Methylphenidate

Additional information

In children and adolescents, Attention Deficit Hyperactivity Disorder (ADHD) is more commonly diagnosed in men, with the sex ratio ranging from 2:1 to 10:1 [1-4], with higher male-to-female ratios found in clinical versus population-based samples. The male-to-female ratio is smaller in adult clinical samples than in childhood and adolescent samples [5]. In women, hyperactivity/impulsivity and conduct problems were stronger predictors of clinical diagnosis and prescriptions of pharmacological treatment, compared to men [6]. Girls more often than boys have ADHD with mainly attention deficit disorder and more rarely clear hyperactivity/impulsivity problems. Therefore girls/women may be more difficult to recognize and be less likely to receive pharmacological treatment, and males with ADHD are more likely to receive ADHD medication than females with ADHD [6-9].

Pharmacokinetics and dosing

In a population pharmacokinetic study in children with ADHD (212 boys, 61 girls; age 5-18 years), clearance and half-life of methylphenidate were similar in boys and girls receiving the same mean daily dose [10]. However, results from studies in adult healthy volunteers show that when the doses are normalized to the body weight (mg/kg), females have lower systemic exposure (AUC) [11-13]. In addition, one study has reported no differences in AUC between males and females receiving the same total dose, even though women generally weigh less. The major metabolite, ritalinic acid, was higher in females [14].

Studies of adult women have identified lower plasma concentrations of methylphenidate after weight-based dosing, relative to men [11, 13]. In a two-way crossover study (10 men, 9 women), each subject received both a 20 mg and 18 mg extended-release methylphenidate dose. The average mg/kg dose in the males was approximately 30% less than in females, yet the mean AUC was not different between sexes. Since the half-life between the sexes was also the same, it could be speculated that more extensive first-pass metabolism of methylphenidate occurs in females [11]. These findings suggest that some women may require higher mg/kg doses to achieve the same methylphenidate plasma concentration as men [12, 15]. However, it is not clear whether both sexes require similar plasma concentrations to achieve the same therapeutic objective [11].

Effects

Even though earlier studies of ADHD treatment included few females, recent RCTs to demonstrate efficacy in the newer extended release preparations have enrolled reasonable numbers of females [15].

Small studies have shown that the response to methylphenidate in girls with ADHD is comparable to that in boys with ADHD [15-19]. These studies suggest that the tolerability and safety of methylphenidate is similar in males and females. However, the effect of methylphenidate in boys and girls may vary in different settings. ADHD symptoms were evaluated after 24 months of treatment with methylphenidate in a clinical prospective study (128 boys, 26 girls). According to parents and clinicians, ADHD symptoms (inattention and hyperactivity/impulsive symptoms) decreased in both boys and girls, although the girls improved more than the boys did. Meanwhile, ADHD symptoms observed by teachers marginally improved in boys, but no improvement was noted in girls. Furthermore, attention scores were improved in boys but not in girls [20]. In contrast, in a double-blind, placebo-controlled trial (27 boys, 27 girls), boys were more impulsive on a sustained attention task, whereas girls had more deficits on tasks measuring selective attention. Girls performed better on the focused attention task [21].

One study has examined sex differences in response to two once-daily methylphenidate formulations in children (136 boys, 48 girls). Girls had superior response at 1.5 hours after drug administration and an inferior response at 12 hours compared with boys. Patient’s sex was independent of drug formulation [22]. The reason behind this is unclear. It has been suggested that the stronger effect of methylphenidate in girls earlier in the day may be due to greater sensitivity to methylphenidate or from higher methylphenidate plasma concentrations. Furthermore, the earlier decline in methylphenidate effect in girls may indicate a more rapid absorption or more rapid clearance in girls than in boys. The responses of girls may require additional assessments later in the day to determine the optimal dose [23].

Children with ADHD and anxiety disorders in absence of other comorbidities were less likely to respond to methylphenidate, according to a randomized, double-blinded, placebo-controlled study (208 boys, 59 girls). Results were irrespective of patient’s sex [24].

In a study evaluating response to single dose methylphenidate in overweight adults (198 men, 152 women), overweight women taking methylphenidate had a greater suppression of appetite and cravings and decline in food consumption compared to placebo. No differences were seen in men [25].

Adverse effects

Several studies report no sex differences in the rate of occurrence of adverse effects from methylphenidate [15, 18, 19].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

A small study (6 men, 6 women) examined sex differences in response to short-acting methylphenidate (0.5 mg/kg) on energy intake in young healthy adults (18-40 years) with normal weight or higher. Relative to placebo, men exhibited a significantly greater reduction in energy intake, fat intake and carbohydrate intake after methylphenidate administration, compared to women [26].