Neuroscience and Psychiatry

神経科学と精神医学

Ian Paul Everall

Cato Professor and Head

Department of Psychiatry

University of Melbourne

North West Mental Health

The Talk 本日の話題

What are we trying to do - help people affected by

mental illness

Why is it so important?

Give some examples of current neuroscience activity

in the Department

some suggestions as to how things could change for

the future

Our Ultimate Aim is To return them to ‘health’

“Health is a state of complete physical, mental and social well-being and not

merely the absence of disease or infirmity”

World Health Organisation

Why is neuroscience

Important? 神経科学が、なぜ重要か?

The Society for Neuroscience states

In 2007, the World Health Organization estimated that neurological disorders

affect up to one billion people worldwide.

Neurological diseases makes up 11 percent of the world’s disease burden, not

including mental health and addiction disorders.

The cost of these diseases is high across the globe. For example, the European

Brain Council estimated in 2010 that neurological diseases in Europe alone cost

one trillion dollars a year.

Mental Illness Costs Society a Lot of Money

(精神疾患は社会に大きな負担を与えている)

For example the total cost of major depressive disorder Total cost = direct cost + indirect cost

• Direct costs

–UK > €534 million (£333 million) (Kind and Sorenson, 1993)

–US > €2,350 million ($2,100 million) (Jones, 2000)

• Indirect costs

–Morbidity and loss of productivity

(€11,190 million = $US 10 billion)

–Loss from increased mortality

(€4,700 million = $US 4.2 billion)

Kind P and Sorensen J. The costs of depression. Int Clin Psychopharmacol 1993; 7: 191–195

Jones ME, Cockrum PC. A critical review of published economic modelling studies in depression. Pharmacoeconomics 2000; 17 (6):

555–583

Depression heavily affects work productivity

(うつ病は仕事の生産性に大きな影響を与えている)

Number of work days lost by patients suffering from MDD compared to non-depressed subjects

DEPRES II (Depression Research in European Society II):

A patient survey of the symptoms, disability and current management of depression in the community.

Int Clin Psychopharmacol 1999; 14: 139–151

Nu

mb

er

of

wo

rkin

g d

ays l

os

t

Major depression

Non-depressed

Depression has a huge impact on workplace productivity

うつ病は職場の生産性に

重大な影響を与えている

Druss et al. Am J Psychiatry 2001;158:731–734 *p<0.001 vs no depressive symptoms

No depressive symptoms (n=4,387)

Acute depressive symptoms (n=652)

Chronic depressive symptoms (n=501)

*

*

*

*

0

10

20

30

40

50

Pe

rcen

tag

e o

f p

ati

en

ts

Absenteeism

(missed work days)

Presenteeism

(decreased effectiveness)

Productivity loss in a working cohort with MDD

うつ病における仕事の生産性の低下 P

erc

en

tag

e o

f sa

mp

le e

nd

ors

ing

50

% o

r m

ore

of

the t

ime

Doing poor

quality work

Making more

mistakes

Getting less

work done

Moderately

depressed (n=44)

Severely

depressed (n=37)

Very severely

depressed (n=25)

0

10

20

30

40

50

60

70

80

90

100

Lam. APA, 2009

*Severity based on QIDS-SR score;

MDD=major depressive disorder

Examples of what we are doing

in Melbourne メルボルン大学における

我々の研究活動の例

Dean et al. 2012, insights into molecular pathology

of schizophrenia, bipolar disorder and major

depressive disorder

Skafidas et al. 2012, diagnostic test for autism

spectrum disorder

Inflammation related Proteins:

Changed in Psychiatric Disorders 精神疾患における炎症関連タンパク質の変化

IRP STUDIED Major Depressive

Disorders

Bipolar Disorders Schizophrenia

20 32 36 7 6 4 1 10 10 5

Levels of inflammation-receptor proteins in blood vary with:

• sleep disturbance (Ryan et al. Circulation (2005) 112, 2660–2667),

• body weight (Wellen & Hotamislioil Journal of Clinical Investigation (2003) 112, 1785–1788),

• glycaemic state (Huerta & Nadler Current Diabetes Reports (2002) 2, 396–402),

• diurnal variation (Miller et al. Brain Behaviour and Immunology (2003) 17, 276–285),

• sample storage conditions (Flower et al. Cytokine (2000) 12, 1712–1716).

RNA HUMAN POSTMORTEM

BRAIN TISSUE

STUDIES ON THE HUMAN CNS TRANSCRIPTOME

死後脳を用いたトランスクリプトームの研究

Dean & Scarr

TNF α

TUMOUR NECROSIS α: AN IMPORTANT

INFLAMMATORY-RELATED PROTEIN

（TNFα:重要な炎症関連タンパク質）

-40 0 40 80 120

% Control

Major Depressive Disorder

-40 0 40 80 120

% Control

Bipolar Disorder

-40 0 40 80 120

% Control

Schizophrenia

(Mikova et al. 2001)

(Tuglu et al. 2003)

(Fitzgerald et al. 2006)

(Yang et al. 2007)

(Kim et al. 2007)

(Pavon et al. 2006)

(Penninx et al. 2003)

