ADHD An update. Dave Coghill

Transcription

1 ADHD An update Dave Coghill Financial Markets Foundation Chair of Developmental Mental Health Departments of Psychiatry and Paediatrics University of Melbourne

2 "Let me see if Philip can Be a little gentleman; Let me see if he is able To sit still for once at table." The Story of Fidgety Philip by Dr. Heinrich Hoffmann 1845

3 The Story of Johnny Head-inthe-Air by Dr. Heinrich Hoffmann 1845 As he trudged along to school, It was always Johnny's rule To be looking at the sky And the clouds that floated by; But what just before him lay, In his way, Johnny never thought about; So that everyone cried out, "Look at little Johnny there, Little Johnny Head-in-Air!"

4 Defining adult ADHD (DSM-5) Criteria A: 5 or more symptoms of inattention or hyperactivity-impulsivity Criteria B: Several symptoms present by the age of 12 Criteria C: Several symptoms present in two or more settings Criteria D: Symptoms interfere with or reduce quality of social, educational or occupational functioning Criteria E: Symptoms are not better explained by another condition, such as mood disorder American Psychiatric Association. Diagnostic and Statistical Manual (DSM) of Mental Disorders. 5th Edition 2013

5 Tax Issues & Relationship Problems Substance use problems Teenage Pregnancy and aggressive behaviour Several Issues! Several High Profile Buisness Failures

6 Inter rater Reliability of Diagnoses From the Initial DSM-5 Field Trials Major Neurocognitive disorder Autism PTSD ADHD Bipolar 1 Schizoprenia Conduct Disorder ODD Major Depressive Disorder Disruptive Mood Dysregulation Disorder Generalised Anxiety Disorder Kappa Am J Psych 2013

7 ADHD is common Prevalence of ADHD in China (Shanghai) Two stage assessment ADHD-RS-IV parent reported questionnaire KIDDIE SADS diagnostic interview Questionnaires 15,412 distributed 12,954 returned 9,900 valid (64.2%) 5,648 eligible for interview stage (several schools opted out of this stage) 5.29% Polanczyk et al 2007 Interviews 1187 were interviewed Overall prevalence 4.6% Gender ratio 2.5 : 1 Boys 6.6%, Girls 2.7% Type Combined type 1.8% Inattentive type 2.4% Hyperactive/Impulsive type 0.4% Age 5-6 years 5.2% 7 10 years 6.3% years 2.4% Coghill, Du, Su in preparation

8 There is considerable cross national variability in prescribing for ADHD Country/Region Cross sectional Prevalence (2010) Australia 1.4% United States 6.7% Canada 1.8% UK 0.6% Northern Europe 1.9% Western/Southern Europe 0.7% Asia-Pacific 0.9% Total 1.9%

9 ADHD IS IMPAIRING Pre-treatment mean domain T-scores for HRQoL in three ADHD study populations and controls Study SPD ADORE study Pooled ATX studies Dundee Data Diabetes mellitus Control Achievement Risk Avoidance Resilience Satisfaction Comfort CHIP CE Domains

10 The age-dependent decline and persistence of attentiondeficit/ hyperactivity disorder throughout the lifetime Faraone, S. V. et al. (2015) Attention-deficit/hyperactivity disorder Nat. Rev. Dis. Primers doi: /nrdp

11 Adult outcomes of ADHD Grade point average Class rank (%) Suspended during high school Special education during high school Retained in grade Graduated high school Enrolled in college Currently full-time student Total years of education Number of full-time jobs Ever fired from employment % Jobs fired from High rates of crime Ever had a credit card High rates of substance misuse Have a savings account Have trouble saving to pay bills Driving offences and accidents Number of lifetime moves Close friends now Social problems Dating partners since high school Age at first sexual intercourse Total no. of sex partners No. of sex partners in past year Time spent watching TV High rates of psychiatric disorder

12 What works for ADHD

13 Which treatments work for ADHD? Effect Size * Restrictive elimination diets Artificial food colourings Omega 3 fatty acids (fish oils) Cognitive Training Neurofeedback Parent training Stimulant Medications (e.g. Ritalin)

14 Negative parenting SMD 0.43 Parent Training Does improve parenting and conduct problems Positive parenting Conduct Problems SMD 0.63 SMD 0.31

