Schizophrenia

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Schizophrenia

• 28/11/05

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A bit of history

• Hideyo Noguchi, 1911 Syphillis (delusions,
  grandiosity, impulsivity, altered thought
  structure) is due to bacterium.
• Emil Kraeplin, 1919 dementia praecox (paranoia,
  grandiose delusions, auditory hallucinations,
  abnormal emotional reg., bizarre thoughts)partly
  genetic
• Eugen Bleuler, 1911 key is dissociative
  thinking also delusions, hallucinations,
  affective disturbance, autism.

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Schizophrenia actually refers to a group of
disorders. There is not one essential symptom
that must be present for a diagnosis. Instead,
patients experience different combinations of the
main symptoms of schizophrenia.
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Schizophrenia actually refers to a group of
disorders. There is not one essential symptom
that must be present for a diagnosis. Instead,
patients experience different combinations of the
main symptoms of schizophrenia.
What is schizophrenia?
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Two categories of symptoms in schizophrenia

• Positive symptoms
• Negative symptoms

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Positive Symptoms

• Distortions or excesses of normal functioning
  (e.g., delusions, hallucinations, disorganized
  speech/thought disturbances, motor disturbances)
• Positive symptoms are generally more responsive
  to treatment than negative symptoms

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Delusions

• False beliefs that are firmly and consistently
  held despite disconfirming evidence,culture or
  logic.
• Individuals with mania or delusional depression
  may also experience delusions. However, the
  delusions of patients with schizophrenia are
  often more bizarre (highly implausible).

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Types of delusions

• Delusions of persecution belief that one is the
  target of others mistreatment, evil plots,
  and/or murderous intent (most common)
• Delusions of reference belief that all
  happenings revolve around oneself, and/or one is
  always the center of attention

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Types of delusions

• Delusions of grandeur belief that one is a
  famous or powerful person from the past or
  present
• Delusions of control belief that some external
  force is trying to take control of ones thoughts
  (thought insertion), body, or behavior

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Example of delusions of controlThought
insertion Believing that thoughts that are not
your own have been placed in your mind by an
external sourceA 29-year-old housewife said, I
look out of the window and I think the garden
looks nice and the grass looks cool, but the
thoughts of Eamonn Andrews come into my mind.
There are no other thoughts there, only his He
treats my mind like a screen and flashes his
thoughts on it like you flash a picture.
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Types of delusions

• Thought broadcasting belief that ones thoughts
  are being broadcast or transmitted to others
• Thought withdrawal belief that ones thoughts
  are being removed from ones mind

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Hallucinations

• Sensory experiences in the absence of any
  stimulation from the environment
• Any sensory modality may be involved auditory
  (hearing) visual (seeing) olfactory (smelling)
  tactile (feeling) gustatory (tasting)
• Auditory hallucinations are most common

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Common auditory hallucinations in schizophrenia

• Hearing own thoughts spoken by another voice
• Hearing voices that are arguing
• Hearing voices commenting on ones own behavior

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Disorganized Speech / Thought Disturbances

• Problems in organizing ideas and speaking so that
  a listener can understand
• Loose Associations (cognitive slippage)
  continual shifting from topic to topic without
  any apparent or logical connection between
  thoughts
• Neologisms new, seemingly meaningless words that
  are formed by combining words

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Disorganized Motor Disturbances

• Extreme activity levels (unusually high or low),
  peculiar body movements or postures (e.g.,
  catatonic schizophrenia), strange gestures and
  grimaces

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Negative Symptoms

• Behavioral deficits that endure beyond an acute
  episode of schizophrenia
• More negative symptoms are associated with a
  poorer prognosis
• Some negative symptoms might be secondary to
  medications and/or institutionalization

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Types of negative symptoms

• Anhedonia inability to feel pleasure lack of
  interest or enjoyment in activities or
  relationships
• Avolition inability or lack of energy to engage
  in routine (e.g., personal hygiene) and/or
  goal-directed (e.g., work, school) activities

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Types of negative symptoms

• Alogia lack of meaningful speech, which may take
  several forms, including poverty of speech
  (reduced amount of speech) or poverty of content
  of speech (little information is conveyed vague,
  repetitive)
• Asociality impairments in social relationships
  few friends, poor social skills, little interest
  in being with other people

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Types of negative symptoms

• Flat affect no stimulus can elicit an emotional
  response. Patient may stare vacantly, with
  lifeless eyes and expressionless face. Voice may
  be toneless. Flat affect refers only to outward
  expression, not necessarily internal experience.

