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

Hyperdopaminergic

state in 22q11.2DS?

DA = dopamine

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+

Boot et al. (2008) Neuropsychopharmacology

Peripheral dopaminergic

markers

Boot et al. (2008) Neuropsychopharmacology

Peripheral dopaminergic

markers

Boot et al. (2008) Neuropsychopharmacology

Peripheral dopaminergic

markers

Prolactin in 22q11.2DS

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

E 22q@uhn.ca