Is schizophreniaIs schizophrenianeurodeve

Prof. Dr. Han

Department Ludwig-MaxMunich, GerMunich, Ger

a a disorder of a a disorder of elopment?

ns-Jürgen Möller

of Psychiatry ximilians-Universityrmanyrmany

KraepelinKraepelin

“ These considerations force us to dthere must be a manifest destructiothere must be a manifest destructiohave been investigated more closelyalterations have actually been demo

h l i W h fother explanation..... . We therefore Dementia praecox there is severe danervous cortical elements, which mindividual cases, but which mostly rimpairment of the psyche.”

n‘s ordsn‘s words

draw the direct conclusion that on of the cortex In those cases thaton of the cortex. In those cases that ly by reliable means, regular onstrated for which there is no

h h l i h ireach the conclusion that in amage to or destruction of the ay be compensated for in results in a peculiar, persistent

Author‘s translation from Kraepelin 1913

The original neurThe original neurhypothesis an

rodevelopmental rodevelopmental d its evidence

The original neurghypothesis and its

• Schizophrenia is related to developmentThi l bilit f t• This vulnerability factor precharacteristic pattern of braor adult life before the first

• The severe/psychotic behavlater in life, at a time when mplaced under functional demplaced under functional dem

• The brain structural abnormperinatally and are static thp y

rodevelopmental ps original meaning

alterations in brain

di ti t tedisposes patients to a ain malfunction in childhood psychotic episodep y pvioural abnormalities appear maturing brain circuits are mandmandmalities occur pre-birth or ereafter.

Murray and Lewis 1987Weinberger 1987

Premorbid behaviindicative for neurodindicative for neurod

altera

• Subtle motor, cognitive, sochave been described in chilschizophreniaschizophrenia

• These subtle behaviour abnindicative for early neurodey

• They are more frequently prrisk for schizophreniaTh l l• They are also seen as a vulconsidered as endophenoty

our abnormalities developmental brain developmental brain ations

cial and emotional changes ldren who later develop

normalities are seen as evelopmental alterationspronounced in children at high

bilit k dnerability marker and ypes for research

Walker et al. 199Marenco and Weinberger 200

McGrath and Murray 200Rapoport et al. 200

Neuropathological evthe neurodevelopmthe neurodevelopm

schizop

• Neuropathological findingsatrophy of some brain lobeshistopathological levelhistopathological level

• This in absence of any age-lack of neuropathological ep gneurodegenerative changescytopathological inclusions

• Structural MRI findings of v• Structural MRI findings of vreduced temporal lobe strufolding, loss of normal assy

vidence in support ofental hypothesis of ental hypothesis of

phrenia

of ventricular enlargement, s, alteration on a

-related effects and with a vidence of s (e.g. no evidence for s, gliosis or neuronal loss)ventricular enlargementventricular enlargement, ctures, reduced cortical ymmetry

Jakob and Beckmann 198Bogerts et al. 199

McCorley et al. 199Harrison and Lewis 200

Pathogenesis of neuroltaltera

• The lack of gliosis and otheevidence of neurodegeneraa pathogenesis that differsa pathogenesis that differs chronic neurogenerative dis

• Abnormal brain maturation,apoptosis, or synaptic pruninterneural neuropil, have bpossible mechanismspossible mechanisms

odevelopmental braintiations

er neuropathological ative changes has suggested

from other adult onset andfrom other adult-onset and seases, which may involve y

ning resulting in loss of been hypothesized as

Harrison and Lewis 200Harrison and Lewis 200Berger et al. 200

Feinberg 198McGlasham and Holtmann 200

Lewis and Levitt 200

Evidence for the assoneurodevelopmental neurodevelopmental

later emergence

• The identification of persistneurodevelopmental alteratprovided useful evidence foprovided useful evidence foschizophrenia

• Such persistent markers incpresence of minor physicalpresence of minor physicalsigns and dermatoglyphic a

