ADHD and Autism Comorbidity: A Comprehensive Review Based on Expert Consensus Recommendations and Latest Research Findings
Attention deficit/hyperactivity disorder (ADHD) and Autism spectrum disorder (ASD) frequently co-exist. ADHD and ASD have traditionally been diagnosed and treated separately, with their established clinical guidance.
ASD was an exclusion criterion in both the DSM-IV and ICD-10. [Murphy et al., 2016]
They were not recognised as co-existing conditions until 2013, when the DSM-5 diagnostic manual was updated to reflect the clinical evidence. [APA, 2013]
In children, the cooccurrence of ADHD symptoms in ASD ranges between 53 and 78%, whereas, in community samples, it is lower at 28–31%. [Young et al., 2020]
A meta-analysis of the co-occurrence of ASD symptoms in young people from clinical and community ADHD samples found a comorbidity rate of 21%. [Hollingdale et al., 2020]
ADHD presents in 30–80% of individuals with ASD, and ASD presents in 20–50% of individuals with ADHD. [Lau-Zhu ,2019].
This suggests that ADHD symptoms may be more likely found in people with ASD than vice versa.
This article summarises the main recommendations for diagnosing and managing comorbid ADHD and ASD based on The 2017 Expert Consensus meeting [Young et al., 2020]and additional review articles found in the references.
AETIOLOGY OF ADHD AND ASD
For an overview of ADHD and ASD, please see our other Psych Scene Hub resources. The most relevant ones are listed here:
- Evidence-Based Summary of the ADHD International Consensus Statement (September 11, 2021)
- Neurobiology of ADHD
- Diagnosis and Management of ADHD.
- Attention Deficit Hyperactivity Disorder Simplified: How to treat ADHD; How to diagnose ADHD (April 27, 2022)
- ADHD comorbidities and management principles (January 12, 2022)
- Shifting Biology in ASD: Future Treatment Prospects – Assessment, Treatment and Research in Autism Spectrum Disorders (February 24, 2020)
- Vitamin D Deficiency in Pregnancy is linked to Autism (January 27, 2017)
- Applications of N-Acetylcysteine (NAC) – From Addiction to Autism by Prof M Berk (March 3, 2017)
ADHD and ASD show a shared aetiology in multiple neurobiological aspects.
In a genome-wide case-control study of psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD)), many genetic copy number variants (CNVs) were shown to confer risks for ADHD and ASD. [Rommelse et al., 2010]
The commonality was also seen within molecular pathways and functional domains impacted by both disorders. [Lee et al., 2013], [Ronald et al., 2008]
Autism has a strong genetic component, with high heritability estimates of both conditions (ranging between 70 and 80% for ADHD and 37 and > 90% for ASD).
Environmental factors contribute to the aetiology. The gene-environment interaction can affect epigenetic expressions such as DNA methylation, histone modification and microRNA expression leading to altered development.
Epigenetic Mechanisms in Psychiatric Disorders – Major Depression, Psychosis and Addiction
There is vast genetic heterogeneity in ASD, involving both locus and allelic heterogeneity. [Rylaarsdam & Guemez-Gamboa, 2019]
Genome-wide linkage studies have identified ASD susceptibility genes on chromosomes 2q, 7q, 15q, and 16p.
However, 75-80% of cases cannot be traced to a specific genetic issue, with only 20-25% of cases classified as either cytogenetically visible chromosomal abnormalities, copy number variants, or single-gene disorders. The genes identified are: [Miles, 2011]
- ENGRAILED 2 was the first gene to be proposed to increase ASD susceptibility. It is a transcription factor that plays a role in the development of the central nervous system, particularly in the formation of serotonergic and noradrenergic nuclei in the mid and hindbrain.
Neuronal activity regulation
- UBE3A is involved in the ubiquitin-proteasome pathway, which plays a role in synaptic development. It has also been suggested to play a role in regulating the circadian clock.
- Fragile X syndrome – Expansion of the CGG trinucleotide repeat (55-200 CGG repeats) in the FMR1 gene has been linked in 1-3% of children with autism.
- Neurotransmitters – GABA receptor subunits (GABRB3, BAGRA5, and GABRG3) play a significant role in inhibitory transmitter receptors in the brain.
- Maternal rubella has been shown to increase the risk of autism.
- However, the MMR vaccine has eliminated this environmental risk, and no evidence links other viral infections such as influenza. [Libbey et al., 2005]
- It has been proposed that circulating maternal antibodies directed against foetal brain proteins may also be a risk factor. [Braunschweig et al, 2008]
- The first indication that a drug administered during pregnancy could be associated with an increased risk of autism was thalidomide.
- Valproic acid [Ronald et al., 2008] and SSRIs [Christakou et al., 2013] have been implicated today. The effect is suggested to be stronger during the first and second trimesters.
- Toxins ranging from pesticides to car exhaust fumes to cigarette smoke have all been proposed as risk factors.
- Although the link is still unclear, there have been small increases in the rate of ASD in families that live near either a motorway or a farm. [Bölte et al., 2019]
- There is unequivocally no link between the MMR vaccine and AS. [Stratton et al, 2011]
- Other possible postnatal factors include severe isolation in institutionalised children. [Rutter et al., 1999]
NEUROSCIENCE OF AUTISM SPECTRUM DISORDER (ASD)
Please read the comprehensive article on the neurobiology of ADHD.
In the following section, we will focus on the neurobiology of ASD.
Advances in neuroimaging techniques have shown that ASD is associated with synaptic deficits in specific brain networks.
In addition, these deficits affect anatomical microstructures and local neural circuitry and the function of brain regions such as the amygdala, prefrontal cortex, and the nucleus accumbens in the basal forebrain.
