prevention in schizophrenia - fapesp

Prevention in Schizophrenia

– from Neuroscience to Community

Rodrigo A. BressanProfessor, Department of Psychiatry, Un. Federal de São Paulo, Brazil

Honorary Visiting Professor, Institute of Psychiatry, King’s College London

LAB INTERDISCIPLINARNEUROCIÊNCIAS CLÍNICAS

0 2 4 6 8 10 12

Percent of Total

Disease Burden by Illness DALY - Disability Adjusted Life Year (15-44 anos)

Unipolar depressive disorders

Alcohol use disorders

Schizophrenia

Iron-deficiency anemia

Bipolar affective disorder

Hearing loss, adult onset

HIV/AIDS

Chronic OPD

Osteorthritis

Road traffic accidents0 2 4 6 8 10 16

Source: WHO – World Health Report, 2001

Challenges for Prevention of

Schizophrenia

• A – Limited biological knowledge

• B – Poor effectiveness of treatments

• C – Stigma

Insel, 2013

Schizophrenia –

neurodevelopmental disease

Murray et al., Lancet 1985; Weinberger, Arch Gen Psychiatry 1987

ENVIROMENT

0 5 10 15 20 25 30

GENES

LAB INTERDISCIPLINARNEUROCIÊNCIAS CLÍNICAS

Schizophrenia

DNA

Gene ExpressionCitokines

Immigration/

Urbanicity

Trauma

Bullying

Brain changesStructural/Funcional

Obstetric

complications

Cannabis

Dopamine

sensitization

“ULTRA-HIGH RISK”

1ST EPISODE PSYCHOSIS SCHIZOPHRENIA

CHRONICITY

or

TREATMENT RESISTANCE

PRE-MORBID

Multiphasic Approach

Risk during Neurodevelopment

Schizophrenia

“HIGH RISK”

LAB INTERDISCIPLINARNEUROCIÊNCIAS

CLÍNICAS Multimodal Approach

ARY GADELHA

Integrative Neuroscience

JAIR MARIEpidemiology

• Psychopathology x x x x x

• Cognition x x x x x

• Genetics x x x x x

• Neuroimaging• Structural/Functional

x x x x x

• Molecular Imaging - - x x x

• Neuropeptidases (Ndel) x x x x x

• Sleep x x x x x

• Neurotrophins/ Cytokines

x x x x x

• Animal Models - x x x -

Risk during Neurodevelopment

Psychosis Severity

LAB INTERDISCIPLINARNEUROCIÊNCIAS CLÍNICAS

“ULTRA-HIGH RISK”

1ST EPISODE PSYCHOSIS

SCHIZOPHRENIA

CHRONICITY

or

TREATMENT RESISTANCE

PRE-MORBID“HIGH RISK”

Multiphasic – Multimodal Approach

Schizophrenia

Clinical: PANSS validation, prediction of Treatment

Resistance

Cognition:

•MCCB Matrics validation in Brazil – Regular FAPESP

•Cognitive Rehabilitation – PRONEX

SCZ

p < 0.001

PI100105043Commercial use protected by:

Biomarker for Schizophrenia

Protected by Patent deposition

Reduced dorso-lateral prefrontal cortex in

treatment resistant schizophrenia

Zugman et al., Schiz. Research. 2013.

• Compare cortical thickness between

61 treatment resistant SCZ, 67 non-

resistant and 80 healthy controls.

• TR-SCZ presented widespread

reduction in cortical thickness in

frontal, temporal, parietal and

occipital regions

• TR-SCZ presented significant

reduced DFPFC thickness than

controls.

• Finding suggest cortical thickness of

DLPFC a more severe form of the

disease. Figure : Decreased DLPFC (BA 46) in the TR-SCZ group.

Brain Structure and Treatment Resistance

Gene Modulation of Brain Structure

Ota et al., Schiz. Research 2013..

• 282 patients and 379 controls were genotyped. 138 went to an

MRI scan.

• GG-genotypes carriers presented reduced frontal grey matter

volume.

ZDHHC8 gene may play a role in cortical volumes of patients with schizophrenia.

BDNF modulating cortical thickness in schizophrenia.

Zugman et al., submitted

• BDNF and cortical thickness showed

different patterns of correlation for

patient and healthy control group in

one cluster in the right hemisphere

distributed across the supramarginal,

post central, and inferior frontal

cortices

Figure : Blue shade represents significantcluster at p<0.05 for group*bdnf interaction.Lines represent Freesurfer parcelation regions.

