 SNPs and CNVs on CYP2D6 gene SNP: tek nükleotid polimorfizmi Kopya sayısı varyasyonu: delesyon, duplikasyon, triplikasyon… belli bir proteini kodlayan genetik materyal miktarında değişme

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CYP450 CYP2D6 CYP2C19 10% of caucasians are poor metabolizers Up to 30% of the North African and the Middle Eastern have multiple copies of the CYP2D6 gene → ultrarapid metabolizers are common In Turkey, ultrarapid metabolizers %10.29, poor metabolizers %1.45 Pre-treatment genotyping? de Leon et al. Psychosomatics47(1),75–85 (2006). Mrazek. Dialogues Clin. Neurosci.12(1),69–76 (2010) Herken et al . Türk Psikiyatri Dergisi 2001;12(2):83-88. The frequency of poor metabolizers of CYP2C19 ↓from the Northern to the Southern Europe Iranian Turkmens have CYP2C19 poor metabolizer phenotype more frequently than the Turks, Europeans, Scandinavians, North and South Americans, West Asians, Africans. Aynacioglu et al.Clin Pharmacol Ther. 1999 Aug;66(2):185-92. Tabari et al. 2013 Jul;28(4):237-44.

CYP450 polymorphisms and treatment response in OCD *Are four CYP2D6 polymorphisms related to the response to paroxetine or venlafaxine? *Polymorphisms are related to plasma levels, not related to response *Plasma levels are *No classification according to metabolizer status (poor, intermediate, extensive or ultrarapid). The study only investigated the relationship between the alleles and treatment response. Van Nieuwerburgh ve ark. Int. J. Psychiatry Clin. Pract.13(1),345–348 (2009). *N=184 (larger study) *CYP2D6 and 2C19 *Venlafaxine, fluoxetine, sertraline *Better response in normal (extensive) metabolizers (p=0.007) Brandl ve ark. Pharmacogenomics J. 2014 Apr;14(2):176-81

OCD-CYP relationship Two studies. Inconsistent results. Plasma and brain levels may not be correlated Paroxetine is an inhibitor of CYP2D6 →the difference between poor and rapid metabolizers decreases. Phenoconversion: 24 % of venlafaxine users who had not originally been CYP2D6 poor metabolizers turned into poor metabolizers in 8 weeks. Genotyping should be reinforced by measuring plasma levels? CYP2D6 also has direct effects on behavior, anxiety and mood (since it is expressed in the brain too). Drug metabolism is not the whole picture.

5-HTT (SERT) 5-hidroxytriptamine transporter (5-HTT) = serotonin transporter (SERT) Serotonin reuptake into the presynaptic neuron Encoded by SLC6A4 (solute carrier family 6 member 4) 17. chromosome (long arm) A polymorphism in its promoter region: 5-HTT gene-linked polymorphic region (5-HTTLPR)

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5-HTTLPR Insertion or deletion of a 44-bp sequence → long or short allele (14 or 16 repeats of 44-bp sequence) Normal carriers have two long alleles Long alleles have three times as high gene expression as short alleles →efficient reuptake of serotonin More recent studies have identified a SNP in the long allele →a second variant of the long allele: -LG (A substituted by G)→ expression drops to the same levels as the short allele → inefficient reuptake of serotonin -LA (No A→G substitution. Normal carrier. Sonraki çalışmalarda trialelik olduğu da gösterilmiş

5-HTTLPR and response to treatment Billett et al., 1997 5-HTTLPR polymorphism is not related to response to SSRIs or clomipramine Zhang et al., 2004 Miguita et al. , 2011 Di Bella et al., 2002 Polymorphism is not related to response to fluvoxamine Homozygotes for the S-allele show more decrease in compulsions if there is no coexisting tic disorder Denys et al., 2007 Better response to venlafaxine in heterozygotes (S/L genotype) No such a relationship with paroxetine *Inconsistent results *Unique pharmacodynamics of drugs? *Lack of trialleleic studies? Billett et al. Mol. Psychiatry2(5),403–406 (1997) Denys et al. Psychiatry68(5),747–753 (2007). Di Bella et al. Pharmacogenomics J.2(3),176–181 (2002). Miguita et al. Arq. Neuropsiquiatr.69(2B),283–287 (2011). Zhang et al. Zhonghua Yi Xue Yi Chuan Xue Za Zhi21(5),479–481 (2004).