The ENIGMA consortium study is the largest structural brain MRI analysis to date of individuals with ADHD and ASD. They found that children with ADHD and ASD had overlapping subcortical volume and thickness compared to controls, with frontal cortices volume increasing with age.
The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) study showed that individuals with ASD had a different pattern of cortical thickness and surface area in several brain regions compared to healthy controls. [Sha et al., 2022]
Specifically, the study found that individuals with ASD, compared to healthy controls, had:
Increased cortical thickness in the left insula:
- The insula is involved in several cognitive and affective functions, including interoception, emotion regulation, and social cognition.
Decreased cortical thickness in the left superior temporal gyrus and left middle temporal gyrus:
- The superior and middle temporal gyrus are involved in language comprehension and social communication.
Decreased cortical thickness in the right entorhinal cortex:
- The entorhinal cortex is involved in memory and spatial navigation.
These differences were observed after controlling for age, sex, and total brain volume.
The differences in cortical thickness in these regions may contribute to the social communication deficits and other behavioural features observed in individuals with ASD.
It’s important to note that the findings regarding these brain regions in ASD are not always consistent across studies and may depend on the methodology, sample size, and other factors.
The amygdala is a limbic system component located in the frontal portion of the temporal lobe.
The amygdala, located within the medial temporal lobe, is divided into at least 13 distinct subnuclei; the most clearly defined nuclei are:
- Basolateral amygdala (BLA)
- Lateral amygdala (LA)
- Central amygdala (CeA)
The CeA connects the amygdala properly with the extended amygdala, located between the amygdala and the nucleus accumbens (NAc).
The extended amygdala comprises the bed nucleus of the stria terminalis (BNST) and other interconnected nuclei.
Optogenetic stimulation of BNST–Ventral Tegmental Area (VTA) circuitry activates BNST GABAergic connections associated with reward and reduced anxiety-like states.
BNST glutamatergic VTA connections are anxiogenic.
Therefore, the BNST mediates the interplay between anxiety, anticipation and reward that comprises social attachment. [Lebow and Chen, 2016]
Primary functions of the amygdala include [Stamatakis et al., 2014]
- Emotional learning and regulation
- Memory formation
- Reward processing
- Detection of relevant social information
The amygdala is over-activated by novel stimuli (e.g. new person’s face or a novel social situation), and its response time is decreased through the person’s repeated exposure to the same stimulus, a phenomenon called familiarity.
Dysfunctional amygdala in ASD:
The amygdala in patients with ASD has been associated with abnormal face processing.
Although not yet fully understood, it is postulated that the failure of the amygdala to develop during the early stages of neurodevelopment may mediate amygdala habituation in ASD (i.e., amygdala responsiveness to repeated presentation of stimuli). [Tam et al., 2017]
Three important phenomena are linked to social communication difficulties:
1. Slower response time :
- The response time of the amygdala to new stimuli (e.g., an unknown person/ face) in individuals with ASD is slower than in individuals without ASD, interfering with the process of familiarity.
2. Lack of decrease in response time:
- The response time does not tend to decrease through repeated exposure to the same person/face as opposed to the average population.
3. Increase in amygdala activation with repeated exposure:
- Amygdala activation in people with ASD increases with repeated exposure to negatively emotionally charged individuals. [Kleinhans et al, 2009]
The PFC plays a vital role in cognition, stress modulation and reward responses.
Dysfunctional prefrontal cortex
- Disturbed neural connections in the PFC are related to speech problems, personality abnormalities, impulsiveness, and organisational difficulties, all of which can be associated with ASD. [Zimmerman et al, 2016]
- Dysfunction to the medial PFC has been shown to manifest as deficiencies in social cognition and understanding of oneself and others, a process known as mentalising. [Frith & Frith, 2006]
- Studies have found that individuals with ASD have differences in the size and connectivity of the frontal lobes.
- Individuals with ASD show evidence of reduced grey matter volume and altered white matter integrity in frontal lobes.
- These differences may contribute to impairments in executive function and social cognition observed in ASD.
The nucleus accumbens is part of the basal forebrain and is the main component of the ventral striatum.
Its functions include motivation and the cognitive processing of aversion. In addition, it is associated with the reinforcement of reward and the translation of an emotional stimulus into a behaviour. [Modestino et al., 2015]
Dysfunctional nucleus accumbens
- It has been proposed that dysfunctional brain reward circuits are linked to restricted and repetitive behaviours that frequently characterise ASD. In addition, hyperactivity in ADHD is also postulated to arise due to dysfunction of the NAc.
- It is postulated that patients with ASD do not assign a sufficient reward value to social interactions. [Dichter et al.,2012]
Aberrant brain development:
- Aberrant brain overgrowth was noted in the cerebellar, cerebral, and limbic structures. These areas are responsible for the process and the use of higher-order cognitive, pragmatic, emotional, social, and language functions. [Kamari et al., 2020]
- Excessive brain growth was followed by abnormal deceleration of cerebral areas.
- According to a 2012 study, there is a possibility that the abnormal development of cerebral white matter pathways during infancy precedes the expression of communication-social phenotypes associated with Autism Spectrum Disorder. [Petinou and Minaidou, 2017]
- Atypical connectivity patterns are observed in the splenium, a brain structure found in the corpus callosum area that connects the right and left cerebral hemispheres.
- 20% of autism cases are associated with mitochondrial abnormalities.
- Elevated levels of peripheral markers of mitochondrial abnormalities suggesting metabolic dysfunction are found in individuals with ASD.
- Elevated lactic acid is found in the locality of the cingulate gyrus, a structure involved in many higher processes, such as the regulation of emotion, cogitation and behaviour regulation. [Goh et al., 2014]
Similar energy dysfunction is also identified in ADHD.
