1. Psychosis in the Young Prof Chris Hollis Developmental Psychiatry Section Division of Psychiatry University of Nottingham

3. Outline Child & Adolescent Onset Schizophrenia (CAOS) History & Concepts Clinical Features Epidemiology Differential Diagnosis Course and Outcome Developmental Features Neurobiology Pharmacological Treatment

4. History of Psychosis & Schizophrenia in the Young Child & adolescent presentations recognised by Kraepelin and Bleuler Mid 20 th century – Broad ‘Childhood Schizophrenia’ concept includes autism and other developmental disorders 1970s: Rutter & Kolvin ->separation of autism from schizophrenia in childhood DSM-III same diagnostic criteria used for schizophrenia in children and adults

5. New Approaches to Schizophrenia Neurodevelopment Dimensional view Genes for ‘risk’ not disorder Focus on ‘intermediate’ neurocognitive processes or endophenotypes Partial dopamine agonists (Aripiprazole) Renewed interest in social & environmental causes and moderation of gene expression

6. PrenatalChildhoodAdolescenceAdult Psychosis GenesEnvironment Subtle developmental & social impairments Negative/ schizotypal/ prodromal symptoms Early intervention ? From Risk to Disorder Drugs ? Stress ?

7. Clinical Features of CAOS Phases of Illness 1. Pre-Psychotic 2. Prodromal/ Peri-Psychotic 3. Psychosis 4. Post-Psychotic

8. 1. Pre-Psychotic Phase Developmental impairments Language Motor Social Attention/ cognition (executive function) Disruption of fronto-striatal circuits (reduced fronto-cortical DA activity?) Non-specific – not useful predictors

9. Premorbid Developmental Problems Schizophrenia Other Psychoses Statistics N=61 N=48 % (N) % (N) P value Language delay19 (11) 9 (4) 0.2 Reading delay28 (17) 22 (10) 0.6 Motor delay 7 (4) 9 (4) 0.7 Primary enuresis36 (20) 18 (8) 0.06 Social impairment: possible20 (12) 9 (4) definite14 (8) 4 (2) <0.04 Definite OCs16 (9) 18 (7) 0.4 Hollis C (2003) British Journal of Psychiatry, 182, 37-44

10. Premorbid adjustment in adolescent psychoses Median PAS score P<0.0002 Impairment

11. 2. Prodromal Phase Progressive social and cognitive decline Incongruous, bizarre behaviour Subtle perceptual & affective changes Early negative symptoms Disorganisation

12. Age of Onset of Prodromal and Psychotic Symptoms Age Frequency

13. 3. Psychotic (Active) Phase Positive symptoms (may be hard to elicit) – non specific for schizophrenia Affective symptoms are common Dopamine dysregulation Increased mesocortical DA activity Cannabis, DA agonists Psychosocial stressors

14. 4. Post Psychotic Phase Probability of remission predicted by: Premorbid functioning Duration of active phase symptoms 50% maintain chronic course

15. Remission From First Psychotic Episode SchizophreniaAffective psychosisX 2 =23; P<0.0001 12% 40% 48% 52% 38% 10% Hollis C (2000) Am J Psychiatry; 157; 1652-1659

16. Clinical Features - Summary Premorbid impairments – resemble other neurodevelopmental disorders e.g. ASD/ ADHD Insidious onset, cognitive & social decline Negative symptoms, disorganisation Hallucinations, delusions can be difficult to elicit Affective symptoms common Diagnostic uncertainty High rates of non-remission

17. Epidemiology Trent EPIC Study Hollis et al. (2004) Incidence of adolescent-onset psychosis in the Trent Region of the U.K. Schizophrenia Research, 67 (Suppl), 65 Numerator: All incident cases of psychosis (ICD- 10 F20.1-29.0 & F30.0-39.0), onset <=16 years in Trent region in 48 month period Denominator: Total population at risk age 6-16

18. EPIC Study Age of Onset of Psychosis Age Number of Cases

19. Age Specific Incidence Rates AgeNumber of cases Incidence rate per 100,000 person years 10 11 12 13 14 15 16 10-16 1 5 5 4 16 14 22 67 0.39 1.93 1.55 6.19 5.42 8.51 3.7 (95% CI 2.9-4.7) 1.4 6.7 Hollis et al. (2004). Schizophrenia Research, 67 (Suppl), 65

20. Incidence rate Ratios for Psychosis (Age 10-16) Risk Variable Incidence Rate Ratio (95% CI) Significance Social Class (SES) low vs. high 2.8 (1.3 - 5.9) Gender male vs. female Ethnicity non- white vs. white African Caribbean vs. white Age 14-16 vs. 10-13 1.0 (0.6 – 1.6) 2.1 (0.9 – 5.4) 10.1 (3.2 – 31.0) 4.6 (2.7 – 7.8) P<0.005 P=0.5 (ns) P=0.02 P<0.001 Hollis et al. (2004). Schizophrenia Research, 67 (Supply), 65

