ADHD Across the Lifecycle: An Overview

Transcription

1 ADHD Across the Lifecycle: An Overview Joseph Biederman, MD Professor of Psychiatry Harvard Medical School Chief, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD Director, Bressler Program for Autism Spectrum Disorders Massachusetts General Hospital

2 Worldwide Prevalence of ADHD in Children N.Y., Mich., Wis. North Carolina Virginia Missouri Oregon Minnesota Tennessee Iowa Pittsburgh New York City Puerto Rico USA Prevalence of ADHD (%) Faraone SV et al. (2003), World Psychiatry 2(2): Spain New Zealand Canada Ireland United Kingdom Israel Switzerland Netherlands/Belgium Germany Ukraine Brazil Japan New Zealand Netherlands China India Ex USA Prevalence of ADHD (%)

3 Akinbami et al. NCHS Data Brief No. 70, August 2011

4 Psychopharmacology Course 2017 Zuvekas al. Am J Psychiatry 2012; 169:

5 Adherence in ADHD is Dismal Only 13% of patients consistently take their medication one year out Patients (%) 100% 80% 60% 40% 20% OROS MPH MPH LA MAS XR Atomoxetine Within 2 to 3 months, a majority of patients with ADHD have stopped taking medication consistently Patients renewed their monthly prescriptions about 2 to 3 times per year 1 0% Month Psychopharmacology Course 2017

6 Percent of Children with ADHD who Renewed their First Stimulant Rx: A Partners Healthcare EMR Review # of patients # of patients who refilled a prescription for 1 medication % of patients who refilled 2, 685 1, % Percent (%) Patients who refilled a prescription for 1 medication

7 Poor Adherence to Treatment in ADHD Poor adherence occurs despite the well documented morbidity of ADHD, the marked efficacy and safety of stimulants as well as the fact that ADHD symptoms return rapidly when the medication is not taken Psychopharmacology Course 2017

8 Long Delays in the Initiation of Treatment (n=1498) p < Age of Onset of Diagnosis Age of Onset of Treatment MGH Pediatric Psychopharmacology Clinic

9 Diagnosis of ADHD Diagnosis is based on clinical assessment of symptoms, associated impairment and age of onset No test is available Symptoms are subjective, as well as developmentally and context sensitive

10 ADHD: Core Symptom Areas Inattention Impulsivity/Hyperactivity Psychopharmacology Course 2017

11 Course of ADHD Symptoms Over Time by Sex: A Growth Curve Model Age by Sex Interaction: NS Psychopharmacology Course 2017 Biederman et al. 2009

12 ADHD: Course of the Disorder Hyperactivity Impulsivity Inattention Time Psychopharmacology Course 2017

13 Age-Dependent Decline and Persistence of ADHD Throughout the Lifetime Psychopharmacology Course 2017 Faraone et al. Nature Reviews Disease Primers 2015

14 Psychopharmacology Course 2017

15 Persistent Controversy BMJ 3 april 2010 Vol 340

16 Changes in DSM-5 ADHD Neurodevelopmental - not disruptive 6/9 inattentive or 6/9 impulsive/hyperactive symptoms over last six months (>5 for adults) Symptoms caused impairment by age 12 (no longer 7) ASDs no longer exclusionary No more subtypes ; Inattentive / Hyperactiveimpulsive / Combined are now Presentations Restricted inattentive subtype: In Appendix, worthy of further study

17 Is ADHD Always a Neurodevelopmental Disorder?:Adult Onset ADHD Recent population studies raised the intriguing question as to whether adult ADHD is always preceded by childhood onset of symptoms (hence neurodevelopmental) or can develop anew in adult life Psychopharmacology Course 2017 Faraone and Biederman JAMA Psychiatry Editorial 2016

18 Is There an Adult Onset ADHD? The age of onset of ADHD by 12 years in DSM-V is completely arbitrary creating the immediate dilemma on how to diagnose patients who have an onset of symptoms >12 Faraone and Biederman JAMA Psychiatry Editorial 2016

