Reducing Risk of Getting Reducing Risk of Getting SchizophreniaSchizophrenia

CannabisCannabis

OOver 30 published scientific research ver 30 published scientific research papers linking marijuana to papers linking marijuana to schizophrenia schizophrenia

Regular Regular cannabis cannabis users users by age 15 by age 15 are are four timesfour times as likely to have a diagnosis as likely to have a diagnosis of schizophreniform disorder at age of schizophreniform disorder at age 26 than controls.26 than controls. (Arseneault et al 2002) (Arseneault et al 2002)

CannabisCannabis

No pre-No pre-existing existing

psychosispsychosis

Pre-existing Pre-existing psychosispsychosis

Psychosis outcomePsychosis outcome

Interaction with pre-existing Interaction with pre-existing psychosispsychosis

Interaction with pre-existing Interaction with pre-existing psychosispsychosis

T1T1

T3T3

2.2%2.2% 54.7%54.7%

American Journal of Epidemiology, 2002American Journal of Epidemiology, 2002

ActionAction

EElimination of cannabis use would reduce the limination of cannabis use would reduce the incidence of schizophrenia by approximately incidence of schizophrenia by approximately 8% 8%

Discourage cannabis use in adolescence Discourage cannabis use in adolescence under the age of 18under the age of 18

Discourage cannabis use in adolescence with Discourage cannabis use in adolescence with +FH+FH

Discourage cannabis use in adolescence Discourage cannabis use in adolescence with schizotypal traits.with schizotypal traits.

UrbanicityUrbanicity

IIndividuals who spent their first 15 years of ndividuals who spent their first 15 years of life in a highly urban area were nearly life in a highly urban area were nearly three three timestimes as likely to be diagnosed with as likely to be diagnosed with schizophrenia, compared with people who schizophrenia, compared with people who grew up in rural areas. grew up in rural areas. ((Pedersen CBPedersen CB and and Mortensen PBMortensen PB 2001) 2001)..

A A fifth to a thirdfifth to a third of individuals exposed to of individuals exposed to bothboth the the urban upbringing urban upbringing and the genetic and the genetic risk factors attract the disorder because of risk factors attract the disorder because of their coparticipation. their coparticipation. (van Os et al 2004)(van Os et al 2004)

0

2

4

6

8

10

12

1 2 3 4 5

Ris

k sc

hizo

phre

nia

Am J Psychiatry, 2004Am J Psychiatry, 2004

DoDo genes enhance urban risk? genes enhance urban risk? (n=7076)(n=7076)

DoDo genes enhance urban risk? genes enhance urban risk? (n=7076)(n=7076)

FH+FH+

FH-FH-

Population Population densitydensity

χχ22=9.1, df=1, =9.1, df=1, PP=0.003=0.003

ActionAction

Living outside a city before age 15 may Living outside a city before age 15 may reduce chances of getting reduce chances of getting schizophrenia schizophrenia

Avoid raising up children in dense urban Avoid raising up children in dense urban environment especially if FH +environment especially if FH +

Dysfunctional familiesDysfunctional families

Risk of getting schizophrenia (for Risk of getting schizophrenia (for children genetically predisposed to children genetically predisposed to schizophrenia) can be up to schizophrenia) can be up to eight eight timestimes higher in high stress " higher in high stress "dysfunctionaldysfunctional familiesfamilies" vs. low stress " vs. low stress households households ((TienariTienari et al 2004) et al 2004)

ActionAction

Attempt to keep stress levels in the Attempt to keep stress levels in the family environment at a relatively low family environment at a relatively low level. Learn how to manage stress well. level. Learn how to manage stress well. Stress InformationStress Information..

Pregnancy InfectionsPregnancy Infections

MMothers who suffer from flu, viruses and others who suffer from flu, viruses and other infections during the other infections during the first trimester first trimester of of pregnancy are at significantly pregnancy are at significantly increased risk of schizophrenia - up to increased risk of schizophrenia - up to seven timesseven times higher than children who higher than children who are not exposed to flu/viruses during the are not exposed to flu/viruses during the first first trimestertrimester of pregnancy. of pregnancy. (Brown et al (Brown et al 2004)2004)

ActionAction

BBecome pregnant only after (at least ecome pregnant only after (at least several weeks after) taking a several weeks after) taking a vaccination shot. Make extra efforts to vaccination shot. Make extra efforts to avoid exposure of mother to influenza avoid exposure of mother to influenza and other viruses during pregnancy. and other viruses during pregnancy.

Obstetric ComplicationsObstetric Complications

RRisk for schizophrenia isk for schizophrenia isis fourfour times times higher for children who suffer from higher for children who suffer from hypoxia during childbirth hypoxia during childbirth (Dalman BJP (Dalman BJP 2001)2001)

ActionAction

For reduced risk of children with For reduced risk of children with schizophrenia, mothers should make schizophrenia, mothers should make extra efforts to avoid any possible extra efforts to avoid any possible delivery complications and to be in the delivery complications and to be in the best possible hospital environment in best possible hospital environment in case complications do occurcase complications do occur..

