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Page 1: Animal models and new therapeutic approaches

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

Page 3: Animal models and new therapeutic approaches

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?

Page 4: Animal models and new therapeutic approaches

Animal models??

Page 5: Animal models and new therapeutic approaches
Page 6: Animal models and new therapeutic approaches

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

Page 7: Animal models and new therapeutic approaches

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!

Page 8: Animal models and new therapeutic approaches

“Schizophrenia, the abandoned illness.”

The Schizophrenia Commission, 2012

Cost approx £60k per patient per year

Page 9: Animal models and new therapeutic approaches

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

Page 10: Animal models and new therapeutic approaches

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)

Page 11: Animal models and new therapeutic approaches

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

Page 12: Animal models and new therapeutic approaches

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.

Page 13: Animal models and new therapeutic approaches
Page 14: Animal models and new therapeutic approaches

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

Page 15: Animal models and new therapeutic approaches

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.

Page 16: Animal models and new therapeutic approaches

Social species

Page 17: Animal models and new therapeutic approaches

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

Page 18: Animal models and new therapeutic approaches

Social interaction test (10 min)

Following Object exploration

Sniffing

Page 19: Animal models and new therapeutic approaches

Social interaction test (10 min)

2 parameters affected

by PCP:

Sniffing duration ()

Avoidances number ()

Following Object exploration

Sniffing Avoidances

(Snigdha & Neill, 2007, 2008)

Page 20: Animal models and new therapeutic approaches

AUT9 restores PCP-induced

social behaviour deficits

Veh + Veh

PCP + Veh

PCP + AUT9 10 m

g/kg

PCP + AUT9 30 m

g/kg

PCP + AUT9 60 m

g/kg

PCP + Risp

eridone 0.1 mg/kg

0

20000

40000

60000

Treatment (mg/kg)

**

###

*

#

Sniff

ing

(ms)

Veh + Veh

PCP + Veh

PCP + AUT9 10 m

g/kg

PCP + AUT9 30 m

g/kg

PCP + AUT9 60 m

g/kg

PCP + Risp

eridone 0.1 mg/kg

0.0

0.5

1.0

1.5

2.0

2.5

Treatment (mg/kg)

***

###

###

######Nu

mbe

r of a

void

ance

s

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

Page 21: Animal models and new therapeutic approaches

Bitopertin restores

PCP-induced social behaviour deficits

Veh + Veh

PCP + Veh

PCP + Bito

pertin 1 m

g/kg

PCP + Bito

pertin 3 m

g/kg

PCP + Bito

pertin 10 m

g/kg

PCP + Risp

eridone 0.1 mg/kg

0

20000

40000

60000

Treatment (mg/kg)

*

#

Sniff

ing (

ms)

Veh + Veh

PCP + Veh

PCP + Bito

pertin 1 m

g/kg

PCP + Bito

pertin 3 m

g/kg

PCP + Bito

pertin 10 m

g/kg

PCP + Risp

eridone 0.1 mg/kg

0.0

0.5

1.0

1.5

2.0

2.5

Treatment (mg/kg)

***

###

##

###

###Num

ber o

f avo

idan

ces

Page 22: Animal models and new therapeutic approaches

LY404039: mGluR2/3 agonist

Presynaptic

localisation: glutamate

reuptake

Glia localisation:

glutamate transporter

expression (glutamate

reuptake)

pathological

glutamate release (Weinberger, 2007)

Page 23: Animal models and new therapeutic approaches

Lack of efficacy of LY404039

on social interaction

Veh

+ V

eh

PCP +

Veh

PCP +

LY

0.3

mg/

kg

PCP +

LY

1 m

g/kg

PCP +

Risper

idon

e 0.

1 m

g/kg

0

20000

40000

60000

Treatment (mg/kg)

******

***

***

Sn

iffi

ng

(m

s)

Veh

+ V

eh

PCP +

Veh

PCP +

LY

0.3

mg/

kg

PCP +

LY

1 m

g/kg

PCP +

Risper

idon

e 0.

1 m

g/kg

0.0

0.5

1.0

1.5

Treatment (mg/kg)

Nu

mb

er o

f avo

idan

ces

Page 24: Animal models and new therapeutic approaches

Play behaviour

Following Object exploration

Sniffing Avoidances

Page 25: Animal models and new therapeutic approaches

Veh

+ V

eh

PCP +

Veh

PCP +

Bito

pertin

1 m

g/kg

PCP +

Bito

pertin

3 m

g/kg

PCP +

Bito

pertin

10

mg/

kg

PCP +

Risper

idon

e 0.

1 m

g/kg

0.0

0.2

0.4

0.6

0.8

1.0

Treatment (mg/kg)

***

Nu

mb

er o

f fi

gh

tin

g r

ats

AUT9 and bitopertin

produce pinning and

pouncing behaviour

Veh

+ V

eh

PCP +

Veh

PCP +

AU

T9

10 m

g/kg

PCP +

AU

T9

30 m

g/kg

PCP +

AU

T9

60 m

g/kg

PCP +

Risper

idon

e 0.

1 m

g/kg

0.0

0.2

0.4

0.6

0.8

Treatment (mg/kg)

**

Nu

mb

er o

f fi

gh

tin

g r

ats

Page 26: Animal models and new therapeutic approaches
Page 27: Animal models and new therapeutic approaches

Affective Bias Test (Stuart et

al. 2013)

Page 28: Animal models and new therapeutic approaches

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 +

Page 29: Animal models and new therapeutic approaches

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)

Page 30: Animal models and new therapeutic approaches

PCP induces a negative affective bias

Page 31: Animal models and new therapeutic approaches

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?

Page 32: Animal models and new therapeutic approaches

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.

Page 33: Animal models and new therapeutic approaches

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?

Page 34: Animal models and new therapeutic approaches

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

Page 35: Animal models and new therapeutic approaches

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