MENTAL DISORDERS LOST IN TRANSLATION?

Transcription

1 MENTAL DISORDERS LOST IN TRANSLATION? GREGERS WEGENER, Professor, MD, PhD, DSc(med) Au TRANSLATIONAL NEUROPSYCHIATRY UNIT DEPARTMENT OF CLINICAL MEDICINE AARHUS AARHUS, DENMARK CENTRE FOR PHARMACEUTICAL EXCELLENCE SCHOOL OF PHARMACY NORTH WEST POTCHEFSTROOM, SOUTH AFRICA 3rd Symposium camarades

2 Disclosures Consultant/advisory board H. Lundbeck A/S, Astra Zeneca AB, Servier SA, & Eli Lilly A/S Grant support from European Union (FP6/7), The Danish Medical Research Council, The Lundbeckfoundation, The Augustinusfoundation, Hede Nielsen Fonden, Hørslev Fonden, NATO Science Foundation, Novo-Nordisk Science Foundation, AP Møller Fonden (Lægevidenskabens Fremme), Desirée og Niels Ydes Fond, Slagtermester Wørzners Fond, The Research Foundation for County Midtjylland

3 Agenda Overall problem definition Modeling disease: current status and tests Future

4 Billion AARHUS Costs of Brain disorders in Europe (2010) European Journal of Neurology 2012, 19:

5 The burden of disease WHO: The global burden of disease: 2004 update (2008)

6 Efficacy of Antidepressants Overall efficacy Antidepressants are efficacious BUT Delayed clinical response (3-6 weeks) Partial clinical response (60-70%)

7 Basic Books, 2009 ISBN

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12 Wegener & Rujescu, IJNP (2013) FDA report (2008)

13 Main Areas The problem of the right samples and target Diagnosis & stratified psychiatry Biomarkers Endophenotypes The problem of translation from animals to humans The problem of study design The problem of increasing costs Wegener and Rujescu 2013

14 Diagnoses and Biology Poor Interrater diagnostic reliability Frequent disease co-morbidities The current diagnostic system is not designed to facilitate biological differentiation Lack of stratification tools (biological markers) Sub-disease specific phenotypes (e.g. different depression phenotypes)

15 Freedman et al., Am J Psychiatry 2013;170:1-5.

16 Psychiatric Disorders: Diagnostic spectrum Burmeister et al 2008, Nat Rev Genet

17 Main Areas The problem of the right samples and target Diagnosis & stratified psychiatry Biomarkers Endophenotypes The problem of translation from animals to humans The problem of study design The problem of increasing costs Wegener and Rujescu 2013

18 Animal Models of Depression What can be investigated? Feelings of depression Loss of pleasure and interest Reduced energy - severe fatigue Reduced self-confidence and self-esteem Self-blame - guilt Thoughts of death and suicide Thought and concentration problems Sleep abnormality Weight and appetite changes

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20 Animal Models Considerations on Validity Face Validity How well the model resembles the psychiatric condition Construct Validity How well the model is consistent with theoretical rationale Predictive Validity How well the model responds favorably to the same drugs as humans with the condition Willner 1995

21 Heim et al., PNEC (2008) 33,

22 Animal model Rationale Reference Repeated maternal separation Inducing a strong vulnerability to depression by applying stressful events during the developmental period (before weaning) Millstein and Holmes, 2007 Spontaneous stress-prone rats Using rats with spontaneous sensitivity to stress such as Flinders sensitive line rat, Wistar Kyoto rat, fawn-hooded rat, learned helpless rat Overstreet, 2012 Learned helplessness Inducing chronic behavioral despair by learning that a situation is without solution Overmier and Seligman, 1967 Social defeat Inducing chronic stress by repeated confrontation with a congener in which mice will experience social defeat Berton et al, 2006 Unpredictable chronic mild stress Chronic corticosterone Inducing chronic mild stress based on the inability of the animals to predict their occurrence Chronic corticosterone in the drinking water Willner et al, 1992 David et al, 2009 Belzung C, Neuropsychopharm 2014

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24 FSL/FRL rats

25 Behavioural Screening methods: interview a few examples Open Field Locomotor test Forced Swim Test/Tail Suspension Depression state (HAM-D) Elevated Plus Maze / Light-Dark Compartment Anxiety level Morris Water Maze Cognitive performance

26 Open Field Perry et al, 2009

27 SALINE AARHUS Stimulant Effects on Locomotion PHENCYCLIDINE AMPHETAMINE S(+)MDMA Geyer & Paulus 1996; Paulus & Geyer 1996

28 Can the animal tests be used in humans? Perry et al, 2009

29 Open Field Perry et al, 2009

30 Perseverative Motor Hyperactivity in Manic Bipolar Patients NORMAL CONTROL BIPOLAR PATIENT SCHIZOPHRENIA PATIENT Perry, Minassian, Paulus, Zhuang, Henry, Masten, Sharp, Geyer, Arch Gen Psychiatry, 2009

31 Perry et al, 2009 AARHUS Open Field

32 Common Behavioural Models Forced Swim Test Struggle Immobile

33 Vortioxetine (Lu-AA21004) Brintillix 250 Grouped Im 200 ** Vehicle AA3 AA10 Imipr Escit Mørk et al., (2012), JPET Immobility (seconds) * FSL *** **

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38 CRF data

39 CRF data

40 Griebel & Holsboer, Nat Rev Drug Disc 2012 Corticotropin-releasing factor receptor 1 (CRFR1) antagonists Compound Doses Study Indication: primary efficacy measures Results CP mg (b.i.d.) Phase IIb, doubleblind, MDD: HAM-D Inactive placebo- controlled trial versus sertraline (100 mg) Emicerfont (GW876008) 125 mg (?) Phase I/IIa trial Social anxiety: VAS Undisclosed NBI (also known as R121919) ONO-2333Ms Pexacerfont (BMS ) SSR Verucerfont (GSK561679) Verucerfont (GSK561679) Escalating: 40 mg, 60 mg and 80 mg 1 mg, 2 mg, 5 mg and 10 mg Phase IIa openlabel trial Phase IIb, doubleblind, placebocontrolled trial 100 mg Phase IIb, doubleblind, placebocontrolled trial versus escitalopram (10 mg) 20 mg, 50 mg and 100 mg Phase IIb, doubleblind, placebocontrolled trial versus escitalopram (10 mg) MDD: HAM-D MDD: HAM-D, MADRS GAD: HAM-A MDD: HAM-D Improvement in HAM- D; higher doses had better effect Inactive Inactive Inactive 350 mg Phase IIb, doubleblind, placebocontrolled trial MDD: HAM-D Inactive 350 mg Phase I/IIa trial Social anxiety: VAS Undisclosed

41 Lost in Translation? Major CNS-drug companies withdraw worldwide - placing Academia in a very important position Diagnostic problems in the clinic makes translation difficult Animal translational models are far from optimal and full of problems

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