Selegiline in the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial

Abstract

Attention deficit hyperactivity disorder (ADHD) is a common disorder of childhood that affects 3% to 6% of school-age children. Conventional stimulant medications are recognized by both specialists and parents as useful symptomatic treatment. Nevertheless, approximately 30% of ADHD children treated with them do not respond adequately or cannot tolerate the associated adverse effects. Such difficulties highlight the need for alternative safe and effective medications in the treatment of this disorder. Selegiline is a type B monoamine oxidase inhibitor (MAOI) that is metabolized to amphetamine and methamphetamine stimulant compounds that may be useful in the treatment of ADHD. The authors undertook this study to further evaluate, under double-blind and controlled conditions, the efficacy of selegiline for ADHD in children. A total of 28 children with ADHD as defined by DSM IV were randomized to selegiline or methylphenidate dosed on an age and weight-adjusted basis at selegiline 5 mg/day (under 5 years) and 10 mg/day (over 5 years) (Group 1) and methylphenidate 1 mg/kg/day (Group 2) for a 4-week double-blind clinical trial. The principal measure of the outcome was the Teacher and Parent ADHD Rating Scale. Patients were assessed by a child psychiatrist at baseline, 14 and 28 days after the medication started. No significant differences were observed between the two protocols on the Parent and Teacher Rating Scale scores. Although the number of dropouts in the methylphenidate group was higher than in the selegiline group, there was no significant difference between the two protocols in terms of the dropouts. Decreased appetite, difficulty falling asleep and headaches were observed more in the methylphenidate group.

The results of this study must be considered preliminary, but they do suggest that selegiline may be beneficial in the treatment of ADHD. In addition, a tolerable side effect profile may be considered as one of the advantages of selegiline in the treatment of ADHD.

Introduction

There has been a great deal of interest over the years in attention deficit hyperactivity disorder (ADHD). Current thinking about ADHD is changing, and clinicians and researchers are beginning to view this disorder as one that appears across the life cycle and may present in many different ways Goldman et al., 1998, Mercuglioano, 1999. In general, ADHD is a common disorder of childhood that affects 3% to 6% of school-age children Goldman et al., 1998, Mercuglioano, 1999. It is associated with impairment of academic and social functioning, and a growing body of data suggests that it is also associated with considerable morbidity and poorer outcomes later in life. Successful management of ADHD relies heavily on the accuracy of its diagnosis, as well as on individualized treatment planning. According to guidelines, significant diagnostic components include (1) using DSM IV criteria (American Psychiatric Association, 1994); (2) collecting information about the child's symptoms in more than one setting Goldman et al., 1998, Mercuglioano, 1999; and (3) looking for coexisting conditions that may impede the diagnostic process or complicate treatment planning Goldman et al., 1998, Mercuglioano, 1999.

Stimulants have been used in the treatment of childhood ADHD for 60 years Wilens and Biederman, 1992, Gillberg et al., 1997, Safer, 1997, Tenreiro, 2001. Preclinical studies have shown that stimulants block the reuptake of dopamine and norepinephrine into the presynaptic neuron, and increase the release of these monoamines into the extraneuronal space (Pliszka and McCracken, 1996). A plausible model for the effects of stimulants in ADHD is that through dopaminergic and noradrenergic pathways, they increase the inhibitory influences of frontal cortical activity on subcortical structures Pliszka and McCracken, 1996, Spencer and Biederman, 1996. The dopaminergic and adrenergic effects of stimulants symptomatically improve ADHD core symptoms as well as associated features including aggression, social interaction, and academic productivity (Spencer and Biederman, 1996). Although methylphenidate is the medication of choice in the treatment of ADHD, approximately 30% of ADHD children treated with it do not respond adequately or cannot tolerate the associated adverse effects Klein and Landa, 1988, Pataki and Carlson, 1993, Findling et al., 1996. Such difficulties highlight the need for alternative safe and effective medications in the treatment of this disorder Prince et al., 2000, Kehpe, 2001. Selegiline is a type B monoamine oxidase inhibitor (MAOI) that is metabolized to amphetamine and methamphetamine, stimulant compounds that may have utility in the treatment of ADHD (Heinonen et al., 1994). By inhibiting the breakdown of dopamine and increasing synaptic dopamine levels, selegiline would be expected to be beneficial in the treatment of ADHD (Jankovic, 1993). Effects of chronic selegiline administration on hyperactive behavior and brain monoamine levels have been studied in spontaneously hypertensive rats and results showed that selegiline could reduce hyperactivity and deficient sustained attention (Boix et al., 1998). The positive effect of selegiline on impulsiveness has been discussed as due to either normalization of an asymmetric dopaminergic activity in the nucleus accumbens or a restoration of normal dopamine function in the prefrontal cortex (Boix et al., 1998). There are a couple of studies that have investigated the efficacy of selegiline in the treatment of ADHD Feigin et al., 1996, Ernst et al., 1996. The authors undertook this study to further evaluate, under double-blind and controlled conditions with an active agent, the efficacy of selegiline for ADHD in children.