HPA Axis Dysfunction: [Makris et al., 2022]
- Individuals with ASD show an enhanced sensitivity of the Hypothalamic-Pituitary-Adrenal axis to stress, with delayed feedback of the axis.
- Elevated prenatal activity of steroid hormones is found in individuals with ASD.
- Sleep dysfunction is a prominent feature in both ASD and ADHD. [Lugo et al., 2020]
- Alterations to serotonin pathways can significantly impact the circadian rhythm, with research highlighting the role of neurexins and neuroligins as vulnerability factors in ASD [Geoffray et al., 2016].
- Furthermore, the nocturnal production of melatonin is significantly reduced in patients with ASD. [Tordjman et al., 2005]
- Dopamine and noradrenaline systems also play an essential role in sleep regulation, and their dysregulation is hypothesised to be involved in the pathophysiology of ADHD. Here, the delayed development of the frontostriatal circuitry (i.e., reduced grey matter volume) mechanistically mediates dopamine/noradrenaline gene expression with ADHD symptoms and sleep disturbances. [Shen et al., 2020]
- Melatonin levels are decreased in 65% of persons with ASD due to the enzyme acetylserotonin O-methyltransferase (ASMT) dysfunction. An ASMT polymorphism causes up to a 50% drop in melatonin concentration. [Pagan et al., 2017]
Excitatory-inhibitory (E/I) imbalance:
A “Proof of Concept” study recently showed that responsivity to the E-I challenge differs in adults with autism and that the autistic brain is pharmacologically atypical. [Ajram et al., 2017]
This unusual E–I responsivity in ASD may help explain other paradoxical findings from studies of the way people with ASD respond to E–I acting medications. For example, GABAA/benzodiazepine receptor agonists typically have an inhibitory effect in non-ASD populations, but can sometimes cause excitation in individuals with ASD.
E/I imbalance can result from the excitatory or inhibitory neural structure and/or function abnormalities. The reduced or increased synaptic transmission may cause overprocessing (noise) and misprocessing (disconnection) of the information, respectively. [Kim et al., 2019]
Shifting Biology in ASD: Future Treatment Prospects – Assessment, Treatment and Research in Autism Spectrum Disorders
The exact causes of E–I responsivity differences are not known.
- ASD has been conceptualised as a developmental disconnection syndrome with underconnectivity between the prefrontal cortex and posterior brain network.
- Riluzole was able to establish functional connectivity between the two areas in high functioning adults with autism. Riluzole is a neuroprotective drug that blocks glutamatergic neurotransmission in the CNS.
Using [1H]MRS and fMRI, we found that E–I flux and functional connectivity of the prefrontal cortex are differentially regulated in adults with ASD compared with the controls.
Importantly, inhibitory tone and functional connectivity can be shifted pharmacologically—and even in adults with ASD. [Ajram et al., 2017]
- ASD has been associated with elevated growth hormone (GH) levels and insulin-like growth factor (IGF-1/) in cerebrospinal fluid.
THE IDENTIFICATION AND ASSESSMENT OF ADHD AND ASD AS COMORBID CONDITIONS IN CHILDREN AND ADULTS:
Diagnostic Criteria in ASD:
Diagnostic Criteria for ADHD: Criteria A1 and A2
The DSM-5 criteria for ASD are now assessed using a severity scale (levels 1 to 3) based on the level of support required for normal functioning.
- Requires support due to deficits in social communication and impairments in initiating social interactions, although is able to speak in full sentences.
- Atypical behavioural responsiveness and lack of behavioural flexibility are present.
- Requires substantial support due to marked reductions in verbal and nonverbal communication skills, even when support is in place.
- Significant interference in responsiveness and a strong inflexibility of behaviour.
- Will often experience distress at changing focus or activity.
- Requires very substantial support with repetitive behaviours, unintelligible speech, and severe difficulty in changing focus or activity.
- This impaired functioning is associated with substantial impairment in social interactions and deficits in verbal and nonverbal communication skills.
DIAGNOSTIC ASPECTS OF COMORBID ADHD AND ASD
General principles: [Young et al., 2020]
- The assessment should include a comprehensive diagnostic formulation and an aetiological formulation of protective, predisposing, precipitating and perpetuating factors.
- A multidisciplinary and integrated approach with medical specialists is needed for children and adolescents with ASD and ADHD due to the high association with medical disorders which span different medical areas, such as immunology, neurology and gastroenterology.
- Clinicians should be aware that ‘problem behaviour’ in developmental disorders may be the only symptom of an underlying somatic disorder.
- Developmental disorders such as autism can be a feature of several underlying genetic syndromes, many of which also entail somatic symptoms.
- Therefore a combination of ASD and medical conditions requires an extensive diagnostic scheme to detect genetic syndromes, and clinicians should consider referral to a clinical geneticist.
- The comprehensive care plan must consider individual needs and explain how these may be met across settings.
Development of a Positive Behavioural Support Plan (PBSP):
- A PBSP is an individualised care plan that involves functional analysis identifying antecedents, behaviours and consequences (ABCs) and addressing these to reduce the likelihood of challenging behaviours.
- PBSP should be developed in collaboration and shared with all relevant parties (including educational establishments, with consent) to promote consistency among caregivers.
1. HISTORY TAKING
- Detailed clinical history of symptom onset, trajectory, persistence, fluctuation, and pervasiveness to help differentiate ADHD from ASD and other comorbidities.
- Assess for past medical history, past and current environmental conditions, family dynamics, and childhood circumstances.
- Mental state exam to rule out comorbidity and include a risk assessment.
- Assess the individual’s functioning and if age-appropriate.
- Assess for difficulties that affect their functioning and development across home, educational, and work environments.