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Serotonin receptors Genes Polymorphism Related to response? 5-HT1Dβ 861 G/C No (1,2,3) 5-HT2A -1438G/A No (4) Better response in the genotype G/G (1) Homozygosity is related to response (5) 102T/C No (3,4,6) 516 C/T No (4,6) Worse response in the genotype CC (3) rs7997012 ve rs1328684 Yes (7) 5-HT2C Cys23Ser No (8) 1)Denys et al. J. Clin. Psychiatry68(5),747–753 (2007). 2)Miguita et al. Arq. Neuropsiquiatr.69(2B),283–287 (2011). 3) Corregiari et al. Clinics. 2012;67(4):335-340. 4) Tot et al. Eur. Psychiatry18(5),249–254 (2003). 5) Zhang et al. Zhonghua Yi Xue Yi Chuan Xue Za Zhi21(5),479–481 (2004). 6) Miguita et al. Arq. Neuropsiquiatr.69(2B),283–287 (2011). 7) Zai et al. The 18th World Congress on Psychiatric Genetics. Athens, Greece, 3–7 October 2010. 8) Cavallini et al. Psychi­atry Res 1998;77:97-104.

Glutamate transporter (EAAC1/EAAT3=excitatory amino acid carrier 1 = excitatory amino acid transporter 3) Clears glutamate away from synapse → terminates excitatory signals→ prevents excitotoxicity and neuron death Neuroimaging: glutamate-mediated corticothalamostriatal dysfunction Increased glutamate in OCD returns to normal after treatment Rosenberg DR, Hanna GL. Biol. Psychiatry48(12),1210–1222 (2000). Encoded by SLC1A1 (solute carrier family 1 member 1) Located on 9p24 The gene having the most established relationship with OCD. Research has usually found SNPs and haplotypes in this gene. Brandl et al Pharmacogenomics J. 2014 Apr;14(2):176-81

SLC1A1 Porton et al., 2013 Fluoxetine increases the transcription of SLC1A1 in patients with OCD, not in normals Kwon et al., 2009 Antipsychotic-induced obsessive-compulsive symptoms are related to SLC1A1 polymorphisms Real et al., 2010 *Three SNPs (rs301434, rs301435 and rs3087879) and a haplotype (A-G-C) are related to unresponse in OCD whose onset is not associated with stressful life events (compared to OCD whose onset is after SLE ) *SNP rs3087879 is the gene variant most related to unresponse Porton et al. Transl Psychiatry. 2013 May 21;3:e259. Kwon et al. Arch. Gen. Psychiatry66(11),1233–1241 (2009). Real et al. The 18th World Congress on Psychiatric Genetics. Athens, Greece, 3–7 October 2010.

BDNF brain-derived neurotrophic factor Neuronal survival, differentiation, apoptosis and synaptic synthesis and release of neurotransmitters BDNF gene is located on the 11th chromosome Met-allele carriers of the Val66Met polymorphism (pro-region, codon 66) respond better to depression treatment (influencing intracellular trafficking and release of BDNF (1) Val66Met polymorphism is more frequent in OCD (2) Patients with Val66Met polymorphism have more severe illness and earlier onset (3,4) Patients with the CC genotype in rs2883187 SNP have more severe illness and more frequent family history (5) 1)Kato M, Serretti A. Mol. Psychiatry15(5),473–500 (2010). 2)Márquez L et al. Eur Neuropsychopharmacol. 2013 Nov;23(11):1600-5. 3)Hemmings et al. World J. Biol. Psychiatry9(2),126–134 (2008). 4)Katerberg et al. Am. J. Med. Genet. B Neuropsychiatr. Genet.150B(8),1050–1062 (2009). 5)Tükel et al. J Clin Neurosci. 2014 May;21(5):790-3.

