ADHD as a circadian rhythm dysfunction: proof and implications for chronotherapy

Abstract

Accumulating evidence indicates that circadian rhythm dysfunction is a clinically significant and highly prevalent phenotype in a substantial subgroup of individuals with Attention-Deficit/Hyperactivity Disorder (ADHD). This perspective synthesizes convergent lines of evidence demonstrating strong associations between ADHD and evening chronotype with phase-delayed biological markers. Sleep disturbances are profound: insomnia and sleep disturbances affect up to 80% of adults with ADHD and similarly up to 82% of children with ADHD, delayed sleep-wake timing occurs in up to 78%, and dim-light melatonin onset (DLMO) is delayed by approximately 45 minutes in children and 90 minutes in adults. These alterations coincide with blunted and delayed cortisol rhythms, reduced pineal volume, and attenuated peripheral clock-gene rhythms (BMAL1/PER2). Intervention studies demonstrate that the circadian phase can be successfully advanced in ADHD populations. Melatonin and bright light therapy has advanced DLMO in both children and adults with ADHD. Emerging data correlate phase advancement with ADHD symptom improvement, and winter trials suggest circadian preference shifts best predict symptom improvement. Sleep programs improve ADHD symptoms, sleep quality, and functioning in children. Exercise and multimodal protocols for evening chronotypes successfully advance circadian timing in non-ADHD populations and warrant investigation in ADHD. Based on this evidence, we propose a pragmatic, behavioral-first clinical pathway: routine screening for sleep/circadian disturbances; phenotypic characterization through chronotype assessment, sleep tracking, and DLMO when feasible; implementation of fixed wake times, morning bright light exposure, evening light restriction with screen hygiene, and regularized zeitgebers; and selective low-dose melatonin for confirmed or probable DLMO delays.

Introduction

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder characterized by impaired levels of inattention, hyperactivity, and impulsivity (1). There is a rising physique of analysis figuring out that ADHD has a big sleep and circadian element (2, 3). Insomnia is current in as much as 80% of adults with ADHD and equally excessive charges (as much as 82%) of youngsters with ADHD (4, 5). Converging proof signifies that circadian rhythm disruption represents a extremely prevalent and clinically essential phenotype that interacts with ADHD signs in complicated, bidirectional methods in a considerable proportion (although not all) of people. In parallel, medical trials have begun focusing on the circadian system and have demonstrated that section shifting the inner clock of individuals with ADHD can enhance signs.

Herein, we suggest the adoption of behavioral circadian interventions as adjuncts in ADHD care. This circadian-informed method is a realistic, scalable, and usually low danger. We invite rigorously future well-designed, stratified trials to quantify results on core ADHD outcomes, outline responder phenotypes, and optimize circadian-focused protocols.

Sleep disturbances, evening chronotype and delayed circadian phase in ADHD

An estimated 73-78% of children and adults with ADHD have a delayed sleep/wake cycle (6). These findings persist even within the absence of comorbid psychological well being situations, with a number of impartial research confirming elevated charges of self-reported sleep issues in adults with ADHD (7). These subjective experiences are corroborated by goal sleep research, which exhibit that sleep onset latency and sleep effectivity issues stay considerably related to ADHD even after controlling for anxiousness and despair (8).

A complete systematic overview discovered sturdy proof for night chronotype predominance in ADHD (2). Approximately three-quarters of adults who developed ADHD in childhood present goal proof of phase-delayed circadian rhythms. Biological markers corresponding to dim-light melatonin onset in saliva, core physique temperature rhythms, and actigraphically-recorded sleep patterns are usually shifted later by roughly 90 minutes in comparison with neurotypical adults (9).

Biological circadian markers and mechanisms in ADHD

Melatonin

Phase delays of melatonin in both individuals with ADHD have been well characterized, with children and adults identified to have a delayed onset of about 45 minutes and 90 minutes, respectively (10). Beyond the section delay of melatonin onset in ADHD, there may be proof that the quantity and sample of melatonin manufacturing might differ (Figure 1). Some research have noticed abnormally excessive ranges of melatonin through the day in youngsters with ADHD, which improves with methylphenidate therapy (6). This capacity to suppress daytime melatonin ranges and shift the melatonin rhythm earlier suggests a fancy interaction between ADHD medicines and circadian methods. Individuals with ADHD have additionally been discovered to have smaller pineal gland (which produces and secretes melatonin) quantity in comparison with wholesome controls, with a constructive correlation between pineal gland quantity and eveningness (11).

