schizophrenia prediction and prevention: what do we know? puru thapa, m.d., m.p.h. associate...

Schizophrenia Prediction and Schizophrenia Prediction and Prevention: What Do We Prevention: What Do We

Know?Know?

Puru Thapa, M.D., M.P.H.Puru Thapa, M.D., M.P.H.

Associate ProfessorAssociate Professor

Department of Psychiatry, UAMSDepartment of Psychiatry, UAMS

Staff Psychiatrist, Arkansas State Staff Psychiatrist, Arkansas State HospitalHospital

03/15/201403/15/2014

ObjectivesObjectives

Review definition, epidemiology and etiology of Review definition, epidemiology and etiology of schizophreniaschizophrenia

Understand the concept of levels of preventionsUnderstand the concept of levels of preventions

Critically review the strategies of prevention in Critically review the strategies of prevention in schizophrenia and evidenceschizophrenia and evidence

Consider future directionsConsider future directions

SchizophreniaSchizophrenia

Syndrome characterized by psychosis and Syndrome characterized by psychosis and dysfunction and probably the most devastating dysfunction and probably the most devastating mental illness with great distress to the mental illness with great distress to the individual and families with heavy costs and individual and families with heavy costs and burden to societyburden to society

Treated with antipsychotics and psychosocial Treated with antipsychotics and psychosocial support and rehabsupport and rehab

Schizophrenia – DSM-5 CriteriaSchizophrenia – DSM-5 Criteria

A.A. Two (or more) of the following, each present for Two (or more) of the following, each present for a significant portion of time during a 1-month a significant portion of time during a 1-month period (or less if successfully treated). At least period (or less if successfully treated). At least one of these must be (1), (2), or (3):one of these must be (1), (2), or (3):

1: Delusions1: Delusions

2: Hallucinations2: Hallucinations

3: Disorganized speech3: Disorganized speech

4: Disorganized or catatonic behavior4: Disorganized or catatonic behavior

5: Negative symptoms5: Negative symptoms

B.B. Social/occupational dysfunctionSocial/occupational dysfunction

Schizophrenia – DSM-5 Criteria Schizophrenia – DSM-5 Criteria

C.C. Duration: continuous signs persist for at least Duration: continuous signs persist for at least six months six months

D.D. Exclude schizoaffective or mood disorderExclude schizoaffective or mood disorder

E.E. Exclude general medical condition or substance Exclude general medical condition or substance inducedinduced

F.F. Relationship to a pervasive developmental Relationship to a pervasive developmental disorderdisorder

Schizophrenia - CostsSchizophrenia - Costs

Cost of Schizophrenia in the US in 2002Cost of Schizophrenia in the US in 2002

Direct CostsDirect Costs 30.3 billion dollars30.3 billion dollars

Indirect CostsIndirect Costs 32.4 billion dollars32.4 billion dollars

Total CostsTotal Costs 62.7 billion dollars62.7 billion dollars

Mental anguish/distress to individuals affected Mental anguish/distress to individuals affected and to familiesand to families

Wu EQ and colleagues, Wu EQ and colleagues, J Clin Psych J Clin Psych 2005;66:1122-11292005;66:1122-1129

Schizophrenia - EpidemiologySchizophrenia - Epidemiology

Life time prevalence approximately 1%Life time prevalence approximately 1%

Incidence estimated .01% to .02%Incidence estimated .01% to .02%

Risk slightly higher in males than femalesRisk slightly higher in males than females

Age of onset: males 15-25 years, females 25-35 Age of onset: males 15-25 years, females 25-35 yearsyears

Phases of SchizophreniaPhases of Schizophrenia PremorbidPremorbid

Contributes to vulnerability to schizophreniaContributes to vulnerability to schizophrenia

ProdromalProdromal Change from premorbid functioning and extends time Change from premorbid functioning and extends time

of onset of frank psychotic symptomsof onset of frank psychotic symptoms Average length 2 – 5 yearsAverage length 2 – 5 years Impairment in psychosocial functioningImpairment in psychosocial functioning

PsychoticPsychotic Onset of frank psychotic symptomsOnset of frank psychotic symptoms Acute phase, Early recovery phase (first 6 months after Acute phase, Early recovery phase (first 6 months after

acute treatment), Late recovery phase (6-18 months)acute treatment), Late recovery phase (6-18 months) Period following recovery from first episode up to 5 Period following recovery from first episode up to 5

years is Critical Period for up to 80% relapseyears is Critical Period for up to 80% relapse

