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Schizophrenia: Overview. Background Schizophrenia symptoms/syndromes Schizotypal personality Dopamine hypotheses Genetic effects on prefrontal functioning in SZ Neurodevelopmental hypothesis Neuropsychological accounts. Psychosis vs. Schizophrenia.

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Schizophrenia: Overview

  • Background

  • Schizophrenia symptoms/syndromes

  • Schizotypal personality

  • Dopamine hypotheses

  • Genetic effects on prefrontal functioning in SZ

  • Neurodevelopmental hypothesis

  • Neuropsychological accounts


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Psychosis vs. Schizophrenia

  • Psychosis is a syndrome (mixture of symptoms) – delusions and hallucinations

  • Psychotic disorders

    schizophrenia

    schizoaffective disorder

    schizophreniform disorder

    drug-induced psychoses

  • Other disorders have psychosis as an associated feature


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Schizophrenia Basics

  • Most common psychotic illness

  • Affects 1% of population

  • costs billions $$$ p.a.

  • Definition

  • Must last >6 months

  • incl. At least one month of halluc., delusions, grossly disorganised speech/behaviour

  • Can be very severe

  • 25-50% of patients attempt suicide


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Delusions

  • Misrepresentations of perceptions or experience

  • Most common are persecutory

  • Others

    referential; somatic; religious; grandiose


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Hallucinations

  • Disordered perception

    perceptions without corresponding physical stimuli

  • Most commonly auditory

    but can occur in any sensory modality


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5 Symptom Dimensions in Schizophrenia

  • Positive symptoms

  • Negative Symptoms

  • Cognitive Symptoms

  • Anxiety and Depressive Symptoms

  • Aggressive Symptoms


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Positive Symptoms

  • Additions to normal function

  • Delusions

  • Hallucinations

  • Distorted language/communication

  • Disorganised speech / behaviour

  • Catatonic behaviour

  • Agitation


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Negative Symptoms

  • Losses of normal function

    Affective flattening

    Alogia

    Avolition

    Anhedonia

    Attentional impairment

    Blunted affect, emotional withdrawal, poor rapport, passivity, apathetic social withdrawal


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Negative Symptoms

  • Different aetiologies

    primary (a core feature)

    secondary to:-

    +ve symptoms

    depression

    extrapyramidal symptoms

    environmental depreivation


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Cognitive Symptoms

  • Thought disorder

  • Odd use of language

    incoherence, loose associations, neologisms

  • Impaired attention / cognition

    reduced verbal fluency

    learning/memory

    executive functions


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Syndromes in Schizophrenia

  • Type 1 vs Type 2 (Crowe)

  • Liddle’s 3-syndromes scheme

    reality distortion(positive)

    psychomotor poverty (negative)

    disorganisation


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What Are Schizotypal Personality Traits?

  • Stable traits in healthy individuals

  • Tendencies to show features of behaviour/cognition that are qualitatively similar to those of schizophrenic patients

  • Underlying continuum model


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Schizotypal Personality: Multidimensionality

Schizotypal personality has 3 or 4 correlated factors …

Positive schizotypy

Disorganised schizotypy

Negative schizotypy

4th factor = Impulsive nonconformity:

Is this really schizotypal personality?


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Schizotypal Personality Measures

  • Positive Schizotypy

  • OLIFE: Unusual experiences (UnEx);

  • SPQ: Cognitive-perceptual factor

  • Negative Schizotypy

  • OLIFE: Introvertive anhedonia (IntAnh); SPQ negative factor

  • Disorganised Schizotypy

  • OLIFE: Cognitive Disorganisation (CogDis); SPQ Disorganisation


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Example OLIFE Items

  • Positive Schizotypy: Measure = Unusual Experiences (30 items)

    -I have felt that I have special, almost

    magical powers

    -Do you ever feel that your thoughts

    don’t belong to you?

    -Sometimes my thoughts are as real as

    actual events in my life


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SPQ Subscales

  • Positive (Cog-Perceptual)

  • Unusual perceptions; odd beliefs;

  • ideas of reference; suspiciousness

  • Negative (Interpersonal)

  • No close friends; excessive social anxiety; constricted affect; susp

  • Disorganised Schizotypy

  • Odd behaviour; Odd Speech


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Why Study Schizotypal Personality Traits?

