1. Course Adult ADHD including DIVA 2.0 Odense, November 28, 2014 Dr. J.J. Sandra Kooij, MD PhD Psychiatrist, head Expertise Centre Adult ADHD PsyQ, psycho-medical programs The Hague, the Netherlands

2. Conflicts of interest Sandra Kooij MD PhD Since 2012: none Before 2012: –2 unrestricted research grants from Shire and Janssen –Speakers bureau of Janssen, Shire and Eli Lilly

3. Subjects Neurobiology, prevalence & gender Assessment of ADHD, including comorbidity DIVA 2.0 & DSM-5 Treatment ADHD in older people The lifespan ADHD clinic

4. Neurobiology of ADHD Highly heritable (80% of variance explained by genetic factors) Neurobiological disorder: –brain 5% smaller and less active –8 kandidate genes, esp. dopaminergic (DRD2,4,5, DAT1) –ADHD as an inhibition deficit (no brakes) based on dopamine deficiency –Methylphenidate: dopamine agonist; acts as inhibitor of associations, moodswings, restlessness and impulsivity Thapar 1999; Faraone 2005; Castellanos 2002; Bush 2006 Kessler 2006; Kooij 2005

5. ADHD symptom scores in twin studies: highly heritable 00.20.40.60.81 Willerman 1973 Matheny 1980 Goodman 1989 Gillis 1992 Edelbrock 1992 Stevenson 1992 Schmitz 1995 Thapar 1995 Gjone 1996 Silberg 1996 Sherman 1997 Levy 1997 Nadder 1998 Hudziak 2000 Willcutt 2000 Thapar 2000 Coolidge 2000 Kuntsi 2001 Martin 2002 Boomsma 2003 Heritability

6. Other biological, non-hereditary factors During pregnancy: High bloodpressure Smoking Alcoholabuse Bleeding/infections Associated with premature birth and low birthweight During delivery: Hypoxia (2%)

7. Developmental trajectories of brainvolumes (Castellanos et al., JAMA,2002)

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

10. The brain in ADHD compared to NCs: Smaller, Hypoactive & Impaired functioning

11. ADHD IS NOT OUTGROWN … … in boys only?

12. ADHD children grow up ADHD in adults is a relatively new diagnosis Professional recognition is increasing But ADHD in adults has not yet been integrated in professional education Children with ADHD may stay as long as possible with pediatrician or GP, or are lost to follow up …(until age 38!) Adults: aware of their condition and actively looking for help (internet) Patient organisations for adults are emerging worldwide

13. Prevalence of ADHD through the lifespan Children: USA4 - 8% % persisting ADHD 50 - 60% Adults: USA4 - 5% 10 countries (mean)3.4% Older people: Sweden3.3% Netherlands2.8 - 4.2% Faraone 2003; Kessler 2006; Murphy & Barkley, 1996; Kooij 2005; Fayyad 2007; Guldberg 2013; Michielsen 2012

14. Children M : F Adults M : F Clinical studies2 - 9 x1 - 2 x General population studies 2 - 3 x1 - 1.5x ADHD and gender: Men more often ADHD? Taylor 2004; Nice guidelines 2008; Kessler 2006; Fayyad 2007; Kooij 2005

15. Gender differences children and adults Childhood Underdiagnosis in girls Adulthood M>>F M=F

16. Girls have more ADD Biederman 1994, 2004

17. Girls and women 2x more often ADHD inattentive type But majority has still ADHD combined type Women have to organise themselves, family, household, childrens’ agenda’s and their job Being a women with ADHD is ‘a job from hell’, always late, forgetting things … Chaos and tiredness their daily bread Low selfesteem and uncertainty about capabilities the result

18. Causes of underdiagnosis of ADHD in girls

19. Assessment is comprehensive Lifetime ADHD symptoms and impairment (DIVA 2.0) Collateral information parent/spouse on ADHD Comorbidity: anx/depr/bipolar/sud/sleep personality/autism/physical/ Biography DSM-IV classification & treatment proposal including order of treatment

20. Adult ADHD is highly comorbid with circadian based disorders 75% has comorbidity (mean 3 disorders): Depression (60% SAD)25-50% Anxiety 25% Substance Use Disorders20-45% Personality Disorders6-25% Eating Disorders (BN) 9% Binge eating 86% Obesity 30% Sleepproblems, DSPS pattern 75% Kooij 2001 NTG;145(31):1498-501; Kooij 2004, Psychol Med;34(6):973- 82, Kooij 2012, book Adult ADHD; van Veen 2010, Biol Psychiatry 67(11): 1091-6; Biederman 1993, AJP;150(12):1792-8; Kessler 2006, AJP;163(4) :716-23; Pagoto 2009, Obesity;17(3):539-44. Davis 2009, J Psychiatr Res;43(7):687-96. Kooij & Bijlenga, 2013

21. Clinical picture of ADHD Lifetime symptoms of Attention-Deficit/Hyperactivity Disorder: Inattention: distracted, chaotic, forgetful, late, difficulty making decisions, organising and planning, no sense of time, procrastination Hyperactive: (inner) restlessness, tense, talkative, busy; coping by: excessive sporting/alcohol abuse/avoiding meetings Impulsive: acting before thinking, impatient, difficulty awaiting turn, jobhopping, binge eating, sensation seeking In addition in 90% of adults, lifetime: Moodswings (5x/day) and Anger outbursts APA 1994; Kooij 2001, 2010; Conners 1996

22. Decrease of hyperactivity in adults Hyperactivity is adjusted, compensated for, or experienced as more ‘inner restlessness’: Avoiding meetings where you have to sit stil Excessive sporting Hectic job full of change Cannabis / alcohol / tranquillisers against restlessness Talkativeness, inner restlessness The decrease in marked outward visible hyperactivity has presumably been the reason why we mistakenly have thought that ADHD was outgrown

23. Inattention most invalidating symptom in adults Adults need more attention than children: Procrastination Chaos Difficulty organising Being late Difficulty reading and remembering Forgetting things or appointments And yet using no watch or agenda!

