Val/Val genotype of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with a better response to OROS-MPH in Korean ADHD children

Abstract

Research on psychostimulants, analysis of animal models and genetic association studies all suggest that the brain-derived neurotrophic factor gene (BDNF) may be a good candidate for pharmacogenetic studies of attention deficit hyperactivity disorder (ADHD). Yet to date there have been no pharmacogenetic studies of BDNF in ADHD. A total of 102 drug-naive ADHD children (8.7±2.1 yr) were treated with osmotic release oral system-methylphenidate (OROS-MPH) for 12 wk, and four kinds of response criteria were applied, based first, on a combined threshold of the ADHD Rating Scale - IV (ARS) and the Clinical Global Impression - Improvement scale (CGI-I); second, on scores of 1 or 2 vs. 3-7 on the CGI - Severity scale; third, on a >50% reduction in ARS scores; and fourth, on satisfaction of all of the aforementioned criteria. The Val⁶⁶Met polymorphism of BDNF and six single nucleotide polymorphisms from the SLC6A2, ADRA2A and NTF-3 genes were tested for association with each criterion. Relative to other genotypes, homozygosity for the Val allele of the BDNF Val⁶⁶Met polymorphism was associated with a greater relative frequency of good response under all four response criteria (after controlling for baseline ARS score, age, gender, final dose (mg/kg) of OROS-MPH at 12 wk, and level of academic functioning). This association was significant at the uncorrected level for the first and third response criteria (p=0.013 and p=0.018, respectively) and significant at a Bonferroni-corrected level for the second and fourth response criteria (p=0.0002, p=0.0003, respectively). Our findings support an association between homozygosity for the Val allele of BDNF and better response to OROS-MPH in Korean ADHD children as assessed by four different response criteria.

ADHD pharmacogenetics across the life cycle: New findings and perspectives

“…Val allele homozygous were more frequently (81%) assessed as “not ill” or “very mild” according to CGI‐I compared to 37% of Met allele carriers ( P = 0.0002). Moreover, more than 50% reduction in ADHD‐RS scores was observed in 95.2% of the Val allele homozygous patients and in 74.1% of Met allele carriers ( P = 0.018) [Kim et al, ]. The Val/Val genotype has been related to increased activity‐dependent secretion of BDNF [Flanagin et al, ].…”

“…Met allele carriers show decreased volume in the dorsolateral prefrontal cortex and subcortical regions [Pezawas et al, ]. An explanation for better MPH response in ADHD children who are Val/Val homozygous might be due to a lower degree of brain anatomical deficit and functional impairment in these individuals [Kim et al, ].…”

Drug Regimen Individualization for Attention‐Deficit/Hyperactivity Disorder: Guidance for Methylphenidate and Dexmethylphenidate Formulations

“…Several candidate genotypic variants have been identified as associated with positive MPH response. For instance, (i) specific polymorphisms in the gene expressing synaptosomal associated protein of 25 kDa (SNAP‐25), a common gene candidate underlying ADHD, have been shown to correlate with the likelihood of MPH efficacy; (ii) also an allelic variant of SLC6A2 , which expresses the norepinephrine transporter, correlates with positive response to MPH; (iii) the Val 66 Met phenotypic variant of brain‐derived neurotrophic factor, a neuronal gene product that facilitates fiber connections and memory, has been predictive of MPH efficacy; (iv) specific indel allelic variants of the gene expressing the D4 dopamine receptor subtype, considered risk alleles for ADHD, have also been associated with an increased probability of MPH efficacy; (v) as have specific indel variants expressing the dopamine transporter (DAT) …”

A candidate gene investigation of methylphenidate response in adult attention-deficit/hyperactivity disorder patients: results from a naturalistic study

“…Previously, the G allele of rs1800544 has been noted to be associated with the improvement of MPH response in children and adolescents (Cheon et al 2009 ; da Silva et al 2008 ; Polanczyk et al 2007 ). However, negative studies have also been reported in children and adolescents (Kim et al 2011 ; Park et al 2013 ) as well as in adults (Contini et al 2011 ). Interestingly, in our study of adult ADHD, the G allele was associated with MPH non-response.…”