Year 2 Biological Psychology C82NAB An Introduction to schizophrenia

1
Year 2 Biological Psychology(C82NAB) An
Introduction to schizophrenia

• Dr. P.M.Moran

2
Schizophrenia

• Series of 5 topics
• Topic 1 General introduction and symptoms
• Topic 2 Structural Brain abnormalities
• Topic 3 Functional Brain abnormalities
• Topic 4 Drug Treatment of schizophrenia
• Topic 5 Genetics of schizophrenia

3
Schizophrenia

• 1851- Falvet Folie circulaire
• 1871- Hecker hebephrenia
• 1878-Kraeplin combined into single disease-
  dementia Praecox
• 1908-Bleuler schizophrenia-split between affect
  and thought
• 1959-Schneider-first rank symptoms

4
Emil Kraeplin (1898)

• used the term dementia praecox. Dementia
  described the global disruption of perceptual and
  cognitive processes. Praecox described the
  early adulthood onset.
• First to describe illness as progressive with no
  return to premorbid funtioning

5
Eugen Bleuler (1911)

• Reformulated dementia Praecox
• Coined the term schizophrenia schizo meaning
  split and phrene meaning mind.
• Characterised fragmented thinking. Breakdown of
  integrated functions that co-ordinate thought
  affect and behaviour. Disturbances of
  association are the primary symptoms of
  schizophrenia

6
Symptoms of schizophrenia

• Positive Vs negative dichotomy
• Tim Crow (1980).
• (Type I) Positive symptoms (delusions,
  hallucinations, thought disorder)
• (Type II) Negative symptoms (anhedonia, flattened
  affect, avolition, alogia)

7
Symptoms of schizophrenia

• Positive symptoms
• Delusion false belief despite evidence to
  contrary
• (persecutory/paranoid, control, grandiose,
  reference)
• Bizarre delusion (thought insertion, thought
  withdrawal, thought broadcasting, made actions)
• Hallucination perceptual experience seems real
  in the absence of physical proof (not an
  illusion/distortion of senses)- most common
  auditory, visual ,olfactory)
• Thought disorders inventing words, having
  trouble understanding common words, changing
  topic frequently)

8
Symptoms of schizophrenia

• Negative symptoms
• Affect Blunted affect, mood or emotional state,
  limited range of emotions,
• Anhedonia inability to feel pleasure
• Thought (cognitive symptoms)
• Avolition (unable to begin tasks, lack of
  motivation)
• Alogia (unable to speak)
• Problems with working memory, planning, learning.

9
Symptoms of schizophrenia

• Peter Liddle (1987) B. J. Psychiatry, 151,
  145-151.
• Re-examined the positive negative dichotomy.
  Factor analytic study 40 patients with chronic
  schizophrenia. Confirmed positive and negative
  dichotomy but included a third factor termed
  disorganisation syndrome which Crow and others
  attributed to the positive dimension.

10
Liddle (1987, 2002)

• Liddle Identified three syndrome categories
• 1) psychomotor poverty (poverty of speech,
  decreased spontaneous movement, blunted affect)
• 2)Reality distortion (delusions, hallucinations)
• 3)Disorganisation syndrome (inapproriate affect,
  distractibility, poverty of conetent of speech,
  thought disturbances).
• Liddle (2002) expanded to include 5 factors
• 1)psychomotor poverty 2) reality distortion
  3)Disorganisation 4)psychomotor excitation
  5)anxiety /depression

11
Symptoms of Schizophrenia

• Negative
• Social withdrawal
• Flattened affect
• Impoverishment of thought speech

Cognitive Memory problems Learning
problems Attentional problems

• Positive
• Hallucinations
• Thought disorder
• Delusions

12
(No Transcript)
13
                                                
                                                  
   Above Decreased brain activity in
schizophrenia subjects (S) compared to normal
controls(N) in an fMRI study examining executive
functioning. Image courtesy of Prof. Philip
Ward, NISAD Cognitive Neuroscience Research Panel.
14
(No Transcript)
15
(No Transcript)
16
                                                
