Abstract
Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety disorders and sleep disorders show high rates of comorbidity with complex bidirectional relationships. This systematic review analyses current research findings on prevalence, neurobiological mechanisms and evidence-based treatment approaches. More than 80% of people with ASD experience sleep problems, while 28% additionally meet criteria for ADHD. Anxiety disorders occur in 27–43% of people with ASD. Disrupted melatonin secretion and circadian rhythm disturbances represent central pathophysiological mechanisms. Meta-analyses demonstrate significant efficacy for melatonin therapy and cognitive behavioural therapy (CBT). Multimodal treatment approaches combining pharmacological and behavioural interventions prove most promising for these complex, interconnected conditions.
Keywords: ADHD, autism spectrum disorder, sleep disorders, anxiety disorders, melatonin, cognitive behavioural therapy
Introduction
Research into neurodevelopmental disorders has produced significant insights in recent years into the complex relationships between attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety disorders and sleep disorders. These conditions frequently co-occur and share common neurobiological mechanisms, which creates both diagnostic and therapeutic challenges.
Prevalence and epidemiological relationships
Comorbidity rates in autism spectrum disorder
Current epidemiological studies document striking statistical relationships between these conditions. Among people with ASD, more than 80% show sleep problems, while 20–70% additionally meet ADHD criteria (with wide variance across studies due to methodological differences). Conversely, 20–50% of people with ADHD also have an autism spectrum disorder. Anxiety disorders occur in 27–43% of people with ASD, compared with markedly lower rates in the general population.
Neurobiological mechanisms and aetiology
Melatonin dysfunction as a central mechanism
A key factor in the pathophysiology is disrupted melatonin secretion. People with ASD and ADHD consistently show abnormal melatonin levels, with low melatonin concentrations documented in urine, serum or plasma in both conditions (Mazurek & Petroski, 2015; Van der Heijden et al., 2005).
Genetic studies have identified rare variants in melatonin-related genes (AANAT, ASMT, MTNR1A, MTNR1B) in people with ASD, affecting melatonin synthesis and the corresponding receptors (Melke et al., 2008; Chaste et al., 2011).
Circadian rhythm disturbances
In ADHD, studies demonstrate delayed DLMO (dim light melatonin onset) and increased excretion of 6-sulphatoxymelatonin. Children with ADHD and sleep disorders characteristically present with delayed DLMO and shifted sleep phases (Van der Heijden et al., 2005).
Anxiety disorders intensify this picture through psychological hyperarousal, which leads to difficulties falling asleep. The combination of ASD with anxiety or ADHD can result in particularly severe and treatment-resistant insomnia (Keefer & Vasa, 2021).
Pharmacological treatment approaches
Melatonin therapy: evidence from randomised controlled trials
Evidence of efficacy
Systematic reviews of randomised controlled trials in children aged 2–18 years with ASD and/or ADHD demonstrated statistically significant improvements in sleep duration and sleep latency compared with placebo. The response rate in the melatonin group was consistently higher.
Meta-analyses show that melatonin has positive effects on total sleep time (SMD = 0.78), sleep latency (SMD = 1.23) and sleep efficiency (SMD = -0.70) (Arslan et al., 2022).
Dosage and response rates
Dosage recommendations range from 2 to 10 mg before bedtime. Clinical studies show that 86% of children experience improvements in falling asleep, 54% in sleep duration and 45% in night-time awakenings (Maras et al., 2018).
Safety profile
Side effects were mild and occurred in 14% of patients: fatigue, vomiting, somnolence, cough, mood swings, increased irritability, headache and rash (Maras et al., 2018).
Prolonged-release versus immediate-release formulations
Studies demonstrate that prolonged-release melatonin is better suited to maintaining sleep, whereas immediate-release formulations mainly support falling asleep (Arslan et al., 2022).
Non-pharmacological treatment approaches
Cognitive behavioural therapy (CBT)
Efficacy in ASD and anxiety disorders
Randomised controlled trials show that adapted CBT programmes for children with ASD and anxiety disorders are highly effective. Remission of anxiety disorders appears to be an achievable goal in high-functioning children with ASD (Wood et al., 2020; Storch et al., 2015).
The SENSE study, with 144 adolescents (12–17 years) with high anxiety levels and sleep disturbance, showed significant improvements in subjective and objective sleep parameters as well as in anxiety symptoms following a cognitive-behavioural/mindfulness-based intervention for sleep problems (Blake et al., 2016).
Telehealth and digital interventions
Telehealth CBT for insomnia shows promising results. Parents and children were able to use telehealth CBT successfully to improve sleep quality in both child and parent, child behaviour and parental fatigue (Johnson et al., 2020).
Integrated and multimodal treatment approaches
Combination therapies
Research findings suggest that melatonin may act on symptoms beyond sleep alone – including anxiety, depression, pain and gastrointestinal dysfunction – which frequently occur as comorbidities in ASD (Gagnon & Godbout, 2018).
Studies indicate that family-based cognitive behavioural treatments can reduce sleep disturbance, and that reducing these symptoms may in turn alleviate sleep problems in people with ASD (Fadini et al., 2018).
Clinical implications and practice recommendations
Diagnostic considerations
It is fundamentally important to rule out primary sleep disorders – in particular sleep-related breathing disorders and periodic limb movement disorder – before diagnosing or treating ADHD (Cortese et al., 2013).
Pharmacological ADHD treatment and sleep
Pharmacological ADHD treatment can be complicated by intricate interactions, since stimulants are often associated with disrupted sleep, while some studies also show that effective control of ADHD symptoms can promote sleep (Stein et al., 2012).
Conclusions and future research directions
Current research findings clearly show that a multimodal treatment approach combining both pharmacological interventions (particularly melatonin) and behavioural therapy is the most promising route for treating these complex, interconnected conditions.
Future research should focus on developing personalised treatment strategies that take individual neurobiological profiles into account, and on further optimising combined intervention approaches.
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