ProdromeProdrome

Early prodromal symptoms non-specific: sleep Early prodromal symptoms non-specific: sleep disturbance, anxiety, irritability, depressed mood, poor disturbance, anxiety, irritability, depressed mood, poor concentration and fatigue, and behavioral symptoms, concentration and fatigue, and behavioral symptoms, such as deterioration in role functioning and social such as deterioration in role functioning and social withdrawalwithdrawal

Late prodromal symptoms: positive symptoms, such as Late prodromal symptoms: positive symptoms, such as perceptual abnormalities, ideas of reference, and perceptual abnormalities, ideas of reference, and suspiciousness – herald imminent onset of psychosissuspiciousness – herald imminent onset of psychosis

Prodrome – really based on retrospective reconstructionProdrome – really based on retrospective reconstruction

Schizophrenia - EtiologySchizophrenia - Etiology

Etiology unknown – can be conceptualized as a clinical Etiology unknown – can be conceptualized as a clinical syndrome that is the “final common pathway of multiple syndrome that is the “final common pathway of multiple different etio-pathogenetic processes”. Similar to concept different etio-pathogenetic processes”. Similar to concept of Congestive Heart Failure or Nephrotic Syndromeof Congestive Heart Failure or Nephrotic Syndrome

Neurodevelopmental – factors during perinatal period, Neurodevelopmental – factors during perinatal period, geneticsgenetics

NeurodegenerativeNeurodegenerative Other factors: season of birth, paternal age, diet during Other factors: season of birth, paternal age, diet during

pregnancy, obstetrical complications, etc. pregnancy, obstetrical complications, etc. Stress-Diathesis Model of disease causationStress-Diathesis Model of disease causation

Stress-Diathesis ModelStress-Diathesis Model

Diathesis: Inherited vulnerability – bad genesDiathesis: Inherited vulnerability – bad genes

Stress: Environmental insult – physical, Stress: Environmental insult – physical, emotional, environmentalemotional, environmental

This model offers our best explanation of This model offers our best explanation of schizophrenia causeschizophrenia cause

Genes/EnvironmentGenes/Environment

• Genetic predispositionGenetic predisposition– 1 parent with schizophrenia 12%1 parent with schizophrenia 12%– Both parents 40%Both parents 40%– Dizygotic twin of schizophrenia patient 12%Dizygotic twin of schizophrenia patient 12%– Monozygotic twinMonozygotic twin 47% 47%

• EnvironmentalEnvironmental– Intrauterine trauma? (physical, drugs, etc)Intrauterine trauma? (physical, drugs, etc)– Later trauma or stress? Often the 1Later trauma or stress? Often the 1stst psychotic break psychotic break

happens during a stressful period such as going away happens during a stressful period such as going away to college, military, etc.to college, military, etc.

Challenges in Prevention of SchizophreniaChallenges in Prevention of Schizophrenia

• Disorder with unclear etiologyDisorder with unclear etiology

• No objective marker or test to diagnosisNo objective marker or test to diagnosis

• Rare diseaseRare disease

• Antecedent factors and prodromal symptoms are Antecedent factors and prodromal symptoms are not specific – high number of not specific – high number of false positivesfalse positives

Predictive ValuePredictive Value

WithoutDisease

Negative

a

c

b

d

WithDisease

Positive

False Negative (FN)

True Positive (TP)

True Negative (TN)

False Positive (FP)

Test Results

Gold Standard

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 PreventionEpidemiology and Prevention

To identify high-risk subgroups in populationTo identify high-risk subgroups in population

Why? Why? Identification of high risk groups may identify Identification of high risk groups may identify

modifiable risk factors. modifiable risk factors. Can direct preventive efforts at such groups – Can direct preventive efforts at such groups –

such as screening programs for early such as screening programs for early detection of diseasedetection of disease

Levels of PreventionLevels of Prevention

1.1. PrimaryPrimaryPrevention of disease by altering susceptibility or Prevention of disease by altering susceptibility or reducing exposure for susceptible individualsreducing exposure for susceptible individualse.g., immunization, exercisee.g., immunization, exercise

2.2. SecondarySecondaryEarly detection and treatment of diseaseEarly detection and treatment of diseasee.g., breast cancer screening, screening for disease e.g., breast cancer screening, screening for disease (occult blood in stool for colon cancer) (occult blood in stool for colon cancer)

3.3. TertiaryTertiaryLimitation of disability and rehabilitationLimitation of disability and rehabilitationAlleviation of disability resulting from disease and Alleviation of disability resulting from disease and attempts to restore function (Post-stroke rehabilitation)attempts to restore function (Post-stroke rehabilitation)