Cortisol

ADHD also involves blunted and delayed cortisol rhythms (Figure 1) (12, 13). In an evaluation of adults with ADHD in comparison with age- and sex-matched controls, adults with ADHD had considerably disturbed rhythmicity of not solely melatonin however cortisol (12). A meta-analysis additionally recognized that youngsters with ADHD exhibit decrease basal cortisol ranges, notably within the morning, in comparison with controls (13). This suggests a deficit within the suprachiasmatic nucleus’ capacity to entrain a traditional circadian rhythm with alterations within the circadian rhythm increasing previous melatonin. However, the causation of that is nonetheless unclear, because it has been postulated that extra eveningness and thus mild publicity is also driving these findings.

Clock gene expression

Brain and Muscle ARNT-like 1 (BMAL1) and Period circadian protein homolog 2 (PER2) are core components of the circadian clock in humans, which form a feedback loop to control gene expression in a cyclical manner. Downstream, attenuated BMAL1/PER2 rhythms in oral mucosa indicate weaker or desynchronized peripheral clocks, and symptom severity tracks with reduced PER2 rhythmicity, tying molecular clock strength to the clinical phenotype (12). Together, these information help a mannequin during which people with ADHD persistently expertise shifted endocrine alerts (melatonin/cortisol) coupled with molecular disruptions through the lack of the rhythmic expression of clock genes.

Clinical interventions: chronotherapy in ADHD

Melatonin supplementation

In a randomized trial of adults with ADHD, 0.5 mg per night of melatonin advanced DLMO by 88 minutes with 14% reduction in ADHD symptoms (14). In a randomized, placebo-controlled trial of 101 medication-free youngsters with ADHD and persistent sleep-onset insomnia, 3–6 mg melatonin nightly for 4 weeks superior DLMO by 44 minutes, whereas the management group had a delay of 13 minutes. Total sleep time additionally considerably improved by 20 minutes with melatonin, versus a lack of 14 minutes within the management group. However, inside this 4 week interval, there was no recognized adjustments in cognitive efficiency or downside conduct (15). In a long-term comply with up research of this cohort, 65% of contributors continued every day melatonin; discontinuation resulted in a section delay of sleep in 92% of youngsters (16). Positive enhancements in conduct (71%) and temper (61%) have been reported. Altogether, these findings recommend melatonin successfully advances circadian section in ADHD; nonetheless, additional trials are wanted to outline optimum dose and timing relative to DLMO, the period required for sleep/section positive factors to translate into core symptom enchancment, and responder phenotypes.

Bright light therapy

Studies in healthy populations have demonstrated a powerful ability to phase advance DLMO using bright light exposure. A week of natural light-dark cycle was able to entrain a ~2.6h earlier DLMO in healthy adults (17). Emerging analysis signifies that morning vivid mild can assist stabilize sleep and circadian rhythms in ADHD (14, 18, 19). Adding vivid mild remedy to melatonin yielded the biggest section advance (~2 hours) in adults with ADHD and delayed sleep section (14). In one other pilot trial, 2 weeks of morning vivid mild remedy with a ten,000 lux lamp section superior DLMO by 31 minutes and mid-sleep time by 57 minutes in adults with ADHD. There was a big interplay between ADHD-Rating Scales and Hyperactive-Impulsive sub-scores with section advances in DLMO and mid-sleep time (18).

A 3-week intervention examined the role of bright light therapy in adults with ADHD during the fall/winter period (19). Phase advance in circadian desire emerged because the strongest impartial predictor of enchancment throughout subjective and goal ADHD indices. These findings, particularly within the winter interval, are particularly related as there’s a robust relationship between ADHD signs and signs of seasonal despair (20). One evaluation urged that circadian disturbance considerably mediated the connection between ADHD and seasonal signs of despair (20). In medical populations, the general price of seasonal affective dysfunction is 27% amongst adults with ADHD, with females on the highest danger (21). While extra trials are required, vivid mild remedy could also be much more efficacious for people with ADHD throughout winter months (20).

Behavioral interventions

In a randomized trial of 244 children with ADHD, a behavioral sleep intervention (two fortnightly sessions with strategies provided by psychologists or pediatricians and a follow-up telephone call) significantly improved severity of ADHD symptoms, sleep, quality of life, behavior, and functioning at 6 months post intervention (22).

Although not explicitly examined in individuals with ADHD, exercise is another adjunctive tool to help improve circadian misalignment. Both morning or evening exercise seem to advance DLMO in those with later chronotypes, suggesting exercise at any time of day could be a useful adjunct for those with ADHD who tend to have later chronotypes (23, 24).

