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 Disclosures (2017) My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose: Research support: AACAP, The Department of Defense, Food & Drug Administration, Headspace, Ironshore, Lundbeck, Magceutics Inc., Merck, Neurocentria Inc., NIH, NIDA, PamLab, Pfizer, Shire Pharmaceuticals Inc., SPRITES, Sunovion, and Vaya Pharma/Enzymotec. Consultation: Aevi Genomics, Akili, Guidepoint, Medgenics, Piper Jaffray Honoraria: Alcobra, APSAR Scientific Advisory Board: Alcobra, Arbor, Shire Royalties paid to the Department of Psychiatry at MGH, for a copyrighted ADHD rating scale used for ADHD diagnoses: Bracket Global, Ingenix, Prophase, Shire, Sunovion, and Theravance Patents (through MGH Corporate Licensing): US Patent (#14/027,676), for a non-stimulant treatment for ADHD; US Patent Application Pending (#61/233,686), for a method to prevent stimulant abuse Financial interest: Avekshan LLC, a company that develops treatments for ADHD. My interests were reviewed and are managed by MGH and Partners HealthCare in accordance with their COI policies

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 Psychopharmacology Course 2017 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 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

7 Poor Adherence to Treatment in ADHD This is so 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 Adult Onset ADHD However, recent three population based studies raise 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 Psychopharmacology Course 2017 Moffitt et al. Am J Psychiatry 2015; 172:

19 Adult Onset ADHD It is important to remember that the age of onset of ADHD of 12 years proposed in DSM-V, while an improvement from the previous age of onset of 7 years, is still completely arbitrary creating the immediate dilemma on how to diagnose patients who have an onset of symptoms after 12 Also important to remember is that children failing to reach diagnostic threshold for ADHD are affected and it does not mean they are free of neurodevelopmental symptoms Faraone and Biederman JAMA Psychiatry Editorial 2016

20 Adult Onset ADHD Because the etiological risk factors of ADHD are multifactorial, there is no clean separation of etiologic factors in people above and below the ages of 12 years set forth in DSM-V Faraone and Biederman JAMA Psychiatry Editorial 2016

21 Adult ADHD This multifactorial etiological view of ADHD posits that symptoms and impairment may emerge due to the accumulation of environmental and genetic risk factors

22 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

23 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

24 Adult Onset ADHD Such intellectual and social scaffolding would help some ADHD youth to compensate in early life and manifest only subthreshold symptoms, only to decompensate into a full ADHD syndrome when the scaffolding is removed Faraone and Biederman JAMA Psychiatry Editorial 2016

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

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

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

28 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:

29 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:

30 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:

31 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.

32 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

33 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:

34 Psychopharmacology Course 2017

35 Nakao et al. Am J Psychiatry 2011

36 Psychopharmacology Course 2017

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

38 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

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

40 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

41 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

42 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

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

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

45 Psychopharmacology Course 2017

46 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):

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

48 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):

49 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

50 Psychopharmacology Course 2017

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

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

53 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: Psychopharmacology Course 2017 Heritability Mean heritability of ADHD =.75

54 Genetics of ADHD Psychopharmacology Course 2017 Faraone et al. Nature Reviews Disease Primers 2015

55 Psychopharmacology Course 2017 The Dopamine Story... Presynaptic Neuron Dopamine Transporter (DAT) Dopamine Methylphenidate (MPH) Dopamine Receptor (DRD4)

56 0 10,000 20,000 30,000 40,000 New Results from Genomewide Association Studies (GWAS) Number of ADHD GWAS Samples sychopharmacology Course 2017 Y2012 Y2014 Q4_2015 Q1_2019 Faraone et al, 2015

57 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

58 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.

59 Volume (x109 mm3) Prenatal Nicotine Exposure: Effects on Brain Structure 2.1 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

60 ADHD Diagnostic Considerations Inattention Impulsivity/Hyperactivity

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

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

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

64 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 Psychopharmacology Course 2017

65 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

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

67 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):

68 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) Psychopharmacology Course 2017 Biederman, Wilens, Mick et al., Pediatric 1999

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70 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

71 Psychopharmacology Course 2017 Humphreys et al. JAMA Psychiatry 2013

72 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; Psychopharmacology Course 2017

73 Hammerness et al. J Pediatr 2012

74 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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76 PTSD and TBI Psychopharmacology Course 2017

77 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

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

79 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)

80 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

81 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 )

82 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