the epidemiology of schizophrenia reflects pathology of ...€¦ · final common pathway to...

The Epidemiology of Schizophrenia

reflects Pathology of Neurodevelopment

and Striatal Dopamine

Robin M Murray

Dept of Psychoses Studies, Institute of

Psychiatry, Kings College, London

[email protected]

Mapping of Epidemiology onto

Pathogenesis

It is commonplace in medicine for the epidemiology of a disease to be readily interpretable in terms of the pathogenesis of the disorder

For example, the risk factors for Coronary Heart Disease all ultimately cause atherosclerotic damage to the endothelium of the coronary arteries –the final common pathway.

The different risk factors increase the likelihood of plaque formation by different mechanisms.

For example, family history is associated with increased LDL cholesterol, smoking increases platelet adhesion, hypertension damages the endothelium.

Epidemiology and Pathogenesis are

not integrated in Schizophrenia

Epidemiological research has made major advances in the last ten years.

However, this research has proceeded separately from research into the two major pathogenic theories, the neurodevelopmental and dopamine hypotheses

Have we reached a point where we can begin to integrate epidemiological findings with pathogenic theory?

Epidemiological Fact 1

Schizophrenia shows a modest

tendency to run in families.

Since 2002 a

number of

susceptibility genes

have been reported

The risk to the identical co-twin of a

Schizophrenic individual is about 50%

Genes involved in

Neurodevelopment

Neuregulin

Dysbindin

DISC 1

Neurexin

Genes involved in

Neurotransmission

DRD2

DAT

COMT

AKT1

Nature held a Press Conference in summer 2009 when 3

GWAS studies reported more risk genes for schizophrenia

Wow,

how

exciting!

There may be hundreds of risk genes for

schizophrenia

Do I have

any?

Normality

Psychosis

Now we know there are >100 genes, this is more compatible with the idea that there is a continuum of

liability to psychosis

Sz

9

SURPRISE! - Copy Number

Variants

deletion

duplication

Copy Number Variations account

for at least 10 % of Autism

Might they account for some

cases of schizophrenia?

Science. 2008;320,539-43.

Copy Number Variants (CNVs) are found in

Excess in Schizophrenia

Large recurrent microdeletions associated with SchizophreniaHreinn Stefansson1*, Dan Rujescu2*, Sven Cichon3,4*, Olli P. H. Pietila¨inen5, Andres Ingason1, Stacy Steinberg1,Ragnheidur

Fossdal1, Engilbert Sigurdsson6, Thordur Sigmundsson6, Jacobine E. Buizer-Voskamp7,Thomas Hansen8,9, Klaus D. Jakobsen8,9,

Pierandrea Muglia10, Clyde Francks10, Paul M. Matthews11,Arnaldur Gylfason1, Bjarni V. Halldorsson1, Daniel Gudbjartsson1,

Thorgeir E. Thorgeirsson1, Asgeir Sigurdsson1,Adalbjorg Jonasdottir1, Aslaug Jonasdottir1, Asgeir Bjornsson1, Sigurborg

Mattiasdottir1, Thorarinn Blondal1,Magnus Haraldsson6, Brynja B. Magnusdottir6, Ina Giegling2, Hans-Ju¨rgen Mo¨ller2, Annette

Hartmann2,Kevin V. Shianna12, Dongliang Ge12, Anna C. Need12, Caroline Crombie13, Gillian Fraser13, Nicholas Walker14,Jouko

Lonnqvist15, Jaana Suvisaari15, Annamarie Tuulio-Henriksson15, Tiina Paunio5,15, Timi Toulopoulou16,Elvira Bramon16, Marta Di

Forti16, ROBIN MURRAY16, Mirella Ruggeri17, Evangelos Vassos16, Sarah Tosato17,Muriel Walshe16, Tao Li16,18, Catalina

Vasilescu3, Thomas W. Mu¨hleisen3, August G. Wang19, Henrik Ullum20,Srdjan Djurovic21,22, Ingrid Melle22, Jes Olesen23,

