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9 Oct 2020

Kok FM et al. PLoS One 2020: 15: e0239257

Conclusions drawn from studies in boys with ADHD cannot be applied routinely to girls with ADHD (Arnold, 1996). This systematic literature review aimed to investigate the sex differences in prescription rates, effectiveness and efficacy of pharmacotherapy treatment in girls and women with ADHD. All available literature on the topic* was searched for, using three electronic databases up to 20 September 2019.

Of the 2671 papers screened, 14 studies were included in the review on the efficacy or effectiveness of stimulant or non-stimulant ADHD pharmacotherapy. An additional seven studies were included, which investigated prescription rates of ADHD pharmacotherapy. Results were grouped by age (children and adolescents [aged <18 years] and adults [aged >18 years]) and by stimulant and non-stimulant ADHD pharmacotherapy. For the analysis of results on efficacy or effectiveness of ADHD pharmacotherapy, effect sizes or group differences were either derived from the original studies or calculated manually in order to determine the size of between-sex differences. Cohen’s d was used because it can differentiate between small (d = 0.2), medium (d = 0.5) and large (d = 0.8) effect sizes. In studies that explored prescription rates of ADHD pharmacotherapy, percentages of prescription rates were mostly used.

Sex differences in prescription rates

In general, both girls and women with ADHD were significantly less likely to be prescribed pharmacotherapy compared with boys and men with ADHD; however, this difference was less pronounced in adults. In children and adolescents with ADHD, one study showed that girls received one-third of the prescriptions that boys did (25.2% vs 74.8%). Moreover, a separate study indicated that girls with ADHD were significantly less likely to be prescribed methylphenidate (MPH) compared with boys (55.8% vs 69.7%; d = 0.33) and were more likely than boys to receive no medication at all for ADHD (18.7% vs 28.4%; d = 0.30). Similarly, in a different study, girls received significantly less prescriptions than boys for dextroamphetamines (dexAMP), atomoxetine (ATX) and MPH (2.1% vs 4.2% across medications). Females consistently received less ADHD medication than males across all age groups. Medication use declined over time for both adult women (aged 18–24 years, 0.93%; aged 45–64 years, 0.18%) and men (aged 18–24 years, 1.19%; aged 45–64 years, 0.21%).

Sex differences in efficacy or effectiveness of ADHD pharmacotherapy

There were several sex differences in efficacy and effectiveness of MPH noted. In one study, girls with ADHD showed significantly lower long-term symptom severity following treatment with MPH than boys, as assessed by parent and clinicians’ rating scales (b = 2.79, p = 0.018). On the other hand, only boys with ADHD who were treated with MPH appeared to improve on the teacher-rating of symptom severity scales (p = 0.058). This finding suggests that MPH may have different effects dependent on the setting. In a study of children and adolescents (aged <18 years) with ADHD who were treated with dexAMP, 51% of girls responded favourably to treatment compared with 78.88% of boys. Additionally, varying effects between adolescent females and males with ADHD were also noted in a study of US healthcare claims: among individuals treated with AMP, females had a 31% lower risk of substance-related events when on medication, compared with males who had a 35% lower risk when on medication. However, a population-based study of people of all ages (n = 12,503 females and n = 26,249 males) with ADHD showed that there was no sex difference (females d = 0.21 versus males d = 0.22) in effect of dexAMP and AMP on depression with ADHD.

In terms of non-stimulants and effectiveness, a pooled analysis of five studies of children and adolescents aged 6–15 years (n = 136 girls and n = 658 boys) who were treated with ATX showed that girls had significantly lower tendencies towards adverse consequences pertaining to themselves (d = 0.6) and in general (d = 0.6) compared with a placebo control group. These effects were smaller in boys, pertaining to themselves (d = 0.5) and in general (d = 0.5) compared with a placebo group. In another study that investigated ATX treatment in adults aged >18 years with ADHD (n = 188 women and n = 348 men) noted that women showed larger treatment effects than men in the emotional dysregulation (d = 0.28) and social life domains (d = 0.19).

There were several limitations of this study. Firstly, the data on ATX in females with ADHD are based on a limited number of studies. There was also variation in the rate of female participants, inclusion of ADHD presentations, investigated domains and outcomes measurements between the studies. Differences in study designs were also noted, such as setting: classrooms, in- and outpatient centres, and experimental laboratories. Additionally, the authors made the assumption that the prescription of medication to individuals with ADHD was based on clinicians’ discretion and individuals’ or caregivers’ willingness to receive medication in the clinical settings. Therefore, the effects reported here are likely to have been influenced by selection or rating bias. Furthermore, some studies used pooled analysis and some used population-based methods, and there was also variation in the type of pharmacotherapy used, which made direct comparison of outcomes difficult. Lastly, there was variation in the size of study samples.

In summary, only 14 of the 2671 clinical trials of ADHD medication identified explicitly sorted their participants by sex. Despite the overall rise in prescription rates, girls with ADHD are consistently prescribed less ADHD pharmacotherapy than boys with ADHD. Additionally, each ADHD pharmacotherapy was shown to have unique effects in males and females with ADHD. The authors suggested that more research into female-specific pharmacotherapy for ADHD that is sorted by sex is required, which could be achieved by reanalysing existing clinical medication trials.

Read more about ADHD pharmacotherapy sex differences here

 

*Primary keywords included ‘ADHD’ or ‘attention deficit hyperactivity disorder’ and were combined with the secondary keywords ‘pharmacotherapy’, ‘effectiveness’, or ‘efficacy’. These were then combined with sex-related keywords: ‘females’, ‘girls’, ‘women’, ‘gender’, or ‘sex’, as well as ADHD pharmacotherapy-related keywords: ‘methylphenidate’, ‘MPH’, ‘amphetamine’, ‘AMP’, ‘dextroamphetamine’, ‘dAMP’, ‘levoamphetamine’, ‘lAMP’, ‘lisdexamphetamine’, ‘lisdexAMP’, ‘atomoxetine’, ‘ATX’, ‘clonidine’ or ‘guanfacine’
Included studies were: (1) written in English; (2) the ADHD sample had a formal diagnosis of this disorder; (3) the study data were sorted explicitly by sex; and (4) the study data included either prescription rates of ADHD pharmacotherapy or data on the efficacy or effectiveness of stimulant or non-stimulant ADHD pharmacotherapy

Arnold LE. Sex differences in ADHD: conference summary. J Abnorm Child Psych 1996; 24: 555-569.

Kok FM, Groen Y, Fuermaier ABM, et al. The female side of pharmacotherapy for ADHD—a systematic literature review. PLoS One 2020: 15: e0239257.

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