Revisiting clonidine: an innovative add-on option for attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder characterized by developmentally inappropriate levels of inattention, hyperactivity and impulsivity. Although much evidence supports the use of psychostimulants as a first-line treatment in children and adolescents, up to 30% of patients may have an inadequate response to these medications. For these patients, addition of an α₂-adrenoceptor agonist can further improve ADHD symptoms. The α₂-adrenoceptor agonists may work in a synergistic fashion with stimulants through regulation of prefrontal cortex function. Early studies were completed with immediate-release clonidine (CLON-IR), which requires multiple daily doses and achieves a higher maximum concentration more rapidly than the more recently developed extended-release clonidine (CLON-XR). Pharmacokinetic properties of CLON-XR may be responsible for differences in efficacy and tolerability between the CLON-IR and CLON-XR formulations. Recent double-blind, placebo-controlled trials have shown that extended-release α₂-adrenoceptor agonists are safe and effective, both as monotherapy and as adjunctive treatment with stimulants. This review will focus on clonidine used in conjunction with stimulants to optimize treatment of ADHD.