Schizophrenia Prediction and
Prevention: What Do We
Know?
Puru Thapa, M.D., M.P.H.
Associate Professor
Department of Psychiatry, UAMS
Staff Psychiatrist, Arkansas State
Hospital
03/15/2014
Objectives

Review definition, epidemiology and etiology of
schizophrenia

Understand the concept of levels of preventions

Critically review the strategies of prevention in
schizophrenia and evidence

Consider future directions
Schizophrenia

Syndrome characterized by psychosis and
dysfunction and probably the most devastating
mental illness with great distress to the individual
and families with heavy costs and burden to
society

Treated with antipsychotics and psychosocial
support and rehab
Schizophrenia – DSM-5 Criteria
A.
Two (or more) of the following, each present for
a significant portion of time during a 1-month
period (or less if successfully treated). At least
one of these must be (1), (2), or (3):
1:
2:
3:
4:
5:
B.
Delusions
Hallucinations
Disorganized speech
Disorganized or catatonic behavior
Negative symptoms
Social/occupational dysfunction
Schizophrenia – DSM-5 Criteria
C.
Duration: continuous signs persist for at least
six months
D.
Exclude schizoaffective or mood disorder
E.
Exclude general medical condition or substance
induced
F.
Relationship to a pervasive developmental
disorder
Schizophrenia - Costs


Cost of Schizophrenia in the US in 2002

Direct Costs
30.3 billion dollars

Indirect Costs
32.4 billion dollars

Total Costs
62.7 billion dollars
Mental anguish/distress to individuals affected
and to families
Wu EQ and colleagues, J Clin Psych 2005;66:1122-1129
Schizophrenia - Epidemiology

Life time prevalence approximately 1%

Incidence estimated .01% to .02%

Risk slightly higher in males than females

Age of onset: males 15-25 years, females 25-35
years
Phases of Schizophrenia

Premorbid


Prodromal




Contributes to vulnerability to schizophrenia
Change from premorbid functioning and extends time
of onset of frank psychotic symptoms
Average length 2 – 5 years
Impairment in psychosocial functioning
Psychotic



Onset of frank psychotic symptoms
Acute phase, Early recovery phase (first 6 months
after acute treatment), Late recovery phase (6-18
months)
Period following recovery from first episode up to 5
years is Critical Period for up to 80% relapse
Prodrome

Early prodromal symptoms non-specific: sleep
disturbance, anxiety, irritability, depressed mood, poor
concentration and fatigue, and behavioral symptoms,
such as deterioration in role functioning and social
withdrawal

Late prodromal symptoms: positive symptoms, such as
perceptual abnormalities, ideas of reference, and
suspiciousness – herald imminent onset of psychosis

Prodrome – really based on retrospective reconstruction
Schizophrenia - Etiology

Etiology unknown – can be conceptualized as a clinical
syndrome that is the “final common pathway of multiple
different etio-pathogenetic processes”. Similar to concept
of Congestive Heart Failure or Nephrotic Syndrome

Neurodevelopmental – factors during perinatal period,
genetics

Neurodegenerative
Other factors: season of birth, paternal age, diet during
pregnancy, obstetrical complications, etc.
Stress-Diathesis Model of disease causation


Stress-Diathesis Model

Diathesis: Inherited vulnerability – bad genes

Stress: Environmental insult – physical,
emotional, environmental

This model offers our best explanation of
schizophrenia cause
Genes/Environment
•
Genetic predisposition
–
–
–
–
•
1 parent with schizophrenia
Both parents
Dizygotic twin of schizophrenia patient
Monozygotic twin
12%
40%
12%
47%
Environmental
–
–
Intrauterine trauma? (physical, drugs, etc)
Later trauma or stress? Often the 1st psychotic break
happens during a stressful period such as going away
to college, military, etc.
Challenges in Prevention of Schizophrenia
•
Disorder with unclear etiology
•
No objective marker or test to diagnosis
•
Rare disease
•
Antecedent factors and prodromal symptoms are
not specific – high number of false positives
Predictive Value
Gold Standard
Test Results
Positive
Negative
With
Disease
Without
Disease
True Positive (TP)
False Positive (FP)
a b
c d
False Negative (FN) True Negative (TN)
PPV = TP/(TP+FP) or a/(a+b) = 80/(80+100) = 44%
NPV = TN/(FN+TN) or d/(c+d) = 800/(800+20) = 98%
Epidemiology and Prevention

To identify high-risk subgroups in population

Why?
 Identification of high risk groups may identify
modifiable risk factors.
 Can direct preventive efforts at such groups –
such as screening programs for early
detection of disease
Levels of Prevention
1.
Primary
Prevention of disease by altering susceptibility or
reducing exposure for susceptible individuals
e.g., immunization, exercise
2.
Secondary
Early detection and treatment of disease
e.g., breast cancer screening, screening for disease
(occult blood in stool for colon cancer)
3.
Tertiary
Limitation of disability and rehabilitation
Alleviation of disability resulting from disease and
attempts to restore function (Post-stroke rehabilitation)
Prevention – can be population-based or high risk group
approach
Primary Prevention of Schizophrenia