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Schizophrenia Subtypes (DSM-IV)

• Paranoid Type preoccupation with one or more
  delusions or frequent auditory hallucinations
• Disorganized Type disorganized speech,
  disorganized behavior, and flat or inappropriate
  affect
• Catatonic Type motoric immobility or excessive
  motor activity, extreme negativism or mutism,
  peculiar voluntary movement, echolalia or
  echopraxia
• Undifferentiated Type none of the above
• Residual Type Absence of prominent delusions,
  hallucinations, disorganized speech/behavior but
  odd beliefs/behavior or negative symptoms

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What causes schizophrenia?

• There is no one accepted cause for
  schizophrenia.
• Interactions between genetic predisposition and
  environmental influences disrupt
  neurodevelopmental processes leading first to
  pre-morbid symptoms and then to the onset and
  progression of schizophrenia.

• Heredity ? schizophrenia is genetically linked
• ? more than one gene may predispose people to
  it
• ? there is currently no reliable way to
  predict whether a person will develop
  the disease.

• Environment ? pregnancy and delivery
  complications
• ? childhood and prenatal virus infection
• ? urban birth and residence
• ? psychosocial factors (dysfunctional family
  environment)

• Changes in brain structure ? enlarged
  ventricles
• ? reduced regional cerebral volumes
• ? reduced activity in the temporal lobes

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Twin studies

• Why does one twin become schizophrenic and the
  other does not?
• Lower birth weight
• More physiological distress
• More submissive, tearful, sensitive
• Impaired motor coordination

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Genes

• Genes scattered across all but 8 chromosomes have
  been implicated
• Most important
• Neuregulin 1 NMDA, GABA, Ach receptors
• Dysbindin synaptic plasticity
• Catechol-O-methyl transferase DA metabol.
• G72 regulates glutamatergic activity
• Others myelination, glial function
• Paternal age more cell divisions in sperm

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Structural changes in brain

• Larger ventricles
• Subgroup inverse correlation between ventricle
  size and response to drugs

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Structural changes in brain

• Hippocampus, amygdala, parahippocamp.
• Smaller in affected twin (static trait)
• Disordered hippocampal pyramidal cells
• Correlation between cell disorder and severity
• May be due to maternal influenza in 2nd trimester
• Also in entorhinal, cingulate, parahippocampal
  cortex

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Structural changes in brain

• Increased loss of gray matter in adolescence

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Structural changes in brain

• Shrinkage of cerebellar vermis
• Thicker corpus callosum
• Frontal lobes
• Abnormal neuronal migration in one study
• Dendrites have fewer spines
• But no major structural abnormalities
• Measures of frontal function impaired

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Functional changes in brain

• Hypofrontality hypothesis
• Discordant twins low frontal blood flow only in
  affected twin
• Wisconsin card sorting task
• Schizophrenics cant shift attn. to other
  criterion
• Functional imaging frontal lobe activity lower
  at rest, esp. in right hemisphere, does not
  increase during task.
• Drug treatment increased activation of frontal
  lobes

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Neurochemical changes

• LSD, mescaline ? confusion, delirium,
  disorientation, visual hallucinations.
• But schizophrenic hallucinations are mostly
  auditory
• Schizophrenics given LSD say its different from
  their symptoms

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Dopamine hypothesis

• Amphetamine (very high doses) ? paranoia,
  delusions, auditory hallucination
• Also exacerbates symptoms of schiz.
• Effects blocked by DA antagonist chlorpromazine
• Phenothiazines (incl. chlorprom.) all other
  typical neuroleptics block D2 receptors and
  alleviate () symptoms.

