11.

05

"
" .
Schizophrenia
28/11/05
11.05

"
" .
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.
11.05

"
" .
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.
11.05

"
" .
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?
11.05

"
" .
Two categories of symptoms
in schizophrenia:
Positive symptoms

Negative symptoms
11.05

"
" .
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

11.05

"
" .
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).
11.05

"
" .
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
11.05

"
" .
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
11.05

"
" .
Example of delusions of control

Thought insertion = Believing that thoughts
that are not your own have been placed in your
mind by an external source

A 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.
11.05

"
" .
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


11.05

"
" .
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
11.05

"
" .
Common auditory hallucinations
in schizophrenia
Hearing own thoughts spoken by another
voice
Hearing voices that are arguing
Hearing voices commenting on ones own
behavior
11.05

"
" .
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
11.05

"
" .
Disorganized Motor
Disturbances
Extreme activity levels (unusually high or
low), peculiar body movements or
postures (e.g., catatonic schizophrenia),
strange gestures and grimaces
11.05

"
" .
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
11.05

"
" .
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
11.05

"
" .
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

11.05

"
" .
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.
11.05

"
" .
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

11.05

"
" .
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.
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
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.
11.05

"
" .
11.05

"
" .
11.05

"
" .
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
11.05

"
" .
11.05

"
" .
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
11.05

"
" .
Structural changes in brain
Larger ventricles
Subgroup: inverse correlation between
ventricle size and response to drugs
11.05

"
" .
11.05

"
" .
11.05

"
" .
11.05

"
" .
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 2
nd
trimester
Also in entorhinal, cingulate, parahippocampal
cortex

11.05

"
" .
11.05

"
" .
11.05

"
" .
11.05

"
" .
Structural changes in brain
Increased loss of gray matter in
adolescence
11.05

"
" .
11.05

"
" .
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

11.05

"
" .
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
11.05

"
" .
11.05

"
" .
Neurochemical changes
LSD, mescaline confusion, delirium,
disorientation, visual hallucinations.
But schizophrenic hallucinations are
mostly auditory
Schizophrenics given LSD say its different
from their symptoms
11.05

"
" .
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.
11.05

"
" .
Neurotransmitter involved in schizophrenia
Clinical observations:
Conventional antipsychotic drugs inhibit D
2

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.
Dopamine-hypothesis of schizophrenia
(Freedman 2003 N Engl J Med 349:1738)
11.05

"
" .
11.05

"
" .
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 5HT
2
receptors.
Blocking of 5HTRs may be a requirement for
the reduction in extrapyramidal symptoms.
11.05

"
" .
Neurotransmitter involved in schizophrenia
Altered activity of GAD and altered
expression of GAT1 and GABAR subunits in
prefrontal cortex and hippocampus in brains
from schizophrenic patients.
Clinical observations:
Enhancing GABAergic function, primarily
through the use of benzodiazepines, has not
yielded convincing results of specific effects
in schizophrenia.
GABA
Relation to disruption of neuronal migration
during cortex development?
11.05

"
" .
11.05

"
" .
Atypical neuroleptics
Clozapine blocks 5-HT2A receptors > 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
11.05

"
" .
11.05

"
" .
Glutamate hypothesis
Problem with DA hypothesis: time course
Phencyclidine (PCP): dissociative
anesthetic
Auditory hallucinations
Depersonalization
Delusions
Noncompetitive NMDA antagonist (blocks
Ca2+ channel)

11.05

"
" .
Neurotransmitter involved in schizophrenia
Altered activity of GAD and altered
expression of GAT1 and GABAR subunits in
prefrontal cortex and hippocampus in brains
from schizophrenic patients.
Clinical observations:
Enhancing GABAergic function, primarily
through the use of benzodiazepines, has not
yielded convincing results of specific effects
in schizophrenia.
GABA
Relation to disruption of neuronal migration
during cortex development?
11.05

"
" .
11.05

"
" .
11.05

"
" .
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)
11.05

"
" .
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?????
11.05

"
" .
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 D
2
R antagonists reverse the
inhibition.
D
2
receptors also reduce GluR-mediated activity in corticostriatal and thalamostriatal
pathways, while D
2
antagonists increase the activity.
In the striatum, an intracellular interaction between D
2
and NMDA receptors induces
increased NMDAR activity.
Dopamine-Glutamate interactions
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..
11.05

"
" .
Implications of Glu hypofunction for schizophrenia
(Konradi & Heckers 2003 Pharm & Ther 97: 153)
Glu is involved in early synapse
formation and stabilisation
A hypoactive system leads
to sparse neuronal circuits
11.05

"
" .
Glutamate hypothesis
Seizures!! (also excitotoxicity)

Try mGluR agonists: 8 subtypes of mGluR
Some modulate glutamate release
Others modulate dopamine systems
11.05

"
" .
Genes for schizophrenia
(Harrison & Owen 2003 The Lancet 361: 417)
Recent genetic linkage studies have identified candidate susceptibility genes for
schizophrenia.
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.
11.05

"
" .
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.
Finding needs replication in larger
and more diverse sample size
GRIN1 (encoding NR1 subunit of NMDARs)
GRM3 (encoding mGluR3 receptors)
11.05

"
" .
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.
11.05

"
" .
Neuregulin-1/erbB signalling and schizophrenia
(Corfas et al 2004 Nature Neuroscience 7: 575)
11.05

"
" .
G72 primate specific gene encodes a 153 aa protein that interacts with DAAO
(D-amino acid oxidase) resulting in the activation of the enzyme.
Genes for schizophrenia:
DAAO and G72
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.
11.05

"
" .
Metabolic pathway for D-serine
DAAO
Serine Racemase
Serine Transporter
Serine Transporter
11.05

"
" .
11.05

"
" .
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 D
2
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, a
1
, H
1
, m
1/4
)
11.05

"
" .
11.05

"
" .
11.05

"
" .
11.05

"
" .
11.05

"
" .
11.05

"
" .
11.05

"
" .
11.05

"
" .