Prodromal psychosis talk 25-11-09

Prodromal Psychosis

November 2009

Jennifer Spencer, ST4, LD Psychiatry, SEPT

Classically a retrospective conceptIn medicine

• An early symptom or set of symptoms that might indicate the start of a disease before definitive symptoms occur.

• Prodromal symptoms may be non-specific or, in a rare instances, may clearly predict onset of a specific disease.

In schizophrenia• The period of decreased functioning that is

postulated to correlate with the onset of psychotic symptoms.

• The term at risk mental state is often preferred, as prodrome can not be confirmed until the condition emerges.

Prodrome

Development of psychosis over time

1. Patient first notices a change in himself2. Family or friends first notice a change in the patient3. Patient first notices psychotic symptoms in himself4. Family or friends first notice psychotic symptoms in the

patient5. First psychotic intervention

(estimated by McGorry in 1996 to be 1 year)(Yung et al 1996)

Historical context• Schizophrenia prodrome recognized in Kraeplin’s

Classification (McGorry 1996)• Delay in treatment associated with poorer

outcome (Northwick Park Study 1986)• Theory of toxic effect of psychosis

(Lieberman 1990, Wyatt 1991)• Cost of treatment for patients with schizophrenia

very high for National Health Services (estimated 20-25% of total cost)

The prodrome as an area of potential intervention

• Potential for a reduction in biological deterioration and social disruption through early intervention

• Aim to decrease morbidity and improve quality of life by• Keeping some at risk people from developing full

blown schizophrenia• Minimizing the severity of symptoms in patients

who did develop schizophrenia• Benefit society and Health Services

• Decrease costs by making people better able to function in society (and return to work)

Yung and McGorry’s Proposal

(Yung et al 1995)

Worldwide programs for 5 yearsCochrane Review (2006) measured 2 objectives

1. Prevention of onset of schizophrenia2. Provision of effective treatment to reduce ultimate

severity of disease (psychological &/or medical therapies)

Conclusion: “Insufficient data to draw reliable conclusions”

Atypical Antipsychotic Efficacy Review (Sikich 2008)• All antipsychotics evaluated were more efficacious than

placebo, similar profiles to adultsConclusion: fragile evidence that atypical antipsychotics

might offer possible protection, at the risk of long term medically significant side effects

Is it effective?

• Funding • Identification of groups at High Risk of illness• Improved ability to predict who will “convert” (Varies according to how High Risk group is selected)• Advances in the understanding of underlying

pathophysiology • Arguments put forward for improved concordance,

familial acceptance and in some studies less frequent and shorter inpatient admissions (studies ongoing)

Benefits

• Factorial analyses suggests there is clinical continuity between normal and at risk presentations, and between at risk presentations and full onset Schizophrenia

• Schizophrenia is thought to represent the most severe form of a spectrum of normal cognitive and neuro-developmental traits (as for many other disorders in medicine and psychiatry)

Hawkins et al 2004

Identification of Risk:The Schizotypal Continuum

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Family history of psychosis

Schizotypalpersonality

Prodromal

Help seeking group

Woods et al 2009

Populations Studied

Brief intermittent Psychotic Syndrome

(BIPS)

Attenuated Positive Symptom Syndrome

(APS)

Genetic Risk and Deterioration

Syndrome(GRDS)

Primarily positive symptoms

Primarily negative symptoms

Gradation towards psychosis

Presence of DSM-IV or ICD 10 Psychotic Syndrome

Gradation towards psychosis

Yung et al 1996

3 Proposed Prodromes

Prodrome syndromes differ from each other and from DSM-VI and ICD-10 classifications in terms of symptom• Type • Severity • Frequency• Duration

Yung et al 1996

Symptom Classification

Positive Symptoms• Unusual thought content

/Delusional ideas• Suspiciousness/Persecutory

Ideas/Grandiosity• Perceptual

Abnormalities/Hallucinations• Disorganized CommunicationNegative Symptoms• Social Anhedonia• Avolition• Expression of Emotion• Experience of Emotions and