- Avoid “double counting” symptoms present in both ADHD and ASD.
- Recognise that no single point of evaluation or instrument should be conclusive in making a diagnostic decision.
- Consider test environments, such as quiet clinic rooms or school offices, as these may not reflect real-world conditions.
- Use caution when using tests that use modes of specific interest, such as computerised tests, as performance improvement can undermine their ecological validity.
- Consider cultural aspects.
- Assess for suicide and self-harm risk
- Assess for self-medication with alcohol and/or substance misuse to manage social anxiety or low mood.
- Recognise that concurrent ADHD and ASD can elevate risks significantly.
- Young people with ASD and suicidal thoughts, with an average IQ score, are at particular risk due to their tendency to rigidly adhere to their plans.
- Individuals with ADHD may be distracted and/or make inadequate plans or have an increased risk due to impulsivity.
- For individuals with ASD, a risk assessment should consider sensory deficits, such as having a high threshold for pain or significant temperature changes.
2. COLLATERAL HISTORY:
- Obtain collateral information from parents/carers regarding the child’s developmental health records, photographs, and school reports before the interview.
- Think about critical transitions in the child’s life, such as moving from home or school changes.
- Collateral information should be obtained from independent sources, such as parent/carer or teacher interviews, observation in school or other settings, and adults.
- Peruse school, college, and/or employment reports to gather relevant information.
3. ASD AND ADHD-SPECIFIC DIAGNOSTIC ASPECTS:
- Symptoms of both ADHD and ASD may be masked in history due to compensatory strategies developed by the individual or family.
- Comorbid symptoms or compensatory behaviours may mask mild symptoms.
- ADHD and ASD may differ in terms of the executive dysfunction domain affected. For example, children with ASD have more planning and cognitive flexibility difficulties, and children with ADHD have more inhibition difficulties.
- In individuals with ASD, a distinction is made between hot and cold executive functions. [Zimmerman et al, 2016]
- Cold executive functions refer to mechanistic higher-order cognitive operations (e.g., working memory)
- Hot executive functions refer to cognitive abilities supported by emotional awareness and social perception. (e.g., social cognition, theory of mind (ToM), emotion recognition, response initiation and suppression)
- High-functioning adults with ASD experience a more generalised impairment in recognising positive and negative emotions. They show impairment of both hot and cold executive functions relative to controls.
- Furthermore, their impairments in emotion recognition and social perception are independent of deficits in working memory, response initiation and suppression. [Zimmerman et al, 2016]
- Genetic testing and counselling are recommended in the evaluation of all patients with neurodevelopmental disabilities, including ASD, because of the high diagnostic yield (~35%). [Moore et al., 2022]
- Genetic tests include Testing for Fragile -X (polymerase chain reaction to detect CGG repeats in the FMR1 gene); chromosomal microarray to detect 22q11.2 deletion syndrome or 15q11.2 duplication; whole exome analysis, whole genome analysis and DNA methylation analysis to rule out Beckwith-Wiedemann, Prader-Willi, and Angelman syndromes.
Compensatory behaviours that can mask a diagnosis:
- Skills may have been developed to ‘camouflage’ difficulties in specific situations or for a brief period.
- Coping by avoiding specific events, settings and/or people
- Coping by avoiding challenges.
- Withdrawal, spending too much time locked away in a room online, and/or not engaging in help-seeking behaviours.
- Individuals may cope by forming damaging relationships such as joining a gang, engaging in promiscuous and unsafe sexual practices and/or being exploited for criminal activities.
Biases in assessment: Potential Pitfalls
- A diagnosis of ASD or ADHD may be missed due to an individual’s ability to sustain eye contact and initiate conversations on topics of interest. In addition, a lack of hyperactivity and the ability to settle or hyperfocus on a topic of interest can also mask overt hyperactivity and make it harder to diagnose.
- For ASD, although an individual may appear friendly and socially proactive, the quality of their interactions may seem ‘odd’ in nature, providing a clue to their diagnosis. Therefore, it’s essential to consider the nature and quality of interactions rather than just the ability to initiate them.
- Distraction and switching tasks may also be influenced by the level of interest in the task and/or modified by a tendency to become preoccupied with the task or due to resistance to change.
- Adults with ADHD who have completed university or work in high-performance environments may employ strategies to remain focused and control the urge to fidget during important appointments or meetings. However, maintaining this social and work façade for a long time can lead to fatigue and distress and increase the risk of mood and anxiety disorders.
4. GENDER DIFFERENCES:
- Compared with males, females with ADHD may present with fewer disruptive behavioural problems, and those with ASD may have lower intellectual abilities.
- Attention Deficit Hyperactivity Disorder (ADHD) in Females – Gender Differences in Neurobiology, Assessment & Management
- Females are at greater risk of developing internalising conditions (e.g., anxiety, depression), whereas males are at greater risk of developing externalising conditions (e.g., disruptive behaviour disorders).
- Females may acquire superficial learned social skills and exhibit milder restrictive stereotyped behaviour, which may mask their underlying social difficulties.
- Rating scales may lack the sensitivity and specificity to identify symptoms in females as they have mainly been validated in male populations.
COMORBIDITIES IN ADHD AND ASD
5. ASSESSMENT OF COMORBIDITIES:
- ADHD and ASD have high rates of comorbidity.
- ASD and ADHD comorbidity increases the risk of a further comorbid diagnosis by approximately 14% (from 70% for ASD and 84% for concurrent ADHD and ASD). [Young et al., 2020]
- Anxiety, dysthymia, and mood disorders are common in ASD, and suicide risk is of particular concern. [Culpin et al., 2018]
- Since there are differences in the age of diagnosis for ASD and ADHD, it is essential to continually monitor young children who receive an initial diagnosis of ASD for the possible development of ADHD in adolescence and adulthood.
