Optimization of Clonazepam Therapy Adjusted to Patient's CYP3A Status and NAT2 Genotype

Int J Neuropsychopharmacol. 2016 Dec 30;19(12):pyw083. doi: 10.1093/ijnp/pyw083. Print 2016 Dec.


Background: The shortcomings of clonazepam therapy include tolerance, withdrawal symptoms, and adverse effects such as drowsiness, dizziness, and confusion leading to increased risk of falls. Inter-individual variability in the incidence of adverse events in patients partly originates from the differences in clonazepam metabolism due to genetic and nongenetic factors.

Methods: Since the prominent role in clonazepam nitro-reduction and acetylation of 7-amino-clonazepam is assigned to CYP3A and N-acetyl transferase 2 enzymes, respectively, the association between the patients' CYP3A status (CYP3A5 genotype, CYP3A4 expression) or N-acetyl transferase 2 acetylator phenotype and clonazepam metabolism (plasma concentrations of clonazepam and 7-amino-clonazepam) was evaluated in 98 psychiatric patients suffering from schizophrenia or bipolar disorders.

Results: The patients' CYP3A4 expression was found to be the major determinant of clonazepam plasma concentrations normalized by the dose and bodyweight (1263.5±482.9 and 558.5±202.4ng/mL per mg/kg bodyweight in low and normal expressers, respectively, P<.0001). Consequently, the dose requirement for the therapeutic concentration of clonazepam was substantially lower in low-CYP3A4 expresser patients than in normal expressers (0.029±0.011 vs 0.058±0.024mg/kg bodyweight, P<.0001). Furthermore, significantly higher (about 2-fold) plasma concentration ratio of 7-amino-clonazepam and clonazepam was observed in the patients displaying normal CYP3A4 expression and slower N-acetylation than all the others.

Conclusion: Prospective assaying of CYP3A4 expression and N-acetyl transferase 2 acetylator phenotype can better identify the patients with higher risk of adverse reactions and can facilitate the improvement of personalized clonazepam therapy and withdrawal regimen.

Keywords: NAT2 genotype; CYP3A4 expression; personalized clonazepam therapy; plasma concentration of 7-amino-clonazepam.

MeSH terms

  • Acetylation
  • Adult
  • Aged
  • Antipsychotic Agents / adverse effects
  • Antipsychotic Agents / pharmacokinetics
  • Antipsychotic Agents / therapeutic use*
  • Arylamine N-Acetyltransferase / genetics*
  • Arylamine N-Acetyltransferase / metabolism
  • Biotransformation
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / enzymology
  • Bipolar Disorder / genetics
  • Clonazepam / adverse effects
  • Clonazepam / pharmacokinetics
  • Clonazepam / therapeutic use*
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism*
  • Drug Monitoring
  • Female
  • Humans
  • Male
  • Middle Aged
  • Pharmacogenetics
  • Pharmacogenomic Testing
  • Pharmacogenomic Variants*
  • Schizophrenia / drug therapy*
  • Schizophrenia / enzymology
  • Schizophrenia / genetics
  • Schizophrenic Psychology
  • Treatment Outcome
  • Young Adult


  • Antipsychotic Agents
  • Clonazepam
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human