Animal models and new therapeutic approaches

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Presentation from the International Congress of the Royal College of Psychiatrists 24-27 June 2014, London

Transcript of Animal models and new therapeutic approaches

  • 1. Update on Negative Symptoms of Schizophrenia Animal models and new therapeutic approaches Friday 27th June 2014 Royal College of Psychiatrists Annual Meeting: June 24th-27th 2014. Professor Jo Neill Manchester Pharmacy School, University of Manchester, UK

2. Manchester!! 3. A talk in 3 parts 1. Animals models: validity issues. 2. The sub-chronic PCP model of cognitive and negative symptom deficits in schizophrenia. 3. Efficacy of novel targets in tests for different domains of negative symptoms: asociality (avolition domain) and affect (expressive domain) in the PCP model. Why do new drug targets work in animal models, but not in patients? 4. Animal models?? 5. Animal Models - Validity? Construct Validity Need for improved understanding of the human pathology, BEHAVIOUR + biomarkers-then simulate in the animal model Face Validity Can a rodent be psychotic, depressed, anxious, or learn? Danger of anthropomorphism-BEHAVIOUR/SYMPTOMS Predictive Validity If the model is designed to predict existing drugs, how do we find new ones? Eg conditioned avoidance for neuroleptics-D2 antagonism, forced swim monoamine antidepressants CATCH 22 6. Animal models: summary Choose your species carefully when designing your animal model. ETHOLOGY Think about the 3 levels of validity, new models/tests required for better prediction of NOVEL targets. Need to simulate the CLINICAL condition: illness and treatment Housing, sex, strain, welfare, circadian variation also vitally important. Translation, translation, translation! 7. Schizophrenia, the abandoned illness. The Schizophrenia Commission, 2012 Cost approx 60k per patient per year 8. No effective drug therapy to treat negative symptoms Clinical Trials Roche adds a slate of PhIII schizophrenia trial failures to bitopertin's obituary April 15, 2014 By John Carroll 9. Bitopertin: GlyT1 inhibitor (RG1678; RO4917838) Glycine reuptake Extracellular glycine concentration Baseline occupancy of the glycine-B site (NMDA receptors) NMDA receptor activation (Harvey and Yee, 2013) 10. Cognitive Test Domain Reversal Learning Problem Solving & Reasoning Attentional Set Shifting Executive Function 5 Choice Continuous Performance Task Attention, Impulsivity & VIGILANCE Novel Object Recognition Visual Recognition Memory 16 Holeboard Maze, odour span task Working Memory Microdialysis of dopamine levels and changes in the prefrontal cortex during cognitive performance in Novel Object Recognition Translational cognitive tests 11. Modeling negative symptoms of schizophrenia in animals, can it be done? Symptoms: Blunted affect Alogia Emotional + social withdrawal Avolition Anhedonia? Poor rapport, passivity Stereotyped thinking no drug has received Food and Drug Administration (FDA) approval for an indication of negative symptoms, and available data indicate that second- generation antipsychotic medications have not met early hopes for a highly effective treatment for alleviation of negative symptoms. 12. NMDA receptor hypofunction hypothesis of schizophrenia NRHypo state induced by genetic and non-genetic factors instilled into brain early in development triggers psychosis in adulthood NRHypo state induces complex disinhibition syndrome this may explain the post-mortem changes observed in some patients PARVALBUMIN GAD67 May be modelled by NMDA receptor antagonism: using PCP: 2 mg/kg twice daily, 7 days, 7 days drug free: female rats! Phencyclidine NMDA receptor hypofunction Disinhibition of pyramidal cell The model 13. Sub-chronic PCP Model: Neuropathology and cognition Reversed by atypical antipsychotics and novel targets. Task/Technique Observation Reference Novel Object Recognition Deficits in retention trial Grayson et al., 2014 McLean et al., 2009 Reversal Learning Deficits in reversal phase McLean et al., 2010 Idris et al., 2010 Attentional Set-Shifting Deficits in the EDS phase McLean et al., 2008 5-CCPT Task dependent deficits Barnes et al. 2012 Autoradiography Reduced receptors Choi et al., 2009 Immunohistochemistry HPLC Reduced parvalbumin Reduced NAA Abdul-Monim et al., 2007 Harte et al. 2013 Ex vivo MRI Reduced cortical thickness and grey matter density Barnes et al, 2014 For reviews see Neill et al., 2010; Pharmacology & Therapeutics; Neill et al. 2013. 