19 Adult ADHD A multifactorial etiological view of ADHD posits that symptoms and impairment emerge due to the accumulation of environmental and genetic risk factors As such, there is no clean separation of etiologic risk factors in people above and below the ages of 12 years

20 Adult Onset ADHD A multifactorial etiological view of ADHD suggests that ADHD is a disorder with a continuum of ages of onsets, with some subjects starting their symptoms earlier while others later Faraone and Biederman JAMA Psychiatry Editorial 2016

21 Adult Onset ADHD Moreover, in many cases, the onset of ADHD symptoms and onset of associated impairment can be separated by many years, particularly among those with strong intellectual abilities and those living in supportive, well-structured childhood environments Faraone and Biederman JAMA Psychiatry Editorial 2016

22 Adult Onset ADHD Such intellectual and social scaffolding could help some ADHD children to compensate in early life (subsyndromal symptoms) and manifest the full ADHD syndrome when the scaffolding is removed Faraone and Biederman JAMA Psychiatry Editorial 2016

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24 Forest plot showing OR & 95% CI for binary outcomes between subthreshold ADHD and controls Kirova et al submitted Measure SCAHILL 1999 ODD/Conduct disorder, full GAD/MDD, full Subtotal KADESJö 2001 Intellectual disability Reading/writing disorder developmental coordination disorder ODD, full Tourette's, full Tic disorder, full Asperger syndrome, full Subtotal LEWINSOHN 2004 Two comorbid subthresold disorders More than two comorbid subthresold disorders MDD, subthreshold Bipolar, subthreshold Bulimia or Anorexia, subthreshold Anxiety disorder, subthreshold Alcohol use disorder, subthreshold Substance use disorder, subthreshold Conduct disorder, subthreshold MDD, full Bipolar disorder, full Bulimia or Anorexia, full Anxiety disorder, full Alcohol abuse/dependence, full Substance abuse/dependence, full Conduct disorder, full Subtotal 7.8e Lower Risk Odds Ratio Increased Risk

25 Forest plot showing OR & 95% CI for binary outcome between subthreshold and full ADHD Measure FERGUSSON 2010 MDD or anxiety in young adulthood Antisocial personality disorder in young adulthood Pregnant or got someone pregnant by age 20 Became a parent by age 20 Delayed reading No secondary school degree Subtotal SELINUS 2016 Current hyperactivity/inattention Peer problems School problems Internalizing problems Antisocial behavior Alcohol misuse Substance misuse Subtotal BIEDERMAN IN PRESS ODD, full and/or Conduct disorder, full Depression, full; Dysthymia, full; Manic syndrome, full Multiple (>2) full threshold Anxiety disorders Language development problems Encopresis, full; enuresis-diurnal, full Substance abuse/dependence, full In-school academic services Special education support Repeat grade Deficient emotional self-regulation Severe emotional dysregulation Social challenges Subtotal Overall Kirova et al submitted Lower Risk Odds Ratio Increased Risk

26 Faraone and Biederman. JAMA Psychiatry Jul 1;73(7):655-6.

27 ADHD as a Brain Disorder: Neuroimaging Findings International Psychopharmacology Course 2017

28 Psychopharmacology Course 2017 Faraone et al. Nature Reviews Disease Primers 2015

29 The DLPC is linked to WM, the VMPFC to complex decision making and strategic planning, and the parietal cortex to attention Faraone et al. Nature Reviews Disease Primers 2015 Brain Mechanisms in ADHD The executive control and cortico-cerebellar networks coordinate EFs The VMPFC, OFC & ventral striatum are the brain network associated with anticipation and reward Psychopharmacology Course 2017 The frontal and parietal cortices and the thalamus support attentional functioning Negative correlations between the DMN and the frontoparietal control network are weaker in patients with ADHD

