Do variations in the 5-HT transporter predispose to clinical depression ?

Supervisor: Dr Joan Jarman Ayaa Mahdee

Aim

To discuss the association between varying levels of the 5-HT transporter due to genetic polymorphisms in the serotonin transporter and the possible predisposition to clinical major depression in individuals.

Methodology • Search engine: PubMed , Science direct, Bio of psychiatry, Google

scholar ,Journals of affective and Psych-INFO disorders.

• 5-HT transporter, major depression, serotonin genetic polymorphism, Serotoninergic pathway.

• Inclusion criteria: relevancy to the 5-HT transporters, and 5-HTT gene, SERT polymorphism ( primary literature)

• Exclusion criteria: Patients with current psychosis history.

Major depression • Monoamine hypothesis states: changing levels in the monoamine transmitters

norepinephrine and serotonin(5-HT) in the brain.

• Impairment of the central modulatory system monoamine transmitters, norepinephrine and serotonin.

• Symptoms: Fatigue, low mood and loss of appetite.

5 -HT transporter pathway

Polymorphism of the 5-HTT

• Polymorphism of the 5-HTT is affected by the variation of the promoter region of the 5-HTT gene SLC6A4.

• The promoter region of the 5-HTT gene has two variant allele, long L and small s.

• Long allele L associated with higher levels of gene expression and short allele s associated with lower expression of the 5-HTT.

Environmental and gene interaction

• Genetic inheritance: The heritability of MDD is 0.33 which indicates inherited factor account of 33% (Sullivan et al., 2000).

• An earlier childhood maltreatment including physical abuse, neglecting and violence has a major impact on individual’s vulnerability to depression(Vranceanu et al., 2007).

Study Result(Lazary et al., 2008) • Subjects with s-allele of 5-HTTLPR have a high

ZSDS score.• S allele variation of 5-HTTLPR could be altered in

the middle region of the rs 140700 gene, carries a significant role in environmental and gene interaction affecting individuals depressive phenotype.

(Hoefgen et al., 2005) Significant difference in allele frequency distribution with a statistically significant association of the 5-HTTLPR short variant with major depressive disorder.

(Rominger et al., 2015) found an alteration of SERT binding to [123]-2β-CIT radioligand in major depressive disorder

(Noskova et al., 2008) Significant allele frequency difference between women and men p<0.001.

Study Result

(Mendlewicz et al., 2004) No significant difference were found between major affective disorder and control group.

(Murthy et al., 2010) Polymorphic variation in the 5-HTTLPR has shown to have no influence on the 5-HTT expression in adult human brain measured by [11C] DASB.

Limitation

• Gender • Sample size

• Seasonal changes

• Age • Location

Future approaches

• Multicentre longitudinal studies.

• Gender and age controlled studies.

Conclusion

• Low levels of SERT are found among depressed patients in the promoter region of the SLC6A4 that has been show to affect transcriptional activity of the 5-HTTLPR among MDD Patients.

• Difference of the s and l allelic levels was shown to cause varying susceptibility levels to developing major depression.

References • Bear M, Connors B and Paradiso M. (2006) Neuroscience. Baltimore, Md.: Lippincott Williams & Wilkins.

• Kupfer D, Frank E, and Phillips M. (2012) Major depressive disorder: new clinical, neurobiological, and treatment perspectives. The Lancet 379(9820): 1045-1055.

• Murthy N, Selvaraj S, Cowen P, Bhagwagar Z, Riedel W, Peers P, Kennedy J, Sahakian B, Laruelle M, Rabiner E and Grasby P. (2010) Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C]

DASB binding in the living human brain. NeuroImage 52(1): 50-54.

• Sullivan PF, Neale MC and Kendler KS. (2000) Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 157:1552–62.

• Vranceanu, A., Hobfoll, S. and Johnson, R. (2007). Child multi-type maltreatment and associated depression and PTSD symptoms: The role of social support and stress. Child Abuse & Neglect, 31(1), pp.71-84.

• Lazary J, Lazary A, Gonda X, Benko A, Molnar E, Juhasz G and Bagdy G. (2008) New Evidence for the Association of the Serotonin Transporter Gene (SLC6A4) Haplotypes, Threatening Life Events, and Depressive Phenotype. Biological Psychiatry 64(6):498-

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• Hoefgen B, Schulze T, Ohlraun S, von Widdern O, Höfels S, Gross M, Heidmann V, Kovalenko S, Eckermann A, Kölsch H, Metten M, Zobel A, Becker T, Nöthen M, Propping P, Heun R, Maier W and Rietschel M. (2005) The power of sample size and homogenous

sampling: Association between the 5-HTTLPR serotonin transporter polymorphism and major depressive disorder. Biological Psychiatry 57(3): 247-251.

• Rominger A, Cumming P, Brendel M, Xiong G, Zach C, Karch S, Tatsch K, Bartenstein P, la Fougère C, Koch W and Pogarell O. (2015) Altered serotonin and dopamine transporter availabilities in brain of depressed patients upon treatment with escitalopram: a

[123I]β-CIT SPECT study. European Neuropsychopharmacology [Preprint]. Available at: http://dx.doi.org/10.1016/jeuroneuro 2014.12.010 (Accessed: January 2015)

• Noskova T, Pivac N, Nedic G, Kazantseva A, Gaysina D, Faskhutdinova G, Gareeva A, Khalilova K, Khusnutdinova E, Kovacic D, Kovacic Z, Jokic M and Seler D. (2008) Ethnic differences in the serotonin transporter polymorphism (5-HTTLPR) in several European

populations. Progress in Neuro-Psychopharmacology and Biological Psychiatry 32(7): 1735-1739.

• Mendlewicz J, Massat I, Souery D, Del-Favero J, Oruč L, Nöthen M, Blackwood D, Muir W, Battersby S, Lerer B, Segman R, Kaneva R, Serretti A, Lilli R, Lorenzi C, Jakovljevič M, Ivezič S, Rietschel M, Milanova V and Van Broeckhoven C. (2004) Serotonin

transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study. Eur J Hum Genet 12(5): 377-382.

• Murthy N, Selvaraj S, Cowen P, Bhagwagar Z, Riedel W, Peers P, Kennedy J, Sahakian B, Laruelle M, Rabiner E and Grasby P. (2010) Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C]

DASB binding in the living human brain. NeuroImage 52(1): 50-54.