Self• Ideational Richness• Occupational Functioning

Disorganization Symptoms• Odd Behaviour and

Appearance• Bizarre Thinking• Trouble with Focus and

Attention• Personal HygieneGeneral Symptoms• Sleep Disturbance• Dysphoric Mood• Motor Disturbances• Impaired Tolerance to Normal

StressPrimary Risk factor: Family

History of Schizotypy or Schizophrenia

Types of Symptoms

Miller et al 2003

Severity

Prodromal States with Mainly Positive Symptoms

Precursors Mild Moderate Severe

Intensity of Belief Unusual thoughts (D)

Considers possibility of apassing thought

Believes but lacks conviction

Believes, fairly convinced

Abnormal perceptions (H) Odd noises Name being

called

Voices mumbled or far awayShadows corner of eye

Disorganized speech (TD) Odd word Unusual phrase

Difficulty getting point across

1 5/63

Miller et al 2003

In Previous Year CriteriaBIPS• Severity of psychotic intensity (6)

on one or more item• Beginning in past 3 months• Occurring at least several minutes

per day at least once per monthAPS• Severity 3-5 on one or more item• Symptoms beginning within the

past year or increasing by 1 or more point in the last year

• Frequency 1/week for last month

Prodromal States with Mainly Positive Symptoms

Months 1 2 3 4 5 6 7 8 9 10 11

Brief intermittent Psychotic Syndrome (BIPS)

BIPS +

Months 1 2 3 4 5 6 7 8 9 10 11

Attenuated Positive Symptom Syndrome (APS)

APSS +

Miller et al 2003

• First degree relative with history of any psychotic disorder

OR• Patient himself has

schizotypal personality disorderAnd

• Global Assessment of Functioning ≤ 30% in last month vs 1 year ago

Prodromal States with Mainly Negative Symptoms

In Previous Year Criteria

Months 1 2 3 4 5 6 7 8 9 10 11

Genetic Risk and Deterioration Syndrome (GRDS)

GRDS -

Miller et al 2003

Screening Tools

North American Prodrome Longitudinal Study (NAPLS)

(2003 - 2009)• Scale of Prodromal Symptoms*• Structured Interview for

Prodromal Syndromes*• Global Assessment of

Functioning• Criteria of Prodromal

Syndromes*• Presence of Psychotic

Symdrome*• DSM-IV

* Based on Comprehensive Assessment for At Risk Mental State (CAARMS) (Yung 1996)

Edinburgh High-Risk Study of Schizophrenia (EHRS) (1994 - 2009)

• Present State Examination• Structured Inventory for

Schizotypy (SIS)• Memory and Learning

• Child Behaviour Checklist (CBC)• WAIS-R• Rivermead Behavioural Memory

test• Minor physical abnormalities

• Ocular Telorism• Dermatoglyphics

• MRI scan

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Prodromal

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Prediction Accuracy

Edinburgh High-Risk Study of Schizophrenia (EHRS)

Johnstone 2005

Single Predictor

Positive pred power

Negativepred power

Sensitivity

Specificity

Rey Aud Verbal Learning Test (RAVLT)

11.8 85.1 61.1 32.8

Social withdrawal (SIS) 40 91.7 44.4 90.2

Oddness (SIS) 28.9 93.2 61.1 78Total Score (SIS) 29.1 97.7 88.9 68.3Rust Inventory of

Schizotypal Cognitions

50 94.3 61.1 91.3SIS - Structural Interview for Schizotypy (SIS) at baseline

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Prediction AccuracyNorth American Prodrome Longitudinal Study (NAPLS)

Cannon 2008

Single Predictor Positive pred power Sensitivity Specificity

Genetic risk w/ f’n’al decline 52 66 59

Unusual thought content (>3) 48 56 62

Suspicion/paranoia (>2) 43 79 37

Social Functioning (<7) 46 80 43

Any substance abuse 43 29 83

Multiple regression1, 2, and 3 74 34 89

1, 2, and 4 81 30 90

1, 3, and 4 67 48 82

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Prodromal

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Other biological markers That might improve prediction• Oro-facial and upper limb movement abnormalities

