The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD

Thakur, Geeta; Grizenko, Natalie; Sengupta, Sarojini M.; Schmitz, N.; Joober, Ridha

doi:10.1186/1471-244x-10-50

Cited by 26 publications

(21 citation statements)

References 45 publications

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“…For 5HTTLPR polymorphisms we followed a procedure that genotypes two promoter polymorphisms: the insertion/deletion polymorphism (L/S) and A/G SNP at rs25531 (Wendland et al 2006). These two polymorphisms are combined as Sa, Sg, La, and Lg, in which only the La combination is considered high-expressing (Hu et al 2006; Steiger et al 2007; Frodl et al 2008; Dombrovski et al 2010;Thakur et al 2010; Wankerl et al 2010; Beevers et al 2011); we treated La/La, La/S, or La/Lg genotypes as high-expressing and S/S, S/Lg or Lg/Lg genotype as low-expressing. For HTR1B, we used the Sequenom™ technology to examine rs11568817, a putatively functional single nucleotide polymorphism (SNP) in the promoter region where GG or GT genotype is considered high-expressing and TT is considered low-expressing (Lenze et al 2013).…”

Section: Methodsmentioning

confidence: 99%

Genetic variation in the serotonin transporter and HTR1B receptor predicts reduced bone formation during serotonin reuptake inhibitor treatment in older adults

Garfield

Müller

Kennedy

et al. 2013

The World Journal of Biological Psychiatry

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Objectives Studies have reported an association between serotonin reuptake inhibitors (SRIs) and accelerated bone loss. Genetic variation in the serotonin system might modulate bone metabolism changes during SRI treatment. In a clinical trial we examined functional genetic polymorphisms of serotonin transporter and receptors involved in bone metabolism to determine whether they predict changes in bone metabolism during SRI treatment. Methods In 69 adults (age ≥ 60) participating in a 12-week, open-label trial of the SRI venlafaxine for major depression, serum markers of bone formation (P1NP) and resorption (β-CTX) were assayed before and after treatment. Participants were genotyped for putative high- versus low-expressing polymorphisms in the serotonin transporter (5HTTLPR) and 1B receptor (HTR1B) genes. Results Bone formation was significantly reduced with administration of venlafaxine in participants with the high-expressing 5HTTLPR genotype and those with the low-expressing HTR1B genotype. This primarily occurred in individuals with the combination of the high-expressing 5HTTLPR genotype and the low-expressing HTR1B genotype. Conclusions These preliminary findings indicate that genetic variation in the serotonin receptors predicts changes in bone metabolism during SRI use. If these results are replicated and clinically confirmed, we will have identified a genetic subgroup at high risk for deleterious bone outcomes with the use of SRIs.

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Section: Methodsmentioning

confidence: 99%

Genetic variation in the serotonin transporter and HTR1B receptor predicts reduced bone formation during serotonin reuptake inhibitor treatment in older adults

Garfield

Müller

Kennedy

et al. 2013

The World Journal of Biological Psychiatry

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“…While the serotonergic system is not targeted directly by stimulant drugs efficacious in the treatment of ADHD, it is thought that pharmacological alteration of the dopamine system by these drugs might influence 5-HT transmission projecting downstream 90. Moreover, some have hypothesized that SSRIs might be useful in the treatment of ADHD patients who do not respond to traditional pharmacotherapy or those with comorbid psychiatric disorders 91.…”

Section: -Htt Variants: Psychopathology and Pharmacotherapy Implicatmentioning

confidence: 99%

Association of the 5-HTT gene-linked promoter region (5-HTTLPR) polymorphism with psychiatric disorders: review of psychopathology and pharmacotherapy