24. Impairment in adult ADHD In clinical as well as epidemiological samples compared to controls: Learning problems (60%) Less graduated Lower education Lower income Less employed, more sickness leave More job changes (longest job 5 yrs) More often arrested, divorced and more social problems More driving accidents, teenage pregnancies, suicide attempts Higher (mental) health care costs Biederman 2006; Kooij 2001, 2005, 2010; Barkley 2002; Manor 2010

25. Aid for Differential Diagnosis Overlapping symptoms with other disorders … Unique symptoms of every disorder … Age of onset Course Heritability Treatment response

26. Ultrashort screening of ADHD in adults 1. Are you usually restless? 2. Are you usually easily distracted or chaotic? 3. Do you usually do things before thinking? If 1 of 3 answers = yes: 4.Did you have this symptom all your life? If yes, further diagnostic assessment of ADHD Kooij 2010

27. Diagnostic Assessment of ADHD in adults, using DIVA 2.0

28. Development of DIVA 2.0 The DIVA was developed in 2007 because there is a need for a structured diagnostic instrument in the field, that is easily available at low costs, in many different languages, for research and clinical assessment purposes.

29. What does DIVA 2.0 look for? The DIVA investigates the DSM-IV criteria of ADHD in childhood and adulthood, as well as impairment in five areas of functioning in both life periods. In order to facilitate understanding of the criteria in daily life in both childhood and adulthood, every DSM-IV criterion is accompanied by several examples that can be probed. The same is true for the five areas of impairment: education, work, social relationships, social activities/leisure time, partner/family relationships and self-esteem.

30. DIVA 2.0 Diagnostic Interview for Adult ADHD Translation in 17 languages All DIVAs are online free of charge at: www.divacenter.eu ALSO: DIVA 2.0 App

32. DIVA 2.0 DIVA 2.0 has been developed to facilitate appropriate and careful diagnostic assessment of ADHD in adults This semi-structured diagnostic instrument still needs interpretation by a (trained) clinician DIVA 2.0 should therefore not be used by patients for selfreport

34. Set-up of DIVA 2.0 DSM-IV Criterion A Part 1) The 9 criteria for Attention Deficit (A1) Part 2) The 9 criteria for Hyperactivity-Impulsivity (A2) DSM-IV Criteria B, C and D Part 3) The Age of Onset and Impairment accounted for by the ADHD symptoms Summary form Score form

35. Order of questioning Part 1 and 2 Always first read the full DSM-IV criterion aloud, ask if it is recognised in adulthood, and if yes to give (an) example(s) The frequency of behaviour has to be often ‘Often’ is not operationalised, but refers to a symptom being more severe and/or frequent compared to an age and IQ matched group, or to be closely linked to impairment Tick the examples mentioned

36. Order of questioning II If no examples are given, read the examples that belong to the criterion and tick those that apply Start always with the adult symptom (> 6 months), continue with the childhood presentation of the same symptom (between 5-12 yrs) It is not necessary to have many examples per criterion, also one convincing example may be enough for the investigator to be able to decide about the absence or presence of the criterion

37. Order of questionning III If spouse and/or parent/sibs are present, ask them after the patient about the same symptom in resp. adulthood and childhood In case of disagreement, the patient usually is the best informant in clinical settings The more outward visible hyperactive behaviour is i.e. better remembered than inattention by family members Collateral information serves as additional information about severity, chronicity and impairment The investigator weighs all information and decides per criterion whether it applies Kooij ea, 2008

38. No collateral information The patient can be the sole informant to make the diagnosis Collateral information serves only to get a more complete picture, but may as well induce doubt in case of disagreement Disagreement about the symptoms is common in ADHD families… School reports may be helpful if the behaviour is described, but cannot be used to reject the diagnosis if no remark was made Former reports of diagnostic assessments may be useful regarding descriptions of the same symptoms earlier in time

39. Part 3: Criterion B Criterion B: Age of onset Have you always had these symptoms of attention deficit and/or hyperactivity/impulsivity? ❑ Yes (a number of symptoms were present prior to the 7th year of age) ❑ No If no is answered above, starting as from …. year of age.

40. Part 3: Criterion C and D Criterion C: Clinical significant impairment of which many examples are given in 5 specified areas in adulthood as well as childhood: Work/ education Relationship/ family Social contacts Freetime/ hobby Self-confidence/ self-image Conclude if there is clinical significant impairment in 2 or more areas

41. Summary form Count the total number of criteria met for inattention (A) and hyperactivity/impulsivity (HI), in both adulthood and childhood

42. Score form Answer the questions on the Score form on: 1.Sufficient number of symptoms in adulthood (≥4) and childhood (≥6)* 2.A lifetime pattern of symptoms and limitations (rather than a strict age of onset!) 3.Symptoms and impairment manifest in 2 or more areas 4.No better explanation of the symptoms by other psychiatric disorders 5.Level of support for the diagnosis by collateral information 6.Diagnosis and subtype***