(Mittal et al)• Olfactory dysfunction

(Tureisky et al 2009)• Rate (and location) of Gray Matter loss across time

(Thompson et al, 2001 and 2008, Johnson et al 2009)

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Prodromal

Help seeking groupTeenagers in

Special Schools

?Schizophrenia and Learning Disability

• Patients at familial risk for schizophrenia • Have consistently lower IQ prior to onset

(Esp specific memory and executive function difficulties)

• Schizophrenia onset is often heralded by cognitive decline

• Point prevalence of of schizophrenia in mild idiopathic intellectual disability = 3%

• Traits in patients with schizophrenia and mild LD are similar to those with schizophrenia alone • Structural brain changes• Positive family history • Rates of chromosomal variants and abnormalities

Schizophrenia and Learning Disability

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Teenagers in Special Schools

Johnstone et al 2007

• Cognitive difficulties often precede the onset of psychotic symptoms and illness by some years

• Adolescents with prodromal symptoms are therefore likely to come to their school’s attention due to intellectual disability and to enter special education

• Johnstone et al (2007) carried out a longitudinal study • Focussing on adolescents in special schools• Following the design of the Edinburgh High-Risk

Study of Schizophrenia

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Study of Prodromal Symptoms in Teenagers with mild learning disabilities

Prodromal Screening Tools Edinburgh High-Risk

Study of Schizophrenia (EHRS)

• Present State Examination (PSE)• Structured Inventory for Schizotypy

(SIS)• Memory and Learning

• Child Behaviour Checklist (CBC)• WAIS-R• Rivermead Behavioural Memory test

• Minor physical abnormalities• Ocular Telorism• Dermatoglyphics

• MRI scan

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• Clinical Interview Schedule (CIS)• Structured Inventory for Schizotypy

(SIS)• Memory and Learning

• Child Behaviour Checklist (CBC)• WAIS-R, WISC-III• Rivermead Behavioural Memory test

• Behavioural Assessment of Dysexecutive Syndrome

• MRI scan

Longitudinal study of Teens with borderline and mild LD


Results• Whole study population vs controls (all risk symptoms)

• Clinical Interview Schedule (CIS) score 200% higher• Structured Inventory for Schizotypy (SIS) score 16% higher

• Cut-off “high” SIS score therefore adjusted to reflect higher background level of symptomatology

• Adjusted “high” SIS score present in all subjects who have since developed schizophrenia

Conclusion • It will soon be possible to use simple screening tools to

detect vulnerability to schizophrenia in this population

Prodromal Symptoms in Teenagers with mild learning disabilities

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• In normal teenagers, cortical gray matter increases in synaptic density above adult levels during postnatal period

• Greatest synaptic volume is reached 11-16 years of age.• Age at which greatest volume is reached varies between

brain regions, adult configuration not achieved until well into 3rd decade.

• In normal teenagers, a synaptic pruning process occurs during adolescence and early adulthood until the number of synapses reaches adult levels

• The normal pruning process is believed to occur in an extreme and exaggerated way in early onset psychosis

Pathophysiology:Gray Matter Loss

Thompson P. M. et.al. PNAS 2001;98:11650-11655

©2001 by The National Academy of Sciences

Dynamic changes in male and female Teenagers with Schizophrenia

Combination studiesGrey matter, Genes and ParametricsGenetically associated Grey Matter changes in the brain

fMRI - NRG 1 (SNP8NRG243177) – Risk allele T/T• Decreased activation in Right medial prefrontal cortex and

Right posterior temporal gyrus during sentence completion• Development of schizotypal symptoms (but not necessarily

full-blown schizophrenia)sMRI and fMRI - COMT Val158Met – Risk allele Val

• Reduced Grey Matter Density in anterior cingulate• Increased activation in lateral prefrontal cortex and

anterior and posterior cingulate with increasing sentence difficulty on Hayling task

• Increased the risk of Schizophrenia in a dose dependent manner

NRG1 and COMT positive predictive power 60-70% in these populations

Lawrie et al 2008

Summary (of Edinburgh findings)1. NRG1 gene = a risk factor for schizotypal traits