Neurotrophins and Brain Structure

First Episode PsychosisEpigenetics: gene expression and methylation

• 175 drug-naïve 1st episode psychotic patients

First Episode Psychosis

Gene expression (RNA) – Risperidone treatment (2 months)

Ultra-High Risk for Psychosis

Transition Rates to Psychosis (2 years)

Centre Transition rate

PACE 41%

PRIME 38%

TOPP 43%

EDIE 26%

PIER 23%

22%… work in progress

Fusar-Poli et al., 2012

Reference Comparison

Group

N Outcome

PACEMcGorry et al., Am J Psychiatr 2002

1. CBT + risperidone2. Support Therapy

3128

1. ↓ conversion in 6 mo (9,7 vs. 35%), p=0,0262. ↔ in 1 yr

EDIEMorrison et al., Br J Psychiatr 2004

1. CBT2. Monitoring

2929

1. ↓ conversion in 1 yr (6% vs. 26%), p<0,052. ↓ conversion in 3 yr

PRIMEMcGlashan et al., Am J Psychiatr 2006

1. Olanzapine2. Placebo

3129

1. ↓ conversion (15% vs. 38%), p>0.052. ↑ Side effects

Amminger et al., Arch Gen Psychiatr 2010

1. Omega 32. Placebo

4140

1. ↓ conversion (4,9% vs. 27,5%), p=0,004

Conversion to psychosis

– is it possibleto prevent?

Cytokines – new opportunities

Treatment: new opportunities

Sleep – new opportunities

The Epigenetic Challenge

Animal Model Schizophrenia (SHR) –preventive effects strategies

Santos, CM - 2015

~ adolescence

Enriched Environment – prevent schizophrenia like symptoms

~ adulthood

Animal Model Schizophrenia (SHR) –preventive effects strategies

~ adolescence

Canabidiol (CBD) – prevent schizophrenia like symptoms

Locomotion Prepulse Inhibition of Startle Contextual Fear Conditioning

Peres FF, 2015

~ adulthood

Instituto Nacional de

Psiquiatria do Desenvolvimento

Salum et al., Intl J Meth Psychiatr Res, 2014

Dimensional Psychopathology

Structural Brain Trajectories –

hippocampus

Andre Zugman , Sato, Bressan, Jackowsky et al., in preparation

Genetic determinants of brain

morphology

Common genetic variants influence subcortical brain

volumes in ancestrally diverse adolescentsPatrick MA Sleiman1,2, Theodore Satterthwaite3, Sintia L Belangero4,5, John Connolly1, Frank Mentch1, HaijunQiu1, Xiao Chang1, Cecilia Kim1, Renata Pellegrino-Silva1, Kelly Thomas1, Andrea P Jackowski4, Helena PBrentani6,7, Euripedes CM Filho6,7, Giovanni A Salum7,8, Ary Gadelha4, Mackenzie Behr1, Rosetta Chiavacci1,Rueben C Gur3, Rodrigo A Bressan5, Raquel E Gur3 and Hakon Hakonarson1,2.

Sleiman et al., submitted

GWAS study of subcortical brain volumes (MRI) of 1957 individuals

• Philladephia Neurodevelopmental Cohort (age 8-21 years)

• Brazilian High Risk Cohort Study (age 7-15 years).

• 2 loci associated with brain volume also associate with neurocognitive

tests

• For the first time that genetic variants associated with intermediate

phenotypes such as brain imaging data can be predictive of a

behavioral phenotype.

Sato et al., J Psychiatr Res 2014

Functional Brain Trajectories

Functional Brain Trajectories

• centrality angular gyrus during the transition to adolescence

• many subcortical and cerebellar regions.

Functional Brain Trajectories

Altered neurodevelopment trajectory identified using a combination of graph theory and one-class support vector machine to analyze neuroimaging data.

• Assessed brain networks rsfMRI of 622

children and adolescents with increased

risk for psychiatric disorders (7-15 y/o)

• Subjects with atypical brain network

organization had higher levels of

psychopatology

Sato et al., submitted

Figure : Box-plots of EVC at each node with significant mean difference (p<0.05) between the OC-SVM labels (typical vsatypical), CBCL Total and age.

Psychotic experiences: cortical thickness

• Findings may indicate subtle deviant brain maturation

processes that may represent risk for schizophrenia

Ary Gadelha et al., in preparation

• Mental Health Literacy for

teachers

• RCT 80 Special Teachers (PMECs)

• Outcome measures:

• Literacy

• Stigma

• Attitude towards MH

• Scale up: 472 PMCs teachers

Translation to Community

School Mental Health

T1

TO

Randomization 80

A

n=41

n=41

B

n=39

n=32

180Inscriptions

45d

Apolinario et al., 2014; Simões et al., Cad Saud Publ, 2015

Mental Health in Schools – what teachers should know

• Multistage research approach – synergistic

• Multimodal – new questions may be answerd

• Challenges:

– Databank integration

– Data analysis methodology

• Prevention: work in progress…

ConclusionsLAB INTERDISCIPLINAR

NEUROCIÊNCIAS CLÍNICAS

Agradecimentos

LAB INTERDISCIPLINARNEUROCIÊNCIAS CLÍNICAS

SÃO PAULO SCHOOL OF ADVANCED SCIENCE

FOR

PREVENTION OF MENTAL DISORDERS

Disclosure

Unrestricted

Research Grants Scholarshps

Private Companies

Astra Zeneca * *

Janssen * *

Eli Lilly *

Novartis *

Lundbek * *

Roche *

Agnowlegments LAB INTERDISCIPLINARNEUROCIÊNCIAS

CLÍNICAS

Research Grants Scholarships

Research Agencies

Pronex

INCT

RCUK

regular

*

*

*

*

*

*

*

*

Pronex

INCT

RCUK

*

*

*

*

*

*

MPhil / PhD

Post-Doc*

MRC - UKAPPLAUSE

RCUK

*

**

*

Fundação Safra *

Fundação ABADS *

DisclosureResearch Grants Speaker/ Board Shareholder

Private Companies

Astra Zeneca *

Janssen * *

Eli Lilly *

Novartis *

Lundbek * *

Roche *

CCTECH Ltda. *

Biomolecular Technology Ltda. *

Research Agencies

FAPESP *

CNPq *

CAPES *

Fundação Safra *

Fundação ABADS *

• The angular gyrus become more central during this maturation

period, while the caudate; cerebellar tonsils, pyramis, thalamus;

fusiform, parahippocampal and inferior semilunar lobe become less

central

• Conclusion: increasing centrality of the angular gyrus during the

transition to adolescence, with a decreasing centrality of many

subcortical and cerebellar regions.Sato et al., Neuroimage 2015

Schizophrenia –

neurodevelopmental disease

Murray et al., Lancet 1985; Weinberger, Arch Gen Psychiatry 1987

0 5 10 15 20 25 30

GENES

LAB INTERDISCIPLINARNEUROCIÊNCIAS

CLÍNICAS

SchizophreniaENVIROMENT

Schizophrenia –

neurodevelopmental disease

Murray et al., Lancet 1985; Weinberger, Arch Gen Psychiatry 1987

ENVIROMENT

0 5 10 15 20 25 30

GENES

LAB INTERDISCIPLINARNEUROCIÊNCIAS

CLÍNICAS

Schizophrenia

GeneticsSuspiciousness

Immigration/

UrbanicityBullying

Personality

Obstetric

complications

Cannabis

Dopamine

sensitization

Schizophrenia –

neurodevelopmental disease

Murray et al., Lancet 1985; Weinberger, Arch Gen Psychiatry 1987

ENVIROMENT

0 5 10 15 20 25 30

GENES

LAB INTERDISCIPLINARNEUROCIÊNCIAS

CLÍNICAS

Schizophrenia

DNA

Gene Expression

Citokines

Immigration/

Urbanicity

Bullying

Brain changesStructural/Funcional

Obstetric

complicationsCannabis

Dopamine

sensitization

Impact

Clinical Findings

Zugman et al., 2013

Psychotic Experiences (CBCL)vs.

Brain Maturation

• Are PE are associated with cortical

thickness? (720 children, 7-15 year-old)

• CBCL Psychotic Experiences scores and

cortical thickness :

– Negative correlation with frontal and

temporal cortices

– Positive correlations with the

occipital cortices

Ary Gadelha et al., in preparation

PRODH polymorphisms, cortical volumes and

thickness in schizophrenia.

Ota et al., Plos One 2014.

• Investigation the effect of 12 polymorphisms of PRODH in

192 patients with schizophrenia.

• One polymorphism associated with schizophrenia

(rs2904552) with the G-allelle

Gene Modulation of Brain Structure

lh_parsorbitalis_volume lh_insula_volume

Clo

se

ness C

oe

ffic

ient

0.0

0.2

0.4

0.6

0.8

1.0

Pars%Orbitalis% Insula%

**%

*%

%Healthy%Controls %%%First%Episode%Psychosis %%%Schizophrenia%Pa<ents%

**%

*%

Chronic SCZ: 143First-episode psychosis: 32Controls: 82

Analysis of brain-netowrk disruptions in First Episode

Psychosis: an approach based on graph analyses of

structural covariance

Zugman et al. , submitted

Etapa 2 - Classifier

Deep Belief Networks are são modelos generativos de redes de arquitetura híbrida com múltiplas camadas ocultas

Etapa 1 - Autoencoder

Results

Differences between groups Input layer

Layer 1 Layer 2 Layer 3 Layer 4

(SCZ-FEP) – (FEP-HC) 0.114 0.039 0.009 1.377 <0.001 (SCZ-FEP) – (SCZ-HC) 0.678 0.237 0.87 1.776 0.012

(FEP-HC) – (SCZ-HC) 0.009 0.027 0.0030 0.99 <0.001

Integrative Neuroscience

• Hierarchical feature representation with deep

learning of schizophrenia MRI data

•

• Walter H. L. Pinaya; Ary Gadelha a; Cristiano Noto

a; Joana B. Balardin; Quirino Cordeiro c; Sintia I. O.

Belangero b; Rodrigo A. Bressan a; Andrea P.

Jackowski a; João Ricardo Sato a, d

• 3 groups of genes:

– Genes expressed in immune-system

– Neurodevelopment

– Transcription Factors Gadelha et al., to be submitted

N=170

Ndel1 Esquizofrenia