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Neurotransmitter involved in schizophrenia
Dopamine-hypothesis of schizophrenia

• Clinical observations
• Conventional antipsychotic drugs inhibit D2
  receptor.
• Schizophrenia-like symptoms occur in amphetamine
  abusers, due to excessive DA release.

• Baseline DA levels and stimulated release of DA
  are abnormal in mesolimbic systems of brains from
  schizophrenic patients.

? DA system plays a role in schizophrenia.
However, it is likely not to be the only and/or
main neurotransmitter system implicated.
(Freedman 2003 N Engl J Med 3491738)
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Neurotransmitter involved in schizophrenia
Serotonin

• 5HT has been implicated in a variety of
  schizophrenia symptoms
• (e.g. hallucinations, cognitive dysfunction,
• sensory gating, aggression)

• Atypical antipsychotic have relatively high
  affinity for 5HT2 receptors.

Blocking of 5HTRs may be a requirement for the
reduction in extrapyramidal symptoms.
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Neurotransmitter involved in schizophrenia
GABA

• Clinical observations
• Enhancing GABAergic function, primarily through
  the use of benzodiazepines, has not yielded
  convincing results of specific effects in
  schizophrenia.

• Altered activity of GAD and altered expression
  of GAT1 and GABAR subunits in prefrontal cortex
  and hippocampus in brains from schizophrenic
  patients.

Relation to disruption of neuronal migration
during cortex development?
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Atypical neuroleptics

• Clozapine blocks 5-HT2A receptors gt D2
• As effective as typical neuroleptics on ()
  symptoms, more effective on (-) symptoms
• Fewer motor side effects (tardive dyskinesia)
• Actually increase DA release in frontal cortex
• L-DOPA can even be beneficial

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Glutamate hypothesis

• Problem with DA hypothesis time course
• Phencyclidine (PCP) dissociative anesthetic ?
• Auditory hallucinations
• Depersonalization
• Delusions
• Noncompetitive NMDA antagonist (blocks Ca2
  channel)

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Neurotransmitter involved in schizophrenia
GABA

• Clinical observations
• Enhancing GABAergic function, primarily through
  the use of benzodiazepines, has not yielded
  convincing results of specific effects in
  schizophrenia.

• Altered activity of GAD and altered expression
  of GAT1 and GABAR subunits in prefrontal cortex
  and hippocampus in brains from schizophrenic
  patients.

Relation to disruption of neuronal migration
during cortex development?
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Neurotransmitter involved in schizophrenia
Glutamate-hypothesis of schizophrenia

• Clinical observations
• PCP and ketamine cause schizophrenia-like
  psychoses and cognitive deficits in normal
  subjects and worsens the symptoms of
  schizophrenia in patients.
• Gly site agonists improve outcome of treatment
  in schizophrenia.
• Sarcosine reduces symptoms in chronic
  schizophrenics under neuroleptic treatment.
• AMPA receptor potentiators administered on
  medicated patients improve performance in
  attention, memory and distractability tests.

• Significant reduction in CSF Glu levels in
  schizophrenic subjects.
• iGluR but not mGluR subunit expression is
  altered in hippocampus, thalamus and cortex)

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Glutamate hypothesis

• 2 weeks PCP in monkeys ? schiz.-like symptoms
• Including poor performance on frontal
  lobe-sensitive task
• Dose- time-sensitive
• Ketamine (NMDA antag)? similar effects
• So, why not give glutamate agonists to treat
  schizophrenia?????

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Dopamine-Glutamate interactions

• DA neurones in the substantia nigra and VTA
  receive glutamatergic inputs and Glu stimulates
  DA activity.
• Conversely, the glutamate system is inhibited by
  DA and D2R antagonists reverse the inhibition.
• D2 receptors also reduce GluR-mediated activity
  in corticostriatal and thalamostriatal pathways,
  while D2 antagonists increase the activity.
• In the striatum, an intracellular interaction
  between D2 and NMDA receptors induces increased
  NMDAR activity.

