Presentation from the International Congress of the Royal College of Psychiatrists 24-27 June 2014, London

1. Update on Negative Symptoms of
Schizophrenia
Animal models and new therapeutic
approaches
Friday 27th June 2014
Royal College of Psychiatrists Annual
Meeting: June 24th-27th 2014.
Professor Jo Neill
Manchester Pharmacy School, University of
Manchester, UK

2. Manchester!!

3. A talk in 3 parts
1. Animals models: validity issues.
2. The sub-chronic PCP model of cognitive and
negative symptom deficits in schizophrenia.
3. Efficacy of novel targets in tests for different domains
of negative symptoms: asociality (avolition domain)
and affect (expressive domain) in the PCP model.
• Why do new drug targets work in animal models, but
not in patients?

4. Animal models??

6. Animal Models - Validity?
• Construct Validity
– Need for improved understanding of the human pathology,
BEHAVIOUR + biomarkers-then simulate in the animal
model
• Face Validity
– Can a rodent be psychotic, depressed, anxious, or learn?
Danger of anthropomorphism-BEHAVIOUR/SYMPTOMS
• Predictive Validity
– If the model is designed to predict existing
drugs, how do we find new ones?
Eg conditioned avoidance for neuroleptics-D2
antagonism, forced swim monoamine
antidepressants
CATCH 22

7. Animal models: summary
• Choose your species carefully when designing your
animal model. ETHOLOGY
• Think about the 3 levels of validity, new
models/tests required for better prediction of
NOVEL targets.
• Need to simulate the CLINICAL condition: illness
and treatment
• Housing, sex, strain, welfare, circadian variation
also vitally important.
• Translation, translation, translation!

8. “Schizophrenia, the abandoned illness.”
The Schizophrenia Commission, 2012
Cost approx £60k per patient per year

9. No effective drug therapy to treat
negative symptoms
Clinical Trials
Roche adds a slate of PhIII schizophrenia trial
failures to bitopertin's obituary
April 15, 2014 By John Carroll

10. Bitopertin: GlyT1 inhibitor
(RG1678; RO4917838)
 Glycine reuptake
Extracellular glycine
concentration
Baseline occupancy of
the glycine-B site (NMDA
receptors)
NMDA receptor activation
(Harvey and Yee, 2013)

11. Cognitive Test Domain
 Reversal Learning Problem Solving &
Reasoning
 Attentional Set Shifting Executive Function
 5 Choice Continuous
Performance Task
Attention, Impulsivity &
VIGILANCE
 Novel Object Recognition Visual Recognition Memory
 16 Holeboard Maze,
odour span task
Working Memory
 Microdialysis of dopamine levels and changes in the
prefrontal cortex during cognitive performance in Novel
Object Recognition
Translational cognitive tests

12. Modeling negative symptoms of
schizophrenia in animals, can it
be done?
Symptoms:
Blunted affect
Alogia
Emotional +
social withdrawal
Avolition
Anhedonia?
Poor rapport, passivity
Stereotyped thinking
no drug has received Food and Drug
Administration (FDA) approval for an
indication of negative symptoms, and
available data indicate that second-
generation antipsychotic medications
have not met early hopes for a highly
effective treatment for alleviation of
negative symptoms.

14. NMDA receptor hypofunction
hypothesis of schizophrenia
• NRHypo state induced by genetic and
non-genetic factors instilled into brain early
in development triggers psychosis in
adulthood
• NRHypo state induces complex
disinhibition syndrome – this may explain
the post-mortem changes observed in
some patients
PARVALBUMIN
GAD67
• May be modelled by NMDA receptor
antagonism: using PCP: 2 mg/kg twice
daily, 7 days, 7 days drug free: female
rats!
Phencyclidine
NMDA receptor hypofunction
Disinhibition of pyramidal cell
The model

15. Sub-chronic PCP Model:
Neuropathology and cognition
Reversed by atypical antipsychotics and novel targets.
Task/Technique Observation Reference
Novel Object Recognition Deficits in retention trial Grayson et al., 2014
McLean et al., 2009
Reversal Learning Deficits in reversal phase McLean et al., 2010
Idris et al., 2010
Attentional Set-Shifting Deficits in the EDS phase McLean et al., 2008
5-CCPT Task dependent deficits Barnes et al. 2012
Autoradiography Reduced receptors Choi et al., 2009
Immunohistochemistry
HPLC
Reduced parvalbumin
Reduced NAA
Abdul-Monim et al., 2007
Harte et al. 2013
Ex vivo MRI Reduced cortical
thickness and grey matter
density
Barnes et al, 2014
For reviews see Neill et al., 2010; Pharmacology & Therapeutics; Neill et al. 2013.