• Findings from the Edinburgt th t h bsuggest that such abnorma

developmental markers, whgenes for schizophrenia

ciation between earlbrain alterations andbrain alterations and of schizophrenia

tant markers of an early tion in adult patients has or the association of NBA andor the association of NBA and

clude evidence for the anomalies neurological soft anomalies, neurological soft

anomaliesgh genetic high risk study

liti ifialities are non-specific hich are not mediated by the

Marenco and Weinberger 20McGrath et al. 19Dazzan et al. 20

Boks et al. 20Chen et al. 20

Laurie et al. 20

Relationship betweenk d b i tmarkers and brain str

• Few studies found an assocneurodevelopmental alteratabnormalities in adult patieabnormalities in adult patie

• Other studies could not find

• The negative findings may bexamined using MRI were n

l l i d/ th ti iearly lesion and/or the timinof any lesion may determineaffected (e.g. second trimes

n neurodevelopmentat l b litiructural abnormalities

ciation between markers of tion and brain structual nts.nts.

McNeil et al. 2000, van Os et al. 2000

d such an associationSee McGrath and Murray 2003 for reviewSee McGrath and Murray 2003 for review

be because the regions not those most relevant to an

d i f t l d l tng during fetal development e which structures are most ster, third trimester, perinatal)

Pantelis et al. 2005

Structural Mdemonstrate pdemonstrate palterations in

patiepatie

MRI findings remorbid brain remorbid brain schizophrenic entsents

Munich bra

Cerebral MRT1.5 Tesla Magnetom Vision. Sequence: Cog qand 3D-MPRAGE, 1.5 mm

Clinical documentationAge weight height handedness (EdinburAge, weight, height, handedness (EdinburPsychopathology: Phillips Scale, BPRS, SAIMS, TDRS, AMDP, HAMD, MADRS

Analysis softwareBRAINS (NC Andreasen), SPM

144 healthy subjects 18- 65 ye100 hi h i ti t 18 61

Cross-sectional data analysed to date:

100 schizophrenic patients 18- 61 ye106 depressive patients 17- 65 ye

in database

oronary TSE Dual-Echo-Sequence y q

rgh Test HDT) WST-IQ SKIDrgh Test, HDT), WST-IQ, SKIDSANS, PANSS, Simpson Scale,

ears old 33.6 ± 12.4ld 31 8 ± 10 6ears old 31.8 ± 10.6

ears old 42.8 ± 12.5

Results of structwhole brain in schizwhole brain in schiz

8

10 **

4

6

8SZ

0

2

CSF TL links CSF TL

HC

ml

33,5

4

CSF TL links CSF TLml** **

11,5

22,5

3

*

00,5

1

pocampus left right 3rd ventric

tural mapping of zophrenic patientszophrenic patients

Temporal lobes:

**Temporal lobes:Ventriclesleft p < 0.0001right p = 0.002

L rechtsL rechts

Hippocampus: left/rightWhole structure p = 0.001/0.003

**

Whole structure p 0.001/0.003Grey matter p = 0.001/0.006White matter p = 0.001/0.004

3rd ventricle: p = 0.01

cle

3rd ventricle: p 0.01

Meisenzahl et al., Am J Psychiatry 2002,Res Neuroimag

CSF volumes: First hosppatients (FH-SZ) versus sc

multiple hospitali

** ** ** ** p = 0.000

5

0

** ** ** p

0

5

0 ** ** ** **

5

0

5 ** ** ** ** **

0

onclusion 3: Enlargement of all CSF spaces in paspitalisations

pitalised schizophrenic chizophrenic patients with

FH-SZ (N=66)

isations (MH-SZ)

0MH-SZ (N=34)

% enlargement MH-SZ:

CSF total 13.8 %3rd ventricle 35.8 %left SV 52.3 %right SV 48 6 %right SV 48.6 %CSF TL l 101 %CSF TL r 114 %CSF FL l 69 %CSF FL r 66 %CSF FL r 66 %CSF PL l 57 %CSF PL r 58 %CSF OL l 72 %CSF OL r 74 %

atients with multiple

CSF OL r 74 %

Meisenzahl et al., Unpublishe

Hippocampal volumes: Firstpatients (FH-SZ) versus sc

ppocampus (HC):

multiple hospital

ppocampus (HC): st manifestation (N = 66) vs. relapse m

FH-SZ

MH-SZ

t hospitalised schizophrenic chizophrenic patients with isations (MH-SZ)

manifestations (N = 34)

ANCOVA (covariate age, gender, ICC)

