erik boot - studying psychosis in 22q11 deletion syndrome
TRANSCRIPT
22q11.2 Deletion Syndromeand the
Dopamine System
Erik Boot, MD, PhD
Toronto General Hospital
Centre for Addiction and Mental Health
University of Toronto
Dopamine hypothesis of schizophrenia
Howes et al. (2015) J Psychopharmacol; Howes et al. (2007) Br J Psychiatry
• Amphetamine -> psychotic symptoms
• Clinical effectiveness of antipsychotic drugs is related
to their affinity for dopaminergic receptors
• Post-mortem studies: increase in striatal dopamine
levels, increase in dopamine D2 receptor density
– Influence of medication?
In-vivo imaging evidence with PET and SPET:
Increased dopamine synaptic availability and
increased presynaptic dopamine synthesis in the
striata of people with psychotic illnesses
COMT expression in
22q11.2DS
Van Beveren et al. (2012) Gothelf et al. (2014)
Approximately 50%
reduction
• In COMT mRNA
• Protein
• Enzyme activity levels
in subjects with 22q11.2
deletion syndrome in
comparison with typically
developing control
subjects
Gothelf et al. (2014) Biol Psychiatry; van
Beveren et al. (2012) PLoS ONE
Boot et al. (2008) Neuropsychopharmacology
Peripheral dopaminergic
markers
22q11DS
No psychiatric history
Healthy
controls
N (M/F) 12 (5/7) 12 (5/7)
Age 27.3 ± 7.0 26.5 ± 6.2
FSIQ 79.8 ± 9.3 100+
Striatal dopamine receptor binding in 22q11.2 deletion
syndrome: an [123I]IBZM SPECT study
D2R BPND 1.17 ± 0.20 vs 1.16 ± 0.18, n.s.
22q11DS
No psychiatric history
Healthy
controls
N (M/F) 12 (5/7) 12 (5/7)
Age 27.3 ± 7.0 26.5 ± 6.2
FSIQ 79.8 ± 9.3 100+ Boot et al. (2010) J Psychopharmacol
Functional polymorphism
COMTVal = high activity
COMTMet = low activity
Boot et al. (2011) J Psychopharmacol
Striatal dopamine receptor binding
22q11DS
Met
22q11Val
Val
N (M/F) 10 (3/7) 12 (3/2)
Age 28.0 ± 2.3 30.2 ± 4.2
FSIQ 77.9 ± 2.8 74.2 ± 6.3
D2R BPND 1.10 ± 0.04 vs 1.33 ± 0.08, P=0.04
Boot et al. (2011) Synapse
Striatal hyperdopaminergic activity in
22q11.2 deletion syndrome?
Butcher et al:
• 13 adults with 22q11.2 DS, 10 matched controls
• PET using 11C‐dihydrotetrabenazine, a vesicular
monoamine transporter (VMAT2) radioligand
∼35% higher striatal VMAT2 binding
22q11.2DS vs. controls (p<0.01)
Butcher et al. (2015) MDS 19th International Congress of
Parkinson's Disease
www.xenazineusa.com
Prefrontal cortex and dorsal striatal
elevations of DOPAC in a 22q11.2 mouse
model
Didriksen et al. (2016) J Psychiatry Neurosci
Summary
• Increased dopamine synaptic availability
and increased presynaptic dopamine
synthesis in the striata of people with
(idiopathic) psychotic illnesses
• Impaired dopamine turnover in
22q11.2DS
• No linear relationship between
biochemical disturbances and
symptomatology
Thank you!
Disclosure: In relation to this presentation, I declare that I have no
conflicts of interest.
The Dalglish Family 22q Clinic
University Health Network
585 University Avenue
Toronto, ON M5G 2N2
T 416-340-5145
F 416-340-5004