dopamine: stress, genes and the prodrome
TRANSCRIPT
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Outline
• Dopamine in prodrome
• Genes and dopamine
• Risk factors and dopamine
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Cognitive, motor and social impairment
Anxiety and depressive symptoms
Prodromal symptoms
Psychosis
Childhood Adolescence Early Adulthood
Severi
ty o
f sym
pto
ms
Figure adapted from Howes & Murray. Lancet 2014;383:1677–1687 DA, dopamine
Striatal DA
synthesis &
release
?DA
Social withdrawal and subjective
cognitive changes
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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
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r=0.48, p=0.02
DA synthesis capacity and symptoms
Howes et al; Arch Gen Psych 2009
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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
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No DA change in psychosis
continuum
Howes et al, SCZ Bull, 2012
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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
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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?
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Genetics and dopamine
Stokes et al Neuropsychopharm 2013
Dopamine synthesis capacity: ~45% inherited
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SCZ genetic risk variants linked
to DA
Howes et al Biol Psych 2017
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DISC and dopamine
Amphetamine induced locomotor activity
Dahoun et al Trans Psych 2017
Amphetamine induced dopamine release
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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
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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
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Egerton et al Scz Res 2016
p<0.01 p<0.01
Dopamine synthesis capacity greater in
immigrants relative to non-immigrants
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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
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Dopamine release and stress
Controls Prodromal signs Schizophrenia
Mizrahi et al. Biol Psychiatry 2012;71:561–567
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Figure adapted from Howes & Murray. Lancet 2014;383:1677–1687
Acute
psychosocial
stressDopamine
release
Sensitized
dopamine
system
But how
does this
lead to
symptoms?
Neurodevelopmental
adversity
Psychosocial
adversity
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Aberrant salience and the
prodrome
Roiser et al Scz Bull 2013
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Acute
psychosocial
stress
Figure adapted from Howes & Murray. Lancet 2014;383:1677–1687
Dopamine
release
Sensitized
dopamine
system
Aberrant
processing
of stimuli
Paranoid
interpretationPsychosis
Biased cognitive
schema
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DA: further increase as psychosis develops
Howes et al,
Mol Psych 2011
No change in non-transition
subjects
p<0.05
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Outstanding questions:
Howes & Kapur BJPsych 2014
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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
DA
synth
esis
capacity/
min
N=12 N=12 N=12
p=0.02;
ES=1.12
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DA and substance misuse
Ashok et al JAMA Psych 2017; Thompson et al 2013; Bloomfield et al 2014
d=-0.8,
p<0.001
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Stone et al Biol Psych 2010
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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