15 Which treatments work for ADHD? Effect Size Restrictive elimination diets Artificial food colourings Omega 3 fatty acids (fish oils) Cognitive Training Neurofeedback Parent training Stimulant Medications (e.g. Ritalin)

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17 133 double-blind RCTs, >24,500 participants

18 Drugs vs placebo - Efficacy Mean change in ADHD symptoms Drug Amphetamines Atomoxetine Bupropion Clonidine Guanfacine Methylphenidate Modafinil CHILDREN & ADOLESCENTS SMD [95% CI] [-1.19,-0.85] [-0.66, -0.45] [-1.69, -0.22] [-1.17, -0.24] [-0.85, -0.50] [-0.93, -0.62] [-0.84, -0.41] ADULTS SMD [95% CI] [-0.99,-0.58] [-0.58,-0.32] [-0.85,-0.07] no data no data [-0.64,-0.35] 0.16 [-0.28,0.59] Favors drug Favors placebo Favors drug Favors placebo Drugs vs placebo - Acceptability Methylphenidate in C&A only and amphetamines in adults only were significantly better than placebo (OR 0 69 and 0 68, respectively)

19 Drugs vs placebo - Tolerability Dropouts due to adverse events CHILDREN & ADOLESCENTS Drug Amphetamines Atomoxetine Bupropion Clonidine Guanfacine Methylphenidate Modafinil OR [95% CI] 2.30 [1.36, 3.89] 1.49 [0.84, 2.64] 1.51 [0.17, 13.27] 4.52 [0.75, 27.03] 2.64 [1.20, 5.81] 1.44 [0.90, 2.31] 1.34 [0.57, 3.18] ADULTS OR [95% CI] 3.26 [1.54,6.92] 2.33 [1.28,4.25] 2.55 [0.33,19.93] no data no data 2.39 [1.40,4.08] 4.01 [1.42,11.33] Favors drug Favors placebo Favors drug Favors placebo Weight decreased by AMPH and MPH in C&A + adults. Systolic blood pressure increased by AMPH in C&A only, and MPH in adults only Diastolic blood pressure increased by AMPH in C&A only, and MPH in C&A + adults.

20 Is there consistent evidence of genetic, environmental or neurobiological risk factors associated with ADHD? Environmental Factors Causal pathways to ADHD

21 Single cause model of ADHD Genetic factors Dopaminergic and Noradrenergic abnormalities in Fronto / striatal pathways Biological 1 o Behavioural Inhibition deficits Cognitive 2 o Broader Executive Dysfunctions e.g. Working memory, planning ADHD Symptoms Behaviour

22 Coghill, Seth and Matthews, 2014

23 A direct comparison of neuropsychological functioning across the six key domains in ADHD Factor ADHD Mean (SD) TYP Mean (SD) p Effect Size (δ) % with deficit Memory Inhibition Delay Aversion Decision Making Timing Variability (1.00) 0.54 (1.04) < (0.44) 0.15 (0.44) < (0.96) 0.47 (1.10) < (0.85) 0.25 (0.79) < (1.16) 0.43 (1.07) < (0.79) 0.13 (0.40) Coghill, Seth and Matthews, 2014

24 A direct comparison of neuropsychological functioning across the six key domains in ADHD % of subjects with deficits Number of Factors on which there are deficits Coghill, Seth and Matthews, 2014

25 Spatial Working Memory BSE Strategy Hyperkinetic disorder vs controls effect size (d) Proportion ADHD cases with deficit (%) Tower of London (Planning, working memory) ID/ED Attentional Set Shifting Spatial Span Delayed Matching to Sample Pattern Recognition Spatial Recognition PAL Tot errors Tot trials Reaction Time Rhodes et al 2005