First hospitalisation vs relapsesHippocampus total:Hippocampus total: left: p < 0.0001right: p = 0.009 Hippocampus grey matter (GM): left: p < 0 0001left: p < 0.0001 right: p = 0.026

Hippocampus white matter (WM):left: p < 0.0001left: p < 0.0001 right: p < 0.0001

Meisenzahl et al., Unpublishe

General problemsconclusions about neurconclusions about neur

from adult structura

• Neuroimaging studies that are necessarily of early neuabnormal gyral patterns) mabnormal gyral patterns), mindication that an early neuetiologically relevant in at lewith schizophrenia

• However, several other MRIin adulthood after illness oin adulthood, after illness ointeraction between the typneurodevelopmental stage

t ti t bi thgestation to birth

s of retrospective rodevelopmental originrodevelopmental origin

al MRI abnormalities

can define anomalies, which urodevelopmental origin (e.g. may provide an indirectmay provide an indirect

rodevelopmental lesion is east a proportion of patients

I brain alterations observed onset may depend on anonset, may depend on an

e of brain alteration and the of the fetus from early

Pantelis et al. 2

Structural Mdemonstrate prdemonstrate pr

changes in scpatiepatie

MRI findings rogressive brain rogressive brain chizophrenic entsents

vidence for progressivth f the course of s

• Harrison and Lewis (2003) sHarrison and Lewis (2003) sevidence to support a progralteration that „by default, it d d l ttowards neurodevelopment

• However, there is now increthat progressive neuroanatthat progressive neuroanatschizophrenia, for several ymanifestationsTh t t t hi h th• The extent to which these cbetween the early aberrant processes and ongoing neup g gadolescence is unclear

ve brain changes durinhi h ischizophrenia

state that it is the lack ofstate that it is the lack of ressive or degenerative brain s the stronger pointer t l i i “tal origin“easing evidence to suggest omical changes do occur inomical changes do occur in years from its earliest

h fl t i t tichanges reflect an interaction neurodevelopmental

urodevelopment in p

Pantelis et al. 2

Early and late stages oterations and their relaterations and their rela

neurodevelopmen

A complex model of brain altefollowing:

• the early (pre- or perinatal) d• the later /(ongoing?) anomal• the later /(ongoing?) anomal

processes such as myelinat• non-developmental, possibly

around the onset of the illne

of neurodevelopmentalationship to progressivationship to progressiv

ntal brain changes

erations might include the

developmental anomaliesies of developmentalies of developmental tion or synaptic pruningy neurodegenerative changes ess and the acute episodes

Pantelis et al. 2

Progressive reductioadolescent schizoadolescent schizo

13 years

18 years

on of brain volume in ophrenic patientsophrenic patients

Thompson et al. 2001,

Grey matter maturahi h i hildschizophrenic childr

ation for healthy and d d l tren and adolescents

Rapoport et al. 20

Longitudinal study of bepisode schepisode sch

Total ventricular volume change in poor ouversus control subjects

ange

(cc)

lar v

olum

e ch

aVe

ntric

ul

Days between scans

Ventricular volume change scores of poowere significantly different compared to (p=0.0028) and control subjects (p=0.03)

rain morphology in first hizophreniahizophreniautcome and good outcome patients

Control

Good outcome

Poor outcome

or outcome patients increased and those of good outcome patients

Lieberman et al. Biol Psychiatry 2001;49:487-

One-year followCNS reduction in firCNS reduction in fir

Total grey matter Tota

w-up: Structural rst episode patientsrst episode patients

l brain Lateral ventricles

Cahn et al. Arch Gen Psychiatry 20

The Munich StructuralLongitudinal Follow

1. First Episode SZ

T0 T2 T3 T4T1

Change during 1 year in gray matter of the te(B) of patients with FES schizo140

80

100

120

**

20

40

60 *

0

left

FLgm

left

FLwm

right

FLgm

right

FLw

m

left

TLgm

left

TLwm

right

TL

l MRI Network Center: w-up MRI Approach I

emporal lobes (A) and temporal CSF spaces ophrenia and healthy controls

HC N = 1

*

A B

HC N 1

SZ N = 1

*****

TLgm

right

TLwm

left

TL C

SFrig

ht T

L CS

F3.

