Serotonin and Beyond training

Attention-Deficit Hyperactivity Disorder Jan Buitelaar Radboud University Medical Center Donders Institute for Brain, Cognition and Behavior Department of Cognitive Neuroscience, and Karakter Child and Adolescent Psychiatry University Center Nijmegen, The Netherlands Webinar Serotonin & Beyond, February 7, 2023 Summary • ADHD has a strong genetic component • ADHD is very heterogeneous at the cognitive and neural level • Both delayed and deviant brain development • Abnormalities of fronto-striatal, frontoparietal and fronto-cerebellar circuits • Cognition: multiple pathway model Inattention Impulsivity/Hyperactivity ADHD -Core Symptom Areas ADHD: DSM-5 Criteria • Inattention to details/ makes careless mistakes • Difficulty sustaining attention • Seems not to listen • Fails to finish tasks Inattention • Difficulty organizing • Avoids tasks requiring sustained attention • Loses things • Easily distracted •Forgetful Six or more of the following -manifested often: DSM-IV, 1994 ADHD: DSM-5 Criteria Impulsivity • Blurts out answer before question is finished • Difficulty awaiting turn • Interrupts or intrudes on others Hyperactivity •Fidgets • Unable to stay seated • Inappropriate running/climbing (restlessness) • Difficulty in engaging in leisure activities quietly • “On the go” • Talks excessively Impulsivity/Hyperactivity Six or more of the following -manifested often: Neurodevelopmental Disorders • Extreme of normal variation • Quantitative variation • Neurodiversity • Dimensional modal 4 D’s •Disease, •Disorder •Disability •Difference • Disease •Abnormality • Qualitative differences • Psychopathology •Categories Figure 1 The history of attention-deficit/hyperactivity disorder Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 ADHD -Diagnostic Considerations Inattention Impulsivity/Hyperactivity Comorbidity –the full spectrum sleep problems motor problems (DCD) learning disorders ODD en CD tics and OCD bipolar disorder substance use/ gambling obesity autism spectrum disorder (ASD) anxiety and depression ADHD NLZYA00380a Genes Environment Brain Clinical symptoms Activity dependent development Compensatory processes may mask primary deficits These neurodevelopmental disorders are thought to result from the disruption of normal brain development and related neurobiological mechanisms during the prenatal and early postnatal period The developmental “snowball”rolls downhill over time…… “ Outcome ” ? …….gathering speed and mass (loadings for psychopathology and atypicality). “ Outcome ” ? …….gathering speed and mass (loadings for psychopathology and atypicality). Environmental Influences Genetic Predispositions Maturation Time Birth “ Outcome ” Child ’ s Own Behavior The developmental pathway of an individual child reflects not only genetic endowment and environmental effects, but also the interactions among these and the child ’ s own activity over time. Time Protective and Supportive Conditions and Adverse Events Risks and Protective Factors Behavior Birth “ Outcome ” Maturation and Maturational Vulnerabilities Genetic Predispositions Environmental Influences Adaptive and Maladaptive Behaviors Influences on development are both positive and adverse. Likewise, the individual ’ s behaviors over time are both adaptive and maladaptive. Is ADHD in Adults a Valid Diagnosis? SYNDROMATIC CONTINUITY Family-Genetic Studies Treatment Effectiveness Comorbidity and Neuropsych Deficits Impairments Imaging Studies Causes of genetic disease (adapted from McCarthy et al., 2008) Very rare Rare Uncommon Common High Intermediate Modest Low Allele frequency Prenetrance Monogenic Diseases Multifactorial diseases 0.10.010.001 Oligogenic Diseases Major Rare Variant About 5-10% of ADHD? Figure 1 The history of attention-deficit/hyperactivity disorder Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 Faraone et al. (2015). Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 Twin studies Faraone & Larsson (2019) Molecular Psychiatry, 24(4):562-575575 Prevalence of ADHD in rare genetic conditions Faraone & Larsson (2019) Molecular Psychiatry, 24(4):562-575575 Gizer et al., 2009 3-5% of genetic contribution explained by known risk alleles XXXX Early development – role of temperament Nigg et al. (2021) Annu Rev Dev Psychol Genetics of ADHD –Latest GWAS Demontis (2019). Nature Genetics, 51, 63-75 Genetics of ADHD –PRS-ADHD Demontis (2019). Nature Genetics, 51, 63-75 ADHD shares genetic factors with many other traits Demontis (2019). Nature Genetics, 51, 63-75 Figure 1 The history of attention-deficit/hyperactivity disorder Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder. Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 Dorsolateral PFC – working memory Figure 1 The history of attention-deficit/hyperactivity disorder Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder. Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 Reward system Figure 1 The history of attention-deficit/hyperactivity disorder Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder. Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.20 Default mode network Structural MRI: subcortical and cortical differences Hoogman et al. (2019). Am J Psychiatry 176(7):531-542 Structural MRI Stop-signal task Van Rooij et al. American Journal of Psychiatry 2015, 172(7):674-83 Van Rooij et al. Neuroimage Clinical 2015, 13;7:325-35. Stop-signal task Functional connectivity, task performance and ADHD severity Conclusions •Longer Stop Signal Reaction Time (SSRT) •Hypoactivation in Left IFG, node of inhibition network •Altered neural connectivity in ADHD: -hypo-connectivity within Response Inhibition Network -hyper-connectivity within Default Node Network •Levels of connectivity are related to both response inhibition performance and ADHD phenotype •Neural connectivity provides important complementary insight into the neurobiological underpinnings of response inhibition deficits Neurophysiology Correlations between disorders in brain abnormalities (7 subcortical and 34 cortical regions) Radonjić et al, Translational Psychiatry, 2020 Greater similarity in brain abnormalities (7 subcortical and 34 cortical regions) between disorders correlates with stronger genetic correlation between disorders Radonjić et al, Translational Psychiatry, 2020 ADHD and Stress Genetics and Imaging Genetics “ Genetic sensitivity to the environment ” Caspi et al. Science; 301:386–389 (2003). Interaction between serotonin transporter and stress / life events 5-HTTLPR Stress Brain correlates of the interaction effect between the serotonin transporter gene and stress exposure mediating ADHD Dennis van der Meer, Pieter J. Hoekstra, Marcel Zwiers, Maarten Mennes, Lizanne J. Schweren, Barbara Franke, Dirk J. Heslenfeld, Jaap Oosterlaan, Stephen V. Faraone, Jan K. Buitelaar # & Catharina A. Hartman # Journal of Child Psychology Psychiatry, 2014, Dec;55(12):1363-71 American Journal of Psychiatry, 2015, Aug 1;172(8):768-75 Van der Meer et al. JCPP (2014). Van der Meer et al. JCPP (2014). ØAge ØGender ØSocio-economic status ØScanning location Regression of stress on the anterior cingulate volume Conclusions 1. 5-HTTLPR moderates the effects of stress on GMV in several frontal regions involved in social-cognitive processes and cognitive control1. 2. GMV of areas involved in cognitive control mediate the effect of the GxE on ADHD symptom count. 1 Olson et al. Brain 2007, 130:1718-1731; Pessoa Nat Rev Neurosci. 2008, 9(2):148-58. Summary • ADHD has a strong genetic component • ADHD is very heterogeneous at the cognitive and neural level • Both delayed and deviant brain development • Abnormalities of fronto-striatal, frontoparietal and fronto-cerebellar circuits • Cognition: multiple pathway model Aims and objectives of treatment – Reduce core symptoms of ADHD and autism – Reduce comorbid symptoms – Reduce risk of further complications – Educate the patient and the environment about the disorder – Adapt the environment to the patient’s needs – Enhance patient, parent, teacher et al’s coping skills – Change maladaptive views More care than cure 88 CAADRA pharmacological treatment recommendations: children (≥ 6 years), adolescents and adults • A combination of medication and psychosocial interventions is recommended • Recommended pharmacological treatments are unchanged from the 2011 Clinical Practice Guideline: − 1st line: long-acting psychostimulants (AMP, MPH and LDX) − 2nd line/adjunctive: non-stimulants (ATX) and short/intermediate acting psychostimulants (MPH and DEX) −The non-stimulant GXR is available for children and adolescents only (6-17 years old) − 3rd line: exceeding recommended maximum doses or treatment with off-label drugs bupropion, clonidine, imipramine and modafinil AMP, amphetamine; ATX, atomoxetine; DEX, dextroamphetamine; GXR, guanfacine; LDX, lisdexamfetamine; MPH, methylphenidate Canadian ADHD Resource Alliance (CADDRA): Canadian ADHD Practice Guidelines, 4th Edition, Toronto, ON; CADDRA, 2018. Available at: https://www.caddra.ca/canadian-adhd-practice-guidelines/ In the 2018 guidelines, generic long-acting psychostimulants are considered 2nd line agents because of the unpredictability of response Comparison of duration of clinical effect between ADHD treatments Adapted from Hazell. CNS Drugs. 2007;21(1):37-46. School activities Extracurricular, homework, driving, part-time work IR stimulant plus SR stimulant SR stimulant plus IR stimulant OROS methylphenidate Atomoxetine 0800 1000 1200 1400 1600 1800 2000 2200 2400 Time (h) Guanfacine Non-stimulants • Atomoxetine • Guanfacine • Both act on the noradrenergic system