- ASD is typically diagnosed in early childhood, usually around age 4, although it may be diagnosed as early as 2.
- On the other hand, ADHD is often not diagnosed until later in childhood or adolescence, typically around age 7 years, but it can be diagnosed as early as 4 years old.
Comorbidity in children:
- 70% of children with ASD will have at least one co-occurring psychiatric condition, and 41% will have two or more, the most common being social anxiety, ADHD and oppositional defiant disorder.
- Intellectual disability is one of the most common comorbidities of ADHD and ASD, 46% and up to 70%, respectively. [Young et al., 2020]
- Bipolar affective disorder
- Obsessive-compulsive disorder [OCD]
Catatonia and ASD:
- There is often significant overlap in symptomatology between catatonic symptoms and some behaviours seen in patients with ASD. These include motor stereotypies, mannerisms, rituals, mutism, echolalia, and negativism.
- A subtype of catatonia, “autistic catatonia”, has been described, which presents as freezing when carrying out actions, resistance to prompting, slow voluntary motor movements, and stopping in the course of movement.
- Catatonia has been observed in patients with established genetic aetiologies such as Prader-Willi syndrome, 22q13.3 deletion syndrome (Phelan-McDermid syndrome), Down syndrome, 22q11.2 Deletion syndrome, SHANK-3 related dysfunction and late-onset Tay-Sachs disease.
- Autoimmune conditions such as Anti-NMDAR encephalitis should be ruled out.
- Severe self-injury or unremitting tics may be uniquely indicative of catatonia in individuals with ASD and other neurodevelopmental disorders.
- Treatment follows the same path as neurotypical patients; however, there is some evidence that of genetically guided treatment for catatonia, where patients with SHANK3 variants and catatonia respond positively to lithium therapy and to immunomodulation. [Moore et al., 2022]
- Catatonia – Pathophysiology, Diagnosis and Management
Medical comorbidities: [Murphy et al.,2016]
- In patients with ASD and ADHD, sleep disorders during childhood can be as high as 86%; unfortunately, the present data on the prevalence during adulthood is unclear. [Souders et al., 2017]
- Daytime sleepiness (38% vs 11.6-17.7%), sleep breathing disorders (8% vs 4-4.5%), and restless legs syndrome (RLS) – (12% vs 2.7-7.2%) were all reported to be higher compared to the general population. [Lugo et al., 2020]
- Approximately 44%-83% of people with ASD encounter sleep quality disruption, such as frequent nocturnal awakenings and longer sleep onset latency, alterations that can worsen the behavioural symptoms of autism.
- Microglial activation has been identified as an immunopathological mechanism in ASD. [Robinson-Agramonte et al., 2022]
- Many children with ASD have evidence of persistent neuroinflammation, altered inflammatory responses, and immune abnormalities. [Al-Beltagi, 2021]
- Allergic diseases are over-represented in ASD. In addition, there is a high incidence of non-IgE-mediated food allergy in younger children with ASD.
Gastrointestinal [GI] disorders:
- GI tract pathology is present in approximately 50% of cases of ASD.
- ASD children have a threefold elevated risk of GI complaints (e.g. reflux), constipation, diarrhoea, and a twofold high risk of abdominal pain. [Al-Beltagi, 2021]
- ASD can be connected to a combination of immune dysregulation and inflammation in early life, and the gut microbiota can influence this disruption [Doenyas, 2018], [Fattorusso et al., 2019]
- The frequent occurrence of GI symptoms implies that microbial dysbiosis can contribute to ASD gastrointestinal pathophysiology.
Both ADHD and ASD are associated with [Pan & Bölte, 2020]
- Immunological dysregulation, including asthma, allergic rhinitis, and atopic eczema
- Obesity and being overweight
- Altered gut microbiome
- The Simplified Guide to the Gut-Brain Axis – How the Gut and The Brain Talk to Each Other
- Symptom overlaps between chronic fatigue syndrome (CFS) and neurodevelopmental conditions. [Keville et al., 2021]
- Individuals with ADHD have more severe symptoms and frequent hospitalisations due to COVID-19, with stimulant treatment having a protective effect on emergency department admissions, intensive care services and 30-day mortality. [Tuan et al., 2022]
- Individuals with ASD also have an increased susceptibility to COVID-19 disease due to a low melatonin output, either due to a genetic variation in the synthetic enzyme pathway (enzyme acetylserotonin O-methyltransferase (ASMT) dysfunction) or due to the sleep irregularity that frequently is seen in ASD. Frequent nighttime awakenings decrease circulating melatonin because of waking and exposure to light. [Brown et al., 2021]
- A case series highlighted the lasting effects of COVID-19 on immune activation, presenting as a marked exacerbation of neuropsychiatric symptoms in patients with ASD, even in the context of mild or asymptomatic COVID-19 infection. [Jyonouchi et al., 2022]
Chronic Fatigue Syndrome | Myalgic Encephalomyelitis – Neurobiology | Diagnosis | Management
Medical comorbidities increase the risk of developing diabetes, heart disease, and cancer in later life for patients with ASD and ADHD.
Specific medical comorbidities:
- Chronic fatigue syndrome (CFS) – CFS patients with adult ADHD had an earlier CFS onset, more severe anxiety and depression symptoms, and a higher risk of suicide than CFS patients without ADHD.
- One study found that 29.7% of individuals with CFS were diagnosed with childhood ADHD; in 20.9%, the condition persisted into adulthood. [Sáez-Francàs , 2012]
- The increased risk may be due to the dopamine dysregulation common to both disorders. How inflammation in CFS affects dopamine dysregulation and affects cognition and activity.
