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 Massachusetts General Hospital

2 Disclosures My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose: Research support: The Department of Defense, Food & Drug Administration, Ironshore, Lundbeck, Magceutics Inc., Merck, Neurocentria Inc., PamLab, Pfizer, Shire Pharmaceuticals Inc., SPRITES, Sunovion, Vaya Pharma/Enzymotec, and NIH Consultant: I have a financial interest in Avekshan LLC, a company that develops treatments for attention deficit hyperactivity disorder (ADHD). My interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies Departmental Royalties (from a copyrighted rating scale used for ADHD diagnoses): Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH

3 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 (%)

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

5 Zuvekas al. Am J Psychiatry 2012; 169:

6 Patients (%) Adherence in ADHD is Dismal Only 13% of patients consistently take their medication one year out Within 2 to 3 months, a 100% 80% 60% 40% 20% OROS MPH MPH LA MAS XR Atomoxetine 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

7 Poor Adherence to Treatment in ADHD This is so despite the well documented morbidity of ADHD and the marked efficacy and safety of stimulants

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

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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 Moffitt et al. Am J Psychiatry 2015; 172:

17 Adult Onset ADHD It is unclear whether such adults do not recall childhood symptoms, are unable to report on them, or are unable to distinguish onset of symptoms form onset of symptomsassociated impairments that may account for the different ages of onset Faraone and Biederman JAMA Psychiatry Editorial 2016

18 Adult Onset ADHD Onset of symptoms and onset of impairment are often 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

19 Adult Onset ADHD This view of ADHD posits that symptoms and impairment emerge due to the accumulation of environmental and genetic risk factors Those with lower levels of risk at birth will take longer to accumulate sufficient risk factors and longer to onset with symptoms and impairment Faraone and Biederman JAMA Psychiatry Editorial 2016

20 Adult Onset ADHD Such a scenario may suggest that ADHD may be 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 ADHD as a Brain Disorder: Neuroimaging Findings

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

23 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:

24 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:

25 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:

26 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.

27 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

28 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:

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30 Nakao et al. Am J Psychiatry 2011

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32 Faraone et al. Nature Reviews Disease Primers 2015

33 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 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

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 Mattfeld et al. Brain: A Journal of Neurology 2014, epub: June 10, 2014

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) Mattfeld et al. Brain: A Journal of Neurology 2014, epub: June 10, 2014

38 Mattfeld et al. Brain: A Journal of Neurology 2014, epub: June 10, 2014

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40 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):

41 ADHD as a Neurobiological Disorder: Catecholamine Dysregulation

42 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):

43 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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45 ADHD as a Neurobiological Disorder: Genetic Findings

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

47 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

48 Genetics of ADHD Faraone et al. Nature Reviews Disease Primers 2015

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

50 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):

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

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

53 0 10,000 20,000 30,000 40,000 New Results from Genomewide Association Studies (GWAS) Number of ADHD GWAS Samples Y2012 Y2014 Q4_2015 Q1_2019 Faraone et al, 2015

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

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 Risk For Alcohol Dependence in Relatives a p<0.05 vs. comparison subjects b p<0.05 vs. comparison subjects plus alcohol dependence c p<0.05 vs. subjects with ADHD a-c a

77 Risk For Drug Dependence in Relatives a p<0.05 vs. comparison subjects b p<0.05 vs. comparison subjects plus drug dependence c p<0.05 vs. subjects with ADHD a a

78 Risk Factors for SUD +FH of SUD Personal or +FH of ADHD +FH of both ADHD & SUD SUD Yule and Biederman 2016

79 Humphreys et al. JAMA Psychiatry 2013

80 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.

81 Hammerness et al. J Pediatr 2012

82 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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84 Lichtenstein et al. New Eng J Med 2012;367(21):

85 Novel Comorbidities

86 Emotional Dysregulation

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

88 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.

89 Autistic Traits

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

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

92 PTSD and TBI

93 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

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

95 Man et al. Pediatrics Dec 15.

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

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

98 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

99 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

100 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.

101 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)

102 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

103 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

104 Chang et al. JAMA Psychiatry Published online January 29, doi: /jamapsychiatry

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

106 Newly Approved Amphetamine Formulations The FDA has approved 2 new amphetamine products for treatment of ADHD in children >6 years old Amphetamine extended-release orally distintegrating tablets (Adzenys XR-ODT Neos Therapeutics) do not have to be swallowed or sprinkled on food Amphetamine oral liquid (Dyanavel XR Tris Pharma) is claimed to have an onset of action at 1 hour and a duration of action that persists throughout the day The Medical Letter 2016

107 In Brief: ER Extended-Release Chewable MPH Tablets The FDA has approved a once-daily, extendedrelease chewable tablet formulation of methylphenidate (Quillichew ER Pfizer) for treatment of ADHD It is the first chewable formulation of the drug to be marketed for once-daily use Short-acting chewable methylphenidate tablets (Methylin, and generics) have been available since 2003 (Med Lett Drugs Ther 2015). The Medical Letter 2016

108 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