21. Differential Diagnosis Affective Psychosis (BAD, MDD, SAD) ASD – Asperger’s MDI/ Schizotypal PD Dissociative disorder, Borderline PD, PTSD Drugs Epilepsy (TLE, frontal seizures) Neuropsychiatric Auto-immune, SLE Degenerative: Wilson’s, MLD, ALD, Huntingdon’s

22. Course & Outcome High diagnostic stability (80%) for DSM-IV schizophrenia in adolescence High levels of chronic social and symptomatic impairment Predictors of poor outcome Premorbid impairment Negative symptoms Hollis C (2000) Am J Psychiatry; 157; 1652-1659

23. Follow-up Time Psychotic 66% years 30% Hollis C (2000) Am J Psychiatry; 157; 1652-1659

24. Accommodation at Follow-Up Schizophrenia Affective psychosis 16% 39% 45% 52% 21% 26% X 2 =15; P=0.01 Hollis C (2000) Am J Psychiatry; 157; 1652-1659

25. Relationships at Follow-Up Schizophrenia Affective psychosis 44% 40% 14% 29% 31% 26% X 2 =21; P<0.001 Hollis C (2000) Am J Psychiatry; 157; 1652-1659

26. Predictors of Poor Outcome Baseline Predictors*Bp value ‘Negative Symptoms’0.58<0.000 ‘Developmental’ factor0.240.002 ‘Disorganisation’0.140.045 ‘Depression’ factor-0.180.007 ‘Mania’ factor-0.170.016 Non-significant predictors: positive symptom factor 1 & 2; diagnosis; family discord; perinatal complications; gender; duration of illness * Model R 2 = 0.72 ; stepwise variable entry

27. Neurobiology Reduced total cortical grey matter volume (20%) Increased ventricular volume (40%) Temporal lobe reductions less marked than in adults Progressive loss of grey matter volume follows “back to front” cortical wave Volume loss plateaus in late adolescence Rate of volume reduction correlates with poor pre-morbid function Sporn et al. (2003) Am J Psychiatry; 160, 2181-2189

28. Developmental Brain Changes 50 10 1520253035 Age Synaptic density 5 10 15 20 (mm -3 x10 8) PS SP PS = proliferative stage SP = synaptic pruning

29. Developmental Brain Changes 50 10 1520253035 Age Synaptic density 5 10 15 20 (mm -3 x10 8) PS SP PS = proliferative stage SP = synaptic pruning Childhood-onset Schizophrenia

30. Developmental Brain Changes 50 10 1520253035 Age Synaptic density 5 10 15 20 (mm -3 x10 8) PS SP PS = proliferative stage SP = synaptic pruning Childhood-onset Schizophrenia

31. Progressive Brain Changes Sporn et al. (2003) Am J Psychiatry; 160, 2181-2189

32. Age of Onset and Familial Risk DSM-IIIR Schizophrenia Probands FH-RDC Positive Adolescent-onset† Adult-onset‡ Statistics status of proband N=61 N=101 % (n) % (n) z-testP value Schizophrenia 20 (12) 13 (13) 0.86 0.39 Any Psychosis 46 (28) 23 (25) 3.18 <0.002 † Maudsley Follow-up study (Hollis, C (2000) Am J Psychiatry, 157; 1652-1659. ‡ Camberwell Collaborative Psychosis Study (Sham et al., 1994)

33. SONAR: Adolescents At-Risk of Schizophrenia Schizophrenia Age 14-20 N=30 Siblings of Schizophrenia Probands Age 14-20 N=30 ADHD Age 14-20 N=30 Healthy Controls Age 14-20 N=30 Cognitive Assessment: Verbal learning, Hayling sentence completion, WAISI, visual backward masking, spatial working memory, CPT (DS) Measures of Brain Activity: ERP: P50, MMN, auditory odd-ball, Go-NoGo fMRI: Auditory odd-ball, Go-NoGo [Hollis, Liddle, Jackson et al.]

34. SONAR: Adolescents At-Risk of Schizophrenia Schizophrenia Age 14-20 N=30 Siblings of Schizophrenia Probands Age 14-20 N=30 ADHD Age 14-20 N=30 Healthy Controls Age 14-20 N=30 Cognitive Assessment: Verbal learning, Hayling sentence completion, WAISI, visual backward masking, spatial working memory, CPT (DS) Measures of Brain Activity: ERP: P50, MMN, auditory odd-ball, Go-NoGo fMRI: Auditory odd-ball, Go-NoGo [Hollis, Liddle, Jackson et al.]