Vent

rikel

The Munich StructuralLongitudinal Follow

50 SZ vs. 50 HC

T0

Change during 6 years: in gray matter of theside ventricles (A) of patients with recur

140 A **

80

100

120

B

**

20

40

60

0

left V

ent

right

Ven

trig

ht F

Lwm

left T

Lgm

left T

Lwm

right

TL

l MRI Network Center: up MRI Approach II

T6

e left temporal lobe (B) and CSF space of the rrent schizophrenia and healthy controls

HC N = 1HC N 1

SZ N = 1TL

gmrig

htTL

wmlef

t TL

CSF

right

TL

CSF

3rd

vent

ricle

Antipsychotic drug emorphology in first-p gy

effects on MRI brain -episode psychosisp p y

Mean changes in whole brain grey matter volumes b t t t (fby treatment group (from baseline to weeks 12, 24, 52, and 104) and healthy control group (from baseline to weeks 12 and 52).

Hal = haloperidolOlz = olanzapineCon = controlsLimit lines = standard error

Lieberman et al. Arch Gen Psychiatry 2005; 62:36

Relationship between Md thand neuropatho

• It should be considered thaIt should be considered thavolume, often used to derivbrain structure, are influencnot always related to brain snot always related to brain sbrain volume

MR volumetric findingsl i l fi diological findings

at MRI measures of cerebralat MRI measures of cerebral ve measures of anatomical ced by a number of factors structure itself but only tostructure itself, but only to

Poor outcome od i tand importance

untreated

of schizophrenia f d ti f e of duration of

psychosisp y

Munich Follow-upschizophrenicschizophrenic

schizoaffective p

Schizophpsycho

Affective psychoses

5% 3% 3%

92% 57%92% 57%

Single episode Courses with relapsl t i icomplete remission

p Study: Course of c, affective and c, affective and sychoses (ICD-10)

hrenic oses

Schizoaffective psychoses

% 15% 17%

40% 68%68%

ses and Chronic courses: course wi ti id l tn persisting residual sympto

LMU, Unpublished

Munich Follow-up Studsymptoms in schizophresymptoms in schizophre

affective psyc

Schizophrenic psychosis Affective p

7

8

9Schizophrenic psychosis Affective p

%

4

5

6

1

2

3

0

NAMDP item composition

Admission to first hospitalisation

D

NAMDP item composition: disturbed conrestricted thinking, thought blocking, incoherence, feeaffective rigidity, lack of drive, mutism, social withdraw

dy: Course of negative enic, schizoaffective andenic, schizoaffective andchoses (ICD-9)

S hi ff ti h ipsychosis Schizoaffective psychosispsychosis

ischarge Follow-Up

ncentration, inhibited thinking, retarded thinking,eling of loss of feeling, blunted affect, parathymia,wal and decreased libido.

LMU, Unpublished

Munich Follow-up Sschizophrenic patientschizophrenic patient

syndrome at 15

343540%

28

253035

101520

05

Schizophrenich

Apsychoses p

Study: Percentage of ts (ICD 9) with a deficit ts (ICD-9) with a deficit 5-year follow-up

AMDP Deficit SyndromeySANS Deficit Syndrome

13

6

16

0

Affective h

Schizoaffectivehpsychoses psychoses

LMU, Unpublished

What is the duratdela

tudy N

) Yung & McGorry, 1998 200

) Larsen et al, 2000 N/A

) Barnes et al, 2000 53

) Loebel et al, 1992 65100

120

140

) Drake et al, 2000 248

) Craig, 2000 155

) Ho et al, 2000 N/A 60

80

Wee

ks

) Syzmanski, 1996 34

) Browne et al, 2000 53

0

20

40

01

tion of treatment ays?

Mean Median

Mean and median duration of untreated psychosis

2 3 4 5 6 7 8 9

Study

Munich Follow-up Syear outcome of sch

Sex

year outcome of sch

Rehospitalis.

Partner +

Job +

GAS (max)

PANSSNegativePositivePositiveGeneral

SANS

DeficitSyndr.

