ADHD Across the Lifecycle: Definitions and Overview

Transcription

1 ADHD Across the Lifecycle: Definitions and Overview Joseph Biederman, MD Professor of Psychiatry Harvard Medical School Chief, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD Massachusetts General Hospital

2 Disclosures My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose: Research support: DOD, FDA, AACAP, Alcobra, Forest Research Institute, Ironshore, Lundbeck, Magceutics Inc., Merck, PamLab, Pfizer, Shire Pharmaceuticals Inc., SPRITES, Sunovion, Vaya Pharma/Enzymotec, and NIH. Royalties paid to the Department of Psychiatry at MGH, for a copyrighted ADHD rating scale used for ADHD diagnoses: Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance US Patent Application (Provisional Number #61/233,686) through MGH corporate licensing, on a method to prevent stimulant abuse.

3 CDC describes ADHD as a serious public health problem Still describes Defect of Moral Control in The Lancet Bradley shows that benzedrine reduces hyperactivity Methylphenidate indicated for behavioral disorders in children Long- acting stimulants developed DSM IV refines criteria Twin studies document high heritability Similar correlates of ADHD in boys & girls Non-stimulants approved DSM-5 extends age at onset to 12 & adjusts criteria for adults ADHD symptoms described as Minimal Brain Dysfunction DSM II Hyperkinetic Reaction DSM III operationalizes diagnostic criteria Neuroimaging documents structural and functional brain anomalies ADHD in adults recognized as valid disorder CBT for adult ADHD Comorbidity with anxiety/mood/autism spectrum disorders & executive dysfuntion confirmed Faraone et al, Nature Reviews Disease Primers (In Press) Rare genomic insertions and deletions discovered Molecular polygenic background confirmed

4 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 (%)

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

6 Zuvekas al. Am J Psychiatry 2012; 169:

7 Poor Adherence to Treatment in ADHD Despite the well documented morbidity of ADHD and the marked efficacy and safety of stimulants, the failure to adhere to medications after one year is as high as 87%!! (Safren 2007)

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 ADHD: Core Symptom Areas Inattention Impulsivity/Hyperactivity

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

11 ADHD: Course of the Disorder Hyperactivity Impulsivity Inattention Time

12 Persistence Rate Persistence of Full and Residual Diagnoses in Prospective Studies Residual Diagnosis Full Diagnosis Age at Follow-up Loss of full diagnostic status is not equivalent to remission. Faraone et al. Psychol Med. 2006;36:

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14 Persistent Controversy BMJ 3 april 2010 Vol 340

15 Changes in DSM-V 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

16 ADHD as a Brain Disorder: Neuroimaging Findings

17 Developmental Trajectories of Brain Volume Abnormalities in Youth w/adhd Design: MRI case control study N=152 youth w/ ADHD and 139 controls of both genders Objective: assess volumetric changes overtime in medicated vs unmedicated youth w/adhd and controls Castellanos et al. JAMA Oct;288(14):1740-8

18 Developmental Trajectories of Brain Volume Abnormalities in Youth w/adhd Main Findings: Smaller brain volumes in all regions independently of medication status Smaller total cerebral (-3.2%) and cerebellar (- 3.5%) volumes Volumetric abnormalities (except caudate) persisted with age No gender differences Volumetric findings correlated with severity of ADHD Castellanos et al. JAMA Oct;288(14):1740-8

19 Milliliters Brain Volumes and ADHD Unadjusted Total Cerebral Brain Volume for Unmedicated and Medicated Children and Adolescents With ADHD and Controls 1,120 1,100 N=139 1,080 N=103 1,060 1,040 N=49 1,020 1,000 Non-ADHD Controls Unmedicated Medicated *p=0.001 by 2-way analysis of variance (group [medicated vs. unmedicated vs. control] by sex); Castellanos FX et al. (2002), JAMA 288(14):

20 Developmental Trajectories of Brain Volume Abnormalities in Youth w/adhd Conclusions: Genetic and or early environmental influences on brain development in ADHD are fixed, nonprogressive and unrelated to stimulant treatment Castellanos et al. JAMA Oct;288(14):1740-8

21 Figure 4a Dorsolateral prefrontal cortex Parietal cortex Ventromedial prefrontal cortex Faraone et al, Nature Reviews Disease Primers (In Press)

22 Figure 4b Dorsal anterior cingulate cortex Ventral anterior cingulate cortex Nucleus caudatus Putamen Nucleus accumbens Cerebellum Amygdala Faraone et al, Nature Reviews Disease Primers (In Press)

23 MRI findings in Adult with ADHD Seidman et al. Biol Psychiatry, 2006; 60:

24 Volume Reductions in Adult ADHD Volumetric reductions in light blue (frontal and cerebellar regions) Superior frontal gyrus Anterior cingulate gyrus Cerebellar cortex Seidman et al. Biol Psychiatry, 2006; 60:

