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 Developmental Features Neurobiology Pharmacological Treatment

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

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

Prenatal Childhood Adolescence Adult

Psychosis

Genes Environment

Subtle developmental & social impairments

Negative/ schizotypal/ prodromal symptoms

Early intervention

?

From Risk to Disorder

Drugs ? Stress ?

Clinical Features of CAOS

Phases of Illness

1. Pre-Psychotic2. Prodromal/ Peri-Psychotic3. Psychosis4. Post-Psychotic

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

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

Premorbid adjustment in adolescent psychoses

0

2

4

6

8

10

Schizophrenia

Other PsychosesMedian

PAS score

P<0.0002

Impairment

2. Prodromal Phase

Progressive social and cognitive decline

Incongruous, bizarre behaviour Subtle perceptual & affective

changes Early negative symptoms Disorganisation

Age of Onset of Prodromal and Psychotic Symptoms

0

5

10

15

20

25

30

35

6 7 8 9 10 11 12 13 14 15 16 17

Behaviouralchange

Psychosis

Age

Frequency

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

4. Post Psychotic Phase Probability of remission

predicted by: Premorbid functioning Duration of active phase

symptoms

50% maintain chronic course

Remission From First Psychotic Episode

0%

20%

40%

60%

80%

100%

None

Incomplete

Complete

Schizophrenia Affective psychosis X2=23; P<0.0001

12%

40%

48%

52%

38%

10%

Hollis C (2000) Am J Psychiatry; 157; 1652-1659

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

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

EPIC Study

0

5

10

15

20

25

10 11 12 13 14 15 16

Age of Onset of Psychosis

Age

Number of Cases

Age Specific Incidence Rates

Age Number 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

1.93

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

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. whiteAge 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

P<0.001

Hollis et al. (2004). Schizophrenia Research, 67 (Supply), 65

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

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

Follow-up Time Psychotic

0 2 4 6 8 10 12

Affectivepsychosis

Schizophrenia

Psychotic

Remission

66%

years

30%

Hollis C (2000) Am J Psychiatry; 157; 1652-1659

Accommodation at Follow-Up

0%

20%

40%

60%

80%

100%

long stay

hostel/ home

independent

Schizophrenia Affective psychosis

16%

39%

45%

52%

21%

26%

X2=15; P=0.01

Hollis C (2000) Am J Psychiatry; 157; 1652-1659

Relationships at Follow-Up

0%

20%

40%

60%

80%

100%

Partner

Friends

Aquaintence

None

Schizophrenia Affective psychosis

44%

40%

14%

14%

29%

31%

26%

X2=21; P<0.001

Hollis C (2000) Am J Psychiatry; 157; 1652-1659

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

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

Developmental Brain Changes

50

10

15 20 25 30 35

Age

Synaptic density

5

10

15

20

(mm-3x108)

PSSP

PS = proliferative stage

SP = synaptic pruning

Developmental Brain Changes

50

10

15 20 25 30 35

Age

Synaptic density

5

10

15

20

(mm-3x108)

PSSP

PS = proliferative stage

SP = synaptic pruning

Childhood-onset Schizophrenia

Developmental Brain Changes

50

10

15 20 25 30 35

Age

Synaptic density

5

10

15

20

(mm-3x108)

PSSP

PS = proliferative stage

SP = synaptic pruning

Childhood-onset Schizophrenia

Progressive Brain Changes

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

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)

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.]

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.]

EEG

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

-50

-25

0

25

50

µv

ms

200 300100 400 5000

P300S R

P300: P300: •stimulus evaluationstimulus evaluation•Up-dating internal context and Up-dating internal context and memory models in situations memory models in situations requiring stimulus categorisationrequiring stimulus categorisation

30

25

20

15

10

5

0

-5

-10

-15

-20

-25

-30

[µV]

-200 -100 0 100 200 300 400 500 600 700 800 [ms]

P300 to target tones at Pz

HealthyADHD

SZSZ High Risk

Specificity?

Groups standardised to healthy group mean

-2

-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

P300 N200 FI N200 SI ERN Error PosHealthy

ADHDSZSZ HR

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

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

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.

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

Side-Effects of AntipsychoticsCan 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

Incidence of EPSE by Age

0

10

20

30

40

50

60

70

10 to 19 20 to 29 30 to 39 40 to 49 50 to 59

DystoniaParkinsonismAkathisia

Inci

den

ce

%

Age [Adapted from Remschmidt 2000]

Weight Gain in Adolescents Olanzepine vs. Risperidone vs. Haloperidol

0

2

4

6

8

10

12

0 1 2 3 4 5 6 7 8 9 10 11 12

OlanzapineRisperidoneHaloperidol

Mean %

Weig

ht

Chan

ge

Week[Ratzoni et al. (2002) JAACAP, 41, 337-343]

N=21

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

Weight Gain on Atypicals: Adolescents vs. Adults

0

1

2

3

4

5

6

7

8

Olanzapine Risperidone Haloperidol

AdolescentsAdults

Mean

Wt

Gain

Kg

*

**

* Ratzioni et al (2002) JAACAP, 41: 337-341

** Allison et al (1999) Am J Psych, 60: 215-220

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

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.