43. DIVA 2.0 App in App store & Google Play store The DIVA 2.0 (Diagnostic Interview for ADHD in adults) is now available as DIVA 2.0 App in both the App store as at Google Play, for Iphone, Android and Ipad! The DIVA 2.0 App contains the Diagnostic Interview for ADHD in adults; the DIVA 2.0 App adds the total number of DSM-IV criteria for ADHD in both child- and adulthood, for careful diagnostic assessment of ADHD. Data will not be stored, but sent via email, both as text and as SPSS file. www.divacenter.eu

44. Website www.divacenter.eu All DIVAs are published online for free, to facilitate carefull diagnostic assessment of adult ADHD worldwide Content divacenter.eu: Text ‘DIVA do´s and don´ts’ English instruction video will be developed Development of DIVA 2.0 DIVA Board Ongoing translations Validation studies: first in Spanish Publications on DIVA Contact button/information about ADHD in all languages

45. DIVA Foundation The DIVA foundation is the responsible legal body taking charge of the quality, coordination and distribution of the translations of DIVA 2.0 The DIVA Foundation is a non-profit organization that is independent from pharmaceutical industry. Every representative of a language pays an entrance fee for the set up of the DIVA Foundation and website Commercial companies and industry pay royalties for use of DIVA 2.0

46. Board DIVA Foundation, 2010

47. Website www.divacenter.eu All DIVAs are published online for free Content www.divacenter.eu: Text ‘DIVA do´s and don´ts’ Development of DIVA 2.0 DIVA Board Ongoing translations Validation studies Publications on DIVA Contact button/information about ADHD in all languages

48. Validation study Validation studies of DIVA 2.0 are necessary The first is performed in Spanish, because they have a formal validated and translated CAADID in Spanish to compare with DIVA 2.0

49. DSM-5 changes in ADHD Subtypes = now Presentation types NEURO- DEVELOP MENTAL DISORDERS Cutoff adoles- cents & adults 5/9 ADHD + ASS Impairment in ≥ 2 situations, but more situations given More examples of behaviour Age of onset < 12 years Severity

50. Training DIVA 2.0 yourself You are now a certified DIVA 2.0 trainer! To train those who want to use DIVA 2.0 in your language These slides can be used for trainings and can be send to you all (please write your email address) More help will be available from the divacenter website

51. Future of DIVA 2.0 DSM-5 was published in 2013 DIVA-5 will be developed in 2014 www.dsm5.org; www.divacenter.eu

52. New diagnostic tests? EEG test distinquishes subtypes of ADHD CPT tests, Qb-test for executive functioning and hyperactivity measures Voxel based MRIs Although FDA acknowledges these methods as ‘diagnostic aids’, they are still not capable to replace the clinical diagnosis of ADHD.

53. Treatment of ADHD and concurrent disorders 1.Psycho- education 2.Discontinue alcohol/drugs 3.Medication for ADHD and concurrent disorders 4.Light Therapy for late sleep and winter depression 5.Coaching 6.Cognitive Behaviour Therapy 7.Relationship therapy 8.Support or Advocacy Groups Safren 2005, Weiss 2003; Kooij 2012

54. Available medications for ADHD Proven effective in controlled studies: Stimulants: Methylphenidate (Ritalin, Equasym, Medikinet, Concerta)®: only licensed for kids Dextro-amphetamine Non-stimulants: Atomoxetine (Strattera)®: licensed for kids and adults (in NLs) Bupropion (Wellbutrin XR) Modiodal (Modafinil)

55. Place of medication in treatment Medication is very effective and comes first after psycho- education ADHD patients have a short attention span After 3 months they quit treatment if medication is not taken or ineffective Coaching without medication is less effective due to less attentiveness, irritability, forgetting appointments and tasks, and no show

56. First treat most severe disorder, usually depression, anxiety, bipolar disorder, SUDs; then add stimulant for ADHD In case of personality disorder: first treat ADHD Order of treatment in comorbid ADHD

57. Methylphenidate (Mph) Best studied (> 250 RCTs) 50 years of clinical experience Response: 70% children, 50-70% adults Effect size.9 Better executive functioning Safe, little side effects Effective 20 min. after ingestion Not addictive when used orally (but short acting can be when injected or snored) Inhibits reuptake of DA / NA Short acting: too difficult to use due to frequent dosing need and low compliance; risk of abuse Long acting best advice Faraone 2003, Volkow ea 2002, Pietrzak 2006

58. Compliance in adults with ADHD? Using shortacting Mph ADHD patiënts: chaotic and forgetful Need to dose 6-8x/day ON TIME Forget tablets, timer, batteries, water bottle and... No one is able to do this properly for a longer time Efficacy low due to bad compliance Medication wearing off generates rebound several times a day, ´roller coaster´ in stead of stability Patiënts stop short acting Mph: ‘medication is worse than disorder´ Kooij 2005

59. Long Acting Mph in adults More stable effect during the day Less rebound Less chance of abuse (gel or small particles hard to snore or inject) Safer in traffic Dose Concerta between 36-108 mg/day Usually after wearing off Concerta, second dose needed at 3 pm (2 x 8 hr duration, total of 16 hrs coverage) In case of later wearing off: 2 nd dose mph of intermediate duration (5-6 hrs) at 5 pm Combinations of Concerta and Equasym/Medikinet Still waiting for stimulant with 16 hour efficacy to better serve adults …

60. Duration of effect and dosing frequency of the methylphenidates Ritalin: 2 - 4 hrs (6 - 8 x/day) Equasym and Medikinet: 5 - 8 hrs (1 - 2 x/day) Concerta: 8 - 12 hrs (1 - 2 x/day) Combinations are possible: C 72 at 8 am and C 36 at 3 pm C 72 at 8 am and E or M 30 at 5 pm C 90 at 8 am and R 10 at 8 pm Max. dose unknown, optimal titration based on efficacy and side effects, under control of blood pressure, pulse and weight