16. Social species

17. Social Interaction
PCP
(2mg/kg)
Vehicle Washout
Washout
Twice daily (7
days)
(7 days)
SI
SI
Vehicle solution
30 min
Female adult
Hooded-Lister
rats (n=10/group)
Social
Interaction
(10 min)
• Sniffing
• Object
exploration
• Following
• Avoiding

18. Social interaction test (10 min)
FollowingObject exploration
Sniffing

19. Social interaction test (10 min)
2 parameters affected
by PCP:
Sniffing duration ()
Avoidances number ()
FollowingObject exploration
Sniffing Avoidances
(Snigdha & Neill, 2007, 2008)

20. AUT9 restores PCP-induced
social behaviour deficitsV
eh
+
V
eh
P
C
P
+
V
eh
P
C
P
+
A
U
T
9
10
m
g/kg
P
C
P
+
A
U
T
9
30
m
g/kg
P
C
P
+
A
U
T
9
60
m
g/kg
P
C
P
+
R
isperidone
0.1
m
g/kg
0
20000
40000
60000
Treatment (mg/kg)
**
##
#
*
#
Sniffing(ms)
V
eh
+
V
eh
P
C
P
+
V
eh
P
C
P
+
A
U
T
9
10
m
g/kg
P
C
P
+
A
U
T
9
30
m
g/kg
P
C
P
+
A
U
T
9
60
m
g/kg
P
C
P
+
R
isperidone
0.1
m
g/kg0.0
0.5
1.0
1.5
2.0
2.5
Treatment (mg/kg)
***
###
###
###
###
Numberofavoidances
Press release June 2013:
Autifony Therapeutics
Announces £2.75m
Collaboration with
Universities of Manchester
and Newcastle to
Progress a First-in-Class
Drug for Schizophrenia

21. Bitopertin restores
PCP-induced social behaviour deficits
V
eh
+
V
eh
P
C
P
+
V
eh
P
C
P
+
B
itopertin
1
m
g/kg
P
C
P
+
B
itopertin
3
m
g/kg
P
C
P
+
B
itopertin
10
m
g/kg
P
C
P
+
R
isperidone
0.1
m
g/kg
0
20000
40000
60000
Treatment (mg/kg)
*
#
Sniffing(ms)
V
eh
+
V
eh
P
C
P
+
V
eh
P
C
P
+
B
itopertin
1
m
g/kg
P
C
P
+
B
itopertin
3
m
g/kg
P
C
P
+
B
itopertin
10
m
g/kg
P
C
P
+
R
isperidone
0.1
m
g/kg
0.0
0.5
1.0
1.5
2.0
2.5
Treatment (mg/kg)
***
###
##
###
###
Numberofavoidances

22. LY404039: mGluR2/3 agonist
Presynaptic
localisation: glutamate
reuptake
Glia localisation:
glutamate transporter
expression (glutamate
reuptake)
 pathological
glutamate release
(Weinberger, 2007)

23. Lack of efficacy of LY404039
on social interactionV
eh
+
V
eh
PC
P
+
V
ehPC
P
+
LY
0.3
m
g/kgPC
P
+
LY
1
m
g/kg
PC
P
+
R
isperidone0.1
m
g/kg
0
20000
40000
60000
Treatment (mg/kg)
***
***
***
***
Sniffing(ms)
V
eh
+
V
eh
PC
P
+
V
ehPC
P
+
LY
0.3
m
g/kgPC
P
+
LY
1
m
g/kg
PC
P
+
R
isperidone0.1
m
g/kg
0.0
0.5
1.0
1.5
Treatment (mg/kg)
Numberofavoidances