A multimodal approach to behavioral therapy has demonstrated significant benefits in a group of “night owls”, which may also translate to those with ADHD. Researchers randomized a group of 22 healthy individuals with late chronotypes to behavioral interventions aimed at advancing their circadian rhythm (25). The basic rules have been to get up 2–3 hours earlier, get up on the identical time on daily basis, maximize morning mild publicity, scale back night mild publicity, keep away from late dinners, keep away from caffeine after 15:00, train within the morning, and keep away from naps within the late afternoon. In simply 3 weeks, the intervention group shifted their DLMO by ~2 hours, wake-up time superior 1.9 hours, and peak cortisol superior by 2.2 hours. Additionally, subjective despair scores decreased by ~58% and stress scores by ~40% within the intervention group. Cognitive efficiency and bodily efficiency additionally improved. Overall, this may very well be an efficient, low-cost technique to supply structured steering to these with ADHD, although particular trials on this inhabitants are wanted.

Conclusion

The accumulated evidence demonstrates that circadian rhythm dysfunction is highly prevalent and clinically meaningful in a substantial proportion of individuals with ADHD, although not universal, and its interaction with ADHD symptoms appears complex and bidirectional. The prevalence of circadian alterations (affecting 73-80% of ADHD patients), consistency of biological markers across studies (phase delays, altered melatonin and cortisol rhythms, disrupted clock gene expression), and efficacy of circadian-targeted interventions in improving both sleep and core ADHD symptoms support a model wherein circadian disruption may play an important role in ADHD pathophysiology in a substantial subgroup, though evidence on remission of ADHD with circadian interventions is lacking.

This evidence warrants reconsideration of current assessment and treatment paradigms. Implementation of routine circadian phenotyping in ADHD evaluation, coupled with evidence-based chronotherapeutic interventions, represents a pragmatic approach to improving outcomes. While not proposing that ADHD be reclassified exclusively as a circadian disorder, the evidence supports recognition of a prevalent circadian phenotype that, when present, may benefit from targeted chronotherapeutic intervention alongside standard ADHD treatments.

The safety profile, accessibility, and potential for synergy with existing treatments make circadian interventions an attractive addition to the ADHD treatment. As the field advances toward precision medicine approaches, circadian phenotyping may prove essential for treatment selection and optimization. Further research is needed to fully elucidate the bidirectional relationships between circadian disruption and ADHD symptoms, identify biomarkers for treatment selection, and establish optimal long-term management strategies.

References

• WolraichMLHaganJF JrAllanCChanEDavisonDEarlsMet al.
  Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. (2019) 144. doi: 10.1542/peds.2019-2528

• AndrewNCooganANMcGowanNMMcGowanNM.
  A systematic review of circadian function, chronotype and chronotherapy in attention deficit hyperactivity disorder. Adhd Attention Deficit Hyperactivity Disord. (2017) 9:129–47. doi: 10.1007/s12402-016-0214-5. Coogan.

• KormanMPalmDUzoniAFaltracoFTuchaOThomeJet al.
  ADHD 24/7: Circadian clock genes, chronotherapy and sleep/wake cycle insufficiencies in ADHD. World J Biol Psychiatry. (2020) 21:156–71. doi: 10.1080/15622975.2018.1523565

• WynchankDBijlengaDBeekmanATKooijJJSPenninxBW.
  Adult attention-deficit/hyperactivity disorder (ADHD) and insomnia: an update of the literature. Curr Psychiatry Rep. (2017) 19:98. doi: 10.1007/s11920-017-0860-0

• BondopandhyayUMcGrathJCooganAN.
  Associations between sleep problems in children with ADHD and parental insomnia and ADHD symptoms. PloS One. (2024) 19:e0298377. doi: 10.1371/journal.pone.0298377

• WajszilberDSantisebanJAGruberR.
  Sleep disorders in patients with ADHD: impact and management challenges. Nat Sci Sleep. (2018) 10:453–80. doi: 10.2147/nss.s163074

• SurmanCBHDanielMWalshDM.
  Managing sleep in adults with ADHD: from science to pragmatic approaches. Brain Sci. (2021) 11:1361. doi: 10.3390/brainsci11101361

• BoonstraAMKooijJJSOosterlaanJSergeantJABuitelaarJKVanSomeren EJW.et al.
  Hyperactive night and day? Actigraphy studies in adult ADHD: a baseline comparison and the effect of methylphenidate. Sleep. (2007) 30:433–42. doi: 10.1093/sleep/30.4.433

• Lunsford-AveryJRScottHKollinsSH.
  Editorial Perspective: Delayed circadian rhythm phase: a cause of late-onset attention-deficit/hyperactivity disorder among adolescents? J Child Psychol Psychiatry. (2018) 59:1248–51. doi: 10.1111/jcpp.12956