61. Most frequent side effects Methylphenidate Less appetite (weight loss 1-2 kg) Difficulty getting asleep Changes in bloodpressure (↑↓) Tachycardia / palpitations (propanolol) Rebound symptoms after wearing off (less or not with longacting stimulants)

62. Rebound when methylphenidate wears off Half life Mph = 2 hours Max. plasmalevel after 1,5 - 2 hours Wears off after 2 - 4 hours Rebound = increase of restlessness, impulsivity, irritability and decrease of concentration Preventing rebound : timely dosing or using longacting methylphenidate

63. Contra-indications and abuse potential Methylphenidate Contra-indications: pregnancy, psychosis Relative contra-indications: hyperthyroidy, hypertension, epilepsy, glaucoma, tics Abuse potential : no indication after 40 yrs experience with oral use in children and > 15 yrs in adults, unless used intravenously or intranasally Longacting stimulants protect against abuse Volkow e.a. 1995

64. Response looks like: ‘Holiday in my head’ More quiet Better able to inhibit talkativeness or action Less moodswings or anger outbursts Clearing and cleaning with less effort Better able to remember/listen Less time needed for tasks (reading, organising) More efficient use of time

65. Living room before treatment with mph

66. Living room after treatment with mph

67. Homework before and after mph

68. Non-response looks like: Tired, fatique, ‘zombie-feeling’ No effect Only side-effects Differentiate from patients with little introspective skills; ask spouse to comment

69. SYNAPS IN NORMAL STUDIES dopamine Dopamine receptors

70. SYNAPS IN ADHD dopamine dopamine receptors

71. SYNAPS IN ADHD WITH METHYLPHENIDATE dopamine dopamine receptors methylphenidate

72. Update on stimulant treatment for ADHD and the brain Stimulants bring the increased density of dopamine transporters back to a normal range Stimulants and atomoxetine may influence long- term brain maturation, esp. when given young enough (during pre-puberty) Stimulants help catching up for developmental delay (gray matter volume increases) Roesner ea 2011; Andersen ea 2011; Rotherberger, 2013 Nakao ea 2011; Spencer 2013

73. Light therapy and ADHD 5 days – 30 min – 10.000 lux – 40 cm: For seasonal affective disorder: in 30% For delayed sleep phase syndrome: in 70% For ADHD? For overeating? Levitan 1999, 2002; Amons & Kooij 2006, Rybak 2006,2007

74. Psychological treatment ‘ Coaching’: practical, supportive and directive, similar to cognitive behaviour therapy interventions: time management (watch, timer, agenda, mobile phone/PDA) organising daily life (household, children, administration) reorientation on education or work planning time/intimacy with spouse getting overview over finances addressing process of acceptance of the disorder and need for medication learning social and organisational skills

75. Coaching and Cognitive Behaviour Therapy Coaching is practical / skills oriented (planning, using watch and agenda) CBT is more cognitive oriented (selfesteem, negative thinking, impulscontrol) Both share: transparency, here and now, structured and goal directed In ADHD patients too much homework or assignments (CBT) may induce feelings of failure, coaching is more practical, decreasing difficulty of tasks as needed by the patient The coach is more equal to the patient, in CBT the therapist is not

76. ADHD in older adults An epidemiological study by M. Michielsen, E. Semeijn, H. Comijs, D.J.H. Deeg, A. Beekman, J.J.S. Kooij Michielsen 2012, 2013; Semeijn 2013a,b

77. ADHD IS NOT OUTGROWN Fayyad J Br J Psychiatry. 2007 May;190:402-9; Kooij JJS Psychol Med. 2005 Jun;35(6):817- 27; Kessler RC J Occup Environ Med. 2005 Jun;47(6):565-72.; Kessler RC Am J Psychiatry. 2006 Apr;163(4):716-23. ?

78. Old people reporting childhood ADHD symptoms Swedish sample, 1599 people aged 65-80 yrs WURS, cutoff ≥ 36 Prevalence of self rated childhood ADHD symptoms 3.3%, comparable to ADHD in children and adults M > F (71 % vs 29%) Young = older groups Taina Guldberg- Kjär, 2009

79. Old people reporting childhood ADHD symptoms II ADHD compared to no ADHD group: more divorce/no relationship (34% vs 12%) more childhood problems more jobs (> 5) worse current health, worse current memory Taina Guldberg- Kjär, 2009

80. Case studies in older adults Case studies in older adults indicate similar symptoms and impairment in old age and similar treatment response Epidemiological and controlled clinical trials lacking - Manor I. Clin. Neuropharmacology 2011 - Biederman J. JAMA 1998 - Da Silva M.A. Journal of Attention Disorders 2008 - Parker R. JAMA 1999 - Brod M. Qual Life Res 2011

81. Marieke Michielsen & Evert Semeijn Presenting their posters on ADHD in old age in Berlin, ADHD Congress, 2011

82. Study on the prevalence of ADHD in older people Data were used from the Longitudinal Aging Study Amsterdam (LASA) Collection started in 1992/93 Physical, emotional, cognitive and social functioning Follow-up every three years

83. Methods Two - phase design: screening and diagnostic interview Phase 1 Screening list sample N=1494 Medium scoring group Invited N=93 High scoring group Invited N=84 Low scoring group Invited N=94 Phase 2 Interviewed N=85 Phase 2 Interviewed N=80 Phase 2 Interviewed N=69 Refused: 7 Unable: 2 Refused: 12 Unable: 2 Deceased : 1 Refused: 12 Deceased : 1