• Acute treatment with NMDAR antagonists increases
  DA release in the PFC and sub-cortical structures
  (in vivo dialysis).
• Chronic treatment with NMDAR antagonists results
  in decreased DA release in the PFC but not
  subcortical structures (in vivo dialysis,
  turnover measurements).

• Modulation of the DA system by antipsychotic
  drugs influences the performance of the Glu
  system.
• Altered function of the Glu system affects the
  performance of the DA system..

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Implications of Glu hypofunction for schizophrenia
(Konradi Heckers 2003 Pharm Ther 97 153)
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Glutamate hypothesis

• Seizures!! (also excitotoxicity)
• Try mGluR agonists 8 subtypes of mGluR
• Some modulate glutamate release
• Others modulate dopamine systems

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Genes for schizophrenia

• Recent genetic linkage studies have identified
  candidate susceptibility genes for schizophrenia.

(Harrison Owen 2003 The Lancet 361 417)

• The modulation of excitatory transmission and in
  particular of NMDAR function appears to be the
  common link among most recently described
  susceptibility genes for schizophrenia.

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Genes for schizophrenia

• RGS4 (regulator of G protein function)
• RGS4 inhibits signalling by the mGluR5, which
  stimulation potentiates NMDA-mediated currents.

• DTNBP1 (encoding dysbindin-1)
• Protein levels are significantly reduced in the
  hippocampal formation of schizophrenic
  individuals.
• However, patients with dysbindin mutations do not
  show symptoms of schizophrenia.

• PPP3CC (encoding calcineurin g subunit)
• Calcineurin k.o. mice display behavioural
  abnormalities reminiscent of altered behaviour
  observed in schizophrenic patients.

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Genes for schizophrenia NRG1

• Neuregulin1 cell-cell signalling protein
  containing an epidermal growth factor (EGF)-like
  motif that bind to membrane-associated Tyr
  kinases of the erbB family.

• NRG1 regulates expression of GluR subunits.
• NRG1 is colocalised with the NMDAR and modulates
  its kinetic properties by phosphorylation of the
  NR2 subunit.

• NRG-1 mRNA is increased in brains from
  schizophrenic patients.
• Significant reduction in the level of erbB3
  expression in brains from schizophrenic patients.

• Mice heterozygous for mutations in the NRG1 gene
  display hyperactivity in behavioural tests
  similar to that observed in PCP treated mice.

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Neuregulin-1/erbB signalling and schizophrenia
(Corfas et al 2004 Nature Neuroscience 7 575)
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Genes for schizophrenia DAAO and G72

• G72 primate specific gene encodes a 153 aa
  protein that interacts with DAAO (D-amino acid
  oxidase) resulting in the activation of the
  enzyme.

• DAAO is responsible for the catabolism of
  D-serine.

• DAAO is heterogeneously distributed in the
  brain. Brainstem and cerebellum are richer in
  enzyme levels than forebrain regions.
• DAAO is prevalent in astrocytes and glial cells,
  although some studies suggest that enzyme can be
  localised also in neurones.
• Subcellular localisation of DAAO appears to be
  peroxisomal.

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Metabolic pathway for D-serine
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How is schizophrenia treated?

• There is currently no cure for schizophrenia.
• Treatment is aimed at reducing symptoms and
  preventing psychotic relapses. Medication needs
  to be continue.

• Two major types of antipsychotic medications (or
  neuroleptics)
• CONVENTIONAL or TYPICAL ANTIPSYCHOTICS
  (haloperidol)
• ? control the positive symptoms very effectively
• ? side effects extrapyramidal symptoms
• (chronic tardive dyskinesia, parkinsonism,
  akathisia
• acute acute dystonia, neuroleptic malignant
  syndrome)
• ? high affinity for D2 dopamine receptors

NEWER or ATYPICAL ANTIPSYCHOTICS
(clozapine, risperidone, olanzapine,
ziprasidone, quietapine, sertindole) ? better
at treating the negative symptoms ? milder motor
side effects but others (weight gain,
diabetes) ? they have affinity to multiple
receptor systems (DARs, 5HTRs, a1, H1, m1/4)
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