Genetic Variations in Attention Deficit Hyperactivity Disorder Subtypes and Treatment Resistant Cases

Unal, D; Ünal, M. Fatih; Alikaşifoğlu, Mehmet; Çetinkaya, Arda

doi:10.4306/pi.2016.13.4.427

Cited by 11 publications

(26 citation statements)

References 50 publications

(71 reference statements)

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“…The values for CGI-S and CGAS improved significantly over time, although with a modest effect size, maybe because 73% of patients were on treatment before the beginning of the study. ADHD subtype was not a significant factor in response to treatment, according to previously studies 20 . In addition, treatment-experienced patients and patients who took extended-release MPH or both formulations had a better response in all the efficacy parameters considered (CGI-S and CGAS scales).…”

Section: Discussionmentioning

confidence: 54%

Pharmacogenetics of methylphenidate in childhood attention-deficit/hyperactivity disorder: long-term effects

Gomez-Sanchez

Carballo

Riveiro-Álvarez

et al. 2017

Sci Rep

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Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in which a significant proportion of patients do not respond to treatment. The objective of this study was to examine the role of genetic risk variants in the response to treatment with methylphenidate (MPH). The effectiveness of MPH was evaluated based on variations in the CGI-S and CGAS scales over a 12-month treatment period using linear mixed effects models. A total of 208 ADHD patients and 34 polymorphisms were included in the analysis. For both scales, the response was associated with time, extended-release MPH/both formulations, and previous MPH treatment. For the CGI-S scale, response was associated with SLC6A3 rs2550948, DRD4 promoter duplication, SNAP25 rs3746544, and ADGRL3 rs1868790. Interactions between the response over time and SLC6A3 and DRD2 were found in the CGI-S and CGAS scales, respectively. The proportion of the variance explained by the models was 18% for the CGI-S and 22% for the CGAS. In this long-term study, the effects of SLC6A3, DRD4, SNAP25, and ADGRL3 on response to treatment reflect those observed in previous studies. In addition, 2 previously unreported interactions with response to treatment over a 12-month period were found (SLC6A3 and DRD2).

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Section: Discussionmentioning

confidence: 54%

Pharmacogenetics of methylphenidate in childhood attention-deficit/hyperactivity disorder: long-term effects

Gomez-Sanchez

Carballo

Riveiro-Álvarez

et al. 2017

Sci Rep

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“…Since the -1291GG homozygotes exhibited a better response to MPH treatment, the data regarding the frequency of -1291G allele in the ADRA2A gene may help estimate the frequency of the subjects who would exhibit a better response under MPH therapy. Previous studies found a lower frequency of -1291G allele (0.26–0.38) in non-Asian children and adolescents with ADHD [ 27 , 29 , 39 ]. Our study on the other hand revealed a higher frequency of -1291G allele (0.63) in Taiwanese subjects.…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that the symptoms of ADHD was associated with the ADRA2A gene -1291C/G SNP [ 23 , 24 ], and the carriers of homozygous -1291G allele displayed better response to MPH treatment [ 25 - 27 ]. Some studies on the other hand failed to relate the MPH response to the ADRA2A gene -1291C/G SNP [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

The Alpha-2A Adrenergic Receptor Gene -1291C/G Single Nucleotide Polymorphism is Associated with the Efficacy of Methylphenidate in Treating Taiwanese Children and Adolescents with Attention-Deficit Hyperactivity Disorder

Huang

et al. 2018

Psychiatry Investig

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ObjectiveThe therapeutic effect of methylphenidate (MPH) in treating attention-deficit/hyperactivity disorder (ADHD) has been related to the alpha-2A adrenergic receptor (ADRA2A) gene -1291C/G single nucleotide polymorphism (SNP). We investigated the effect of MPH in treating Taiwanese children and adolescent with ADHD and its relation to the ADRA2A gene -1291C/G SNP. MethodsThe subjects with DSM-IV ADHD diagnosis underwent a titration period to find out the dose of MPH for maintenance treatment. After 4 weeks maintenance treatment, the effect of MPH was evaluated by the Swanson, Nolan and Pelham version IV total scores. The subjects with more than 25% score reduction were referred to responders and those with ≥50% improvement were considered as better responders. The -1291C/G variant of the ADRA2A gene was identified by DNA sequencing and what relevance it has to the MPH response was examined by binary logistic regression analysis. ResultsOf the 59 subjects, 44 (74.6%) were responsive to MPH treatment and the responsiveness was not shown to be associated with the ADRA2A gene -1291C/G SNP. As the responsive subjects were categorized as moderate responders and better responders and subjected to statistical analysis, the GG homozygotes showed a greater chance to have a better response to MPH treatment than CC homozygotes (p=0.02), with an odds ratio of 32.14 (95% CI=1.64–627.80). ConclusionThe ADRA2A gene -1291C/G SNP is associated with the efficacy of MPH for the treatment of ADHD in Taiwanese children and adolescents. The responsive subjects bearing homozygous -1291G allele are more likely to have a better response to MPH treatment.