Lambertus A. Kiemeney24, Barbara Franke25, GROUP{,Chiara Sabatti26, Nelson B. Freimer27, Jeffrey R. Gulcher1, Unnur

Thorsteinsdottir1, Augustine Kong1, Ole A. Andreassen21,22, Roel A. Ophoff7,27, Alexander Georgi28, Marcella Rietschel28,

Thomas Werge8,Hannes Petursson6, David B. Goldstein12, Markus M. No¨then3,4, Leena Peltonen5,29,30, David A. Collier16,18,

David St Clair13 & Kari Stefansson1,31

Nature, 2008, 455,232-236

Effect of CNVs and Mens‟ Cars

Corollas have a very small effect on individual

girls but because they are so common overall,

they may explain 30% of overall effect.

Similarly common variants like neuregulin have

a small effect but this adds up

Ferraris have a very big effect on individual girls

but they are rare and therefore may explain only

5% of overall male attractiveness .

Similarly, CNVs have a big effect on risk of Sz

but explain only 5% of cases

Copy Number Variations may account for a small proportion of schizophrenia (5%+)

The CNVs implicated overlap with autism and mental handicap.

They may account for some of the developmental impairment in schizophrenia

Not so far reported in excess in Bipolar Disorder (Grozeva et al, 2010)


Schizophrenia but not bipolar disorder is associated with childhood cognitive and neuromotor impairments

Pre-schizophreniform

Dunedin Study: Motor and language

development in pre-symptomatic children

Mary Cannon et al 2002

-0.4

-0.3

-0.2

-0.1

0.0

0.1

0.2Co-efficient

Pre-manic

0.0

0.1

0.2

0.3

0.4Co-efficient

Swedish Cohort Study

907,000 715,000

At age 15, graded

in 16 subjects 280 Bipolar

493 Schizophrenia

Dec 3

1 2

003

MacCabe et al 2009

Risk of schizophrenia in 716,000 Swedish

people according to scholastic ratings

0

1

2

3

4

5

-2 -1 0 1 2

Grade by SD

HRSchizophrenia

Low High

MacCabe et al 2009

0.0

0.5

1.0

1.5

2.0

2.5

3.0 BipolarHR

Risk of bipolar disorder in 716,000 Swedish

people according to scholastic ratings

Low High

Grade by SD

MacCabe et al 2009

-2 -1 0 1 2


Exposure to obstetric events especially hypoxia increases risk of schizophrenia but not bipolar disorder

Dunedin Study: those who met criteria

for schizophreniform disorder at 26

years, compared to controls, showed:-

Higher overall obstetric complications (t=5.5;

p<0.001)

Higher neonatal insults (t=5.95; p<0.001)

Smaller for gestational age (0R=2.8; p<0.001)

More Hypoxia (OR=6.8; p<0.001)

Meta-analysis shown no excess of obstetric

complications in bipolar disorder (Scott et al)

Developmental cascade towards

schizophrenia

P

s

y

c

h

o

s

i

s

2015100 5

Subtle motor,

cognitive and

social deficits

Social anxiety,

depression

Pre & perinatal

events

Quasi

psychotic

ideas

CNVsDevelopmental Genes:

eg NRG1; DISC1,

Developmental Models of Schizophrenia

all implicate Dopamine

Early lesion of hippocampus

(hypoxic)

MAM damage to hippocampus

(prenatal)

Vitamin D Deficiency Model

Dysregulation of the Dopamine System – the

Final Common Pathway to Schizophrenia?*

Post-synaptic receptor

DopamineRe-uptake pump

Striatal dopamine neuron

*This is not to deny the role of GABA, glutamate, endocannabinoids

18F-Dopa Uptake: presynaptic dopamine synthesis

0.0115

0.0125

0.0135

0.0145

0.0155

0.0165

0.0175

0.0185

Controls ARMS Psychosis

Ki

valu

e (

1/m

in)

p=0.02p=0.038

When does the Striatal

DA abnormality arise?