84. ADHD diagnoses Two diagnostic categories, based on DIVA 2.0 were used: Syndromatic ADHD, full blown DSM-IV diagnosis - 6/9 symptoms in present time and childhood Symptomatic ADHD, sub-clinical diagnosis - 4/9 symptoms in present time and 6/9 childhood

85. Prevalence of ADHD in older people in the general Dutch population Syndromatic ADHDSymptomatic ADHD %95% Cl % Total2.80.86–4.644.22.05–6.39 Sex Men3.0-0.20–6.124.60.96–8.39 Women2.60.38–4.723.81.39–6.24 Age: 61-95 years: lower prevalence of ADHD in the older old. Women: 59% Michielsen 2012

86. ADHD and anxiety/depression in older people ADHD was associated with more anxiety and depressive symptoms cross- sectionally as well as longitudinally compared to controls. Michielsen 2013

87. ADHD and physical health in older people ADHD in older people was associated with chronic nonspecific lung diseases (CNSLD), cardiovascular diseases, and number of chronic diseases. ADHD was negatively associated with self- perceived health. Semeijn 2013

88. ADHD and social functioning in older people ADHD in older people: was associated with being divorced or never married less family members in their network emotional loneliness Level of ADHD symptoms was associated with more emotional and social loneliness lower income level NB depressive symptoms play an important role in the association between ADHD and loneliness Michielsen ea 2013

89. Conclusions The prevalence and comorbidity with anxiety and depression in older people with ADHD, show similar patterns as in younger age groups Regarding physical health there are indications that older people with ADHD may have worse health outcomes and may die younger Lower income, less intimate relationships, less family relationships, more loneliness and depression in older people with ADHD

90. Can ADHD be treated in older people? 15 case studies: patients (m, f), age 67-81 yrs ADHD from childhood, diagnosis in (grand)children, who respond favorable to medication for ADHD Lifespan restlessness, irritability, impulsiveness and distractedness leading to impairment Succesfully treated with stimulants in old age Monitoring cardiovascular side effects before and during treatment Wetzel 2008; Da Silva & Louza, 2008; Standaert, Kok & Kooij, 2010; Manor ea, 2011

91. ADHD is not outgrown in older people Impairment is not diminishing Similar prevalence rates Similar medication response Needed: RCT’s! Needed: Lifespan clinics!

92. The ADHD Lifespan Clinic

93. The ADHD Lifespan Clinic? A place where ADHD patients of all ages can be diagnosed and treated A place where professionals are specialists in ADHD and comorbidities throughout the lifespan A place where you can easily return to in case of relapse or need of adjustment of treatment, and where your lifetime patient record file is always available An excellent place for longitudinal cohort and family studies of ADHD

94. Current organisation of Mental Health Care for ADHD 1.General Child Psychiatry 2.General Adult Psychiatry 3.General Psychiatry for older people

95. IMAGINE HAVING ADHD … … in childhood Your parents will turn to a pediatrician or to child psychiatry where you usually get help after a long time waiting

96. IMAGINE HAVING ADHD … … in adulthood Your GP will tell you that ADHD does not exist in adults, and send you to general mental health care … where you will be diagnosed with one or more other disorders that are usually comorbid with ADHD, but your ADHD is not recognised This is due to lack of knowledge in professionals who have never been educated about this highly prevalent disorder in adulthood

97. IMAGINE HAVING ADHD … in old age Your GP now really starts laughing when you ask for diagnostic assessment, although your daughter and granddaughter were recently diagnosed with ADHD, and successfully treated … you really thought there was still some hope for you as well, but you find out that innovative new knowledge is usually very reluctantly implemented in mental health care

98. IMAGINE HAVING ADHD - IN OUR TIME - The good news is that new knowledge and treatment options are available The bad news is that general mental health care services usually don’t deliver it When you outgrow the safe heaven of child psychiatric care, you’ re facing a desert of ignorance and disbelief among professionals When you enter adult psychiatry YOU are the one to teach your physician and therapist about ADHD When you enter old age psychiatry, you will have to repeat the same effort for the second time

99. Conclusion You will have difficulty finding expertise on your disorder during a lifetime Or: Your life will be over before new knowledge will be implemented in general mental health care!

100. Results of the current age related gaps in services Adolescents stop their treatment in large numbers after age 15 … they only return as adults in their thirties, with an increased rate of comorbidity and a lot of damage to education, career, relationships Where parents are supposed to be the reliable persons to educate their children with ADHD, they themselves are often impaired by the same disorder This leads to impaired families, and high (mental) health care costs without the desired outcomes

101. Who can deliver lifespan services to ADHD patients? The hands of child psychiatry are too short to continue treatment in / after adolescence The last two decades, adult psychiatry, let alone general mental health care for older people, has not taken the challenge of implementing care for ADHD in their daily practice This has not happened anywhere in the world … So why wait any longer? An organisation that does not take into account the lifespan course of ADHD cannot do the job So: let’s get started!!

102. The Lifespan ADHD Clinic? IT’ S ABOUT TIME!

103. How to set up a lifespan ADHD clinic? 1. Start cooperation with child, adult and old age psychiatry involved, or interested in ADHD 2. Determine similar assessment routes and treatment algorhythms for each age group, based on their needs 3. Pay special attention to adolescents who quit treatment around age 15 4. Build a team that works together in the same building

104. Set up a lifespan clinic? Is it easy? Eh, not really! It takes different organisations Different people Different management Different financial routes You must really be determined and motivated to do it!