• Van VeenMMKooijJJSBoonstraAMGordijnMCMVan SomerenEJW.
  Delayed circadian rhythm in adults with attention-deficit/hyperactivity disorder and chronic sleep-onset insomnia. Biol Psychiatry. (2010) 67:1091–6. doi: 10.1016/j.biopsych.2009.12.032

• BumbJMMierDNoelteISchredlMKirschPHennigOet al.
  Associations of pineal volume, chronotype and symptom severity in adults with attention deficit hyperactivity disorder and healthy controls. Eur Neuropsychopharmacol. (2016) 26:1119–26. doi: 10.1016/j.euroneuro.2016.03.016

• BairdALCooganANSiddiquiADonevRMThomeJ.
  Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels. Mol Psychiatry. (2012) 17:988–95. doi: 10.1038/mp.2011.149

• ChangJPSuKPMondelliVParianteCM.
  Cortisol and inflammatory biomarker levels in youths with attention deficit hyperactivity disorder (ADHD): evidence from a systematic review with meta-analysis. Trans Psychiatry. (2021) 11:430–0. doi: 10.1038/s41398-021-01550-0

• vanAndel EBijlengaDVogelSWNBeekmanATFKooijJJS.
  Effects of chronotherapy on circadian rhythm and ADHD symptoms in adults with attention-deficit/hyperactivity disorder and delayed sleep phase syndrome: a randomized clinical trial. Chronobiology Int. (2020) 38:260–9. doi: 10.1080/07420528.2020.1835943

• van der HeijdenKBSmitsMGVan SomerenEJWRidderinkhofKRGunningWB.et al.
  Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. . J Am Acad Child Adolesc Psychiatry. (2007) 46:233–41. doi: 10.1097/01.chi.0000246055.76167.0d

• HoebertMvander Heijden KBvanGeijlswijk IMSmitsMGet al.
  Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia. J Pineal Res. (2009) 47:1–7. doi: 10.1111/j.1600-079x.2009.00681.x

• StothardERMcHillAWDepnerCMBirksBRMoehlmanTMRitchieHKet al.
  Circadian entrainment to the natural light-dark cycle across seasons and the weekend. Curr Biol. (2017) 27:508–13. doi: 10.1016/j.cub.2016.12.041

• FargasonREFobianADHablitzLMPaulJRWhiteBACropseyKLet al.
  Correcting delayed circadian phase with bright light therapy predicts improvement in ADHD symptoms: A pilot study. J Psychiatr Res. (2017) 91:105–10. doi: 10.1016/j.jpsychires.2017.03.004

• RybakYEMcNeelyHEMackenzieBEJainURLevitanRDet al.
  An open trial of light therapy in adult attention-deficit/hyperactivity disorder. J Clin Psychiatry. (2006) 67:1527–35. doi: 10.4088/jcp.v67n1006

• WynchankDSBijlengaDLamersFBronTIWinthorstWHVogelSWet al.
  ADHD, circadian rhythms and seasonality. . J Psychiatr Res. (2016) 81:87–94. doi: 10.1016/j.jpsychires.2016.06.018

• AmonsPJTKooijJJSHaffmansPMJHoffmanTOHoencampE.
  Seasonality of mood disorders in adults with lifetime attention-deficit/hyperactivity disorder (ADHD). J Affect Disord. (2006) 91:251–5. doi: 10.1016/j.jad.2005.11.017

• HiscockHSciberrasEMensahFGernerBEfronDKhanoSet al.
  Impact of a behavioural sleep intervention on symptoms and sleep in children with attention deficit hyperactivity disorder, and parental mental health: randomised controlled trial. BMJ. (2015) 350:h68–8. doi: 10.1136/bmj.h68

• ThomasJ.
  Circadian rhythm phase shifts caused by timed exercise vary with chronotype in young adults. In: Theses and dissertations–kinesiology and health promotion (2019) Lexington, Kentucky, USA:
  University of Kentucky. doi: 10.13023/etd.2019.406

• ThomasJMKernPABushHMMcQuerryKJBlackWSClaseyJLet al.
  Circadian rhythm phase shifts caused by timed exercise vary with chronotype. JCI Insight. (2019) 5:e134270. doi: 10.1172/jci.insight.134270

• Facer-ChildsERMiddletonBSkeneDJBagshawAP.
  Resetting the late timing of ‘night owls’ has a positive impact on mental health and performance. Sleep Med. (2019) 60:236–47. doi: 10.1016/j.sleep.2019.05.001