Study: DUP und 15-hizophrenic patients

AgeType of beginDUP

hizophrenic patients

gyp g

- -

MultivariaMultivariaanalysis

Bottlender et al. 2

Munich Follow-up Syear outcome of schyear outcome of sch

Negative symptoms SANS

100

II) Deficit syn

%**

50

60

70

80

90%

10

20

30

40

50

Long DUP Short DUP0

Long DUP

Long (> 6 months) and short DUP (< 6 m

Study: DUP and 15-hizophrenic patientshizophrenic patients

ndromes

70

III) GAS

re** **

40

50

60

∅Su

m s

cor

10

20

30

Short DUP0

Long DUP Short DU

months)

Bottlender et al. 2002

ncrease of the frequenwith increasing dwith increasing d

Freque3914 schizophrenic patients according to ICD-9. The frequency of deficit syndromes at discharge is

15

20

25

rom

es (%

)syndromes at discharge is presented for groups of patients with the same duration of illness.

5

10

15ef

icit

synd

r

1 = 0 - 4 years

2 = 5 - 9 years

0

De

Patien

3 = 10 - 14 years

4 = > 14 yearsPatien

ncy of deficit syndromeduration of illness duration of illness

ency of deficit syndromes according to the duration of illness

1 2 3 4nt groups with different durations of illnessnt groups with different durations of illness

Bottlender et al. 20

Natural history oNatural history o

H lth

Premorbid Prodromal Onde

Healthy

WorseningWorsening severity of signs and symptoms The vulnerability to schiz

to its neurodevelopmentato its neurodevelopmentaits morbidity and disabilipathophyiologic progres

G /Gestation/Birth 10 Puberty 20

of schizophreniaof schizophrenia

nset/ terioration

Residual/ stable

zophrenia is due al diathesis butal diathesis but ity are due to its sion after onset

30 40 50

Years

Schizophrenia is a nand neuroprogrand neuroprogr

Active phahi

Neurodevelop-t l b i schizopmental basis

Unspecificstressors

Modulating (Therapy, G

„ NeurotoxicityHypothesis“

neurodevelopmental ressive disorderressive disorder

Impaired therapyresponseProlongation

ase ofh i

Prog. neuro-degenerativehrenia degenerativechangesNeurotoxic

effects

Poor outcomefactors

Gender...)

Bottlender et al. 20

The recent reforThe recent reforneurodevelopme

rmulation of the rmulation of the ental hypothesis

„The neurodevelohi h ischizophrenia:

• Originally, neurodevelopmehave largely focussed on al/perinatal) brain developme/perinatal) brain developme

• In recent years, longitudinaadult onset schizophrenia pp pprogressive brain changes apreviously thought, with grestriking in adolescence andstriking in adolescence andexaggeration of the normal

opmental model of U d t 2005“: Update 2005“

ntal models of schizophrenia terations on early (pre-ntntl studies of both early and

populations indicate that p pare more dynamic than ey matter loss particularly

appearing to be an appearing to be an developmental pattern

Rapoport et al. 20

Evidence from strucdiff t t f bdifferent stages of b

The available data provide evidThe available data provide evidof processes occurring at differneurodevelopment

Early stage:• There is evidence for an early

d l l l ineurodevelopmental alteratio• This may render the brain vu

(particularly postpubertal) ne(particularly postpubertal) neprocesses, as indicated by evof grey matter and aberrant cprefrontal regionsprefrontal regions

ctual MRI studies for b i lt ti (I)brain alterations (I)

ence to support a numberence to support a number rent stages of

y (pre- or perinatal) onlnerable to anomalous late

eurodevelopmentaleurodevelopmental vidence for accelerated loss connectivity, particularly in

Pantelis et al. 20Pantelis et al. 20

Wood et al. 20Pantelis et al. 20

Evidence from strucdifferent stages of bdifferent stages of b

Late stage:• These abnormal neurodevelop

with other causative factors apsychosis (e.g. substance abupsychosis (e.g. substance abuHPA-axis function), which togsequelae that may be neurodetemporal and orbital prefrontatemporal and orbital prefrontaimaging studies around trans