Can lead to schizophrenia if prolonged labour or birth trauma also present

2. COMT Val allele = a risk factor for schizophreniaIn future

2. Imaging indices and gene variants may be used as ‘biomarkers’ to ID those at high risk for schizophrenia

3. Very high risk people could be targeted for close monitoring and early intervention with therapies as they wished.

Combination studiesGrey matter, Genes and Parametrics

Haloperidol

Olanzapine

Effect of medical treatment on Grey Matter loss

Thompson et al 2008

Time dependent trajectory of Gray Matter Loss

Rate of PANSS Score Loss Does Not Vary with Treatment

Thompson et al 2008

Should Prodromal Syndromes be included in DSM-V and ICD-11?1. Does a clinical need exist (is DSM-IV

inadequate)? Yes

2. Can diagnostic reliability and validity be reproduced in clinical practice?

Unknown (field trials)

3. When high-risk cases convert to DSM-IV illness • Is it predominantly psychosis? Yes• Is it specifically schizophrenia? Yes• Should the new class be placed with the group of psychoses or placed elsewhere? Psychoses

4. Do the criteria reflect behaviours that are so common that a distinction between ill and non-ill is difficult (high likelihood of false-positive)?

Yes

5. Will this diagnostic category do more harm than good to the patient? Undetermined

Carpenter et al 2009

• Prodromal psychoses are currently receiving a lot of attention

• Predictive screening tests are becoming more and more accurate

• Predictive screening tests will be appropriate for patients with borderline and mild learning disabilities

• Development of effective treatments is currently advancing at a slower pace

• Decision to screen patients will need to be made with great care

• Population screening may not be appropriate until after effective treatments have been identified

Conclusion

統合失調症 - the integration disorderΣχίζω - “I split”

severe madness - ماصفال精神分裂症

एक प्रकार का पागलपनШизофренияSchizofrenieSkizofreni

Schizophrenia

References (1)Addington J, Cadenhead KS, Cannon TD, Cornblatt B, McGlashan TH, Perkins DO, Seidman LJ, Tsuang M,

Walker EF, Woods SW, Heinssen R. North American Prodrome Longitudinal Study: a collaborative multisite approach to prodromal schizophrenia research. Schizophr Bull. 2007 May;33(3):665-72.

Cannon TD, Cadenhead K, Cornblatt B, Woods SW, Addington J, Walker E, Seidman LJ, Perkins D, Tsuang M, McGlashan T, Heinssen R. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Arch Gen Psychiatry. 2008 Jan;65(1):28-37.

Carpenter WT. Anticipating DSM-V: should psychosis risk become a diagnostic class? Schizophr Bull. 2009 Sep;35(5):841-3.

Einfeld S, Tonge B, Chapman L, Mohr C, Taffe J, Horstead S. Inter-Rater Reliability of the Diagnoses of Psychosis and Depression in Individuals with Intellectual Disabilities. J Appl Res Intellect Disabil. 2007 Sep;20(5):384-390.

Fletcher RJ, Havercamp SM, Ruedrich SL, Benson BA, Barnhill LJ, Cooper SA, Stavrakaki C. Clinical usefulness of the diagnostic manual-intellectual disability for mental disorders in persons with intellectual disability: results from a brief field survey. J Clin Psychiatry. 2009 Jul;70(7):967-74.

Goldberg DP, Cooper B, Eastwood MR, Kedward HB, Shepherd M. A standardized psychiatric interview for use in community surveys. Br J Prev Soc Med. (1970)

Hawkins KA, McGlashan TH, Quinlan D, Miller TJ, Perkins DO, Zipursky RB, Addington J, Woods SW. Factorial structure of the Scale of Prodromal Symptoms. Schizophr Res. 2004 Jun 1;68(2-3):339-47.