24. Play behaviour
FollowingObject exploration
Sniffing Avoidances

25. V
eh
+
V
eh
PC
P
+
V
eh
PC
P
+
Bitopertin
1
m
g/kg
PC
P
+
Bitopertin
3
m
g/kg
PC
P
+
Bitopertin
10
m
g/kg
PC
P
+
R
isperidone0.1
m
g/kg
0.0
0.2
0.4
0.6
0.8
1.0
Treatment (mg/kg)
***
Numberoffightingrats
AUT9 and bitopertin
produce pinning and
pouncing behaviour
V
eh
+
V
eh
PC
P
+
V
eh
PC
P
+
A
U
T9
10
m
g/kg
PC
P
+
A
U
T9
30
m
g/kg
PC
P
+
A
U
T9
60
m
g/kg
PC
P
+
R
isperidone0.1
m
g/kg
0.0
0.2
0.4
0.6
0.8
Treatment (mg/kg)
**
Numberoffightingrats

27. Affective Bias Test (Stuart et
al. 2013)

28. Affective Bias Test
(Stuart et al., 2013)
No treatment
D1
• Vehicle solution
• AUT9 (30 mg/kg; IP)
• Risperidone (0.1 mg/kg; IP)
• Haloperidol (0.05 mg/kg; IP)
• FG7142 (10 mg/kg; IP)
30 min
Female adult
Hooded-Lister rats
(n=10/group)
D2 D3 D4 D5
30 min
C B
+
C
C B
+
C
B
+
Choice
test
30 trials
Determination of % choice:
%A > %B : positive bias
%A = %B : no bias
%A < %B : negative bias
A
+
A
+
A
+

29. Will AUT9 produce a positive bias
in PCP-treated rats?
D1
30 min
Female adult
Hooded-Lister rats
(n=10/group)
D2 D3 D4 D5
30 min
C B
+
C
C B
+
C
B
+
Choice
test
30 trials
A
+
A
+
A
+
PCP (2mg/kg)
Vehicle
Washout
Washout
Twice daily
(7 days) (7 days)

30. PCP induces a negative affective bias

31. Summary
• Low dose risperidone, bitopertin and AUT9 restore
PCP-induced social behaviour and cognitive deficits.
LY404039 ineffective.
• AUT9 and bitopertin enhance social behaviour.
• AUT9 and low dose antipsychotics induce a positive
affect bias.
• KV3.1 channel modulation shows promise as a new
treatment for schizophrenia: potentially disease
modifying?

32. The animal model MUST mimic the
clinical situation
• The PCP model mimics an UHR group for schizophrenia
NOT a chronic clinical condition.
• 21 days antipsychotic followed by 7 days withdrawal: then
test a novel antipsychotic.
• 21 days antipsychotic: then test a novel add-on treatment
for cognitive or negative symptoms.

33. Conclusions
• Consider negative symptom domains
separately-different tests
• Include antipsychotic treatment in the
animal model
• Could patients be stratified into negative
symptom subtypes and treated
accordingly?

34. Manchester team
Thank you!
 Megan Gurney and Marianne Leger
 Ben Grayson, Peter Haddad, Mike Harte,
Sam Marsh, Chloe Piercy
 Bill Deakin, Samaneh Maysami, Rhona
Stephen, Steve Williams
 Charles Large
 Giuseppe Alvaro
 Barbara Domayne-Hayman
 Peter Harris
Autifony
Collaborators
 Frank Tarazi
 Jorgen Scheel-Kruger
Newcastle
 Mark Cunningham
 Fiona Lebeau
 Claire Gillougley
 Margaret Lawlor
Technology Strategy Board
 Gavin Whitlock

35. BRITISH ASSOCIATION FOR
PSYCHOPHARMACOLOGY
40th Anniversary
Summer Meeting
20 ̶̶̶̶̶̶̶̶̶ 23 July 2014
Cambridge
Online CPD
Resource
Schizophrenia Substance
misuse including
comorbidity Bipolar disorder
Perinatal disorders ADHD
focussing on adults
Depression Anxiety
disorders Sleep Old Age
Child and Adolescent
(coming soon)
www.bap.org.uk