Dopamine is the

“Wind of Psychotic Fire”

When individuals are acutely psychotic, they show an excessive striatal release of dopamine1

Dopamine is involved in reward learning and normally mediates the attachment of salience to ideas and objects2

Excessive dopamine release leads to aberrant assignment of salience to unimportant stimuli3

Delusions arise from attempts to explain this abnormal salience4

1Laruelle et al 1996; 2Berridge and Robinson 1998; 3Kapur 2003; 4Maher 1983


schizophrenia

P

s

y

c

h

o

s

i

s

2015100 5

Subtle motor,

cognitive and

social deficits

Social anxiety,

depression

Pre & perinatal

events

Quasi

psychotic

ideas


eg NRG1; DISC1, BDNF

Dopamine

Dysregulation

of Salience


Stimulant drugs can produce a

schizophrenia-like picture

Psychopathology of individuals

with methamphetamine psychosis

0

20

40

60

80

100

Chen et al Psychological Medicine 2003

Auditory

halluc-

inations

Delusions

of

persecution

Delusions

of

reference

Visual

halluc-

inations

Reading

their

minds

Thought

insertion

Odd

speech

Patients(%)

n=163


schizophrenia

P

s

y

c

h

o

s

i

s

2015100 5

Subtle motor,

cognitive and

social deficits

Social anxiety,

depression

Pre & perinatal

events

Quasi

psychotic

ideas



Drug abuse

Dopamine

Dysregulation

of Salience


Schizophrenia has its maximum onset in early adult life and thereafter incidence declines.

Rates of schizophrenia per 100 000 population in Camberwell

0

10

20

30

40

50

60

0-15 16-25 26-35 36-45 46-55 56-65 66-75 76+

Males

Age at onset (years)

During reward anticipation younger subjects recruit the ventral striatum

and anterior cingulate to a greater extent than older subjects


Certain types of social adversity

increase risk of schizophrenia

South East

LondonBristol

Nottingham

ÆSOP Study – Social Factors that

increase the risk of schizophrenia

Kirkbride, Morgan et al 2006, 2007,2008

Urbanicity – lack of cohesion

Migration/ethnic minority status

Childhood adversity

Social isolation

Adverse life events

Mesolimbic Dopamine System can be

altered by Social Manipulation

Isolation rearing increases DA release in response to amphetamine in adult rats

PET Scan study of changing housing of primates shows differences in dopamine receptor occupancy between the subordinate and dominant animal

Placing a mouse in with a “Bully” alters expression of BDNF and therefore the Dopamine system

Cortisol levels in First Episode

Psychosis

0

3

6

9

12

15

18

Awakening Noon 8:00 PM

Co

rtis

ol

(nm

ol/

l)

Patients < 2 weeks of treatment Controls

*

**

* 55 % increase in cortisol AUC

p=0.001

Increased cortisol is associated with

hippocampal volume decrement

Mondelli et al, 2010

This is reminiscent of Tony‟ Grace „s model in which the

developmetally MAM damaged hippocampus suffers a second hit

with resultant dysregulation of dopamine

Developmental cascade towards dopamine

dysregulation and schizophrenia

P

s

y

c

h

o

s

i

s

2015100 5

Subtle motor,

cognitive and

social deficits

Social anxiety,

depression

Pre & perinatal

events

Quasi

psychotic

ideas



Drug abuseEarly and late social

adversity

HPA

Hyperactivity

Dopamine

Dysregulation

of Salience

Conclusion

Most of the epidemiological characteristics of schizophrenia can be understood in terms of abnormalities of neurodevelopment and of striatal dopamine.

The challenge is now to accurately delineate the mechanistic pathways which link risk factors with development and dopamine and to devise ways of interfering with them

the epidemiology of schizophrenia reflects pathology of ...€¦ · final common pathway to...

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