- Cerebrovascular accidents
- Inborn errors of metabolism, including mitochondrial disorders, disorders of creatine metabolism, selected amino acid disorders, disorders of folate or B12 metabolism, and selected lysosomal storage disorders.
- Genetic conditions such as Fragile X syndrome, Down syndrome, Duchenne muscular dystrophy, neurofibromatosis type I, and tuberous sclerosis complex should be ruled out.
- Studies looking individually at ASD and CFS populations highlight overlaps with fatigue, brain fog, cognitive impairments, increased pain and tenderness, impaired emotional contact and increased sensitivity to sound, light, and odour.
- A direct link between CFS and ASD has not been found. [Keville, 2021]
Parkinson’s disease and ASD: [Mai et al., 2023]
- Evidence suggests that middle-aged and older adults with ASD with no intellectual disabilities have a higher prevalence of parkinsonian symptoms such as bradykinesia and gait abnormalities.
- The rates of parkinsonism are unexpectedly high among ASD patients, even after excluding those (both currently and previously) on atypical antipsychotics. [
- This may be due to shared genetic vulnerability, e.g. Gene loci PARK2 associated with parkinsonism could confer susceptibility to ASD as well.
RATING SCALES IN ASD AND ADHD
- Rating scales are not to be considered diagnostic instruments but tools to aid diagnosis and monitor clinical progress.
- When used as a screening tool, individuals receiving borderline scores (i.e., falling just below cut-offs) should not be excluded from referral for a comprehensive clinical diagnostic assessment.
- Adults with specific learning or motor difficulties may need support to complete them.
- Individuals with ASD may have language problems and may struggle with arbitrary phrasing and/or undefined concepts; may have difficulty identifying or describing their thoughts, feelings and sensations.
- Some individuals may have limited insight into their current and past difficulties.
- Individuals with ADHD may make careless errors due to poor concentration. E.g. items may be completely missed out in questionnaires and/or for more than one response to be endorsed on a scale by accident.
- Scales may not be sensitive to females or individuals with intellectual impairment, and hence adaptations are needed in interpretation.
- An intellectual assessment should always be considered (especially in cases when the intellectual impairment or an uneven cognitive profile is suspected)
- Clinicians should recognise that results may not reflect performance in the ‘real world’.
- Neuropsychological testing is neither necessary nor sufficient for a diagnosis of ADHD; however, tests that assess executive dysfunction are helpful in determining deficits in higher-order processing skills such as task switching, perseveration, planning, sequencing and organising information.
Autism-specific Rating Scales:
- Social Communication Questionnaire (SCQ) for use with a mental age of 2+
- Social Responsiveness Scale SRS-2 (age 2½ +)
- Social and Communication Disorders Checklist (SCDC) (3–19 years)
ADHD-specific Rating Scales
- Conners’ Comprehensive Behaviour Rating Scales (CBRS) to identify ADHD and comorbid conditions (6–18 years)
- Conners’ Adult Rating Scales (CAARS) (age 18+)
- SNAP-IV Rating Scale (6–18 years)
- Adult ADHD Self-report Rating Scale (ASRS) (age 18+)
- RATE and RATE-C self- and informant-report scales (for children 8–11 years and adults 16–54 years)
- The Vanderbilt ADHD Diagnostic Rating Scale (VADRS)
Rating scales suitable for both ASD and ADHD
- Kiddie-SADS DSM-5 Screen Interview (K-SADS-PL) (6–18 years)
- Strengths and Difficulties Questionnaire (SDQ) (2–17 years)
- The Development and Well-being Assessment (DAWBA) (5–17 years)
CLINICAL INTERVIEWS SUITABLE FOR BOTH ASD AND ADHD
Clinicians should recognise that ‘diagnostic scales’, neuropsychological tests and observation schedules are aids, not conclusive diagnostic instruments.
For example, The ADOS-2, a standardised measure to assess communication, social interaction, play/imagination, and restricted/repetitive behaviours in individuals suspected of having ASD, is not a diagnostic instrument but a useful measure to support clinical assessment. [Young et al., 2020]
Moreover, there are gender differences. Females with ASD may score lower on the ADOS-2 than males due to their ability to develop superficial social skills and exhibit milder restrictive stereotyped behaviours, which may camouflage underlying difficulties. [Young et al., 2020]
Autism-specific clinical interviews:
- Diagnostic Autism Spectrum Interview (DASI) (age > 2)
- Autism Diagnostic Interview-Revised (ADI-R) (age > 2)
- The Autism Diagnostic Observation Schedule Second Edition (ADOS-2)
- Diagnostic Interview for Social Communication Disorders (DISCO) (age range unspecified)
- Developmental, Dimensional and Diagnostic Interview [3Di] (highly structured computerised interview > 2 years
ADHD-specific clinical interviews:
- ADHD Child Interview (ACE) and the adult version, ACE+ (5–16 and > 16 years, respectively
- Diagnostic Interview of Adult ADHD (DIVA-2) (lower age limit not specified)
- Visual representations of mood states or visual analogue scales for individuals with difficulty identifying or describing their thoughts, feelings, and sensations.
- Assessment of intellectual and adaptive functioning (using a low threshold for administration) for children, adolescents and adults to determine cognitive strengths and weaknesses, establish treatment goals, and target appropriate educational and vocational interventions.
NON-PHARMACOLOGICAL MANAGEMENT OF ASD AND ADHD COMORBIDITY
Non-pharmacological practice recommendations for children and adolescents with comorbid ADHD and ASD: [Young et al., 2020]
- All treatment approaches should be integrated into a comprehensive care plan.