26 ADHD is associated with significant deficits in both executive and non-executive aspects of working memory Rhodes, Coghill and Matthews 2004, 2005 Between Seacrch Errors % correct DMtS: ADHD vs Control (Drug Naive) Percentage Correct DMtS: Controls Vs. DAT Redrawn from - Sahakian et al. (1988) Brain, 111, Controls DAT sim 0 delay 4 delay 12 delay Difficulty Level Delay delay HD Control Sim 0 sec 4 sec 8 sec 16 sec ADH D Cont rol ADHD is also associated with clear deficits in non- executive aspects of working memory. These contribute to the executive deficits and are not mediated by inhibitory problems These are non executive deficits are very similar in type and severity to those seen in: Alzheimer s Percentage Correct 50 DMtS: Placebo vs. Scopolamine 600mcg in Healthy Young Men Redrawn from - Robbins et al. (1997) Psychopharmacology. 134, ADHD is associated with clear deficits in executive aspects of working 100 memory. However these deficits were not associated with altered response latencies or 90 inhibitory control 70 Neither were deficits in any of the other executive functions measured (data not healthy young adults treated with scopolamine 60 Placebo Scopolamine 600mcg shown) Individuals with temporal lobe of amygdale/ hippocampal damage These data present a strong challenge to the primacy of fronto-striatally mediated executive deficits in ADHD 80 Sim 0 sec 4 sec 12 sec Delay These data present a strong challenge to the primacy of inhibition deficits in ADHD

27 These deficits in non working memory are restored by an acute challenge with methylphenidate. However acute methylphenidate fails to restore executive memory planning or set shifting deficits % correct DMtS: Acute Challenge with methylphenidate (including baseline for comparison) Baseline ADHD Baseline Control Acute Placebo Acute MPH 0.6 mg/kg Chronic challenge with methylphenidate also results in improvement of non-executive memory functioning. There is however evidence that a degree of tolerance may develop with chronic exposure Chronic exposure still does not impact on executive deficits Despite clear evidence for clinical response in these subjects there was no association between clinical and neuropsychological response % correct sim 0 sec 4 sec 12 sec delay DMtS: ADHD - chronic methylphenidate treatment Total Subscale Restless/Impulsive subscale Emotional Lability subscale sim 0 sec 4 sec 12 sec Delay placebo baseline controls Chronic MPH 0.3mg/kg Chronic MPH 0.6mg/kg Rhodes, Coghill & Matthews 2004, 2006, Coghill, Rhodes & Matthews 2007

28 Genes & Environment Brain Structure and Function Cognition Symptoms Improves Cognition X Improves Symptoms Methylphenidate Coghill et al 2007 Biological Psychiatry

29 Coghill et al 2014 Psychological Med. Development Cognition Improve X Symptoms Improve Genes & Environment Brain Structure and Function Cognition Symptoms Improves Cognition X Improves Symptoms Methylphenidate Coghill et al 2007 Biological Psychiatry

30 Coghill et al 2014 Psychological Med.

31 Potential Impacts Can explain why cognitive training approaches (e.g. working memory training) does not impact on symptoms but may still improve functioning A need to measure both symptom and cognitive outcomes Presents and opportunity to provide more concrete evidence as to why the regulators should consider cognitive outcomes when licensing medications Symptoms Genes Brain Structure and Function Impairment Cognition Coghill et al 2014 Psychological Med.

32 AADPA Annual Conference 27th and 28th of July 2019 in Brisbane. 32

33 Cohort Summary for GWAS studies Cohort Cases Controls Design PGC Batch CHOP Trios PGC ADHD1 IMAGE-I Trios PGC ADHD1 IMAGE-II Case/control PGC ADHD1 PUWMa Trios PGC ADHD1 Toronto, Canada Trios PGC CDG Barcelona, Spain Case/control PGC CDG Cardiff, UK Case/control PGC CDG Germany Case/control PGC CDG Beijing, China Case/control Solo (Yang et al. 2013) Bergen, Norway Case/control New (Zayas et al. 2015) Yale-Penn Case/control New Denmark ipsych Case/control New Total

34 PGC + ipsych Meta-Analysis

35 Is there consistent evidence of genetic, environmental or neurobiological risk factors associated with ADHD? Kaplan Meier curves illustrating the proportion of cortical points that had attained peak thickness at each age for all cerebral cortical points (Left) and the prefrontal cortex (Right) by National Academy of Sciences Shaw P et al. PNAS 2007;104:

36 Effects of age and stimulants Meta-analysis, Nakao et al., 2011

37 Brain-based diagnostics Patients with ADHD had significantly reduced grey matter in the putamen (P) and cerebellum (C) and significantly reduced white matter in the brainstem (B) and cerebellum (C). Using Feature Selection with a Gaussian SVM resulted in individual scan predictive accuracies of 91% using grey matter alone and 97% using grey and white matter data (p<0.001). Johnston et al., 2014