Prevention – can be population-based or high risk group Prevention – can be population-based or high risk group approachapproach

Primary Prevention of SchizophreniaPrimary Prevention of Schizophrenia

Limited understanding about etiology and Limited understanding about etiology and pathogenesis of schizophreniapathogenesis of schizophrenia

Long latency between primary insult and onset Long latency between primary insult and onset of schizophreniaof schizophrenia

Much research ongoing but not currently Much research ongoing but not currently feasiblefeasible

Tertiary PreventionTertiary Prevention

Tertiary prevention – reducing the burden of Tertiary prevention – reducing the burden of disease by optimizing treatment and disease by optimizing treatment and rehabilitation and reducing relapserehabilitation and reducing relapse

In Schizophrenia, with tertiary prevention if In Schizophrenia, with tertiary prevention if remission rates increase, then prevalence may remission rates increase, then prevalence may fall with lower burdenfall with lower burden

Very important to address but disease has Very important to address but disease has already manifest already manifest

Secondary PreventionSecondary Prevention

Secondary prevention - modify course of illness by early Secondary prevention - modify course of illness by early detection, intervention and possibly preventiondetection, intervention and possibly prevention

Potentially feasible through intervention at the prodromal Potentially feasible through intervention at the prodromal phasephase

Aim is to reduce full transition from prodromal to Aim is to reduce full transition from prodromal to schizophreniaschizophrenia

Interventions could Interventions could Delay onset of illnessDelay onset of illness Mitigate profile of illness to “milder” or “less disabling”Mitigate profile of illness to “milder” or “less disabling” Hope is to reduce cost and burden of diseaseHope is to reduce cost and burden of disease

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

Genetically Vulnerable PopulationGenetically Vulnerable Population

Research has focused on genetically vulnerable Research has focused on genetically vulnerable individualsindividuals

Unable to identify which individuals within Unable to identify which individuals within genetic high-risk group will eventually develop genetic high-risk group will eventually develop schizophrenia with sufficient predictive value to schizophrenia with sufficient predictive value to justify interventionjustify intervention

Problem with this approach is that of low Problem with this approach is that of low sensitivity since nearly 80% of affected sensitivity since nearly 80% of affected individuals with schizophrenia have no 1individuals with schizophrenia have no 1stst degree relatives and nearly 60% have negative degree relatives and nearly 60% have negative family historyfamily history

Factors Predicting Schizophrenia Factors Predicting Schizophrenia Spectrum Outcomes in Offsprings of Spectrum Outcomes in Offsprings of

Schizophrenia PatientsSchizophrenia Patients Maternal influenza during gestationMaternal influenza during gestation Obstetrical complicationsObstetrical complications Neurointegrative deficits in infancyNeurointegrative deficits in infancy Separation during first year of lifeSeparation during first year of life Social, affective, and motor coordination deficits in early Social, affective, and motor coordination deficits in early

childhoodchildhood Social dysfunction in later childhoodSocial dysfunction in later childhood Attention deficits, neuribehavioral deficits and poor Attention deficits, neuribehavioral deficits and poor

motor coordination in preadolescencemotor coordination in preadolescence Teacher rated timidity and day dreaming behaviors at Teacher rated timidity and day dreaming behaviors at

age 15 yearsage 15 years Absence of protective family environmentAbsence of protective family environment

Prodromal Phase Focus of InterventionProdromal Phase Focus of Intervention

Why Intervention in Prodromal Phase?Why Intervention in Prodromal Phase?

1.1. Neurobiological deficit processes associated with Neurobiological deficit processes associated with severity and chronicity with schizophrenia are already severity and chronicity with schizophrenia are already present at time of first episodepresent at time of first episode

2.2. Evidence suggests early treatment can result in Evidence suggests early treatment can result in significant reduction in morbidity and better quality of lifesignificant reduction in morbidity and better quality of life DUPDUP – Duration of untreated psychosis is defined as time between – Duration of untreated psychosis is defined as time between

onset of first psychotic symptoms and first adequate treatmentonset of first psychotic symptoms and first adequate treatment Average DUP is 1 – 2 yearsAverage DUP is 1 – 2 years Longer DUP associated with male gender, poor premorbid Longer DUP associated with male gender, poor premorbid

functioning, insidious onset of psychosis, and presence of functioning, insidious onset of psychosis, and presence of negative symptomsnegative symptoms

A review of 25 DUP studies showed two thirds of them had better A review of 25 DUP studies showed two thirds of them had better outcome on one or more measures for shorter DUP and none outcome on one or more measures for shorter DUP and none showed better outcomes with longer DUPshowed better outcomes with longer DUP

Why Intervention in Prodromal Phase?Why Intervention in Prodromal Phase?