35. EEG

36. ERP tasks Auditory Odd-Ball Stimuli: sine wave tones delivered through headphones Standard: 1000Hz – 85% Target: 1500Hz – 15% Instruction to press a response button on presentation of each target tone P300: stimulus evaluationstimulus evaluation Up-dating internal context and memory models in situations requiring stimulus categorisationUp-dating internal context and memory models in situations requiring stimulus categorisation

37. 30 25 20 15 10 5 0 -5 -10 -15 -20 -25 -30 [µV] -200-1000100200300400500600700800[ms] P300 to target tones at Pz Healthy ADHD SZ SZ High Risk

38. Specificity? Groups standardised to healthy group mean Healthy ADHD SZ SZ HR

39. Are Adolescents Different?  Phenomenology same  Stability of diagnosis same  Predictive validity of schizophrenia same  Outcome of psychoses worse  Premorbid/ developmental functioning worse  Familial psychiatric risk worse

40. Treatment Pharmacotherapy is cornerstone Reduce environmental stress Psychoeducation: patient, family, school Psychotherapy: CBT, family therapy Education/ training Social support – voluntary groups N.B. NICE Clinical Guidance on Schizophrenia (December 2002) doesn’t cover < age 18

41. Response to Traditional Antipsychotics Treatment resistance common Poor response of negative symptoms Side effects common: sedation, dystonias, EPSE, WD -> reduced compliance Long life-time exposure increases risk of TD Enlargement of caudate nucleus (Frazier et al 1996) reversed by clozapine.

42. Atypical Antipsychotics Risperidone, Olanazepine, Quetiapine, Clozapine, Amisulpiride, (Zotepine)…. Now standard antipsychotic choice for children & adolescents (70-80%) Very limited evidence-base in younger patients (1 RCT) Possible increased efficacy against negative symptoms, cognitive impairment Variable profile of side effects, reduced EPSE

43. Side-Effects of Antipsychotics Can be more severe in children/ adolescents than adults and include: Dystonias/ EPSE/ TD Increased appetite and weight gain Type II diabetes & lipid changes Blood dyscrasias (neutropenia/ agranulocytosis) Cardiac arrhythmias, QTc interval Elevated prolactin -> estrogen, osteoperosis Seizures

44. Incidence of EPSE by Age Incidence % Age [Adapted from Remschmidt 2000]

45. Weight Gain in Adolescents Olanzepine vs. Risperidone vs. Haloperidol Mean % Weight Change Week [Ratzoni et al. (2002) JAACAP, 41, 337-343] N=21 N=8 * * * p<0.01 wk12 vs. baseline Mean age 17 yrs Mean dosage: Olanzapine 12.7mg Risperidone 3.2mg Haloperidol 7.6mg

46. Weight Gain on Atypicals: Adolescents vs. Adults Mean Wt Gain Kg * ** * Ratzioni et al (2002) JAACAP, 41: 337-341 ** Allison et al (1999) Am J Psych, 60: 215-220

47. Treatment - Summary Schizophrenia in children and adolescents requires early, aggressive, treatment Atypicals are first-line treatment All atypicals have side-effects Side effect profiles differ between drugs – may influence choice e.g. quetiapine in adolescent girls Children and adolescents may be more sensitive to side effects e.g. EPSE, weight gain, seizures Urgent need for more empirical data on effectiveness and side-effect profiles of longer term treatment

48. References Hollis C (2003) developmental precursors of child- and adolescent-onset schizophrenia and affective psychoses: diagnostic specificity and continuity with symptom dimensions. British Journal of Psychiatry, 182, 37-44. Hollis, CP & Taylor E (1997) Schizophrenia: a critique from the developmental psychopathology perspective. In: (Eds: Murray, R & Keshavan MS) Neurodevelopment and Adult Psychopathology, Cambridge: Cambridge University Press, 1987 Hollis CP (2000) Adolescent schizophrenia. Advances in Psychiatric Treatment. 6, 83-92 Hollis CP (2000) The adult outcomes of child and adolescent-onset schizophrenia: Diagnostic stability and predictive validity. American Journal of Psychiatry, 157; 1653-1659. Cannon M, Walsh E, Hollis C et al. (2001) Predictors of later schizophrenia and affective psychosis among attendees at a child psychiatry department. British Journal of Psychiatry, 178: 420-426. Hollis C (2001) Diagnosis and differential diagnosis. In: Schizophrenia in Children and Adolescents, Ed. H. Remschmidt. Cambridge: Cambridge University Press. Hollis C (2002) Schizophrenia and allied disorders. In, Child and Adolescent Psychiatry (4th Edition). Eds. M Rutter and E Taylor. Blackwell: Oxford. Hollis C (2003) Child and adolescent-onset schizophrenia. In, Schizophrenia (2nd Edtion). Ed SR Hirsch & DL Weinberger). Blackwell: Oxford.