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Dopamine: Stress, Genes and the Prodrome
- 1. Dopamine: stress, genes and the prodrome Dr Oliver Howes [email protected]
- 2. Outline • Dopamine in prodrome • Genes and dopamine • Risk factors and dopamine
- 3. Cognitive, motor and social impairment Anxiety and depressive symptoms Prodromal symptoms Psychosis Childhood Adolescence Early Adulthood Severityofsymptoms Figure adapted from Howes & Murray. Lancet 2014;383:1677–1687DA, dopamine Striatal DA synthesis & release ?DA Social withdrawal and subjective cognitive changes
- 4. 0.0125 0.013 0.0135 0.014 0.0145 0.015 0.0155 0.016 0.0165 0.017 0.0175 Controls Prodromal Schizophrenia DA elevation in prodrome to Schizophrenia effect size=0.8, p=0.004 Howes et al, 2009
- 5. r=0.48, p=0.02 DA synthesis capacity and symptoms Howes et al; Arch Gen Psych 2009
- 6. Howes et al A J Psych 2011 DA synthesis capacity: elevation specific to those about to develop psychosis Effect size=0.81, p=0.01
- 7. No DA change in psychosis continuum Howes et al, SCZ Bull, 2012
- 8. Presynaptic DA in UHR Author Tracer Region Finding Effect size Antipsycho tic Howes et al 2009 F-DOPA DA synthesis 0.8 No Egerton et al 2013 F-DOPA DA synthesis 0.8 No Mizrahi et al, 2012 PHNO DA release 0.9 No Bloemen et al 2014 IBZM Baseline DA -*r=0.7 No
- 9. Elevated dopamine synthesis and release Howes et al. Curr Pharm Des 2009;15:2550–2559 Dopamine synthesis capacity Dopamine release Psychosis How does this link to risk factors for schizophrenia?
- 10. Genetics and dopamine Stokes et al Neuropsychopharm 2013 Dopamine synthesis capacity: ~45% inherited
- 11. SCZ genetic risk variants linked to DA Howes et al Biol Psych 2017
- 12. DISC and dopamine Amphetamine induced locomotor activity Dahoun et al Trans Psych 2017 Amphetamine induced dopamine release
- 13. Environmental risk factors Odds Ratio SCZ Childhood adversity 2.82 (abuse, parental separation) Migration 2.93 Urbanicity 1.74 Life-events 3.25 1. Cannon et al. Am J Psychiatry 2002;159:1080–1092; 2. Varese et al. Schizophr Bull 2012; 3. Cantor- Grae & Selten A J Psych 2005; 4. Krabbendam & van Os Scz Bull 2005; 5. Beards et al Scz Bull 2013 OR, odds ratio
- 14. Common factor Psychosocial stressors Childhood adversity Life-events Urbanicity Migration Van Winkel et al Scz Bull 2008; Walker et al 2013; Haddad et al 2015 Biological effects Psychological effects
- 15. Egerton et al Scz Res 2016 p<0.01 p<0.01 Dopamine synthesis capacity greater in immigrants relative to non-immigrants
- 16. Dopamine synthesis capacity greater in immigrants relative to non-immigrants Immigrant vs non-immigrant p<0.05 Clinical x immigrant group interaction: NS Egerton et al 2017
- 17. Dopamine release and stress Controls Prodromal signs Schizophrenia Mizrahi et al. Biol Psychiatry 2012;71:561–567
- 18. Figure adapted from Howes & Murray. Lancet 2014;383:1677–1687 Acute psychosocial stress Dopamine release Sensitized dopamine system But how does this lead to symptoms? Neurodevelopmental adversity Psychosocial adversity
- 19. Aberrant salience and the prodrome Roiser et al Scz Bull 2013
- 20. Acute psychosocial stress Figure adapted from Howes & Murray. Lancet 2014;383:1677–1687 Dopamine release Sensitized dopamine system Aberrant processing of stimuli Paranoid interpretation Psychosis Biased cognitive schema
- 21. DA: further increase as psychosis develops Howes et al, Mol Psych 2011 No change in non-transition subjects p<0.05
- 22. Outstanding questions: Howes & Kapur BJPsych 2014
- 23. DA & treatment resistance Demjaha et al, AJPsych 2012 0.008 0.009 0.01 0.011 0.012 0.013 0.014 0.015 0.016 Controls Responders Treatment resistant DAsynthesiscapacity/min N=12 N=12 N=12 p=0.02; ES=1.12
- 24. DA and substance misuse Ashok et al JAMA Psych 2017; Thompson et al 2013; Bloomfield et al 2014 d=-0.8, p<0.001
- 25. Stone et al Biol Psych 2010
- 26. Summary Elevated dopamine synthesis and release capacity • seen in prodrome • Linked to symptoms and development of psychosis Genetic and environmental risk factors for SCZ linked to DA alterations Psychosis could feedback to further dysregulate DA