Limited understanding about etiology and
pathogenesis of schizophrenia

Long latency between primary insult and onset
of schizophrenia

Much research ongoing but not currently
feasible
Tertiary Prevention

Tertiary prevention – reducing the burden of
disease by optimizing treatment and
rehabilitation and reducing relapse

In Schizophrenia, with tertiary prevention if
remission rates increase, then prevalence may
fall with lower burden

Very important to address but disease has
already manifest
Secondary Prevention




Secondary prevention - modify course of illness by early
detection, intervention and possibly prevention
Potentially feasible through intervention at the prodromal
phase
Aim is to reduce full transition from prodromal to
schizophrenia
Interventions could
 Delay onset of illness
 Mitigate profile of illness to “milder” or “less disabling”

Hope is to reduce cost and burden of disease
 How
Do We Define the Population to
Target for Secondary Prevention?
Genetically Vulnerable Population

Research has focused on genetically vulnerable
individuals
 Unable to identify which individuals within
genetic high-risk group will eventually develop
schizophrenia with sufficient predictive value to
justify intervention
 Problem with this approach is that of low
sensitivity since nearly 80% of affected
individuals with schizophrenia have no 1st
degree relatives and nearly 60% have negative
family history
Factors Predicting Schizophrenia
Spectrum Outcomes in Offsprings of
Schizophrenia Patients

Maternal influenza during gestation
 Obstetrical complications
 Neurointegrative deficits in infancy
 Separation during first year of life
 Social, affective, and motor coordination deficits in early
childhood
 Social dysfunction in later childhood
 Attention deficits, neuribehavioral deficits and poor
motor coordination in preadolescence
 Teacher rated timidity and day dreaming behaviors at
age 15 years
 Absence of protective family environment
Prodromal Phase Focus of Intervention
Why Intervention in Prodromal Phase?
1.
2.
Neurobiological deficit processes associated with
severity and chronicity with schizophrenia are already
present at time of first episode
Evidence suggests early treatment can result in
significant reduction in morbidity and better quality of life




DUP – Duration of untreated psychosis is defined as time
between onset of first psychotic symptoms and first adequate
treatment
Average DUP is 1 – 2 years
Longer DUP associated with male gender, poor premorbid
functioning, insidious onset of psychosis, and presence of
negative symptoms
A review of 25 DUP studies showed two thirds of them had
better outcome on one or more measures for shorter DUP and
none showed better outcomes with longer DUP
Why Intervention in Prodromal Phase?
3
Treatment in prodrome may prevent or
delay onset
4
Important to treatment prodromal
symptoms themselves to relieve distress
for parents and families
Specialized Early Intervention Programs

PACE – Personal Assessment and Crisis Evaluation
clinic, Melbourne, Australia

RAP – Hillside Recognition and Prevention Program,
NY

EDIE – Early Detection and Intervention Evaluation
Program, Manchester, UK

PRIME – Prevention through Risk Identification,
Management, and Education Program, Yale Univ, CT

CARE – Cognitive Assessment and Risk Evaluation
Clinic in San Diego, CA
Prevention Strategies
 Psychopharmacology
 Cognitive/Cognitive
 Case
Management
Behavior Therapy
McGorry et al. Arch Gen Psychiatry.
2002;59:921-928


Design: Single blind (researchers) randomized controlled
trial comparing two treatments in 59 patients (age 14-30
years) at “ultra-high risk”
Interventions:





Needs Based (focus on needs based supportive therapy re social,
family issues, case management) vs
Specific Preventive (Needs Based and low dose risperidone and
cognitive behavior therapy)
Outcome: progression to frank psychosis lasting a week
or more
Treatment duration 6 months. After this all patients were
offered Needs Based Intervention.
Assessment at baseline, 6 months, 12 months
Note: 43 of 59 (73%) did not progress to psychosis at 12 months
McGorry et al. Arch Gen Psychiatry.
2002;59:921-928




Number Needed to Treat (NNT) = 4. (NNT = 13 for
antihypertensives to prevent stroke)
In other words, 4 ultra-high risk patients would need to
be treated to prevent 1 patient from progressing to
psychosis over a 6 month period
Conclusions: Specific pharmacotherapy and
psychotherapy reduces risk of early transition to
psychosis in these patients but unclear which modality
more contributory
Ethical dilemma: 73% did not transition to psychosis. Is
using AP justified?
Potential Benefits of Prepsychotic
Interventions.
McGorry et al. Arch Gen Psychiatry. 2002;59:921-928