Johnstone EC, Crow TJ, Johnson AL, MacMillan JF. The Northwick Park Study of first episodes of schizophrenia. I. Presentation of the illness and problems relating to admission. Br J Psychiatry. 1986 Feb;148:115-20.

http://www.ncbi.nlm.nih.gov/pubmed/17255119?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=4












http://www.ncbi.nlm.nih.gov/pubmed/5435083?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch&log$=citationsensor






Johnstone EC, Ebmeier KP, Miller P, Owens DG, Lawrie SM. Predicting schizophrenia: findings from the Edinburgh High-Risk Study.Br J Psychiatry. 2005 Jan;186:18-25.

Johnstone EC, Owens DG, Hoare P, Gaur S, Spencer MD, Harris J, Stanfield AW, Moffat V, Brearley N, Miller P, Lawrie SM, Muir WJ. Schizotypal cognitions as a predictor of psychopathology in adolescents with mild intellectual impairment. Br J Psychiatry. 2007 Dec;191:484-92.

Lawrie SM, Hall J, McIntosh AM, Cunningham-Owens DG, Johnstone EC. Neuroimaging and molecular genetics of schizophrenia: pathophysiological advances and therapeutic potential. Br J Pharmacol. 2008 Mar;153 Suppl 1:S120-4

Marshall M, Rathbone J. Early intervention for psychosis. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD004718. Review.

McGorry PD, Yung AR, Bechdolf A, Amminger P. Back to the future: predicting and reshaping the course of psychotic disorder. Arch Gen Psychiatry. 2008 Jan;65(1):25-7.

Miller TJ, McGlashan TH, Rosen JL, Somjee L, Markovich PJ, Stein K, Woods SW. Prospective diagnosis of the initial prodrome for schizophrenia based on the Structured Interview for Prodromal Syndromes: preliminary evidence of interrater reliability and predictive validity. Am J Psychiatry. 2002 May;159(5):863-5.

Mittal VA, Neumann C, Saczawa M, Walker EF. Longitudinal progression of movement abnormalities in relation to psychotic symptoms in adolescents at high risk of schizophrenia. Arch Gen Psychiatry. 2008 Feb;65(2):165-71.

Moorhead TW, Stanfield A, Spencer M, Hall J, McIntosh A, Owens DC, Lawrie S, Johnstone E. Progressive temporal lobe grey matter loss in adolescents with schizotypal traits and mild intellectual impairment. Psychiatry Res. 2009 Nov 30;174(2):105-9.

References (2)






















Thompson PM, Bartzokis G, Hayashi KM, Klunder AD, Lu PH, Edwards N, Hong MS, Yu M, Geaga JA, Toga AW, Charles C, Perkins DO, McEvoy J, Hamer RM, Tohen M, Tollefson GD, Lieberman JA; HGDH Study Group. Time-lapse mapping of cortical changes in schizophrenia with different treatments. Cereb Cortex. 2009 May;19(5):1107-23

Thompson PM, Vidal C, Giedd JN, Gochman P, Blumenthal J, Nicolson R, Toga AW, Rapoport JL. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11650-5.

Turetsky BI, Hahn CG, Borgmann-Winter K, Moberg PJ. Scents and nonsense: olfactory dysfunction in schizophrenia. Schizophr Bull. 2009 Nov;35(6):1117-31. Epub 2009 Sep 30.

Walker EF, Cornblatt BA, Addington J, Cadenhead KS, Cannon TD, McGlashan TH, Perkins DO, Seidman LJ, Tsuang MT, Woods SW, Heinssen R.The relation of antipsychotic and antidepressant medication with baseline symptoms and symptom progression: a naturalistic study of the North American Prodrome Longitudinal Sample. Schizophr Res. 2009 Nov;115(1):50-7.

Woods SW, Addington J, Cadenhead KS, Cannon TD, Cornblatt BA, Heinssen R, Perkins DO, Seidman LJ, Tsuang MT, Walker EF, McGlashan TH.Validity of the prodromal risk syndrome for first psychosis: findings from the North American Prodrome Longitudinal Study. Schizophr Bull. 2009 Sep;35(5):894-908.

Yung AR, McGorry PD. The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophr Bull. 1996;22(2):353-70. Review.

References (3)



















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Prodromal psychosis talk 25-11-09

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