25 Cortical Thickness Analysis in Adult with ADHD Angular Gyrus (BA 39) Supramarginal Gyrus (BA 40) Dorsolateral Frontal Cortex (BA 8, 9) Middle Temporal Gyrus (BA 21) Superior Temporal Gyrus (BA 22) Makris et al. Cerebral Cortex June 2007; 17:

26 Cortical Thickness Analysis in Adult with ADHD Anterior Cingulate Gyrus (BA 24) Orbital Frontal Cortex ((BA 11, 12, 13, 14) Orbital Frontal Cortex ((BA 11, 12, 13, 14) Makris et al. Cerebral Cortex June 2007; 17:

27 A DTI-MRI Study of Connections in ADHD Makris et al. Cerebral Cortex 2008 May;18(5): Reproduced from Makris N, et al. Cerebral Cortex. 2007; doi: /cercor/bhm156.

28 Dorsal Anterior Cingulate Cortex (Cognitive Division) Fails to Activate in ADHD Normal Controls ADHD y = +21 mm 1 x 10-2 y = +21 mm 1 x x x 10-3 MGH-NMR Center & Harvard- MIT CITP Bush et al, Biological Psychiatry 1999

29 Methylphenidate Activates Dorsal Anterior Midcingulate Cortex OROS MPH Placebo P = 0.02 vs PBO Baseline 6 Weeks fmri at baseline and again at week 6 OROS MPH group showed higher damcc activation at 6 weeks vs placebo N=21 adults with ADHD; dosing to 1.3 mg/kg/day OROS MPH or placebo Bush et al. Arch Gen Psychiatry. 2008:65:

30 Cortical Thickness Differences Functional ROI Dorsal ACC (dacc) Cognition DTI ROI Perigenual ACC (pacc) Emotion Volumetric ROI

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32 Nakao et al. Am J Psychiatry 2011

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34 Resting-State Functional Connectivity in a Longitudinal Sample of ADHD Children Grown Up

35 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

36 Reduced MPFC-PCC Coupling Reflects Current Diagnostic State of ADHD

37 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 (vs. controls & vs. remitting ADHD)

38 Spencer et al. J Clin Psychiatry 2013 Sep;74(9):

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

40 ADHD as a Neurobiological Disorder: Catecholamine Dysregulation

41 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):

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

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44 ADHD as a Neurobiological Disorder: Genetic Findings

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

46 Laarson 2004 Panic Disorder Schizophrenia ADHD Height 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 Faraone et al. Biol Psychiatry. 2005;57: Heritability Mean heritability of ADHD =.75

47 Gene finding in ADHD Effect size High - 22q11.2 deletion syndrome - Jacobsen syndrome (deletions of end of 11q) - Turner s syndrome (X0) - Klinefelter s syndrome (XXY) Rare chromosomal anomalies - 16p q11-13 region containing nicotinic alpha-7 acetylcholine receptor subunit gene -Rare point mutations expected from sequencing studies Intermediate Rare & Low frequency copy number variants - Monoamine system genes - Neurite outgrowth genes Modest Low Common variants explain about 40% of heritability Very rare Rare Low frequency Common Allele frequency Faraone et al, Nature Reviews Disease Primers (In Press)

48 The Dopamine Story... Presynaptic Neuron Dopamine Transporter (DAT) Dopamine Methylphenidate (MPH) Dopamine Receptor (DRD4)

49 Measuring Changes in Dopamine Dopamine Stress Test T Y R O S I N E T Y R O S I N E D O P A D O P A D A D A D A M A O D O P A C D A D A D A M A O D O P A C H O C O N H C H 2 H O 1 1 C H 3 C l C l [ 11 C ] r a c l o p r i d e N C 2 H 5 R R D A D A D A R R D A D A D A R D A D A D A D A D A R m e t h y l p h e n i d a t e H O C O N H C H 2 H O 1 1 C H 3 N C 2 H 5 C l C l [ 1 1 C ] r a c l o p r i d e Volkow, Swanson. Am J Psychiatry Nov;160(11):

50 DAT PET Imaging (Altropane) with and without oral MPH Baseline After Oral MPH

51 DAT Binding DAT Binding (age-corrected) in Right Caudate by Diagnosis % p < ADHD Controls N=21 N=26 Spencer et al Biol Psychiatry 2007

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54 ADHD Genetics The literature is predominated by candidate gene studies Genome-wide association studies are emerging CNV studies are emerging ADHD Genetics Publications 20 0

55 History of Maternal Smoking (%) Maternal Smoking During Pregnancy: Results in Children 25% 20% P=0.002 * P=0.04, controlling for SES, parental ADHD, and parental IQ 15% 10% 22% 5% 8% 0% ADHD Controls N=140 N=120 Milberger et al. Am J Psychiatry 1996;153:1138.