• In this context, the features of,neuropsychological deficits amanifestations, can be untersthese multiple pathological prthese multiple pathological prneurodevelopmental stages

ctual MRI studies for brain alterations (II)brain alterations (II)

pmental processes interact associated with the onset of use, stress dysregulation ofuse, stress dysregulation of

gether have neuroprogressive egenerative, involving medial, al regions as suggested byal regions, as suggested by ition to active psychosisf schizophrenia, including the p , g

and behavioural stood as direct effects of rocesses at various

Pantelis et al. 20Pantelis et al. 20

Wood et al. 20Pantelis et al. 20

rocesses at various

Genetic influestrucstruc

ences on brain cturecture

Genetic overlapping obipolar dbipolar d

18q2221q21

18p13qq

4p1612q24

13q10p

22q1q 22q1

of schizophrenias anddisordersdisorders

11.2q32

6p226q21q32

p1411-13

6q218p22

11-13

Genes implicated ischizophrenia and/schizophrenia and/

Gene/Locus Chromosomal locat

Dysbindin 6p22

Neuregulin 1 (NRG1) 8p12

Disrupted-in-Schizophrenia 1 (DISC 1q42Disrupted-in-Schizophrenia 1 (DISC 1)

1q42

RGS4 1q23

COMT 22q11

D-amino-acid oxidase activator DAOA(G72)/G30

13q33

BDNF 11p13

DAO 12q23

Increasing evidence of overlap in genetic susceIncreasing evidence of overlap in genetic suscesystems that dichotomised psychotic disordersmost notably with DAOA, DISC1 and NRG1

in pathogenesis of /or bipolar disorder/or bipolar disordertion Evidence in

schizophreniaEvidence in bipolar disorder

+++++

++++ +

+++ ++++ +

++

+ +

++ ++

++

++

eptibility across traditional classificationeptibility across traditional classification s into schizophrenia and bipolar disorder,

Genetic influences

In animal experimentsgenetic influence on no. gof neurones, brain weight

and volume

Identification of the genetic ingA contribution to the aetiological unde

on brain structure

Cerebral changes in disorders such as in disorders such as

schizophrenia, which hasa genetic loading

nfluence on brain morphology:p gyerstanding of schizophrenic disorders?

IL1ß and its roresponse response

inhibition of IL1ß secretion reducestraumatic brain damage in mice

high IL1ß concentrationgof apoptosis of v

strong IL1ß immunoreactivity aroundß-amyloid plaques in M. Alzheimer

ole in the stress in the brainin the brain

inhibition of IL1ß delays onset of Chorea Huntington in mouse models

s increase the probability p yvulnerable neurons

alterations of immunological parameters in schizophrenia

Association between Il-1structure: allele 2 is asso

reductions in schi

1500

Allel 1 Allel 2ccmccmp= 0.02p= 0.02

500

1000p= 0.03p= 0.03

p= 0.002p= 0.002

0

500

total braintotal brain graygray white matter white matter

Similar results for 1/1 homozygotes vs.1 carriers in schizophreniaN=48 schizophrenic patientsNo association in healthy controls!

ß polymorphism and braiociated with brain volumizophrenic patients

120

Allel 1 Allel 20.020.02 0.040.04

406080

100 0.020.02n.s.n.s.

0.0020.002

0.0090.009

0.0050.005

n.s.n.s.

02040

left / rightleft / rightfrontal lobefrontal lobe

left / rightleft / righttemporal lobetemporal lobe

gm gm wm wm gm gm wm gm wm gm wm wm gm gm wmwm

Meisenzahl et al., Am J Psychiatry.

Genes involved in theproc

• Schizophrenia susceptibilityabnormalities, particularly apopulations (i.e. GAD1, 22gpremorbid neurodevelopme

S l did t f• Several candidate genes fordysbindin) are associated win both schizophrenia and op

e neurodevelopmental cess

y genes and chromosomal as examined for early onset 11DS) are associated with

ental abnormalities

hi h i (r schizophrenia (e.g. with lower cognitive abilities other pediatric populationsp p p

Rapoport et al. 20

Evidence for gend lneurodevel

GAD1 translates to GAGAD1: GAD1 translates to GAGlutamic acid decarbAssociation with schi

GAD1:

GAD67 is the key enzyPolymorphisms of the

GAD67:

of GABA synthesizing→ Is involved in cortichypocampal developm→ Associated with MR→ Associated with poscore (prefrontal lobe

nes relevant for l t (I)lopment (I)

AD67AD67oxylaseizophrenia

yme in the synthesis of GABAe GAD gene lead to a decrease g enzymecal, thalamic, cerebellar and mentR findings of grey matter lossoor qualitative age-tracking e function)

