University of Groningen

The female side of ADHD and ASD

Kok, Francien Maria

DOI:
10.33612/diss.179073089

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Publication date:
2021

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Kok, F. M. (2021). The female side of ADHD and ASD. [Thesis fully internal (DIV), University of Groningen].
University of Groningen. https://doi.org/10.33612/diss.179073089

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General introduction

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Although sex differences in psychiatric disorders are well-recognised, research is still in its

infancy due to the complex interplay between various biological, psychological and social

factors (Gobinath, Choleris & Calea, 2017; Riecher-Rossler, 2017). Adding to this complexity,

psychiatric disorders are currently diagnosed based on behaviorally defined criteria (Diagnostic

and Statistical Manual 5th edition [DSM-5]; American Psychiatric Association, 2013),

reflecting a heterogeneous group of disorders associated with various underlying biological

mechanisms. When comparing females and males with these behaviorally defined DSM-5

disorders, results may be confounded by heterogeneity. Despite this complexity, in the past

decade the call for sex-oriented prevention, diagnosis and treatment of psychiatric disorders has

become stronger (Green, Flash & Reiss, 2019; Kokras & Dalla, 2014). This was particularly

strengthened after reports of sex-specific differences in (psychiatric) drug efficacy, in the

treatment of Alzheimer’s Disease (Chen et al., 2016; Scacchi et al., 2014) and depression (Gex-

Fabry, 1990; Kokras et al., 2011; Saland & Kabbaj, 2018).

It is well-known that males are at increased risk of the neurodevelopmental disorders

attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), while

females are more susceptible to anxiety disorders and depression (Bangasser & Valentino,

2014; Green, Flash & Reiss, 2019). ADHD and ASD are the two most common

neurodevelopmental disorders, with recent prevalence rates of 4%-8% for ADHD (Canals Sans

et al., 2020; Danielson et al., 2018; Joshi & Angolkar, 2021; Mohammadi et al., 2019; Zorlu et

al., 2020) and 1-2.5% for ASD (Alshaban et al., 2019; CDC, 2018; Maenner at al., 2020; Qiu

et al., 2020, Xu et al., 2019) of children between the age of six and 12. ADHD is characterized

by a persistent pattern of inattention and/or hyperactivity/impulsivity, while ASD is

characterized by deficits in social communication and interaction and by restricted interests and

repetitive behaviour (APA, 2013). Both ADHD and ASD are increasing in prevalence and the

symptoms and impairments of both conditions often persist into adulthood (Baio et al., 2018;

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Hartmann et al., 2016; Visser et al., 2014) and it has been found that taken together, these

disorders account for nearly one-fourth of all children receiving school-based services (Kena et

al., 2016). ADHD-ASD comorbidity is seen in 40-70% of cases and differential diagnosis is

thus quite difficult. Both disorders are highly heritable and the hyperactive-impulsive

symptoms associated with ADHD have been found to correlate strongly with the restricted and

repetitive behaviours associated with ASD. Both disorders have many overlapping features,

including attention deficit and overactivity (i.e. Mayes & Calhoun, 2008, 2011; Sturm et al.,

2004), behaviour problems (i.e. Mayes & Calhoun, 2011), and difficulty with social skills (i.e.

de Boo & Prins, 2007). Another issue that ADHD and ASD share is that both in the prevalence

and the clinical manifestation of these disorders, differences between females and males have

been confirmed. Several clear sex differences in the presentation of ADHD were reported in

recent studies, that are now starting to include a reasonable percentage of female participants

(i.e. Loyer Carbonneau et al., 2020; Mayes et al., 2020; Meyer et al., 2020). Similarly, recent

studies on ASD often include substantial numbers of females, and found clear sex differences

between females and males with ASD (i.e. Cummings et al., 2020; McDonnell et al., 2020;

Prosperi et al., 2020). The complexity in comparing females and males is however clear from

the results of these studies; although many studies report significant sex differences in ADHD

and ASD symptoms, overall results are inconsistent with some studies reporting more

impairment on a certain domain in females, while others show less such impairment. As the

vast majority of clinical studies on neurodevelopmental disorders have used predominantly

male samples, and higher number of females are only included more recently, results of most

studies on ADHD and ASD features are likely more representative of males. In recent years the

need for female-specific research has become clear, with several studies even suggesting a

female ASD phenotype (Allely, 2019; Bargiela et al., 2016; Hull et al., 2020; Jamison et al.,

2017; Lehnhardt et al., 2016). Similarly, several studies have aimed to clarify the female

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presentation of ADHD (i.e. Dorani et al., 2021; Isaksson et al., 2020; Meyer, 2020; Mowlem et

al., 2019; Stenner at al., 2019; Young et al., 2020). With higher number of females now

receiving a diagnosis of ADHD and ASD, there is an increased need for evidence-based

knowledge of the female presentations of these disorders as well as sex-oriented treatment. This

thesis focuses on the role of biological sex and sex differences reported refer to biological sex

rather than gender, as the majority of studies are biomedically oriented and only biological sex

is described in studies. Gender is however an important factor to include in ADHD and ASD

research. According to the World Health Organization (WHO), ‘sex’ refers to biological and

physiological characteristics, including sex-related chromosomes. Although sex is generally

considererd to be a binary construct, it can actually be multidimensional (Joel & McCarthy,

2017). ‘Gender’, on the other hand, encompasses experiential, social and cultural components

such as ‘gender norms’, ‘gender roles’ and ‘gender identity’. Gender in the context of

ADHD/ASD research is very relevant, and gender related issues are further discussed in the

discussion of this thesis. Due to the changing context of this thesis, the earlier studies (e.g. the

study on peer functioning in girls with ADHD, 2016) still use the terms ‘gender’ and ‘sex’ when

referring to biological sex.