(Kudoh et al. 2001)

(Milaneschi et al. 2009)

(Simon et al. 2008)

(O'Brien et al. 2007)

(Schlatter et al. 2001)

(Brambilla et al. 2004)

(O'Brien et al. 2006)

(Kim et al. 2007)

(Lee et al. 2009)

(O'Brien et al. 2008)

(Kim et al. 2009)

(Erbagci et al. 2001)

TUMOUR NECROSIS α: FINDINGS IN BLOOD

（TNFα: 血液における所見）

tmTNF

TNFR1 TNFR2

ADAM17 sTNF sTNFR2

ADAM 17 sTNFR1

TUMOUR NECROSIS α: BIOLOGY

（TNFαの分子経路）

TUMOUR NECROSIS α: BIOLOGY（TNFαの分子経路）

MAJOR

DEPRESSIVE

DISORDERS

No Change

+ 458 %

No Change

No Change

53 %

BIPOLAR

DISORDERS

No Change

No Change

No Change

No Change

71 %

SCHIZOPHRENIA

No Change

No Change

No Change

+ 179 %

No Change

MEASURE

TNF α

(mRNA)

tmTNF α

sTNF α

TNFR1

(mRNA)

TNFR2

(mRNA)

Dean B et al. (2010) Journal of Affective Disorders 120: 245-248.

Dean B et al. (In Press) Molecular Psychiatry (mp201295

[pii];10.1038/mp.2012.95 [doi])

TUMOUR NECROSIS α IN PSYCHIATRIC DISORDERS

（TNFα：精神疾患における変化）

MAJOR DEPRESSIVE

DISORDERS

TUMOUR NECROSIS α PSYCHIATRIC DISORDERS:

POTENTIAL CONSEQUENCES

（TNFα: 精神疾患では何が起きているのか）

Diagnostic Classifier for Autism Spectrum

Disorder using SNPs (Single Nucleotide

Polymorphisms)

一塩基多型(SNP)による自閉症圏の診断分類

a SNP is a DNA sequence

variation that occurs when a

single nucleotide differs

within a population or

individual

2 sequenced DNA fragments

AAGCCTA & AAGCTTA differ

by a single nucleotide

allelic frequency various

between ethnic groups

DNA molecule 1 differs from DNA molecule 2 at a single

base-pair location (a C/T polymorphism)

Genetic classification of Autism Spectrum

自閉症圏の遺伝的分類

Autism Genome Research

Exchange (AGRE)

database (6,774

individuals (2,609 ASD)

distribution of autistic

and non-autistic

individuals based on

genetic classification

Classification accuracy of

85% using 237 SNPs.

this is the 1st time that we

have a diagnostic test

(Skafidas et al, iMol Psych 2012)

autism score

Autism Subjects Control Subjects

Genetic classification of Autism Spectrum

自閉症圏の遺伝的分類

distribution of autistic and non-autistic individuals based on genetic (SNP) classification

Classification accuracy for Central Europeans and Tuscans was >85% using 237 SNPs

accuracy in an independent sample was >74%

(Skafidas et al, Mol Psych 2012)

autism score

Autism Subjects Control Subjects

Parents of Autism Subjects

Does Neurosciene Benefit Society? 神経科学を社会に還元できるか？

I hope that the two examples indicate how we

can help patients

Relates molecular and cellular pathology with

clinical symptoms or disorder classification

Is there Recovery? 統合失調症は回復するか?

Our view of disorders such as schizophrenia

coloured by the original descriptions of Emil

Kraeplin and Eugene Bleuler who emphasized

the chronic nature of the disorder and poor

recovery

Burghozli Hospital Study - Manfred Bleuler: 53%

of all subject and 66% of first admissions had

recovered significantly

20% had recovered fully

Iowa 500 study (Tsuang and Winokur, 1975) -

46% with schizophrenia had either improved or

recovered

Meta-analysis > 100 outcome studies in schizophrenia in high-

income countries in the 20th century assessed whether

individuals had achieved ‘social recovery’ (economic and

residential independence and low social disruption) or ‘complete

recovery’ (loss of psychotic symptoms and return to the pre-

illness level of functioning).

Revealed a substantial rate of recovery

Approx 20% complete recovery and

40% social recovery (which includes those who achieved

complete recovery)

What about those Living with

Mental Health Issues? 精神疾患を抱えて生きることとは？

Not so interested in the diagnosis

While symptoms such as depressed mood,

hallucinations etc can be distressing

More interested in issues pertinent to the recovery

model of mental health

Their own level of functioning

Recovery Model (Warner, The

Psychiatrist 2010) 回復モデル

Social movement influencing mental health service development

It refers to the subjective experience of optimism about outcome from

psychosis,

to a belief in the value of the empowerment of people with mental illness,

and

to a focus on services in which decisions about treatment are taken

collaboratively with the user and which aim to find productive roles for

people with mental illness

So What Could we do

Better? 今後我々がすべきことは？

We could consider correlating our findings to issues that are important

to those living with mental illness

Have markers of everyday functioning:

employment

relationships

cognition

This will be challenging but may help us understand functional issues

that are important to everyday life