56 Volume (x10 9 mm 3 ) Prenatal Nicotine Exposure: Effects on Brain Structure Cingulate Cortex * 1.5 Nicotine (6) Control (6) (14% reduction, P<0.001) Prenatal nicotine exposure reduces the volume of the cingulate cortex Bhide et al 2009

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58 Prenatal Exposure (PNE (F1) Mice Have Increased Spontaneous Locomotor Activity F1 - Male F1 - Female

59 Zhu et al. J Neuroscience 2012; 32(27):

60 ADHD Diagnostic Considerations Inattention Impulsivity/Hyperactivity

61 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,

62 Biederman et al. AJP. April 2010

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64 Parental Support at the 16-Year Follow-Up 40% 35% 30% 25% 20% 15% 10% 5% 0% z=2.13 p= % 26.6% Controls Financially Dependent on Parents ADHD z=2.45 p= % 38.0% Lives with Parents Biederman et al. JCP 2012

65 College Graduate at the 16-Year Follow-Up Controls ADHD 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 84.6% z=-4.78 p< % Biederman et al. JCP 2012

66 Hollingshead Mean Score (Higher Score = Higher SES Overall SES at the 16-Year Follow-Up Controls ADHD z=3.47 p= Biederman et al. JCP 2012

67 Hollingshead Mean Score (Higher Score = Higher SES Educational and Occupational Level at the 16- Year Follow-Up Controls ADHD z=-5.36 p< z=-3.12 p= Educational Level (1 to 7) Occupational Level (1 to 9) Biederman et al. JCP 2012

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

69 Protective Effect of Stimulants on Comorbidity 2 (1) =19.7, p< (1) =17.8, p< (1) =3.5, p=0.063 Biederman et al. Pediatrics 2009

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

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

72 Risk for SUD (%) ADHD and Substance Abuse 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):

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

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75 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

76 Humphreys et al. JAMA Psychiatry 2013

77 Survival Probability Onset of Nicotine Use in Children and Adolescents with ADHD ADHD Control P< Age (years) Milberger S, et al. J Am Acad Child Adolesc Psychiatry. 1997:36;37-44.

78 Hammerness et al. J Pediatr 2012

79 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

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81 Novel Comorbidities

82 Emotional Dysregulation

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

84 Deficient Emotional Self Regulation in Youth with ADHD % % 0 Controls Rates of DESR 44% 2 (1)=108.4, p<0.001 ADHD % subjects with ADHD-associated severe impairment 60 50% 50 z=2.49, p= % 32% ADHD ADHD+DESR Spencer et al. Postgrad Med Sep;123(5):50-9.

85 Autistic Traits

86 From Autism to Autistic Traits Autism Clinical and Research Programs in Pediatric Psychopharmacology

87 Autistic Traits in ADHD Children 25% 20% 15% 18.0% p < % 5% 0% ADHD Probands 1.0% Control Probands

88 PTSD and TBI

89 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. Spencer-Kimchi et al submitted

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

91 Man et al. Pediatrics Dec 15.

92 Mikolajczyk et al. JAMA Pediatr. 2015; doi: /jamapediatrics

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94 Functional Impairments Results of A Survey of 1000 Subjects with and without ADHD

95 Educational Impairment in High School Percentage of Those Who Attended High School "C" average or lower * 27% 52% Had a tutor * 13% 37% Had special classes * 10% 37% ADHD (N=464) Had to repeat a grade * 8% 30% Non-ADHD (N=487) * p.001 Biederman et al. J Clin Psychiatry Apr; 67(4):524-40

96 Current Employment Status Percentage of Each Group Currently employed * 52% 72% Employed full time * 34% 57% Not currently employed * 27% 48% Looking for work * 5% 14% ADHD (N=500) Non-ADHD (N=501) * p.001 Biederman et al. J Clin Psychiatry Apr; 67(4):524-40

97 Average Household Income by Education Level Attained Control ADHD $100,000 $90,000 $91,316 $80,000 $70,000 $66,683 $63,086 $60,000 $52,404 $50,000 $46,471 $38,733 $40,000 $29,577 $30,000 $23,859 $20,000 $10,000 $0 Less than High School High School/Some College College/Some Post- Grad Post-graduate Degree Education (Highest Degree Obtained) Biederman and Faraone. Medscape General Medicine 2006; 8:12.

98 Probability of Accident Accidents and Near Misses 80% P<0.05* 70% P<0.05* 60% 50% 40% ADHD ADHD 30% 20% 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)

99 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

100 Mean Number of Impaired Health Risk Indicators P=0.003 Impaired Health Risk indicators: cutoffs defined by values outside the normal range Spencer et al submitted

101 Dalsgaard, S., Østergaard, S. D., Leckman, J. F., Mortensen, P. B., & Pedersen, M. G. The Lancet. 2015;

102 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