                                                  
                                           Image
Source Laboratory of Neuro Imaging, UCLA,
Derived from high-resolution magnetic resonance
images (MRI scans), the above images were created
after repeatedly scanning 12 schizophrenia
subjects over five years, and comparing them with
matched 12 healthy controls, scanned at the same
ages and intervals. Severe loss of gray matter is
indicated by red and pink colors, while stable
regions are in blue. STG denotes the superior
temporal gyrus, and DLPFC denotes the
dorsolateral prefrontal cortex. Note This study
was of Childhood onset schizophrenia which occurs
in 1 of every 40,000 people and is frequently a
significantly more aggressive form of
schizophrenia (than later onset schizophrenia
which afflicts approximatley 1 of every 100
people).
17
Schizophrenia Has a Genetic Basis
18
Neurochemistry of Schizophrenia

• Four approaches to investigating the
  neurochemistry of schizophrenia
• 1) post mortem studies
• 2) peripheral markers
• 3) mechanism of action of antipsychotic
  drugs- animal human studies
• 4) In vivo receptor binding (PET)

19
Dopamine theory of Schizophrenia

• Schizophrenia results from an abnormality in
  brain dopamine (DA) function.
• Hyperactivity in mesolimbic dopamine gives rise
  to pos symptoms, hypoactivity in frontal cortex
  gives rise to negative

20
Dopamine Theory of Schizophrenia

• Clinical potency of effective neuroleptics
  parallels their pharmacological potency in
  blocking dopamine binding
• Parkinsonian side-effects of neuroleptics
• Amphetamine which releases dopamine induces
  psychosis that responds to neuroleptics

21
(No Transcript)
22
Metabolite Measurements (Peripheral markers)

• Brain DA turnover can be reflected by plasma
  Homovanillic acid concentrations
• chronic neuroleptic treatment lowers plasma HVA
  which relates to good treatment outcomes

23
Post mortem studies

• Receptor affinity studies have found increased D2
  but not D1 receptors in the striatum.
• Mixed results for D4 receptors. Seeman (1993) 6
  fold elevation in schiz. Other studies found no
  D4 receptors even in controls

24
In -Vivo methods- patient studies

• In vivo measurement of D2 receptor affinity in
  humans using PET (positron emmission tomography).
• Some studies find increase in D2 binding (Wong et
  al,1986) no change in other studies (eg.,
  Pilowsky, 1994).
• possible reasons for discrepancies specificity
  of ligands, patient populations.

25
In Vivo methods (animal studies)

• Mesolimbic dopamine systems implicated in animal
  models of disrupted selective attention in
  schizophrenia
• Latent inhibition, pre-pulse inhibition
• Chronic neuroleptic decrease DA firing in
  A9(nacc) and A10 (striatum).
• Chronic atypical antipsychotics decrease firing
  in A10 only.

26
Neurochemistry of Schizophrenia (2)

• Glutamate schiz. Drugs that block glutamate
  receptor such as PCP produce psychosis.
• Serotonin schiz. Atypical antipsychotic drugs
  have high affinity for 5-HT2 receptor.Could be
  via modulatory role on DA function
• GABA schiz. moulatory role on DA function

27
Gluatamate Schizophrenia

• Abnormalities of the NMDA and kainate receptors
  in the schizophrenic prefrontal cortex. The NMDA
  abnormalities are found in multiple regions of
  the prefrontal cortex, and are associated with an
  up-regulation of the NR1 subunit.
• Decrease in GLU synthesis and release in the
  cortex and also a decrease in certain receptor
  sites for GLU in certain areas of the brain such
  as the cingulate and hippocampus.
• Cog deficits may be consequent to reductions in
  transcript mRNA for receptor subunits NMDAR1,
  GLUR1,GLUR7 and KA1 in forntal cortex
• PCP which induces psychosis is a non competitive
  NMDA antagonist.

28
Animal Models of Schizophrenia

• Difficult to model in animals
• Use selective attentional models that can be
  disrupted by augmentation of dopamine function
• Latent inhibition disrupted by amphetamine - this
  effect reversed by antipsychotic drugs,
  haloperidol, clozapine.

29
Focus points for study

• What are the symptoms of schizophrenia
• What is the major neurochemical hypothesis
  regarding the aetiology of schizophrenia
• What lines of evidence lead to this hypothesis
• What are animal models of schizophrenia and how
  do they work
• Does the mechanism of action of antipsychotic
  drugs help to understand the disease.