Methylphenidate
Classification: C!ATC code: N06BA04
Summary
The effect and safety of methylphenidate in ADHD are similar in men and women. Studies have shown that women achieve lower plasma concentration of methylphenidate than men when treated with weight-adjusted doses. This indicates that some women need a higher dose methylphenidate per kilogram body weight. The lowest effective dose should be used in treatment with methylphenidate. Girls/women may need a higher dose per kilogram body weight.
Additional information
In children and adolescents, Attention Deficit Hyperactivity Disorder (ADHD) is more commonly diagnosed in boys, 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, the diagnosis in 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 informatin
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].
Updated: 2021-01-26
Date of litterature search: 2020-10-21
References
- Nøvik TS, Hervas A, Ralston SJ, Dalsgaard S, Rodrigues Pereira R, Lorenzo MJ et al. Influence of gender on attention-deficit/hyperactivity disorder in Europe--ADORE. Eur Child Adolesc Psychiatry. 2006;15 Suppl 1:I15-24. PubMed
- Ramtekkar UP, Reiersen AM, Todorov AA, Todd RD. Sex and age differences in attention-deficit/hyperactivity disorder symptoms and diagnoses: implications for DSM-V and ICD-11. J Am Acad Child Adolesc Psychiatry. 2010;49(3):217-28e1-3. PubMed
- Willcutt EG. The prevalence of DSM-IV attention-deficit/hyperactivity disorder: a meta-analytic review. Neurotherapeutics. 2012;9(3):490-9. PubMed
- Gaub M, Carlson CL. Gender differences in ADHD: a meta-analysis and critical review. J Am Acad Child Adolesc Psychiatry. 1997;36(8):1036-45. PubMed
- Biederman J, Faraone SV, Monuteaux MC, Bober M, Cadogen E. Gender effects on attention-deficit/hyperactivity disorder in adults, revisited. Biol Psychiatry. 2004;55(7):692-700. PubMed
- Mowlem FD, Rosenqvist MA, Martin J, Lichtenstein P, Asherson P, Larsson H. Sex differences in predicting ADHD clinical diagnosis and pharmacological treatment. Eur Child Adolesc Psychiatry. 2019;28(4):481-489. PubMed
- Socialstyrelsen. Stöd till barn, ungdomar och vuxna med adhd. Socialstyrelsen.
- Mowlem F, Agnew-Blais J, Taylor E, Asherson P. Do different factors influence whether girls versus boys meet ADHD diagnostic criteria? Sex differences among children with high ADHD symptoms. Psychiatry Res. 2019;272:765-773. PubMed
- Kok FM, Groen Y, Fuermaier ABM, Tucha O. The female side of pharmacotherapy for ADHD-A systematic literature review. PLoS One. 2020;15(9):e0239257. PubMed
- Shader RI, Harmatz JS, Oesterheld JR, Parmelee DX, Sallee FR, Greenblatt DJ. Population pharmacokinetics of methylphenidate in children with attention-deficit hyperactivity disorder. J Clin Pharmacol. 1999;39:775-85. PubMed
- Markowitz JS, Straughn AB, Patrick KS. Advances in the pharmacotherapy of attention-deficit-hyperactivity disorder: focus on methylphenidate formulations. Pharmacotherapy. 2003;23:1281-99. PubMed
- Patrick KS, González MA, Straughn AB, Markowitz JS. New methylphenidate formulations for the treatment of attention-deficit/hyperactivity disorder. Expert Opin Drug Deliv. 2005;2:121-43. PubMed
- Patrick KS, Straughn AB, Minhinnett RR, Yeatts SD, Herrin AE, DeVane CL et al. Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2007;81:346-53. PubMed
- Modi NB, Lindemulder B, Gupta SK. Single- and multiple-dose pharmacokinetics of an oral once-a-day osmotic controlled-release OROS (methylphenidate HCl) formulation. J Clin Pharmacol. 2000;40:379-88. PubMed
- Cornforth C, Sonuga-Barke E, Coghill D. Stimulant drug effects on attention deficit/hyperactivity disorder: a review of the effects of age and sex of patients. Curr Pharm Des. 2010;16:2424-33. PubMed
- Pelham WE, Walker JL, Sturges J, Hoza J. Comparative effects of methylphenidate on ADD girls and ADD boys. J Am Acad Child Adolesc Psychiatry. 1989;28:773-6. PubMed
- Sharp WS, Walter JM, Marsh WL, Ritchie GF, Hamburger SD, Castellanos FX. ADHD in girls: clinical comparability of a research sample. J Am Acad Child Adolesc Psychiatry. 1999;38:40-7. PubMed
- Mikami AY, Cox DJ, Davis MT, Wilson HK, Merkel RL, Burket R. Sex differences in effectiveness of extended-release stimulant medication among adolescents with attention-deficit/hyperactivity disorder. J Clin Psychol Med Settings. 2009;16:233-42. PubMed
- Barbaresi WJ, Katusic SK, Colligan RC, Weaver AL, Leibson CL, Jacobsen SJ. Long-term stimulant medication treatment of attention-deficit/hyperactivity disorder: results from a population-based study. J Dev Behav Pediatr. 2006;27:1-10. PubMed
- Wang LJ, Chen CK, Huang YS. Gender Differences in the Behavioral Symptoms and Neuropsychological Performance of Patients with Attention-Deficit/Hyperactivity Disorder Treated with Methylphenidate: A Two-Year Follow-up Study. J Child Adolesc Psychopharmacol. 2015;25(6):501-8. PubMed
- Günther T, Herpertz-Dahlmann B, Konrad K. Sex differences in attentional performance and their modulation by methylphenidate in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2010;20:179-86. PubMed
- Sonuga-Barke EJ, Coghill D, Markowitz JS, Swanson JM, Vandenberghe M, Hatch SJ. Sex differences in the response of children with ADHD to once-daily formulations of methylphenidate. J Am Acad Child Adolesc Psychiatry. 2007;46:701-10. PubMed
- Storebø OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database Syst Rev. 2015(11):CD009885. PubMed
- Ter-Stepanian M, Grizenko N, Zappitelli M, Joober R. Clinical response to methylphenidate in children diagnosed with attention-deficit hyperactivity disorder and comorbid psychiatric disorders. Can J Psychiatry. 2010;55:305-12. PubMed
- Davis C, Levitan RD, Kaplan AS, Carter-Major JC, Kennedy JL. Sex differences in subjective and objective responses to a stimulant medication (methylphenidate): Comparisons between overweight/obese adults with and without binge-eating disorder. Int J Eat Disord. 2016;49(5):473-81. PubMed
- Goldfield GS, Lorello C, Cameron J, Chaput JP. Gender differences in the effects of methylphenidate on energy intake in young adults: a preliminary study. Appl Physiol Nutr Metab. 2011;36:1009-13. PubMed
- Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2019 [cited 2020-03-10.] länk
Reviewed by: Diana Rydberg, Carl-Olav Stiller
Approved by: Karin Schenck-Gustafsson