Rapoport et al. 20

GAD1 and frontalduring ado

Slope of frontal grey matter loss during adolesce

5

t = 2 67 df = 36 p = 0 01

Slope of frontal grey matter loss during adolesce2/2) alleles of GAD1 for children with schizophre

ter s

lope

0

t = 2.67, df = 36, p = 0.01

tal g

rey

mat

-5

Fron

t

-1010161/1

rs22

grey matter loss olescenceence for the risk (1/1) vs non-risk (1/2 andence for the risk (1/1) vs non risk (1/2 and

enia

221/2 or 2/2

270335Rapoport et al. 20

Evidence for gend lneurodevel

DAOA = D-aminoacid Association with schiG72 may discriminate

G72:

G72 may discriminate

Association with premand academic adjustm

Dysbindin:(DTNBP1) and academic adjustm

Association with schiDysbindin influences e tracell lar gl tamat

(DTNBP1)

extracellular glutamatand protection agains

nes relevant for t (II)opment (II)

oxidase activatorizophrenia. It was speculated that e between later and early onsete between later and early onset

morbid enophenotypes of poor social mentmentizophreniaexpression of presynaptic proteins,

te le els and release of gl tamatete levels and release of glutamate st cortical cell death

Rapoport et al. 20

Evidence for gend lneurodevelo

Susceptibility gene foI l d i l

Neuregulin:(NRG ) Involved in neuronal m

signalling and myelinCould be involved in

d ti f ti

(NRG1)

and synaptic function

Disrupted in schizophDISC1:Associated with schizMay play an importanalso associated with cfunction

Plays a critical role inReelin: Plays a critical role inAbnormalities in the ein postmortem brains

Reelin:

nes relevant for t (III)opment (III)

or schizophreniai ti ti it llmigration, connectivity, cell

ationneuronal organisation in prenatal life th h t th lif ln throughout the life cycle

hrenia gene zophrenia

nt role in hippocampal development, comprised neuronal integrity and p g y

n neuronal migration

Rapoport et al

n neuronal migrationexpression of reelin gene were found s of schizophrenic patients

Timing of geTiming of ge

• Genes may have multiple dev• Genes may have multiple devdifferent time points

• „This phenomenon is so widepthe concept of neurodevelopmwould avoid debate about neuneurodegenerative interpretatneurodegenerative interpretat

• This has clear implications foas specific abnormalities mayparticular gene action at the p

• In addition, certain regions ofsusceptible to different envirosusceptible to different envirodevelopmental stages

ne activitiesne activities

velopmental effects atvelopmental effects at

espread that simply extending p p y gment throughout the life cycle urodevelopmental vs. tions of CNS changes“tions of CNS changesr many stages of the disorder

y be related only to a particular timepointf the brain may be more onmental effects at different

Rapoport et al. 20

onmental effects at different

P ibl Possible mecprogressive brap g

schizop

h i f chanisms for in alterations in phrenia

Hypotheses of pathoghischizop

• Disturbances of

• Glutamate ‚intox

I l i l• Immunological m

• Others

enetic mechanisms ih iphrenia

neuroplasticityp y

xication‘

h imechanisms

Rapoport et al. 20

Activation of thschizopschizop

Raised serum IL-6 level in sc(Maes et al, 1995; Ganguli et al, 1994; LAkiyama, 1999)y )

High IL-6 level in relation to uresistence (Lin et al, 1998) and lo1994)1994)

Raised IL-6 level in CSF (van K

Strong relationship between paranoid-hallucinatory syndr(Müller et al, 1997)

Decreased sgp130 level in CSDecreased sgp130 level in CS(Schwarz et al, in press)

e IL-6 system in phreniaphrenia

hizophreniaLin et al, 1998; van Kammen et al, 1999;

unfavourable course: Treatment ong illness duration (Ganguli et al,

Kammen et al, 1999)

sIL-6R level in CSF and rome

SFSF

Schizophrencyclooxycyclooxy

Raised IL-6 level in serum of sc(Frommberger et al, 1995; Maes et Higher IL-6 level with - longer illness duration (Gangulonger illness duration (Gangu- treatment resistence (Lin et al, CSF-sgp130 decreased in schiz

