Old drug tipepidine as new hope for children with ADHD

Attention deficit/hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder among children. This disorder is typically diagnosed in childhood, and can continue into adulthood. Children with ADHD are characterized by inattention, hyperactivity, impulsivity, or a combination of these symptoms, which are associated with poor grades, disruption of classroom activities, and poor peer relationships (Feldman and Reiff, 2014).

Although medications with stimulants (methylphenidate or amphetamines) have a clinically significant benefit in reducing these symptoms in ADHD patients, sustained release and long-acting preparations of stimulants have been used because of adverse side effects, including anorexia, headaches, stomach aches, insomnia, pyrexia, and tics (Feldman and Reiff, 2014). Therefore, non-stimulant medications play an important role in the management of ADHD when parents do not want their children to receive stimulants, when stimulants are contraindicated or have adverse effects, or when there is a history or high likelihood of addiction or diversion of medication for recreational use (Feldman and Reiff, 2014). In this context, atomoxetine, a selective norepinephrine reuptake inhibitor, and two α2-adrenergic agonists, such as clonidine and guanfacine, are considered an alternative or adjunctive treatment for patients with ADHD (Feldman and Reiff, 2014). However, a meta-analysis showed that the frequency of suicidal ideation in the atomoxetine-treated group was greater than in the placebo-treated group (Bangs et al., 2008). A recent meta-analysis showed that α2-adrenergic agonists – both in monotherapy and as add-on treatment to stimulants – were significantly more effective than placebo for total and specific ADHD symptoms (Hirota et al., 2014). However, α2-adrenergic agonist monotherapy and add-on treatment were associated with similar risks for discontinuation because of intolerability compared with placebo. Importantly, there were significantly higher incidences of hypotension, bradycardia, fatigue, somnolence, and sedation in patients treated with α2-adrenergic agonists, indicating that clinicians should monitor these side effects routinely (Hirota et al., 2014).

Tipepidine (3-[di-2-thienylmethy lene]-1-methyl-piperidine) has been used as a non-narcotic antitussive of children in Japan since 1959. It is reported that tipepidine can inhibit G-protein-coupled inwardly rectifying potassium (GIRK)-channel currents, and that inhibition of GIRK channels by tipepidine is suggested to modulate the levels of monoamines in the brain (Kawahara et al., 2010). An in vivo microdialysis study showed that tipepidine significantly increased extracellular levels of monoamines such as serotonin and dopamine in the prefrontal cortex of rats (Kawahara et al., 2010). Recently, we reported that treatment with tipepidine (30 mg/day for 4 weeks) significantly (p<0.001) improved all the ADHD Rating Scale IV scores (total scores, hyperimpulsive subscores, and inattentive subscores) in pediatric patients with ADHD, although this is an open pilot study of small numbers (Sasaki et al., 2014). Tipepidine was well tolerated, with no patients discontinuing medication because of side effects. In addition, no significant effects on blood parameters, urine analysis, weight, height, blood pressure, or cardiac frequency during the 4-week treatment period were shown (Sasaki et al., 2014). Adverse effects are known to be the loss of appetite, constipation, drowsiness, insomnia, dizziness, stomach discomfort, feeling of fullness, nausea, and itch sensation, although the frequency is low (<1%). The precise mechanisms underlying the beneficial effects of tipepidine on ADHD symptoms are currently unclear.

In conclusion, it is likely that tipepidine would be an alternative (non-stimulant) drug for stimulants, atomoxetine or α2-adrenergic agonists, since this is a safe drug in children. Nonetheless, a double-blind, placebo-controlled study of tipepidine in pediatric patients with ADHD is needed.