Schizophrenia Prediction and Prevention: What Do We Know?

1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. Stress-Diathesis Model • Diathesis: Inherited vulnerability – bad genes • Stress: Environmental insult – physical, emotional, environmental • This model offers our best explanation of schizophrenia cause

12. 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.

13. 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

14. a b c d Predictive Value Gold Standard With Disease Without Disease Test Results True Positive (TP) False Positive (FP) Positive Negative 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%

15. 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

16. 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

17. 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

18. 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

19. 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

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

21. 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

22. 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

23. Prodromal Phase Focus of Intervention

24. 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

25. Why Intervention in Prodromal Phase? • Treatment in prodrome may prevent or delay onset • Important to treatment prodromal symptoms themselves to relieve distress for parents and families

26. 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

27. Prevention Strategies • Psychopharmacology • Cognitive/Cognitive Behavior Therapy • Case Management

28. McGorryet 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

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

31. McGorryet 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?

32. Potential Benefits of Prepsychotic Interventions. McGorryet 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

33. McGlashanet 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

34. 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

35. McGlashanet 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

36. Cornblattet 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

39. Cornblattet 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

41. Cornblattet 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.

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