Paternal AgePaternal Age

Children born to fathers aged over 50 Children born to fathers aged over 50 could be as much as could be as much as four timesfour times more more likely to develop schizophrenia than likely to develop schizophrenia than those born to fathers aged 21 to those born to fathers aged 21 to 2424((Rasmussen Rasmussen et al 2004 BMJ)et al 2004 BMJ)

ActionAction

For reduced risk of children with For reduced risk of children with schizophrenia, men schizophrenia, men may choose to may choose to have children while they are younger have children while they are younger (under 40) rather than older. (under 40) rather than older.

PREVENTION upon indicators of developmental vulnerability

the great majority of preschizophrenia children scoring well within the normal range.

predictive value will be too low for the purpose of screening and prevention.

Prepsychotic Expression of Illness

Continuity: PredictionContinuity: Prediction

Hanssen, BakHanssen, Bak et al, 1998 et al, 1998

TT11

TT22

T3T3

±± 7000 7000

±± 5500 5500

±± 4700 4700

1 year1 year

2 years2 years

Psychotic symptomPsychotic symptom

Psychotic disorderPsychotic disorder

CIDI ratings at T1 as independent predictors of being incident patient at T3

CIDI ratings at T1 as independent predictors of being incident patient at T3

HanssenHanssen et al, 2000 et al, 2000

3.1 2.1

5.2

11.1

0

2

4

6

8

10

12

OR

The number of people screening positive for subclinical psychotic experiences who needed to be treated to prevent

one case of full-blown psychoticdisorder

PV(%) Treatment Success

Rate (%)

NNT NNI

5 25 80 79

5 50 40 39

20 25 20 19

20 50 10 9

50 25 8 7

50 50 4 3

• Early intervention in the general population is not feasible, at least not on the basis of the subclinical psychosis screening criterion.

• The answer is increase Prevalence from 1% to say 50 %. Then PV will be 50 %.

Making schizophrenia more predictable but for fewer patients

Sample Enrichment Strategy

• most widely used approach but possibly also the worst understood.

• the predictive value of any factor, whether it be schizotypal symptoms, sex, color of the eyes, or any other random variable, would have been at least 50%

Predictors of schizophrenia dividing the ‘high risk ill’ group from other high-risk participants

Johnstone et al 2004 BJP

Filter model of psychotic symptoms and psychotic disorder

5. Psychiatric hospital

1. General population

Filter 1: Illness behaviour

2. Population attending GP

Filter 2: GP recognition

4. Mental health out-patients

Filter 4: Psychiatrist referral

3. GP recognised

Filter 3: GP referral

ASPISASPIS (N = 2000)(N = 2000)

SCHIZOTYPYSCHIZOTYPY

COGNITIONCOGNITION

GENESGENES

Endophenotypes for SchizophreniaEndophenotypes for Schizophrenia

Brain Structure Cognition

Schizotypy

GENES

Candidate genes for Schizophrenia

Effect of COMT genotype on Effect of COMT genotype on SSchizotypal chizotypal DDimensionsimensions

COMT GENOTYPECOMT GENOTYPE

VAL / VALVAL / VAL

DOPAMINE DOPAMINE

VAL / METVAL / MET

MET / METMET / MET

SCHIZOTYP. SCHIZOTYP. PHENOTYPEPHENOTYPE

POSITIVEPOSITIVE

NEGATIVENEGATIVE

DISORGANIZEDDISORGANIZED

PARANOIDPARANOID

Stefanis et al. 2004 Biol. Psychiatry

COMT GENOTYPE EFFECT ON COMT GENOTYPE EFFECT ON NEGATIVE SCHIZOTYPY: ASPISNEGATIVE SCHIZOTYPY: ASPIS

Young conscripts Young conscripts (n=542) with lower (n=542) with lower level of dopamine level of dopamine transmission in PFC, transmission in PFC, score significantly score significantly higher on “negative” higher on “negative” schizotypal items, schizotypal items, related to social related to social isolation and isolation and indifference for social indifference for social contact.contact.

181249112N =

COMT GENOTYPE

val/valmet/valmet/met

SP

Q N

EG

ATIV

E S

CH

IZO

TYP

Y F

AC

TOR

Stefanis et al. 2004 Biol. Psychiatry

DOPAMINE : Tuning Cognitive PerformanceDOPAMINE : Tuning Cognitive Performance

Low levels of Low levels of dopamine dopamine transmission in PFC transmission in PFC associated with associated with increased increased inconsistency of inconsistency of response (noise) response (noise) during cognitive tasks during cognitive tasks

177242109N =

COMT GENOTYPE

val/valmet/valmet/met

VARI

ABIL

ITY

OF R

ESPO

NSE(

CPT)

Stefanis et al. American Journal of Psychiatry (in press)