Goals

This thesis sheds light on the female side of the neurodevelopmental disorders ADHD and ASD.

The two main aims are to investigate female-specific impairments associated with ADHD and

to examine those impairments associated with ASD. In order to elucidate such female-specific

impairments, comparisons were made between females with ADHD/ASD and their

neurotypical counterparts, and between females and males with ADHD/ASD. Due to the

inherent sex differences in behaviour that are present in the general population, examining the

clinical population only would not provide a full picture. Hence this thesis utilizes three

approaches; 1) comparing females from the clinical group to neurotypical females on a specific

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domain, 2) zooming in on a female-specific topic, and 3) investigating sex differences in ADHD

and ASD core features as per diagnostic criteria. The first approach of comparing females with

ADHD/ASD to females without this disorder led to two studies (chapter 2 and 5) examining

peer functioning in ADHD and self-reported empathy in ASD respectively. The second

approach of focusing on two female-specific topics led to two studies (chapter 3 and 6)

examining female-specific effects of ADHD pharmacotherapy and elucidating a female ASD

phenotype respectively. The third approach led to the investigation of sex differences in core

ADHD/ASD features as per diagnostic criteria (chapter 4 and 7).

Two lines of research corresponding to the two main objectives are followed in the current

thesis; female-specific impairments associated with ADHD (study 1, 2 and 3) and female-

specific features of ASD (study 4, 5 and 6).

Female-specific impairments associated with ADHD

The first study has three aims; to identify the domains in which school-aged girls with ADHD

experience problematic peer functioning, to describe to what extent these girls differ from

typically developing girls (TDs) on the identified aspects of peer interaction problems, and to

identify potential risk factors and protective factors for peer functioning, and describe their

influence. I systematically review relevant literature comparing school-aged girls with ADHD

to typically developing girls in relation to peer functioning, with the peer relationship domains

being grouped into ‘friendship’, ‘peer status’, ‘social skills/competence’, and ‘peer

victimisation and bullying’. This offers a broad profile of female-specific peer functioning

impairments in ADHD.

The second study aims to shed light on the female side of pharmacotherapy for ADHD.

I systematically review relevant studies of sex differences in prescription rates and efficacy or

effectiveness of pharmacotherapy treatment in girls and women with ADHD. This enables a

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description of the unique effects of the different pharmacological approaches to the treatment

of ADHD on females and males.

The aim of the third study is to obtain a better understanding of sex differences in ADHD

in order to improve functional and clinical long-term outcomes. I systematically review recently

published (i.e. from 2015) clinical studies on sex differences in core ADHD domains and

symptoms ‘inattention’, ‘impulsivity’, ‘hyperactivity’, ‘hyperactivity-impulsivity’ and ‘total

ADHD symptoms’. This review provides a synthesis of sex comparisons of ADHD symptoms

and ADHD symptom severity, based on recent studies with a relatively high number of females

included (average 41.3%).

Female-specific features of ASD

The fourth study of this thesis examines sex differences in self-reported empathy in adults with

ASD, in order to raise awareness for female-specific autism and male biased ASD diagnostics.

I systematically review clinical studies on self-reported empathy in adult women and men with

ASD and neurotypical women and men. This enables a comparison of differences in levels of

empathy experienced by these groups of participants, and a description of patterns of self-

reported empathy in adult ASD.

The fifth study is a Delphi consensus study aiming to elucidate (a) possible female ASD

phenotype(s). A Delphi study is a consensus-seeking technique widely used as an accepted

method for gathering data from respondents within their domain of expertise, where various

rounds of questionnaires are presented to an expert panel. This method was selected because it

combines information from clinical practice and scientific research, to enrich the scientific

knowledge on an understudied topic. This study enables the identification of female-specific

ASD items that are considered characteristic for the female autism phenotype by the expert

panel involved in the study.

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 The sixth and final study aims to identify a clear sex-specific pattern of core ASD

features. I systematically review recently published (i.e. from 2015) clinical studies that

compared female and male levels of the ASD features social communication/interaction,

restricted and repetitive behaviour, and ASD symptom severity. This provides a synthesis of

sex comparisons of ASD symptoms and ASD symptom severity, based on recent studies with

an increasing number of females included (23.7%).

Outline of this thesis

Chapter 1:

• General introduction.

Chapter 2:

• Investigation of peer functioning difficulties in school-aged girls with ADHD as

compared to typically developing girls.
Chapter 3:

• Description of the unique effects of the different pharmacological approaches to the

treatment of ADHD on females and males.
• Examination of sex differences in prescription rates.
Chapter 4:

• Investigation of recently published clinical studies on sex differences in core ADHD

domains and symptoms.
Chapter 5:

• Investigation of self-reported empathy in adult women with ASD.

Chapter 6:

• Examination of female-specific ASD features that are considered characteristic for a

female autism phenotype by an expert panel.
Chapter 7:

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 • Investigation of recently published clinical studies that compared female and male
levels of core ASD features.
Chapter 8:

• Discussion and concluding remarks.

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