33 Treatment in prodrome may prevent or Treatment in prodrome may prevent or delay onsetdelay onset

44 Important to treatment prodromal Important to treatment prodromal symptoms themselves to relieve distress symptoms themselves to relieve distress for parents and familiesfor parents and families

Specialized Early Intervention ProgramsSpecialized Early Intervention Programs PACE – Personal Assessment and Crisis Evaluation clinic, PACE – Personal Assessment and Crisis Evaluation clinic,

Melbourne, Australia Melbourne, Australia

RAP – Hillside Recognition and Prevention Program, NYRAP – Hillside Recognition and Prevention Program, NY

EDIE – Early Detection and Intervention Evaluation EDIE – Early Detection and Intervention Evaluation Program, Manchester, UKProgram, Manchester, UK

PRIME – Prevention through Risk Identification, PRIME – Prevention through Risk Identification, Management, and Education Program, Yale Univ, CTManagement, and Education Program, Yale Univ, CT

CARE – Cognitive Assessment and Risk Evaluation Clinic CARE – Cognitive Assessment and Risk Evaluation Clinic in San Diego, CA in San Diego, CA

Prevention StrategiesPrevention Strategies PsychopharmacologyPsychopharmacology

Cognitive/Cognitive Behavior TherapyCognitive/Cognitive Behavior Therapy

Case ManagementCase Management

McGorry McGorry et alet al. . Arch Gen PsychiatryArch Gen Psychiatry. . 2002;59:921-9282002;59:921-928

Design: Single blind (researchers) randomized controlled Design: Single blind (researchers) randomized controlled trial comparing two treatments in 59 patients (age 14-30 trial comparing two treatments in 59 patients (age 14-30 years) at years) at “ultra-high risk”“ultra-high risk”

Interventions: Interventions: Needs Based Needs Based (focus on needs based supportive therapy re social, (focus on needs based supportive therapy re social,

family issues, case management) vs family issues, case management) vs Specific Preventive Specific Preventive (Needs Based and low dose risperidone and (Needs Based and low dose risperidone and

cognitive behavior therapy)cognitive behavior therapy)

Outcome: progression to frank psychosis lasting a week Outcome: progression to frank psychosis lasting a week or moreor more

Treatment duration 6 months. After this all patients were Treatment duration 6 months. After this all patients were offered Needs Based Intervention.offered Needs Based Intervention.

Assessment at baseline, 6 months, 12 monthsAssessment at baseline, 6 months, 12 months

Note: 43 of 59 (73%) did not progress to psychosis at 12 months

McGorry McGorry et alet al. . Arch Gen PsychiatryArch Gen Psychiatry. . 2002;59:921-9282002;59:921-928

Number Needed to Treat (NNT) = 4. (NNT = 13 for Number Needed to Treat (NNT) = 4. (NNT = 13 for antihypertensives to prevent stroke)antihypertensives to prevent stroke)

In other words, 4 ultra-high risk patients would need to In other words, 4 ultra-high risk patients would need to be treated to prevent 1 patient from progressing to be treated to prevent 1 patient from progressing to psychosis over a 6 month periodpsychosis over a 6 month period

Conclusions: Specific pharmacotherapy and Conclusions: Specific pharmacotherapy and psychotherapy reduces risk of early transition to psychotherapy reduces risk of early transition to psychosis in these patients but unclear which modality psychosis in these patients but unclear which modality more contributorymore contributory

Ethical dilemma: 73% did not transition to psychosis. Is Ethical dilemma: 73% did not transition to psychosis. Is using AP justified?using AP justified?