- The plan should include a Positive Behavioural Support Plan (PBSP) that ensures consistency of interventions and education across all caregivers, staff and service users and should be shared with relevant parties with appropriate consent.
- Psychoeducation about the lifespan approach to ASD and ADHD, including aetiology, treatments, comorbidities, symptom presentation and management
- Psychoeducation can be provided as a stand-alone or group intervention.
- Involve the individual and carers.
Parent/care interventions (support and mediated interventions)
- To reduce the burden on carers, parent/carer-mediated sessions are conducted to teach specific interventions to develop skills, reduce unwanted behaviours and minimise distress.
- The parent/carer is empowered to be the agent of change, with the child as the direct beneficiary.
If behaviours persist, targeted interventions, such as functional behavioural analysis, can be provided after psychoeducation and parenting programmes.
- The functional behavioural analysis measures ABCs (antecedents, behaviours, consequences) to identify triggers and develop collaborative goals.
- Applied behavioural analysis (ABA) has been developed for toddlers
- Functional analysis may need to be modified to include more frequent and shorter sessions with mid-session breaks.
- Greater structure and adherence to a precise routine can reduce anxiety, and environmental adaptations may be necessary to minimise sensory discomfort and distractions.
Educational and classroom interventions for children and adolescents with comorbid ADHD and ASD:
- Specific training for school staff to understand how ADHD and ASD impact children’s learning and social interactions in the classroom.
- Collaboration between school staff, health professionals, and social care professionals.
- Recognition for school staff about the ‘achievement gap’ between chronological and developmental age, particularly in mainstream education.
- Early identification and referral to allied health professionals can help address specific learning difficulties, such as dyslexia, dyscalculia, dysgraphia, and language and communication deficits.
- The Strengths and Difficulties questionnaire can be used in educational settings to screen at-risk pupils and guide further intervention and assessment.
- The Collaborative Life Skills Program (CLS) is a promising intervention for ADHD in primary schools, which provides integrated support to students, parents, and teachers.
- CLS improved ADHD symptoms, organisational skills, academic competence, and social/interpersonal skills.
Other therapeutic interventions:
- Tailored semi-structured sessions can reduce anxiety and increase confidence for individuals or groups with intellectual limitations or severe symptoms.
- Narrative therapy can benefit young people without intellectual limitations, promoting social adaptation, self-esteem, and self-efficacy.
- Adapted cognitive-behavioural therapy (CBT) is effective for adolescents, increasing self-awareness and social adaptation through problem-solving and constructive planning.
- CBT is particularly effective for children with ADHD and co-existing ASD because it emphasises social skills training, emotion, and risk recognition.
- Key life stages, such as adolescence, school, or job changes, can be challenging for those with ADHD and ASD.
- Peer relationship difficulties can worsen, and risk behaviours may increase.
- Alert cards can help individuals access support from relevant agencies rather than being punished by the criminal justice system in case of agitation or aggression.
- People with ASD can be disadvantaged when taking specific criminal tests, such as lie detector tests, due to their unreliability, which can result in false negative or false positive results.
NON-PHARMACOLOGICAL MANAGEMENT OF ASD AND ADHD COMORBIDITY IN ADULTS
Adults – Non-pharmacological clinical interventions for adults with comorbid ADHD and ASD: [Young et al., 2020]
- Transitioning into adulthood can be challenging for individuals with ADHD and ASD.
- Consent and capacity issues should be considered when sharing information with parents/carers.
- When assessing needs financial and social needs should also be considered when assessing needs, especially when a guardianship or court protection order is required.
- Psychoeducational interventions, peer group support interventions, and cognitive approaches such as Cognitive remediation therapy (CRT) and CBT are effective for adults with ADHD and ASD. However, adaptations may be needed for those with social communication and intellectual limitations.
- Assistance for daily activities with text or phone app reminders, medication prompts, and self-care prompts.
- Social cognition skills training in ASD through computer-based programs or group-based cognitive behavioural interventions
- Cognitive Enhancement Therapy for treating impairments in “social and non-social information processing” in adults with ASD.
- Tailored support to adults with ADHD and ASD who become parents to maintain their children’s welfare.
Further education, career advice and occupational interventions for adults with comorbid ADHD and ASD:
- Career officers, special educational needs coordinators, and occupational therapists should collaborate to guide individuals towards realistic career goals and independent living.
- Educational support services should be aware of students’ potential challenges in further education, including anxiety, difficulties living independently, sleep disruption, social isolation, and substance use.
- Individuals with ADHD and ASD may benefit from a supervised mid-point break during examinations rather than standardised disability provisions in tertiary education settings.
- Coaching and support can help individuals manage personal finances and plan for financial commitments.
- Support may be needed for job applications, interviews, and recruitment processes.
- Voluntary and supported work placements can help individuals understand work expectations.
PHARMACOLOGICAL MANAGEMENT OF COMORBID ADHD AND ASD
Pharmacological Interventions for children and adults with comorbid ADHD and ASD: [Young et al., 2020]
- Behavioural observation and psychological intervention should be used as first-line treatment for children with ADHD and ASD. Medication should only be considered if non-pharmacological interventions have been unsuccessful.
- When pharmacological treatments for ADHD and ASD are used, they closely mirror the treatments given to children and adults with each disorder separately.
- Medication for ADHD symptoms should be offered to adults with co-occurring ASD and ADHD as appropriate, with regular monitoring. Medication should not be delayed until psychological treatment has been completed.
- The pharmacological treatment for co-occurring ASD and ADHD in children and adults differs from the treatment of each disorder separately.
- ADHD medications should not be offered to treat people with ASD (without co-occurring ADHD) as there is no evidence of a positive effect in this population.