)press)CSF sIL-6R level correlates withhallucinatory syndrome (Müller Prostaglandin E2 stimulates IL-6(Williams & Shacter, 1997)COX-2 inhibitors inhibit the IL-6COX-2 inhibitors inhibit the IL-6

nia, IL-6 and ygenase 2ygenase-2

chizophrenic patientsp pal, 1995)

li et al, 1994)li et al, 1994)1998)

zophrenics (Schwarz et al, in

h severity of paranoid-et al, 1997)6 synthesis in macrophages

6 synthesis (Anderson et al 1996)6 synthesis (Anderson et al, 1996)

Celecoxib PANSS Total SPANSS - Total S

85

80

85

ore

70

75

S to

tal S

c

60

65

PAN

S

50

55

50

week 0 week 1 week 2*t-test

– Study:Score (LOCF)Score (LOCF)

Risperidone & CelecoxibRisperidone & Placebo

ANCOVA* COp < 0.05

*p < 0 05p < 0.05**p < 0.01

week 3 week 4 week 5****

Müller et al. Am J Psychiatry, 20

Towards aa synthesisy

Pathogenesis oPathogenesis o

Environmental insults (str

C

GenesMultiple-

susceptibility alleles each of small effect

Cellular programming

Gene and protein expression

C

aindu

seach of small effect

f schizophreniaf schizophrenia

Stressorressors, toxins)

StressorMaturation

Environme

Psychotdisorde

Cell development

Neural systemsAbnormal

connectivity in local

Behavioufunctio

DisturbanCell developmentMultiple subtle

abnormalities in uction, patterning, synaptogenesis

connectivity in local circuits and

macrocircuitsperceptiinformatprocessi

moodregulationregulation

cognitio

Model of the of schizoof schizo

DNA, Geneexpression

Prenatalinfection

Complicat birth

Neurodevelopmental distur

Altered anatomical-functional cCognitive deficits

Acute psychosis

roce

ss

Deficit syndrome

pr neurobiology ophreniaophreniacations Nutrition „First Hit“

rbance

connectivity„Second Hit“

GeneticsMetabolismStress, Life Events

s„Third Hit“

Neurotoxic factors

e

e.g. glutamate, immunological mechnisms

Genetic link between scGenetic link between scdisor

• Multiple cases of schizophrenia, psychosis and mood disorder oc

• Statistically significant evidence y g– At increased rate in relatives o– At increased frequency in the

• Susceptibility genes:p y g– Some specific to schizophren– Some specific to bipolar diso– Yet others influence susceptiYet others influence suscepti

schizophrenia and bipolar dis

chizophrenia and mood chizophrenia and mood rders

bipolar disorder and concurrent ccur in some familiesthat bipolar disorder occurs:pof schizophrenic probands

e relatives of bipolar probands

niarderbility to schizoaffective disorder,bility to schizoaffective disorder,

sorder

The biological eginvolved in sch

• Dysbindin regulates glutamate rereceptors to the PSD and in vesicglutamate

• NRG1 modulates NMDAR and GArecruits CHRNA7 receptors to sy

• DISC1 is involved in centrosomamigration, neurite outgrowth, andreceptors and possibly mitochonreceptors and possibly mitochon

• RGS4 negatively modulates G prdopamine, metabotropic glutamadopamine, metabotropic glutama

effects of genes ghizophrenia (I)

elease, is involved in tethering cular trafficking of presynaptic

ABAA receptor expression and ynapses

l and microtubule function, cell d membrane trafficking of ndrial functionndrial function.

otein-mediated signaling via ate, and muscarinic receptors.ate, and muscarinic receptors.

The biological eginvolved in sch

• COMT modulates cortical dopamwhich amplify NMDAR currents acell membrane by NMDAR signal

• DAOA activates D-amino acid ox

• BDNF is a neuroprotective proteiinterneurons

• DAAO is involved in the metaboliglycine site of the NMDAR.

effects of genes ghizophrenia (II)

mine signaling via D1 receptors, and are themselves recruited to the ls

idase

in and a trophic factor for

ism of D-serine, an agonist at the

SchizopSchizopWhat does your ba

S hi h iSchizophreniais a genetic neurodevelopmental disorder

Schizophreniaoccurs inoccurs inall racesall culturesall social classesand both sexes

SchizophreniaSchizophreniacan be treated but not cured....... yet!

phrenia:phrenia:aby‘s future hold?