BDNF gene and response to OCD treatment Study Polymorpism Result Real et al., 2009 Eight SNPs *rs1491850→better response *haplotype rs1491850–rs908867→better response (5’upstream region) *T-G-T-G-T haplotype (rs1050187, rs6265 [Val-66Met], rs12273363, rs908867 and rs1491850 SNP’lerinde)→response rate is the half of what it is in others. Zai et al., 2010 -270C/T rs2049045 *Better response to all SSRIs in those with the C-allele of the –polymorphism 270C/T *rs2049045→better response to paroxetine only. Fullana et al., 2012 (CBT) Val66Met (rs6265 ) Worse response in Met-allele carriers (more obvious in contamination/washing dimension) Real et al. Biol. Psychiatry66(7),674–680 (2009). Zai G et al. The 18th World Congress on Psychiatric Genetics. Athens, Greece, 3–7 October 2010. Fullana et al. Eur Psychiatry. 2012 Jul;27(5):386-90.

Other genes COMT Half of those responding to citalopram are the Met/Met carriers of the polymorphism Val158Met (but none of the non-responders are) (1) Val158Met polymorphism is not related to response (2) MAO-A Not related to response (3) Norepinephrine transporter (SLC6A2) Not related to response (2) Dopamin transporter (SLC6A3) Dopamin receptors D2 and D4 Not related to response (1,3) 1)Vulink et al. Int J Psychiatry Clin Pract. 2012 Oct;16(4):277-83. 2) Miguita et al. Arq. Neuropsiquiatr.69(2B),283–287 (2011). 3)Zhang et al. Zhonghua Yi Xue Yi Chuan Xue Za Zhi21(5),479–481 (2004).

 Study Gene N Tedavi Sonuç Brandl et al., 2014 CYP2D6 CYP2C19 184 Fluoxetine Sertraline Venlafaxine Better response in normal metabolizers Van Nieuwerburgh et al., 2009 91 Paroxetine Polymorphisms not related to response Polymorphisms related to plasma levels Di Bella et al., 2002 5-HTT (5-HTTLPR) 181 Fluvoxamine Homozygotes for the S-allele show more decrease in compulsions if there is no coexisting tic disorder Billett et al.., 1997 72 SSRIs  Polymorphisms not related to response Miguita et al., 2011 5-HTTLPR and STin2 (in SLC6A4) 5-HT1Dβ (in HTR1B) (polymorphisms 861G/C=rs6296) 5-HT2A (HTR2A) Dopamine transporter (SLC6A3) (DAT UTR, DAT intron 8 and DAT intron 14) COMT (Val-158-Met ]rs4680]) Norepinephrine transporter gene (SLC6A2 (silent mutation G1287A [rs5569]) 41 Clomipramine Denys et al., 2007 5-HTT 5-HT1B 5-HT2A Paroxetine Venlafaxine Better response to venlafaxine in 5-HTTLPR S/L genotype Better response to paroxetine in 5-HT2A G/G genotype Corregiari et al., 2011 5-HT-1Dβ (polymorphism 861G/C) 5-HT2A (polymorphisms 102T/C and 516C/T) 60 Citalopram Clomipramine Fluoxetine Fluvoxamine Paroxetine C/C genotype of the polymorphism 516C/T of the 5-HT2A gene is more common in nonresponders Tot et al., 2003 5-HT2A (polymorphisms 102T/C and 516C/T ) 58 Zhang et al., 2004 D2 receptor D4 receptor COMT MAO-A 113 Responders and nonresponders differ in homozygosity in the locus -1438G/A of the 5-HT2A gene Real et al., 2009 BDNF (eight SNPs) 131 Fluoxetine Fluvoxamine rs1491850: better response A haplotype (rs1491850–rs908867): better response (5’upstream region) Response rate is as half as others in the haplotype T-G-T-G-T (rs1050187, rs6265 [Val-66Met], rs12273363, rs908867 and rs1491850 SNPs) Zai et al., 2009 BDNF (polymorphisms -270C/T and rs2049045) 119 Better response to all SSRIs in those with the C-allele of the -270C/T polymorphism Rs2049045 is related to better response to paroxetine only Fullana et al., 2012 BDNF (Val66Met) 106 CBT Worse response in Met-allele carriers (more obvious in contamination/washing dimension) Vulink et al., 2012 COMT (Val158 Met) Dopamine D2 receptor 64 Citalopram plus quetiapine Half of responders to carried the Met/Met (48%) genotype of the COMT polymorphism compared to none of the nonresponders