  • Testbed for schizophrenia in readily-available, healthy individuals

  • Performance of high scorers should be similar to schizophrenics

  • Behaviour not contaminated by medication, illness, hospitalisation etc


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More Reasons to Study Schizotypal Personality Traits

  • May find specific associations with one schizotypal factor

  • Generates predictions for associations with specific SZ symptoms


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Schizotypal Personality Traitsand Psychosis Proneness

  • Alternative definitions of schizotypy

    -a prodrome for schizophrenia

    -schizotypal personality disorder

    -psychosis proneness

  • Follow-up studies of high-scoring subjects on schizotypal personlity traits


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Schizotypal Personality Follow Up Studies

  • Kwapil, Chapman and Chapman

    -10 year follow-ups

    -small increase in Sz for positive schizotypy measures

    -Follow-ups of high scorers on the ImpNon dimension did not show inc. Sz but small increases in other psychopathologies


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Neuroscience of Schizophrenia

  • Dopamine and schizophrenia

  • Recent genetics advances

  • Neurodevelopmental hypothesis


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Brain Dopamine Pathways

  • Nigrostriatal

    degenerates in Parkinson’s disease

  • Mesolimbic

    positive symptoms of schizophrenia

  • Mesocortical

    neg symptoms of schizophrenia

  • Tuberoinfundibular


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Signals of reward availability

Addictive drugs:

opiates, cocaine, cannabis, nicotine

Food/drink

EBS

Sex

Effective goal-directed behaviour


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Evidence for DA Hypothesis

  • Stimulant drugs

    -release DA

    -amphet/cocaine abuse -> paranoid

    psychosis

  • Antipsychotic drugs

  • which are effective at treating positive symptoms are DA receptor (DR) blockers esp. D2 DR


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Mesolimbic DA Hypothesis

  • Hyperactivity of mesolimbic DA mediates positive symptoms of psychosis

  • Accounts for these psychotic symptoms whether in SZ or other disorders


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Mesocortical DA Hypothesis

  • Deficit of mesocortical DA mediates negative and cognitive symptoms of psychosis

    - more controversial

    - affects areas such as DLPFC

    - degenerative in some SZ patients

    - may be primary deficit

    - may be secondary drug effect


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New Developments in DA Hypotheses of SZ: 1

Good recent review at:-

http://www.acnp.org/g4/GN401000115/Default.htm


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New Developments in DA Hypotheses of SZ: 2

Recent advances in molecular genetics make it possibly to explore the effects of …

specific genetic polymorphisms

relevant to the DA hypothesis


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Studies of the COMT gene

see Egan et al (2001).

Proceedings of the National Academy of Sciences (PNAS)

98, 6917-6922


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The COMT gene and SZ

  • Catechol-o-methyl transferase is a catabolic enzyme that degrades DA

  • The COMT gene has two variants which affect the functioning of the gene (val and met alleles)

  • The gene is on chromosome 22 close to regions which have been implicated in linkage studies with SZ

  • Family and association studies have implicated the COMT gene in SZ


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Egan et al 2001: 1

  • Argued that “abnormal PFC function” is a useful intermediate phenotype for SZ

  • Intermediate phenotypes are more likely to be related to gene function than the clinical diagnosis

  • SZ show reliable PFC disturbances on cognitive tests

  • So do healthy sibs inc. MZ co-twins


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Egan et al 2001: 2

  • DA plays role in modulating PFC during working memory (WM) tasks

  • As COMT gene affects prefrontal dopamine levels then may affaect WM

  • COMT knockout mice have increased DA in PFC and enhanced memory performance


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Egan et al 2001: 3

  • Measured WM and exec function using Wisconsin Card Sorting Test (WCST)

    -WCST activates PFC

    -DA-mimetic drugs improve WCST performance in SZ

  • Measured prefrontal neurophysiology using fMRI and the n-back WM task

    -task activates DLPFC

    -in SZ, and unaffected sibs, DLPFC activation is inefficient


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Egan et al 2001: Results

Controls

Sibs

patients


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Egan et al 2001: Results

  • fMRI during the n-back task showed, for patients and sibs, that DLPFC and ACC activation efficiency was affected by genotype:-

    val/val < val/met < met/met


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Egan et al 2001: Results

  • Analysed 104 family trios (2 parents plus case)

  • In 126 gene transmissions from heterozygous parents to probands the val allele was transmitted 75 times (p=0.03)

  • In unaffected sublings 77 val vs 87 met transmissions


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The COMT gene and schizotypy

Various studies have shown that the COMT gene may be linked to schizotypal personality (Stefanis et al, 2002, 2004), although what aspects are not clear, with high schizotypy associated with presence of val allele


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Neurodevelopmental Hypothesis of Schizophrenia

  • Proposes that Sz arises from ?genetic? abnormalities in fetal brain development (evidence?)

  • Why should such this give rise to peak incidence of Sz in teens and early 20s?

  • Ans: Adolescent neural restructuring reveals earlier deficit (evidence?)

  • Maybe additional neurodegeneration during symptomatic phase of disease


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Neuropsychological accounts of SZ

  • Usually propose a deficit in a specific cognitive process as responsible for a specific subset of SZ symptoms

  • Thus SZ perform worse/differently from controls on a cognitive task designed to measure the specific process


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Neuropsychological accounts of SZ: Examples

  • Latent Inhibition (Gray)

  • Negative Priming (various)

  • Contextual processing (various)


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