- Due to high comorbidity rates associated with ADHD and ASD, such as anxiety, mood problems and sleep disturbance, medications to address comorbidity should be considered.
- A ‘start low and go slow’ approach to titration should be considered, as people with both conditions may be more treatment resistant and more sensitive to the effects of medication.
Specific medications with efficacy:
Risperidone and Aripiprazole:
- Risperidone and aripiprazole are approved for treating ASD, with beneficial results in reducing irritability.
- They are indicated for short-term treatment of angry outbursts in children and adolescents with ASD, some of whom may have ADHD.
- However, there is variability in recommendations across countries regarding antipsychotics for ADHD and ASD.
Methylphenidate and Atomoxetine:
- Methylphenidate and atomoxetine improve symptoms such as hyperactivity and impulsivity, which may not be associated with the patient’s ASD diagnosis.
- Atomoxetine and methylphenidate show evidence for treating ADHD symptoms in individuals with ASD. However, effect sizes from the ASD population are somewhat smaller than the non-ASD population, and side effects are more common in the ASD population. [Antshel et al., 2013]
- In individuals with ASD and an intellectual disability, atomoxetine was efficacious for reducing ADHD symptoms in 43% of the children.
- Some individuals may experience an increase in tics with stimulants.
- Stimulant medications should not be prescribed for pregnant women.
- A cautious approach should be taken when prescribing stimulant medications to older adults or individuals with a history of cardiac problems.
- The British Association for Psychopharmacology (BAP) recommends the use of methylphenidate, atomoxetine, and guanfacine (in that order) for ADHD management in individuals with ASD. [Howes et al, 2018]
- An 8-week trial of extended-release guanfacine in youth with ASD+ADHD resulted in significant reductions in parent-reported oppositional behaviours compared to placebo. [Politte et al, 2018]
- Melatonin has been shown to improve sleep quality for individuals with ADHD and ASD.
- In addition, melatonin may be helpful for insomnia associated with stimulant medications.
- In individuals with ASD, melatonin resulted in an 80% improvement in sleep quality, with longer overall sleep duration and easier onset. [Lalanne et al., 2021]
- Melatonin may have specific benefits in the context of neurodevelopmental disorders. Melatonin administration reduces oxidative stress in infants exposed to an infection or foetal distress, thus showing a neuroprotective effect. [Chaste & Leboyer, 2012]
- Melatonin also shows a neuroprotective effect on developing damaged white matter through decreased microglial activation and oligodendroglial maturation, normalising the myelination process. Melatonin may thus benefit perinatal brain injury and inflammatory and demyelinating diseases observed in adults. [Olivier et al, 2009]
Selective serotonin reuptake inhibitors (SSRIs):
- SSRIs may be used in comorbid depression and /or anxiety.
- They are used in treating repetitive behaviours in individuals with comorbid ADHD and ASD, but their efficacy is questionable. [Reiersen et al., 2011]
- A meta-analysis involving nine randomised control trials demonstrated insufficient evidence for the efficacy of the SSRIs fluoxetine, citalopram, and fluvoxamine in children with ASD. [Williams et al., 2011]
- On the other hand, treatment with fluoxetine significantly decreased obsessive-compulsive behaviours in children and adolescents with ASD. [Reddihough et al., 2019]
- Caution is advised when prescribing SSRIs with stimulants, as they may interact adversely with amphetamines. Amphetamines increase serotonin levels.
- Individuals with ASD may have difficulty consuming medications in tablet form, and liquid preparations should be prescribed if necessary.
- Visual representations of mood states, visual analogue scales, sketches and drawings may help obtain subjective reports of treatment outcomes and side effects.
ADHD and ASD frequently coexist, which can exacerbate the challenges either diagnosis faces alone.
Identifying and assessing these conditions is difficult due to shared causes and symptoms.
Managing both disorders is complicated by their core features and other mental health conditions.
Barriers to effective care include poor access, inadequate training, comorbidities, stigma, and poor self-advocacy.
Integrated multidisciplinary services can be more efficient, cost-effective, and user-friendly.
Training in recognising and treating ADHD, ASD, and comorbidities and inter-agency collaboration is essential.
Consensus among professionals can improve diagnoses and interventions and increase positive outcomes.
More research is needed on the most effective treatments and longer-term outcomes.
Christakou, A., Murphy, C. M., Chantiluke, K., Cubillo, A. I., Smith, A. B., Giampietro, V., … & Rubia, K. (2013). Disorder-specific functional abnormalities during sustained attention in youth with attention deficit hyperactivity disorder (ADHD) and with autism. Molecular psychiatry, 18(2), 236-244.
Shen, C., Luo, Q., Chamberlain, S. R., Morgan, S., Romero-Garcia, R., Du, J., … & Sahakian, B. J. (2020). What is the link between attention-deficit/hyperactivity disorder and sleep disturbance? A multimodal examination of longitudinal relationships and brain structure using large-scale population-based cohorts. Biological psychiatry, 88(6), 459-469.
Pagan C, Goubran-Botros H, Delorme R, Benabou M, Lemière N, Murray K, Amsellem F, Callebert J, Chaste P, Jamain S, Fauchereau F, Huguet G, Maronde E, Leboyer M, Launay JM, Bourgeron T. Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders. Sci Rep. 2017 May 18;7(1):2096
Reddihough, D.S.; Marraffa, C.; Mouti, A.; O’Sullivan, M.; Lee, K.J.; Orsini, F.; Hazell, P.; Granich, J.; Whitehouse, A.J.O.; Wray, J.; et al. Effect of Fluoxetine on Obsessive-Compulsive Behaviors in Children and Adolescents with Autism Spectrum Disorders: A Randomized Clinical Trial. J. Am. Med. Assoc. 2019, 322, 1561–1569