105. Is it rewarding? Yes! People with ADHD like it! Professionals are ready for it and like it as well Mental health care is not ready, but this will not happen unless we do get started!

106. ADHD, circadian rhytm, sleep, mood and season Goikolea 2007, Psychol Med;37 (11):1595-9; Amons 2006, J Affect Disord;91(2-3):251-5; Lewy 2006, Proc Natl Acad Sci U S A;103(19):7414-9; Van Veen 2010, Biol Psychiatry 67(11): 1091-6 Bijlenga 2013, J Att Disord; 17(3):261-75 Bijlenga 2013, J Sleep Res. Aug 16 epub ADHD BP II SAD DSPS 100% Overweight 75% 30% 10%

107. Sleep questionnaire in 120 adults with ADHD Difficulty … going to bed on time: 78% falling asleep: 70% sleeping through: 50% getting up in the morning: 70% daytime sleepiness: 62% This pattern lifetime in 60%, suggestive of Eveningness or Delayed Sleep Phase Syndrome Kooij, Society of Light Treatment and Biological Rhythms 2007

108. Chronotypes: being a lark or an owl Morningtype: gets up early, active in morning (20-25%) Eveningtype: late to bed, active in evening (20-25%) In between: 50% Normal variation may differ +/- 2 hrs More variation disallows normal participation in society Clockgenes define chronotype and biological rhythm Zeitgebers: light through the eyes in the morning, and melatonin production in the brain at night synchronise us with the light/dark cycle of the world Artificial light may delay melatonin production at night (computer!)

109. Are most adults with ADHD evening types? Evening types are more active at night, prefer to go to bed late They get up late as well Evening types may be late due to a delayed onset of melatonin If sleeping longer is not possible due to work or school obligations, a chronic sleep dept can result Working in evening- or nightshifts may be adaptive Question: do adults with ADHD work more often in nightshifts? And if so, is that a problem? Morningness is associated with low impulsiveness / sensation seeking. Eveningness the other way round… Barkley 1997, J Dev Behav Pediatr,18(4):271-9. Caci 2004, Eur Psychiatry.;19(2):79-84. Levitan 2004, Biol Psychiatry;56(9):665-9. Van Veen 2010, Biol Psychiatry 67(11): 1091-6; Kooij 2012, book Adult ADHD

110. ADHD patients lack any sense of time Clinical experience: adults with ADHD seem to lack any sense of time, as well as any rhythm in day/night Their habitually being late has been regarded as part of their inattentiveness, a planning problem, but may in fact reflect a fundamental problem of the biological clock

111. Nucleus supra chiasmaticus (NSC): the biological clock Hypothalamic nucleus, just above the chiasma opticum

112. Delayed Sleep Phase Syndrome DSPS is characterized by: -(Very) late chronotype -A chronic pattern of (very) late sleep and preference for late rise -May result in daytime sleepiness and/or insomnia -May be compensated for by an irregular sleep pattern -Leads to dysfunctioning due to increased inattentiveness and/or social problems -Main complaint is sleep onset insomnia

113. Sleep phase delay in ADHD Melatonin level Time

114. Biological clock and body rhythms

115. Characteristics of 40 consecutive ADHD patients Sleep Onset Insomnia (SOI) No SOI N31 (78%)9 (22%) Male17 (55%)4 (44%) Age, mean (SD)28.2 (7.6)30 (11.9) ADHD, combined type29 (94%)5 (56%) ADHD, inattentive type2 (6%)4 (44%) Alcohol (U/wk)6.765.67 Nicotine (Sig/day)8.161.11 Sleep diagnosisns Van Veen 2010, Biological Psychiatry;67(11):1091-6.

116. Dim Light Melatonin Onset (DLMO): delayed N=40 adults with ADHD w/wo Sleep Onset Insomnia versus healthy controls ADHD Total SOIno-SOIHCp: ADHD vs HC p: SOI vs HC DLMO (hr ± sd) 22:57 ± 1:2023:15 ± 1:1922:00 ± 0:5421:34 ± 0:450.000 Van Veen ea, 2010 - 78% of consecutive ADHD patients had SOI - DLMO: 105 min later in SOI vs HC - After DLMO, it generally takes 2 hours to fall asleep

117. Van Veen ea 2010 24 hour movement patterns ADHD + SOI compared to controls (actigraphy)

118. New study: core and skin temperature, DLMO and activity patterns N=12 ADHD+DSPS (medication naïve) and 12 controls 5 consecutive days and nights Results: More variable bedtimes in ADHD, but melatonin onset is the same every day in both groups DLMO 1.5 hours later in ADHD Sleep duration 1 hr shorter on days before workdays in ADHD Second delay, between DLMO and sleep onset was ≥ 1 hr longer in ADHD Melatonin, activity and temperature were all delayed to a similar degree in ADHD Overall temperatures were lower in ADHD Colder hands in ADHD, related to sleep onset difficulties Bijlenga, J Sleep Res, 2013 Aug 16

119. 24 hr Activity, Core and Skin Temperature, in ADHD versus controls Bijlenga, J Sleep Res 2013, Aug 16

120. ADHD and disturbed rhythms ADHD may not only be associated with circadian, but also with cyclical and seasonal disturbances, leading to problems with impulsiveness, eating, sleeping and mood: Impulsivity/novelty seeking has been associated with eveningness Lack of sleep rhythm may lead to lack of rhythm in eating and activity patterns as well Evening types, or those with a delayed sleep phase may prefer irregular work or work in night-shifts, thereby increasing the sleep phase delay, as well as obesity ADHD has a higher percentage of Seasonal Affective Disorder (SAD) or winter depression, and possibly also of Premenstrual Dysphoric Disorder than normal Barkley 1997, J Dev Behav Pediatr,18(4):271-9; Amons 2006, J Affect Disord;91(2-3):251-5 Caci 2004, Eur Psychiatry.;19(2):79-84. Levitan 2004, Biol Psychiatry;56(9):665-9 Antunes 2010, Nutr Res Rev.(1):155-68.