30 Resting-State Functional Connectivity in a Longitudinal Sample of ADHD Children Grown Up Psychopharmacology Course 2017

31 Adult ADHD: Decreased Positive Correlations Between PCC-MPFC 20 ADHD participants (mean age = 34.9; 16 male) Ascertained retrospectively 20 Controls (mean age = 31.2; 14 male) Castellanos et al., 2008 Psychopharmacology Course 2017

32 Reduced MPFC-PCC Coupling Reflects Current Diagnostic State of ADHD Psychopharmacology Course 2017 Mattfeld et al. Brain: A Journal of Neurology 2014, epub: June 10, 2014

33 Neural Basis of Persistent ADHD Persistent ADHD alters intrinsic functional organization of the brain Findings supports the idea that adult ADHD diagnosis reflects a true brain difference Mattfeld et al. Brain: A Journal of Neurology 2014, epub: June 10, 2014

34 Psychopharmacology Course 2017 Mattfeld et al. Brain: A Journal of Neurology 2014, epub: June 10, 2014

35 Hoogman at el. (ENIGMA ADHD Working Group) Lancet Psychiatry 2017 Feb 16. doi: /S (17) Psychopharmacology Course 2017

36 Psychopharmacology Course 2017

37 ADHD Imaging Studies Summary Neuroimaging studies confirm that brain abnormalities in fronto-subcortical networks are associated with ADHD Neuroimaging techniques are not valid tools for ADHD diagnosis; imaging measures are not sensitive or specific enough to be used for diagnostic purposes Treatment attenuate neural deficits Spencer et al. J Clin Psychiatry 2013 Sep;74(9):

38 ADHD as a Neurobiological Disorder: Catecholamine Dysregulation Psychopharmacology Course 2017

39 Frontosubcortical Networks and Catecholamines Dopaminergic and noradrenergic dysregulation abnormalities in fronto subcortical pathways Medications that are effective in ADHD are either dopaminergic or noradrenergic Zametkin. J Am Acad Child Adolesc Psychiatry. 1987;26(5): Zametkin. J Am Acad Child Adolesc Psychiatry. 1987;26(5):

40 Brain Stem to diencephalon and cerebrum Substantia nigra tegmentum (dopamine) MESENCEPHALON to cerebellum Locus ceruleus (norepinephrine) PONS Raphe nuclei (serotonin) Psychopharmacology Course 2017 to cord MEDULLA

41 Psychopharmacology Course 2017

42 ADHD as a Neurobiological Disorder: Genetic Findings Psychopharmacology Course 2017

43 ADHD: Genetics Twin Studies Family Studies Genetic Basis of ADHD Adoption Studies Molecular Genetics

44 Twin Studies of ADHD (Faraone & Larsson, Molecular Psychiatry, 2018) Rydell 2017 Chen 2016 Chang 2013 Langner 2013 Polderman 2011 Greven 2011 Lichtenstein 2010 Ilott 2010 Bornovalova 2010 Cole 2009 Tuvblad 2009 Spatola 2007 Polderman 2007 Derks 2007 Hudziak 2005 Dick 2005 Laarson 2004 Rietveld 2003 Martin 2002 Kuntsi 2001 Coolidge 2000 Thapar 2000 Willcutt 2000 Hudziak 2000 Nadder 1998 Levy 1997 Sherman 1997 Silberg 1996 Gjone 1996 Thapar 1995 Schmitz 1995 Stevenson 1992 Edelbrock 1992 Gillis 1992 Goodman 1989 Willerman 1973 Matheny Heritability Mean heritability across 37 studies = 74% Symptom Counts Diagnoses

45 Common Genetic Variants Mostly the Same for Childhood and Adult ADHD (Ribases et al., in preparation) h 2 SNP = 0.20 (SE = 0.023) h 2 SNP = 0.21 (SE = 0.025) Genetic Correlation R g = 0.81 (0.08) P-Value= e-21

