Schizophrenia Prediction and Prevention: What Do We Know?

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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

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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

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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

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Schizophrenia DSM-5 Criteria

• 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 Delusions
• 2 Hallucinations
• 3 Disorganized speech
• 4 Disorganized or catatonic behavior
• 5 Negative symptoms
• Social/occupational dysfunction

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Schizophrenia DSM-5 Criteria

• Duration continuous signs persist for at least
  six months
• Exclude schizoaffective or mood disorder
• Exclude general medical condition or substance
  induced
• Relationship to a pervasive developmental disorder

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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
  2005661122-1129

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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

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Phases of Schizophrenia

• Premorbid
• Contributes to vulnerability to schizophrenia
• Prodromal
• 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

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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

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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

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Stress-Diathesis Model

• Diathesis Inherited vulnerability bad genes
• Stress Environmental insult physical,
  emotional, environmental
• This model offers our best explanation of
  schizophrenia cause

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Genes/Environment

• Genetic predisposition
• 1 parent with schizophrenia
  12
• Both parents
  40
• Dizygotic twin of schizophrenia patient 12
• Monozygotic twin 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.

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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

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Predictive Value
Gold Standard
Without Disease
With Disease
Test Results
True Positive (TP)
False Positive (FP)
Positive
Negative
False Negative (FN)
True Negative (TN)
PPV TP/(TPFP) or a/(ab) 80/(80100) 44
NPV TN/(FNTN) or d/(cd) 800/(80020) 98
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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

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Levels of Prevention

• Primary
• Prevention of disease by altering susceptibility
  or reducing exposure for susceptible individuals
• e.g., immunization, exercise
• Secondary
• Early detection and treatment of disease
• e.g., breast cancer screening, screening for
  disease (occult blood in stool for
  colon cancer)
• 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

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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

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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

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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

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• How Do We Define the Population to Target for
  Secondary Prevention?

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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

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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

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• Prodromal Phase Focus of Intervention

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Why Intervention in Prodromal Phase?

• 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

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Why Intervention in Prodromal Phase?

1. Treatment in prodrome may prevent or delay onset
2. Important to treatment prodromal symptoms
   themselves to relieve distress for parents and
   families

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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

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Prevention Strategies

• Psychopharmacology
• Cognitive/Cognitive Behavior Therapy
• Case Management

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McGorry et al. Arch Gen Psychiatry.
200259921-928

• 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

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Note 43 of 59 (73) did not progress to
psychosis at 12 months
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McGorry et al. Arch Gen Psychiatry.
200259921-928

• 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?

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Potential Benefits of Prepsychotic Interventions.
McGorry et al. Arch Gen Psychiatry.
200259921-928

• 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

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McGlashan et al. Am J Psychiatry. 2006163790-799

• 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) N31
• Placebo N29
• Outcome progression to frank psychosis
• Treatment duration 1 year a second year of
  follow-up with no treatment

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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
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McGlashan et al. Am J Psychiatry. 2006163790-799

• 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

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Cornblatt et al. J Clin Psychiatry.
200768(4)546-557

• Design Prospective naturalistic treatment study
  of adolescents (mean age 15.8 years) considered
  to be prodromal (i.e., prepsychotic)
• Interventions
• Antidepressants (N20)
• Second generation antipsychotics (N28)
• 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

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Cornblatt et al. J Clin Psychiatry.
200768(4)546-557

• Results
• 12 of 48 subjects (25) converted to psychosis
• 0 from the AD group (N20)
• 12 (43) from the AP group (N28)
• BUT, 11 of 12 converters were non-adherent to
  the AP

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Cornblatt et al. J Clin Psychiatry.
200768(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.

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• Van Os J, Delespaul P. Toward a world consensus
  on prevention of schizophrenia. Dialogues in
  Clinical Neuroscience. 2005 753-67.

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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

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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

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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)284-290.
• 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 68546-557.
• 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.

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Bibliography

• Lee C, McGlashan TH, Woods SW. Prevention of
  Schizophrenia Can it be achieved? CNS Drugs.
  2005 19(3)193-206.
• McEvoy JP. The costs of schizophrenia. Journal
  of Clinical Psychiatry, 2007 68 (suppl 14) 4-7.
• McGlashan TH, Zipursky RB, Perkins D et al.
  Randomized, double-blind trial of olanzapine
  versus placebo in patients prodromally
  symptomatic for psychosis. American Journal of
  Psychiatry. 2006 163790-799.
• McGorry PD, Killackey E, Yung AR. Early
  intervention in psychotic disorders detection
  and treatment of the first episode and the
  critical early stages. The Medical Journal of
  Australia. 2007 187(7 suppl)S8-S10.
• 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 59921-928.

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Bibliography

• Tsuang MT, Stone WS, Auster TL. Prevention of
  schizophrenia. Expert review of
  Neurotherapeutics. 2010 10(7)1165-1174.
• Van Os J, Delespaul P. Toward a world consensus
  on prevention of schizophrenia. Dialogues in
  Clinical Neuroscience. 2005 753-67.
• Wu EQ, Birnbaum HG, Shi L et al. The economic
  burden of schizophrenia in the United States in
  2002. Journal of Clinical Psychiatry. 2005
  661122-1129. McGrath JJ, Brown AS, St Clair D.
  Prevention and Schizophrenia-- The Role of
  Dietary Factors. Schizophrenia Bulletin. 2011
  37(2)272-283.
• Yung AR, Killackey E, Hetrick SE et al. The
  prevention of schizophrenia. International
  Review of Psychiatry. 2007 19(6) 633-646.
• Yung AR, McGorry PD, Francey SM et al. PACE a
  specialized service for young people at risk of
  psychotic disorders. The Medical Journal of
  Australia. 2007 187(7 suppl) S43-S46.