121. ADHD & seasonal mood changes Adult ADHD co-occurs with lifetime depressive disorder in 55% Most of them (60%) have Seasonal Affective Disorder (SAD) or winterdepression Open trial of Light therapy effective for SAD and ADHD, as well as for Delayed Sleep Phase SAD has a circadian phase delay in 70% Are SAD and ADHD related via circadian disturbances? Clockgenes associated with ADHD Levitan 1999, Compr. Psychiatry, 40(4), 261-7; Johansson 2003, Neuropsychopharmacol;28(4):734-9; Amons 2006, J Affect Disord;91(2-3):251-5; Rybak 2007, Compr Psychiatry;48(6):562-71; Lewy 2006, Proc Natl Acad Sci U S A;103(19):7414-9; Kissling 2008, Am J Med Genet B, Neuropsychiatr Genet;147(3):333-8.

122. Circadian disturbance, ADHD and health ADHD is associated with chronic DSPS ADHD patients often work in night shifts or are active at night May be gene-environment interaction: circadian preference based on (clock)genes and dopaminergic pathways But: chronic work (>30 yrs) in night shifts is associated with higher risk of (breast)cancer Melatonin acts as a circadian anti-cancer signal at night Among others (light at night), chronic low melatonin levels may protect less well against development of cancer is ADHD a high riskgroup for cancer? Schernhammer 2001, J Natl Cancer Inst;93(20):1563-8; Schernhammer 2005, Eur J Cancer;41(13):2023-32; Hansen 2001, J Natl Cancer Inst;93(20):1513-5; Blask 2005, Endocrine;27(2):179-88. Moser 2006, Conf Proc IEEE Eng Med Biol Soc;1:424-8; Verkasalo 2005, Cancer Res;65(20):9595-600.

123. >7 children Breastfeeding First birth <20 Physical activity Nulliparous Current use of contraceptives First birth > 35 BMI> 30 Hormone Replacement Therapy Shiftwork Flight attendants First degree relatives Alcohol > 45 g/day Relative risk of breastcancer Moser 2006, Conf Proc IEEE Eng Med Biol Soc;1:424-8 1 full time pregnancy 1.00 0.50 1.50 2.00 Increased risk Decreased risk

124. Does cancer risk cluster in ADHD? Several lifestyle risk factors may cluster in ADHD individuals: Night shift work High BMI Alcohol/drug abuse Smoking Low melatonin levels?

125. Short sleep and cancer risk Shift work is considered carcinogenic in the long term (IARC 2007) Sleep loss by shiftwork is associated with higher incidence of breast- and prostate cancer Short sleep short exposure to and/or low levels of melatonin Melatonin has anti-oxidative properties and protects against cancer growth Animal research shows inhibiting effects of melatonin on cancer growth and increased survival In humans, first studies with melatonin in cancer patients ongoing Schernhammer 2004, 2006; Parent ea 2012; Sigurdardottir ea 2012; Anisimov ea 2012

126. Cancer risk and exposure to light@night Use of artificial light at night stops melatonin production through the eyes, feedback to pineal gland The light coming from TV, PC or Ipad also suppresses melatonin production and delays natural sleep onset easily by hours Light is the natural antidote to melatonin and wakes us up every day … Timing of light may be crucial for health in general Women with total visual blindness have less cancer than sighted women Flynn-Evans ea, 2009

127. ASESA study To explore the sleep/wake patterns, psychiatric and somatic comorbidity, BMI and eating patterns in adults with ADHD (n=202) compared to the general population (n=189) Bijlenga ea, 2013

128. General characteristics ADHD, n=202Controls, n=198p Women47 %65 %<.001 Age: mean34.933.0.121 BMI: mean24.823.2<.001 BMI ≥ 30 (obese)17 %4 %<.001 Unemployed27 %6 %<.001 Smokes52 %18 %<.001 >14 U alcohol p/wk17 %7 %.016

129. Self-reported Morbidities (showing only significant differences) % ADHD, n=202% Controls, n=198p Depressed mood186<.001 Stress/ burnout/ fatigue51<.001 Pulmonary problems3116<.001 Cardiovascular problems4318<.001 Gastro-intestinal problems3319.001 Metabolic problems126.042 Immune system problems73.049 Skeletal problems5036.005

130. Sleep characteristics Age ≤ 30 yrsAge > 30 yrs ADHD n=83 Controls n=106 P ADHD n=119 Controls n=83 p Bed time work days: mean23:4523:10.00223:3323:00.001 Bed time free days: mean01:020:13<.0010:2023:41.002 Sleep length work days: mean7:257:55.0297:017:42<.001 Sleep-onset latency work days: mean 0:390:22.0020:340:12<.001 Indication of DSPS: 26% in ADHD vs. 2% in controls (p<.001)

131. Summary More morbidities, complaints, and unhealthy lifestyle in ADHD More (extreme) evening chronotype in ADHD More sleep problems in ADHD: shorter sleep, longer sleep-onset latency, later mid-sleep, more variable bed times DSPS relates to SAD and to health issues This is also apparent within the control group Shorter sleep is related to a higher BMI