46 Genetic Correlations with other Traits Ever vs never smoked Age at menarche College completion Years of schooling 2016 Neuroticism Subjective well being PGC cross disorder Major depressive disorder Depressive symptoms Upper line: ADHD children + adults Middle line: ADHD children Lower line: ADHD adults

47 New Results from Genomewide Association Studies (GWAS) 0 10,000 20,000 30,000 40,000 sychopharmacology Course 2017 Number of ADHD GWAS Samples Y2012 Y2014 Q4_2015 Q1_2019 Faraone et al, 2015

48 Preliminary ADHD meta-analysis 18,284 cases 33,836 controls Psychopharmacology Preliminary analyses Course suggest 2017 eight genome-wide PGC ADHD/iPSYCH-SSI-Broad significant loci Collaboration

49 Van Hulzen et al. Biol Psychiatry 2017.

50 Maternal Smoking During Pregnancy: Results in Children 25% P= % * P=0.04, controlling for SES, parental ADHD, and parental IQ History of Maternal Smoking (%) 15% 10% 5% 22% 8% 0% ADHD Controls N=140 N=120 Milberger et al. Am J Psychiatry 1996;153:1138.

51 Prenatal Nicotine Exposure: Effects on Brain Structure Volume (x109 mm3) Cingulate Cortex * Nicotine Control (6) (6) (14% reduction, P<0.001) Prenatal nicotine exposure reduces the volume of the cingulate cortex Bhide et al 2009

52 Ra et al. JAMA. 2018;320(3):

53 ADHD Diagnostic Considerations Inattention Impulsivity/Hyperactivity

54 Cumulative Morbidity Risks for Psychiatric Disorders in ADHD and Control Probands Cumulative Morbidity Risk Control ADHD P.009 for all categories Biederman et al. Psychological Medicine, 2006, 36,

55 Psychopharmacology Course 2017 Biederman et al. AJP. April 2010

56 Biederman et al. Pediatrics 2009 Jul;124(1):71-8.

57 Protective Effect of Stimulants on Comorbidity χ 2 (1) =19.7, p<0.001 χ 2 (1) =17.8, p<0.001 χ 2 (1) =3.5, p=0.063 Biederman et al. Pediatrics 2009 Psychopharmacology Course 2017

58 Protective Effect of Stimulants on Comorbidity χ 2 (1) =1.3, p=0.258 χ 2 (1) =21.4, p<0.001 χ 2 (1) =19.9, p<0.001 Biederman et al. Pediatrics 2009

59 Protective Effect of Stimulants χ 2 (1) =18.4, p<0.001 Biederman et al. Pediatrics 2009

60 ADHD and Substance Abuse Risk for SUD (%) Risk for Substance Use Disorder (SUD) Onset in Adults With Untreated ADHD ADHD Control Earlier onset Higher risk P 0.05, ADHD vs control at end point Age at onset (years) Wilens et al. J Nerv Ment Dis. 1997;185(8):

61 SUD in ADHD Youth Growing Up: Overall Rate of Substance Use Disorder Percent of Group Control (n=344) p < Medicated (n=117) Unmedicated (n = 45) Psychopharmacology Course 2017 Biederman, Wilens, Mick et al., Pediatric 1999

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63 Stimulant Therapy and Subsequent Risk for Substance Dependence Disorders *p<0.05 vs. Controls Stimulant Therapy* No Stimulant Therapy* % Controls Age Biederman et al. Am J Psychiatry Mar 3 Psychopharmacology Course 2017

64 Psychopharmacology Course 2017 Humphreys et al. JAMA Psychiatry 2013

65 Onset of Nicotine Use in Children and Adolescents with ADHD 0.6 ADHD Survival Probability P<.003 Control Age (years) Milberger S, et al. J Am Acad Child Adolesc Psychiatry. 1997:36; Psychopharmacology Course 2017

