Noradrenergic genes polymorphisms and response to methylphenidate in children with ADHD: A systematic review and meta-analysis

Medicine (Baltimore). 2021 Nov 19;100(46):e27858. doi: 10.1097/MD.0000000000027858.


Background: Attention-deficit hyperactivity disorder (ADHD) is the most common childhood-onset neurodevelopmental disorder, and methylphenidate (MPH) is considered one of the first-line medicine for ADHD. Unfortunately, this medication is only effective for some children with ADHD. This meta-analysis was conducted to evaluate whether noradrenergic gene polymorphisms impact the efficacy of MPH in children with ADHD.

Methods: Candidate gene studies published in English until March 1, 2020, were identified through literature searches on PubMed, Web of Science, and Embase. Data were pooled from individual clinical trials considering MPH pharmacogenomics. According to the heterogeneity, the odds ratio and mean differences were calculated by applying fixed-effects or random-effects models.

Results: This meta-analysis includes 15 studies and 1382 patients. Four polymorphisms of the NET gene (rs5569, rs28386840, rs2242446, rs3785143) and 2 polymorphisms of the α2A-adrenergic receptor gene (ADRA2A) gene (MspI and DraI) were selected for the analysis. In the pooled data from all studies, T allele carriers of the rs28386840 polymorphism were significantly more likely to respond to MPH (P < .001, ORTcarriers = 2.051, 95% confidence interval [CI]:1.316, 3.197) and showed a relationship with significantly greater hyperactive-impulsive symptoms improvement (P < .001, mean difference:1.70, 95% CI:0.24, 3.16). None of the ADRA2A polymorphisms correlated significantly with MPH response as a whole. However, G allele carriers of the MspI polymorphism showed a relationship with significantly inattention symptoms improvement (P < .001, mean difference:0.31, 95% CI: 0.15, 0.47).

Conclusion: Our meta-analysis results indicate that the noradrenergic gene polymorphisms may impact MPH response. The NET rs28386840 is linked to improved MPH response in ADHD children. And the ADRA2A MspI is associated with inattention symptom improvements. Further investigations with larger samples will be needed to confirm these results.Registration: PROSPERO (no. CRD42021265830).

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Attention Deficit Disorder with Hyperactivity / genetics
  • Central Nervous System Stimulants / therapeutic use*
  • Child
  • Humans
  • Methylphenidate / therapeutic use*
  • Norepinephrine / therapeutic use
  • Norepinephrine Plasma Membrane Transport Proteins
  • Pharmacogenetics
  • Polymorphism, Genetic
  • Receptors, Adrenergic, alpha-2
  • Treatment Outcome


  • ADRA2A protein, human
  • Central Nervous System Stimulants
  • Norepinephrine Plasma Membrane Transport Proteins
  • Receptors, Adrenergic, alpha-2
  • SLC6A2 protein, human
  • Methylphenidate
  • Norepinephrine