Translational Clinical Science

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Ursula McBride
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1 Translational Clinical Science Alasdair Vance Head, Academic Child Psychiatry Department of Paediatrics University of Melbourne Royal Children s Hospital

2 Outline of Presentation 1. Translational Clinical Science definition 2. Practical Clinical Trials definition 3. The Developmental Neuropsychiatry Program as an example 4. Two key future directions: fmri and molecular genetics

3 Tools for Translation: 2009 Genes Cells Systems Individual Social WGAS Sequencing Transgenics Epigenetics Databases Stem Cells Transcript profiles Proteomics Optical imaging Databases Electrode Arrays Zebrafish PET fmri DTI Databases Sensors Eye gaze Cognitive tools Repositories Data Sharing - Integration Web 2.0 Knowledge management

4 A Developmental Model of Mood Disorders Genetic variation Cg25 Altered Development Biased Information Processing Mood Disorder

5 Practical clinical trials: March et al. (2005): clear clinical question, representative sample, power to identify modest effects, randomization, clinical uncertainty about outcome, ax and rx =best practice, clear outcomes, limited participant and investigator burden Practical clinical trials: Tunis et al. (2003): hypothesis and study design selected to address decision maker questions: clinically relevant alternative interventions compared, diverse participant population, recruit heterogeneous settings, broad range of health outcomes data collected

6 Academic Child Psychiatry Unit - patients referred for diagnostic clarification and/or - patients who have been through one or more psychological and/or medical treatment regimens and who remain treatment non-responsive All the information collected - fed back to young people and their families with a diagnostic formulation, biopsychosocial formulation and a treatment plan

7 Academic Child Psychiatry Unit ACPU Structured Assessment components: [1] Structured clinical interview with child and separately with the parent(s)/caregiver(s) [2] Parent/Caregiver report: Child Behaviour Checklist, Children's Depression Scale, Connors Rating Scales Hopkins Symptom Checklist, Spanier Dyadic Adjustment Scale, Family Assessment Device, [3] Child-report: Youth Self Report, Childrens Depression Inventory, Revised Children's Manifest Anxiety Scale [4] Teacher report: Child Behaviour Checklist, Connors Rating Scales, Clinician rated Rutter and Graham Interview Schedule [5] Demographic screen and developmental history of child, including key biological and psychosocial milestones [6] Neurological/Endocrine screen of child [7] Cognitive assessment with child/adolescent Wechsler Intelligence Scale for Children Fourth Edition (WISC-IV) Wide Range Achievement Test Third Edition (WRAT-3) Cambridge Neuropsychological Test Automated Battery (CANTAB - Memory Component)

8 Patient profile initial assessment 2. Academic Child Psychiatry Unit patient profile initial assessment

9 Patient profile 12 month follow up

10 Significant reduction - primarily externalising domain: Internalising symptoms Wilks s Lamba =.97 (F1, 179) = 5.78, p<.02, multivariate partial eta squared=.03 Externalising symptoms Wilks s Lamba =.90 (F1, 179) = 1.97, p<.0005, multivariate partial eta squared=.10

11 DNP: THE CHALLENGE - multi-disciplinary clinical service delivery and research program - focused on understanding the aetiological risk factors - applying best practice assessment and treatment methodologies - enhances the integration of psychological strategies with targeted psychopharmacology across key developmental phases - evaluates treatment effects pre- and post-treatment - informs randomised controlled trials of synergistic treatments - informs new medication algorithms and psychological treatment manuals being developed

12 Case example

13 Our translational clinical science approach - pure ADHD inattentive dimension -defined structured clinical interview and parent/teacher gold standard questionnaires -pre-pubertal children or post-pubertal adolescents -visuospatial not verbal domain -non-human primate derived tests -defined fmri task components, block/event design -FSL (GLM) versus SPM Prof. A. Vance

14 Our current findings mental rotation task 10s/1s ISI block design Prof. A. Vance

15 Prof. A. Vance

16 Silk, Vance et al, B J Psych 2005 N=14, CBCL inattention subscale T score: (10.72)

17 Control>DD Control > Dysthymic disorder DD Control 5 z-score 1 N=14, CBCL inattention subscale T score: (9.75)

18 Prof. A. Vance

Region of activation BA C (mm) Z Control Group greater than ADHD-CT Group Parieto-Occipital R Precuneus 19 24-70 32 3.53 R Cuneus 19 32-90 28 2.

19 Region of activation BA C (mm) Z Control Group greater than ADHD-CT Group Parieto-Occipital R Precuneus R Cuneus Posterior Parietal R Inf. Parietal Frontal/Subcortical R Caudate Nucleus, Body Vance et al, Mol Psych 2007 N=24, CBCL inattention subscale T score: (9.43)

20 Control > Dysthymic disorder Control>Dysthymic disorder Dysthymic disorder Control 5 z-score 1 N=16, CBCL inattention subscale T score: (9.44)

Region of activation BA C (mm) size Control group greater than OCD group Right Precuneus 7 26-74 56 993 Left Precuneus 7-10 -54 42 1236 Right

21 Region of activation BA C (mm) size Control group greater than OCD group Right Precuneus Left Precuneus Right DLPFC Left DLPFC Left lateral globus pallidus N=16, CBCL inattention subscale T score: (9.23)

22 Our current findings General Summary ADHD DD OCD Parietal/Precuneus A /C A/C A /C Basal ganglia A /C C A /C Prefrontal cortex A A /C A /C Prof. A. Vance

23 Our current findings Specific Summary ADHD Parietal/Precuneus R>L DD Parietal/Precuneus R>L OCD Precuneus R=L ADHD Caudate nucleus R>L DD Caudate nucleus R (C only) OCD Globus pallidus L>R ADHD Sup/Inf FG R=L (A only) DD Mid/Inf FG R OCD DLPFC R=L Prof. A. Vance

24 Future clinical directions - biomarker for clinical inattention - biomarker-developmental stage independent - target for medication and/or specific psychological treatment - target for monitoring of the above treatment - ADHD: parietal lobe main risk factor site? - OCD: global pallidus main risk factor site? - DD: insula main risk factor site? NB: methodological problems of parsing neural network components

25 Future research directions -interpretation: the problem of epiphenomena -comorbidity -developmental stage; age; gender -more specific cognitive neuroscience constructs. VSWM capacitance versus strategy. VSM encoding versus retrieval -more specific fmri tasks. Parietal BG PFC -multiple neuroimaging modalities. Oculomotor MRS DTI - target phenotypes for mol gen studies Prof. A. Vance

Depressive disorders and ADHD

Depressive disorders and ADHD Professor Alasdair Vance Head, Academic Child Psychiatry Department of Paediatrics University of Melbourne Royal Children s Hospital avance@unimelb.edu.au www.rch.org.au/acpu