Patients more easily engaged and can receive
treatments regardless of whether preventive treatment
may be ineffective or unnecessary
Those who progress to psychosis have developed a
level of trust enabling them to accept treatment, have
minimal DUP and reduced comorbidity
Psychosocial impact of psychosis may be diminished
and better chance to recover
McGlashan et al. Am J Psychiatry.
2006;163:790-799


Design: Double blind randomized controlled trial
comparing two treatments in 59 patients (age 14-30
years) at “ultra-high risk”
Interventions:




Olanzapine (Dose 5-15 mg/d) N=31
Placebo N=29
Outcome: progression to frank psychosis
Treatment duration 1 year; a second year of follow-up
with no treatment
At one year, 16.1% of olanzapine and 37.9% of placebo converted to psychosis
(p=.08). Olanzapine group had more improvement in symptoms.
At two years, most were lost to follow-up; but of remaining no difference
McGlashan et al. Am J Psychiatry.
2006;163:790-799

Treatment difference not significant

Olanzapine group had improvement in symptoms

Major side effect of olanzapine – GUESS?

Authors admit study had low power - they tried to recruit
more subjects but were not successful
Cornblatt et al. J Clin Psychiatry.
2007;68(4):546-557


Design: Prospective naturalistic treatment study of
adolescents (mean age 15.8 years) considered to be
“prodromal” (i.e., prepsychotic)
Interventions:





Antidepressants (N=20)
Second generation antipsychotics (N=28)
Outcome: progression to frank psychosis defined as a
score of 6 in any 1 of 5 positive symptom scale of the
SOPS (Scale of Prodromal Symptoms) lasting 2 weeks or
more
Treatment duration at least 6 months (mean duration 30.5
months).
Recognition and Prevention Program (RAP), Zucker
Hillside Hospital, NY
Cornblatt et al. J Clin Psychiatry.
2007;68(4):546-557

Results:




12 of 48 subjects (25%) converted to psychosis
0 from the AD group (N=20)
12 (43%) from the AP group (N=28)
BUT, 11 of 12 converters were non-adherent to the AP
Cornblatt et al. J Clin Psychiatry.
2007;68(4):546-557

Non-random assignment limits comparison of
AD with AP

But number of adolescents with prodromal
features did well on AD

True prevention or False Positive? Underscores
retrospective nature of prodrome and challenge
in prevention.

Van Os J, Delespaul P. Toward a world consensus on
prevention of schizophrenia. Dialogues in Clinical
Neuroscience. 2005; 7:53-67.
Challenges

Unclear understanding of disease and lack of better early
identification of high risk individuals with lower false
positives. Promising research describing better
endophenotypes.

Stigma – especially relevant because of high degree of
false positives

Lack of resources
Conclusions

Primary prevention of schizophrenia continues to be
elusive because of our inadequate understanding of
etiology resulting in high degree of false positives

Selective intervention shows promise but use of
pharmacotherapy for prevention still not established

Have to consider issues of stigma and public awareness
and education

Lack of resources for preventive activity
Bibliography






Brown AS, McGrath JJ. The Prevention of Schizophrenia.
Schizophrenia Bulletin. 2011; 37(2):257-261.
Brown AS, Patterson PH. Maternal Infection and Schizophrenia:
Implications for Prevention. Schizophrenia Bulletin. 2011; 37(2):284290.
Cornblatt BA, Lencz T, Smith CW et al. Can antidepressants be used
to treat the schizophrenia prodrome? Results of a prospective,
naturalistic treatment study of adolescents. Journal of Clinical
Psychiatry. 2007; 68:546-557.
Cornblatt BA, Auther AM. Treating early Psychosis: who, what, and
when? Dialogues in Clinical Neuroscience. 2005; 7(1):39-49
Kirkbridge JB, Jones PB. The Prevention of Schizophrenia- What Can
We Learn From Eco-Epidemiology? Schizophrenia Bulletin. 2011;
37(2):262-271.
Knapp M, Mangalore R, Simon J. The global costs of schizophrenia.
Schizophrenia Bulletin. 2004: 30(2):279-293.
Bibliography





Lee C, McGlashan TH, Woods SW. Prevention of Schizophrenia: Can
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McEvoy JP. The costs of schizophrenia. Journal of Clinical
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McGlashan TH, Zipursky RB, Perkins D et al. Randomized, doubleblind trial of olanzapine versus placebo in patients prodromally
symptomatic for psychosis. American Journal of Psychiatry. 2006;
163:790-799.
McGorry PD, Killackey E, Yung AR. Early intervention in psychotic
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McGorry PD, Yung AR, Phillips LJ et al. Randomized controlled trial
of interventions designed to reduce the risk of progression to first
episode psychosis in a clinical sample with subthreshold symptoms.
Archives of General Psychiatry. 2002; 59:921-928.
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



Tsuang MT, Stone WS, Auster TL. Prevention of schizophrenia.
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