Potential Benefits of Prepsychotic Potential Benefits of Prepsychotic InterventionsInterventions. . McGorry McGorry et alet al. . Arch Gen PsychiatryArch Gen Psychiatry. 2002;59:921-928. 2002;59:921-928

Patients more easily engaged and can receive Patients more easily engaged and can receive treatments regardless of whether preventive treatment treatments regardless of whether preventive treatment may be ineffective or unnecessarymay be ineffective or unnecessary

Those who progress to psychosis have developed a Those who progress to psychosis have developed a level of trust enabling them to accept treatment, have level of trust enabling them to accept treatment, have minimal DUP and reduced comorbidityminimal DUP and reduced comorbidity

Psychosocial impact of psychosis may be diminished Psychosocial impact of psychosis may be diminished and better chance to recoverand better chance to recover

McGlashan McGlashan et alet al. . Am J PsychiatryAm J Psychiatry. . 2006;163:790-7992006;163:790-799

Design: Double blind randomized controlled trial Design: Double blind randomized controlled trial comparing two treatments in 59 patients (age 14-30 comparing two treatments in 59 patients (age 14-30 years) at years) at “ultra-high risk”“ultra-high risk”

Interventions: Interventions: Olanzapine (Dose 5-15 mg/d) N=31 Olanzapine (Dose 5-15 mg/d) N=31 Placebo N=29Placebo N=29

Outcome: progression to frank psychosis Outcome: progression to frank psychosis Treatment duration 1 year; a second year of follow-up Treatment duration 1 year; a second year of follow-up

with no treatmentwith 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 McGlashan et alet al. . Am J PsychiatryAm J Psychiatry. . 2006;163:790-7992006;163:790-799

Treatment difference not significantTreatment difference not significant

Olanzapine group had improvement in symptomsOlanzapine group had improvement in symptoms

Major side effect of olanzapine – GUESS?Major side effect of olanzapine – GUESS?

Authors admit study had low Authors admit study had low powerpower - they tried to recruit - they tried to recruit more subjects but were not successful more subjects but were not successful

Cornblatt Cornblatt et alet al. . J Clin PsychiatryJ Clin Psychiatry. . 2007;68(4):546-5572007;68(4):546-557

Design: Prospective naturalistic treatment study of Design: Prospective naturalistic treatment study of adolescents (mean age 15.8 years) considered to be adolescents (mean age 15.8 years) considered to be “prodromal”“prodromal” (i.e., prepsychotic) (i.e., prepsychotic)

Interventions: Interventions: Antidepressants (N=20)Antidepressants (N=20) Second generation antipsychotics (N=28)Second generation antipsychotics (N=28)

Outcome: progression to frank psychosis defined as a score Outcome: progression to frank psychosis defined as a score of 6 in any 1 of 5 positive symptom scale of the SOPS of 6 in any 1 of 5 positive symptom scale of the SOPS (Scale of Prodromal Symptoms) lasting 2 weeks or more(Scale of Prodromal Symptoms) lasting 2 weeks or more

Treatment duration at least 6 months (mean duration 30.5 Treatment duration at least 6 months (mean duration 30.5 months). months).

Recognition and Prevention Program (RAP), Zucker Hillside Recognition and Prevention Program (RAP), Zucker Hillside Hospital, NYHospital, NY


Results: Results:

12 of 48 subjects (25%) converted to psychosis12 of 48 subjects (25%) converted to psychosis 0 from the AD group (N=20)0 from the AD group (N=20) 12 (43%) from the AP group (N=28)12 (43%) from the AP group (N=28)

BUT, 11 of 12 converters were non-adherent to the APBUT, 11 of 12 converters were non-adherent to the AP


Non-random assignment limits comparison of Non-random assignment limits comparison of AD with APAD with AP

But number of adolescents with prodromal But number of adolescents with prodromal features did well on ADfeatures did well on AD

True prevention or False Positive? Underscores True prevention or False Positive? Underscores retrospective nature of prodrome and challenge retrospective nature of prodrome and challenge in prevention.in prevention.

Van Os J, Delespaul P. Toward a world consensus on prevention of schizophrenia. Dialogues in Clinical Neuroscience. 2005; 7:53-67.

ChallengesChallenges

Unclear understanding of disease and lack of better early Unclear understanding of disease and lack of better early identification of high risk individuals with lower false identification of high risk individuals with lower false positives. Promising research describing better positives. Promising research describing better endophenotypes.endophenotypes.

Stigma – especially relevant because of high degree of Stigma – especially relevant because of high degree of false positivesfalse positives

Lack of resourcesLack of resources

ConclusionsConclusions

Primary prevention of schizophrenia continues to be Primary prevention of schizophrenia continues to be elusive because of our inadequate understanding of elusive because of our inadequate understanding of etiology resulting in high degree of false positivesetiology resulting in high degree of false positives

Selective intervention shows promise but use of Selective intervention shows promise but use of pharmacotherapy for prevention still not establishedpharmacotherapy for prevention still not established

Have to consider issues of stigma and public awareness Have to consider issues of stigma and public awareness and educationand education

Lack of resources for preventive activityLack of resources for preventive activity

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