132. Next step: biomarkers in ADHD and DSPS PHASE study: Phase shift in ADHD of sleep and appetite: 50 adults with ADHD and DSPS 3 wk treatment: Mel, Plac, Mel+LT Measurement at baseline, after 3 wks Tx and after 3 wks washout: DLMO, cortisol, leptin/ghrelin, glucose, insuline markers, inflammation markers, HRV Vogel ea, in preparation

133. ADHD index CAARS Probability Normal weight group Obese group Binge eating group Davis 2009, J Psychiatr Res;43(7):687-96 ADHD index predicts weight and binge eating

134. Late sleep = short sleep late meals Possible impact of a delayed rhythm on weight and health: Sleeping late may lead to a short sleep duration Short sleep duration is associated with obesity Adults with ADHD tend to skip breakfast Breakfast skipping is associated with obesity ADHD patients suffer from eating problems in 80%, mostly binge eating Their weight fluctuates 10 - 20 kg’s ADHD is associated with increased BMI Obesity is associated with diabetes, cardiovascular disease and cancer Kooij 2012, book Adult ADHD; Dubois 2009, Public Health Nutr;12(1):19-28; Boere 2008, NTG;152(6):324-30; Davis 2009, J Psychiatr Res;43(7):687-96; Mota 2008, Ann.Hum.Biology;35(1)1-10; Copinschi 2000, Novartis Found Symp;227:143-57 Spiegel 2005, J Appl Physiol;99(5):2008-19

135. Sleep loss causes loss of control over appetite Leptin (satiety hormone) and ghrelin (hunger hormone): Reducing sleep duration by 2 hours already lowers levels of leptin, the satiety ("fullness") signal Sleep restriction study (n=12): leptin ↓ by 18% and ghrelin ↑ by 28%, leading to increased appetite and feelings of hunger 13 epidemiologic studies in adults and 8 in children: sleep loss is associated with increased BMI Sleep loss is a novel risk factor for insulin resistance and type 2 diabetes Lauderdale 2006, Am J Epidemiol;164(1):5-16; Lauderdale 2009, Am J Epidemiol;170(7):805-13. Spiegel 2005, J Appl Physiol;99(5):2008-19; Copinschi 2005, Essent Psychopharmacol;6(6):341-7; Shea 2005, J Clin Endocrinol Metab;90(5):2537-44;

136. Sleep duration USA Kripke 2002; Keith 2006; Lauderdale 2006 As sleep time fell in USA, average weights rose Whether and how sleep time and weight are connected is still unclear

137. Treatment of ADHD in obese patients N=242 patiënts with severe therapy resistent obesity, ADHD in 32%! Comorbidity: depression, sleep apnea, binge eating 75% of the ADHD group got stimulant treatment Stimulants: effective for ADHD, and inhibit appetite Weight loss: 15 kg in stimulant treated group, while others increased 3 kg during treatment for obesity After follow up at 1.5 yrs, in which medication was continued, the results remained Patiënts: less restlessness, anxiety and tiredness, & needed less food to compensate for these feelings. Binge eating disappeared, better contact with feeling of hunger and satiety. Better able to plan and comply to the treatment for obesity. Pagoto ea 2010; Albayrak ea 2011; Levy ea 2009

138. Proposed treatment / prevention of obesity in ADHD To reset the clock and increase sleep duration: Psycho education on the meaning of time, the light/dark cycle for sleep, appetite, metabolic entrainment, mood and health Sleep hygiene (early to bed and early to rise …) No light@night, shower before going to bed, bedsocks Melatonin in evening* Light in morning To reduce binge eating and weight gain: Treatment of comorbidity (depr/anx) Treatment of ADHD with stimulant Exercise, diet *Melatonin has not been reviewed or approved by the FDA for the treatment of sleep disorders. Kooij, book Adult ADHD 2012

139. Melatonin treatment To fall sleep: 3 mg at 22:00 in order to sleep at 23:00 To reset the clock: 0.1 mg - 0.5 mg between 16:00 and 19:00, in steps of 1.5 hour/wk from the normal sleep time to the desired bedtime Circadin 2 mg for those who wake up nevertheless at 03:00 am No light exposure of tablets of melatonin! Lewy 2005, 2006, continued; Kooij 2012 Book Adult ADHD

140. Desired sleep time – 8 uur = time of intake of 0.5 mg melatonine Desired sleep timeTime of intake Melatonin 01:00 am5 pm 00:30 am4.30 pm 11-12 pm4 pm Do not use melatonine 12 pm!

141. Light therapy in the morning Especially in winter more sleep phase delay More difficult to get up on time Inducing strong early morning light artificially, usually does work as sunlight in summer Melatonin is reduced through closed eyelids by light, which is our natural wake up call Light box of 500 W, or Light therapy device 10.000 lux and timer 30 min before wake up time Wake Up Light uses only 75 W and does not wake all patients with delayed sleep phase Warning: 500 W light becomes hot and contains UVA+B Rybak ea 2006

142. Adult ADHD Diagnostic Assessment and Treatment JJS Kooij, 3rd edition 2012 www.springer.com Search for ‘Adult ADHD’ Including DIVA 2.0

143. 10 year Anniversary of (the 28) PsyQ Programs Adult ADHD in the Netherlands, October 2013

144. For patient driven & patient oriented research First: online questionnaire inventarising most needed subjects from both patients and researchers Preferred research subjects (n=219): ADHD & Mood, Health, ASS, and Sleep Patients determine which research will be funded ADHDFund = Patient empowerment! www.adhdfund.com

145. Support Taina’s Guldberg’s research at ADHDFund! www.adhdfund.com First study on ADHD in older people with cognitive decline! Online: December 2014 – February 2015!