14. Social species 15. Social Interaction PCP (2mg/kg) Vehicle Washout Washout Twice daily (7 days) (7 days) SI SI Vehicle solution 30 min Female adult Hooded-Lister rats (n=10/group) Social Interaction (10 min) Sniffing Object exploration Following Avoiding 16. Social interaction test (10 min) FollowingObject exploration Sniffing 17. Social interaction test (10 min) 2 parameters affected by PCP: Sniffing duration () Avoidances number () FollowingObject exploration Sniffing Avoidances (Snigdha & Neill, 2007, 2008) 18. AUT9 restores PCP-induced social behaviour deficitsV eh + V eh P C P + V eh P C P + A U T 9 10 m g/kg P C P + A U T 9 30 m g/kg P C P + A U T 9 60 m g/kg P C P + R isperidone 0.1 m g/kg 0 20000 40000 60000 Treatment (mg/kg) ** ## # * # Sniffing(ms) V eh + V eh P C P + V eh P C P + A U T 9 10 m g/kg P C P + A U T 9 30 m g/kg P C P + A U T 9 60 m g/kg P C P + R isperidone 0.1 m g/kg0.0 0.5 1.0 1.5 2.0 2.5 Treatment (mg/kg) *** ### ### ### ### Numberofavoidances Press release June 2013: Autifony Therapeutics Announces 2.75m Collaboration with Universities of Manchester and Newcastle to Progress a First-in-Class Drug for Schizophrenia 19. Bitopertin restores PCP-induced social behaviour deficits V eh + V eh P C P + V eh P C P + B itopertin 1 m g/kg P C P + B itopertin 3 m g/kg P C P + B itopertin 10 m g/kg P C P + R isperidone 0.1 m g/kg 0 20000 40000 60000 Treatment (mg/kg) * # Sniffing(ms) V eh + V eh P C P + V eh P C P + B itopertin 1 m g/kg P C P + B itopertin 3 m g/kg P C P + B itopertin 10 m g/kg P C P + R isperidone 0.1 m g/kg 0.0 0.5 1.0 1.5 2.0 2.5 Treatment (mg/kg) *** ### ## ### ### Numberofavoidances 20. LY404039: mGluR2/3 agonist Presynaptic localisation: glutamate reuptake Glia localisation: glutamate transporter expression (glutamate reuptake) pathological glutamate release (Weinberger, 2007) 21. Lack of efficacy of LY404039 on social interactionV eh + V eh PC P + V ehPC P + LY 0.3 m g/kgPC P + LY 1 m g/kg PC P + R isperidone0.1 m g/kg 0 20000 40000 60000 Treatment (mg/kg) *** *** *** *** Sniffing(ms) V eh + V eh PC P + V ehPC P + LY 0.3 m g/kgPC P + LY 1 m g/kg PC P + R isperidone0.1 m g/kg 0.0 0.5 1.0 1.5 Treatment (mg/kg) Numberofavoidances 22. Play behaviour FollowingObject exploration Sniffing Avoidances 23. V eh + V eh PC P + V eh PC P + Bitopertin 1 m g/kg PC P + Bitopertin 3 m g/kg PC P + Bitopertin 10 m g/kg PC P + R isperidone0.1 m g/kg 0.0 0.2 0.4 0.6 0.8 1.0 Treatment (mg/kg) *** Numberoffightingrats AUT9 and bitopertin produce pinning and pouncing behaviour V eh + V eh PC P + V eh PC P + A U T9 10 m g/kg PC P + A U T9 30 m g/kg PC P + A U T9 60 m g/kg PC P + R isperidone0.1 m g/kg 0.0 0.2 0.4 0.6 0.8 Treatment (mg/kg) ** Numberoffightingrats 24. Affective Bias Test (Stuart et al. 2013) 25. Affective Bias Test (Stuart et al., 2013) No treatment D1 Vehicle solution AUT9 (30 mg/kg; IP) Risperidone (0.1 mg/kg; IP) Haloperidol (0.05 mg/kg; IP) FG7142 (10 mg/kg; IP) 30 min Female adult Hooded-Lister rats (n=10/group) D2 D3 D4 D5 30 min C B + C C B + C B + Choice test 30 trials Determination of % choice: %A > %B : positive bias %A = %B : no bias %A < %B : negative bias A + A + A + 26. Will AUT9 produce a positive bias in PCP-treated rats? D1 30 min Female adult Hooded-Lister rats (n=10/group) D2 D3 D4 D5 30 min C B + C C B + C B + Choice test 30 trials A + A + A + PCP (2mg/kg) Vehicle Washout Washout Twice daily (7 days) (7 days) 27. PCP induces a negative affective bias 28. Summary Low dose risperidone, bitopertin and AUT9 restore PCP-induced social behaviour and cognitive deficits. LY404039 ineffective. AUT9 and bitopertin enhance social behaviour. AUT9 and low dose antipsychotics induce a positive affect bias. KV3.1 channel modulation shows promise as a new treatment for schizophrenia: potentially disease modifying? 29. The animal model MUST mimic the clinical situation The PCP model mimics an UHR group for schizophrenia NOT a chronic clinical condition. 21 days antipsychotic followed by 7 days withdrawal: then test a novel antipsychotic. 21 days antipsychotic: then test a novel add-on treatment for cognitive or negative symptoms. 30. Conclusions Consider negative symptom domains separately-different tests Include antipsychotic treatment in the animal model Could patients be stratified into negative symptom subtypes and treated accordingly? 31. Manchester team Thank you! Megan Gurney and Marianne Leger Ben Grayson, Peter Haddad, Mike Harte, Sam Marsh, Chloe Piercy Bill Deakin, Samaneh Maysami, Rhona Stephen, Steve Williams Charles Large Giuseppe Alvaro Barbara Domayne-Hayman Peter Harris Autifony Collaborators Frank Tarazi Jorgen Scheel-Kruger Newcastle Mark Cunningham Fiona Lebeau Claire Gillougley Margaret Lawlor Technology Strategy Board Gavin Whitlock 32. BRITISH ASSOCIATION FOR PSYCHOPHARMACOLOGY 40th Anniversary Summer Meeting 20 23 July 2014 Cambridge Online CPD Resource Schizophrenia Substance misuse including comorbidity Bipolar disorder Perinatal disorders ADHD focussing on adults Depression Anxiety disorders Sleep Old Age Child and Adolescent (coming soon) www.bap.org.uk