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Psychosis in the Young

Psychosis in the Young. Prof Chris Hollis Developmental Psychiatry Section Division of Psychiatry University of Nottingham. Outline. Child & Adolescent Onset Schizophrenia (CAOS) History & Concepts Clinical Features Epidemiology Differential Diagnosis Course and Outcome

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Psychosis in the Young

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

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

  3. History of Psychosis & Schizophrenia in the Young • Child & adolescent presentations recognised by Kraepelin and Bleuler • Mid 20th 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

  4. 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

  5. From Risk to Disorder Psychosis Subtle developmental & social impairments Negative/ schizotypal/ prodromal symptoms Prenatal Childhood Adolescence Adult Genes Environment Drugs ? Stress ? ? Early intervention

  6. Clinical Features of CAOS Phases of Illness • Pre-Psychotic • Prodromal/ Peri-Psychotic • Psychosis • Post-Psychotic

  7. 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

  8. Premorbid Developmental Problems Schizophrenia Other Psychoses Statistics N=61 N=48 % (N) % (N) P value Language delay 19 (11) 9 (4) 0.2 Reading delay 28 (17) 22 (10) 0.6 Motor delay 7 (4) 9 (4) 0.7 Primary enuresis 36 (20) 18 (8) 0.06 Social impairment: possible 20 (12) 9 (4) definite 14 (8) 4 (2) <0.04 Definite OCs 16 (9) 18 (7) 0.4 Hollis C (2003) British Journal of Psychiatry, 182, 37-44

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

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

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

  12. 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

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

  14. Remission From First Psychotic Episode 10% 48% 38% 40% 52% 12% Schizophrenia Affective psychosis X2=23; P<0.0001 Hollis C (2000) Am J Psychiatry; 157; 1652-1659

  15. 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

  16. Epidemiology Trent EPIC Study 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 Hollis et al. (2004) Incidence of adolescent-onset psychosis in the Trent Region of the U.K. Schizophrenia Research, 67 (Suppl), 65

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

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

  19. Incidence rate Ratios for Psychosis (Age 10-16) Significance Risk Variable Incidence Rate Ratio (95% CI) Social Class (SES) low vs. high 2.8 (1.3 - 5.9) P<0.005 Gendermale vs. female 1.0 (0.6 – 1.6) P=0.5 (ns) Ethnicity non-white vs. white 2.1 (0.9 – 5.4) P=0.02 African Caribbeanvs. white 10.1 (3.2 – 31.0) P<0.001 Age14-16 vs. 10-13 4.6 (2.7 – 7.8) P<0.001 Hollis et al. (2004). Schizophrenia Research, 67 (Supply), 65

  20. 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

  21. 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

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

  23. Accommodation at Follow-Up Hollis C (2000) Am J Psychiatry; 157; 1652-1659 26% 45% 21% 39% 52% 16% X2=15; P=0.01 Affective psychosis Schizophrenia

  24. Relationships at Follow-Up Hollis C (2000) Am J Psychiatry; 157; 1652-1659 14% 26% 40% 31% 29% 44% 14% X2=21; P<0.001 Schizophrenia Affective psychosis

  25. Predictors of Poor Outcome Baseline Predictors* B p value ‘Negative Symptoms’ 0.58 <0.000 ‘Developmental’ factor 0.24 0.002 ‘Disorganisation’ 0.14 0.045 ‘Depression’ factor -0.18 0.007 ‘Mania’ factor -0.17 0.016 Non-significant predictors: positive symptom factor 1 & 2; diagnosis; family discord; perinatal complications; gender; duration of illness * Model R2 = 0.72; stepwise variable entry

  26. 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

  27. Developmental Brain Changes PS SP 20 PS = proliferative stage 15 Synaptic density SP = synaptic pruning 10 (mm-3x108) 5 0 5 10 15 20 25 30 35 Age

  28. Developmental Brain Changes PS SP 20 PS = proliferative stage 15 Synaptic density SP = synaptic pruning 10 Childhood-onset Schizophrenia (mm-3x108) 5 0 5 10 15 20 25 30 35 Age

  29. Developmental Brain Changes PS SP 20 PS = proliferative stage 15 Synaptic density SP = synaptic pruning 10 Childhood-onset Schizophrenia (mm-3x108) 5 0 5 10 15 20 25 30 35 Age

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

  31. 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-test P 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)

  32. 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.]

  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. EEG

  35. 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 evaluation • Up-dating internal context and memory models in situations requiring stimulus categorisation

  36. P300 to target tones at Pz Healthy ADHD SZ SZ High Risk [µV] -30 -25 -20 -15 -10 -5 0 5 10 15 20 25 30 -200 -100 0 100 200 300 400 500 600 700 800 [ms]

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

  38. 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

  39. 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

  40. 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.

  41. 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

  42. 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

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

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

  45. 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

  46. 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

  47. 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.

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