1. 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

2. 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.

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

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

5. .

6. 60 different CYP genes (on different chromosomes)
Different Phenotypes:
Poor metabolizer
Intermediate metabolizer
Extensive (normal) metabolizer
Ultrarapid metabolizer
Brandl et al. Pharmacogenomics J 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

7. .

8. 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 Aug;66(2):
Tabari et al Jul;28(4):

9. 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 Apr;14(2):176-81

10. 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.

11. 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)

12. .

13. 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

14. 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).

15. .

16. 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)
rs ve rs
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):
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:

17. 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 Apr;14(2):176-81

18. 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, rs and rs ) 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 rs is the gene variant most related to unresponse
Porton et al. Transl Psychiatry 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.

19. 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 rs 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 Nov;23(11):
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 May;21(5):790-3.

20. BDNF gene and response to OCD treatment
Study
Polymorpism
Result
Real et al., 2009
Eight SNPs
*rs →better response
*haplotype rs –rs908867→better response
(5’upstream region)
*T-G-T-G-T haplotype (rs , rs6265 [Val-66Met], rs , rs and rs SNP’lerinde)→response rate is the half of what it is in others.
Zai et al., 2010
-270C/T rs
*Better response to all SSRIs in those with the C-allele of the –polymorphism 270C/T *rs →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 Jul;27(5):

21. 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 Oct;16(4):
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).

22.  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
rs : better response
A haplotype (rs –rs908867): better response (5’upstream region)
Response rate is as half as others in the haplotype T-G-T-G-T (rs , rs6265 [Val-66Met], rs , rs and rs SNPs)
Zai et al., 2009
BDNF (polymorphisms -270C/T and rs )
119
Better response to all SSRIs in those with the C-allele of the -270C/T polymorphism
Rs 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