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“…These data support the hypothesis that COMTval158met modulates the “inverted U” effects of dopamine signaling on PFC functions such as working memory. No significant association was found between COMTval158met and response to methylphenidate treatment in adolescent and adult patients with ADHD (Contini et al, 2012; Unal et al, 2016). However, a meta-analysis ( n = 889) reported increased response to methylphenidate in ADHD children carrying the Val/Val genotype (Myer et al, 2018), suggesting that the COMT-dependent effects of methylphenidate may be age-dependent.…”

Section: Discussionmentioning

confidence: 99%

Heritable Differences in Catecholamine Signaling Modulate Susceptibility to Trauma and Response to Methylphenidate Treatment: Relevance for PTSD

Deslauriers

Tóth

Zhou

et al. 2019

Front. Behav. Neurosci.

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Alterations in cortical catecholamine signaling pathways can modulate acute and enduring responses to trauma. Heritable variation in catecholamine signaling is produced by a common functional polymorphism in the catechol-O-methyltransferase (COMT), with Val carriers exhibiting greater degradation of catecholamines than Met carriers. Furthermore, it has recently been suggested that drugs enhancing cortical catecholamine signaling may be a new therapeutic approach for posttraumatic stress disorder (PTSD) patients. We hypothesized that heritable differences in catecholamine signaling regulate the behavioral response to trauma, and that methylphenidate (MPD), a drug that preferentially blocks catecholamine reuptake in the prefrontal cortex (PFC), exerts COMT-dependent effects on trauma-induced behaviors. We first examined the contribution of the functional mutation COMTval158met to modulate enduring behavioral responses to predator stress in a unique “humanized” COMTval158met mouse line. Animals were exposed to a predator (cat) for 10 min and enduring avoidance behaviors were examined in the open field, light-dark box, and “trauma-reminder” tests 1–2 weeks later. Second, we examined the efficacy of chronic methylphenidate to reverse predator stress effects and if these effects were modulated by COMTval158met genotype. Mice were exposed to predator stress and began treatment with either saline or methylphenidate (3 mg/kg/day) 1 week after stress until the end of the testing [avoidance behaviors, working memory, and social preference (SP)]. In males, predator stress and COMTval158met had an additive effect on enduring anxiety-like behavior, with Val stressed mice showing the strongest avoidance behavior after stress compared to Met carriers. No effect of COMT genotype was observed in females. Therefore methylphenidate effects were investigated only in males. Chronic methylphenidate treatment reversed the stress-induced avoidance behavior and increased social investigation independently of genotype. Methylphenidate effects on working memory, however, were genotype-dependent, decreasing working memory in non-stressed Met carriers, and improving stress-induced working memory deficit in Val carriers. These results suggest that heritable variance in catecholamine signaling modulates the avoidance response to an acute trauma. This work supports recent human findings that methylphenidate might be a therapeutic alternative for PTSD patients and suggests that methylphenidate effects on anxiety (generalized avoidance, social withdrawal) vs. cognitive (working memory) symptoms may be modulated through COMT-independent and dependent mechanisms, respectively.

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Genetic Variations in Attention Deficit Hyperactivity Disorder Subtypes and Treatment Resistant Cases

Cited by 11 publications

References 50 publications

Pharmacogenetics of methylphenidate in childhood attention-deficit/hyperactivity disorder: long-term effects

Pharmacogenetics of methylphenidate in childhood attention-deficit/hyperactivity disorder: long-term effects

The Alpha-2A Adrenergic Receptor Gene -1291C/G Single Nucleotide Polymorphism is Associated with the Efficacy of Methylphenidate in Treating Taiwanese Children and Adolescents with Attention-Deficit Hyperactivity Disorder

Heritable Differences in Catecholamine Signaling Modulate Susceptibility to Trauma and Response to Methylphenidate Treatment: Relevance for PTSD

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