Kenna

N²,

Leggio³

et al. 2012

PGPM

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Serotonin (5-HT) regulates important biological and psychological processes including mood, and may be associated with the development of several psychiatric disorders. An association between psychopathology and genes that regulate 5-HT neurotransmission is a robust area of research. Identification of the genes responsible for the predisposition, development, and pharmacological response of various psychiatric disorders is crucial to the advancement of our understanding of their underlying neurobiology. This review highlights research investigating 5-HT transporter (5-HTTLPR) polymorphism, because studies investigating the impact of the 5-HTTLPR polymorphism have demonstrated significant associations with many psychiatric disorders. Decreased transcriptional activity of the S allele (“risk allele”) may be associated with a heightened amygdala response leading to anxiety-related personality traits, major depressive disorder, suicide attempts, and bipolar disorder. By contrast, increased transcriptional activity of the L allele is considered protective for depression but is also associated with completed suicide, nicotine dependence, and attention deficit hyperactivity disorder. For some disorders, such as post-traumatic stress disorder and major depressive disorder, the research suggests that treatment response may vary by allele (such as an enhanced response to serotonin specific reuptake inhibitors in patients with major depressive disorder and post-traumatic stress disorder with L alleles), and for alcohol dependence, the association and treatment for S or L alleles may vary with alcoholic subtype. While some studies suggest that 5-HTTLPR polymorphism can moderate the response to pharmacotherapy, the association between 5-HTTLPR alleles and therapeutic outcomes is inconsistent. The discovery of triallelic 5-HTTLPR alleles (LA/LG/S) may help to explain some of the conflicting results of many past association studies, while concurrently providing more meaningful data in the future. Studies assessing 5-HTTLPR as the solitary genetic factor contributing to the etiology of psychiatric disorders continue to face the challenges of statistically small effect sizes and limited replication.

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“…Joober et al [120] showed that the 3’-UTR VNTR polymorphism in the dopamine transporter gene modulated the behavior response to methylphenidate (see also [287–290]). Thakur et al [291] assessed ADHD patients, aged 6 to 12 years (n=157) with regard to their behavior response to methylphenidate and genotyped them for the triallelic 5-HTTLPR polymorphism in the SLC6A4 gene. They obtained a significant Gene × Treatment interaction effect for CGI-parents (assessment) but not CGI-teachers.…”

Section: Epigenetic Regulation Of Interventionmentioning

confidence: 99%

Epigenetics in Developmental Disorder: ADHD and Endophenotypes

Archer

Oscar‐Berman²,

Blum³

2011

J Genet Syndr Gene Ther

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Heterogeneity in attention-deficit/hyperactivity disorder (ADHD), with complex interactive operations of genetic and environmental factors, is expressed in a variety of disorder manifestations: severity, co-morbidities of symptoms, and the effects of genes on phenotypes. Neurodevelopmental influences of genomic imprinting have set the stage for the structuralphysiological variations that modulate the cognitive, affective, and pathophysiological domains of ADHD. The relative contributions of genetic and environmental factors provide rapidly proliferating insights into the developmental trajectory of the condition, both structurally and functionally. Parent-of-origin effects seem to support the notion that genetic risks for disease process debut often interact with the social environment, i.e., the parental environment in infants and young children. The notion of endophenotypes, markers of an underlying liability to the disorder, may facilitate detection of genetic risks relative to a complex clinical disorder. Simple genetic association has proven insufficient to explain the spectrum of ADHD. At a primary level of analysis, the consideration of epigenetic regulation of brain signalling mechanisms, dopamine, serotonin, and noradrenaline is examined. Neurotrophic factors that participate in the neurogenesis, survival, and functional maintenance of brain systems, are involved in neuroplasticity alterations underlying brain disorders, and are implicated in the genetic predisposition to ADHD, but not obviously, nor in a simple or straightforward fashion. In the context of intervention, genetic linkage studies of ADHD pharmacological intervention have demonstrated that associations have fitted the "drug response phenotype," rather than the disorder diagnosis. Despite conflicting evidence for the existence, or not, of genetic associations between disorder diagnosis and genes regulating the structure and function of neurotransmitters and brainderived neurotrophic factor (BDNF), associations between symptoms-profiles endophenotypes and single nucleotide polymorphisms appear reassuring.

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The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD

Cited by 26 publications

References 45 publications

Genetic variation in the serotonin transporter and HTR1B receptor predicts reduced bone formation during serotonin reuptake inhibitor treatment in older adults

Genetic variation in the serotonin transporter and HTR1B receptor predicts reduced bone formation during serotonin reuptake inhibitor treatment in older adults

Association of the 5-HTT gene-linked promoter region (5-HTTLPR) polymorphism with psychiatric disorders: review of psychopathology and pharmacotherapy

Epigenetics in Developmental Disorder: ADHD and Endophenotypes

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