66 Prospective Study of OROS MPH vs. non-adhd and ADHD Omnibus test, chi-squared(1)=8.44, p=0.04 p=0.02 % current smoking according to Fagerstrom Tolerance Questionnaire p= Non-ADHD (n=177) OROS MPH (n=154) ADHD Current Meds (n=36) ADHD Not Current Meds (n=49) Not significant (all p>0.60) Hammerness and Biederman, Jounal of Pediatrics 2012

67 Hammerness et al. J Pediatr 2012

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69 Compton et al. Am J Psychiatry 2018; 175:

70 EVOLVING COMORBIDITIES

71 Amgydala-Prefrontal Circuitry Amygdala: Red Ventromedial prefrontal cortex: Blue Dorsomedial prefrontal cortex: Green (Kim 2011 Behavioral Brain Research)

72 DESR in ADHD and Control Adults (Surman et al., American J Psychiatry, 2011) p< Controls ADHD

73 From Autism to Autistic Traits Autism

74 Prevalence of CBCL-AT Profile 25% 20% 15% 18% p < % 5% 0% ADHD Probands 1% Control Probands Because there were N=2 controls meeting criteria for the AT profile, we did not include them in further analyses

75 PTSD and TBI Psychopharmacology Course 2017

76 Forest Plot of Studies Examining the ORs of PTSD in ADHD Citation NORMAL CONTROLS Antshel 2013 Ruhl 2009 Kessler 2006 Bernardi 2012 Park 2010 Biederman 2012 Hurtig 2007 Smalley 2007 Wozniak 1999 Subtotal PSYCHIATRIC CONTROLS McLeer 1994 (PSY) Ford 2000 Subtotal TRAUMA CONTROLS Daud 2009 (non-tp) Daud 2009 (TP) McLeer 1994 (SA) Husain 2008 Subtotal Age Adult Adult Adult Adult Adult Adult Child Child Child Child Child Child Child Child Child Sample ADHD Population Population Population Population ADHD ADHD ADHD ADHD Population ADHD Population Population Population Population For each comparison, the dot gives the relative risk and the horizontal line gives the 95% confidence interval The center of the diamond at the bottom gives the weighted relative risk across all studies and the width of the diamond gives its 95% confidence interval Relative Risk for PTSD PSY=psychiatric sample. SA=Sexually abused sample. TP=Sample of refugee children with tortured parents. Non-TP=Sample of refugee children with nontraumatized parents. AE Spencer et al submitted

77 Forest Plot of Studies Examining the ORs of ADHD after mtbi

78 Accidents and Near Misses 80% P<0.05* Probability of Accident 70% 60% 50% 40% 30% 20% P<0.05* ADHD ADHD 10% 0% Accident Accident and Near Misses *Indicates P<0.05 after controlling for gender, age, time of day and the age*adhd interaction (Reimer et al., submitted)

79 Percent of Subjects Involved in Collisions During Surprise Events * LDX = lisdexamfetamine dimesylate During the five surprise events, drivers in the medication group were 67% less likely to have a collision than drivers in the placebo group Biederman et al submitted

80 Chang et al. JAMA Psychiatry. doi: /jamapsychiatry Published online May 10, 2017.

81 Lu et al. JAMA Psychiatry 2017 Jun 28.

82 Pharmacotherapy of ADHD ADHD remains the most treatable disorder in Psychiatry Stimulants (amphetamines and methylphenidate compounds) remain the mainstay of treatment for ADHD due to their robust (High Effect Size) efficacy and safety FDA-approved Non Stimulants (Atomoxetine and Alpha-2 Agonist (guanfacine and clonidine extended release) are generally less effective than the stimulants (moderate effect sizes of )

83 Goode et al. Pediatrics Jun;141(6).

84 Summary ADHD is a neurobehavioral disorder with a: Complex etiology Neurobiologic basis Strong genetic component ADHD Affects millions of people of both genders Persists through adolescence and adulthood in a high percentage of cases Can have negative impact on multiple areas of functioning ADHD is a highly treatable disorder