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Dopamine: stress, genes and the prodrome
Dr Oliver Howes
oliver.howes@kcl.ac.uk
Outline
• Dopamine in prodrome
• Genes and dopamine
• Risk factors and dopamine
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
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
r=0.48, p=0.02
DA synthesis capacity and symptoms
Howes et al; Arch Gen Psych 2009
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
No DA change in psychosis
continuum
Howes et al, SCZ Bull, 2012
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
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?
Genetics and dopamine
Stokes et al Neuropsychopharm 2013
Dopamine synthesis capacity: ~45% inherited
SCZ genetic risk variants linked
to DA
Howes et al Biol Psych 2017
DISC and dopamine
Amphetamine induced locomotor activity
Dahoun et al Trans Psych 2017
Amphetamine induced dopamine release
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
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
Egerton et al Scz Res 2016
p<0.01 p<0.01
Dopamine synthesis capacity greater in
immigrants relative to non-immigrants
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
Dopamine release and stress
Controls Prodromal signs Schizophrenia
Mizrahi et al. Biol Psychiatry 2012;71:561–567
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
Aberrant salience and the
prodrome
Roiser et al Scz Bull 2013
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
DA: further increase as psychosis develops
Howes et al,
Mol Psych 2011
No change in non-transition
subjects
p<0.05
Outstanding questions:
Howes & Kapur BJPsych 2014
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
DA and substance misuse
Ashok et al JAMA Psych 2017; Thompson et al 2013; Bloomfield et al 2014
d=-0.8,
p<0.001
Stone et al Biol Psych 2010
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
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