Symptoms Characterised by
Delusions, Hallucinations (auditory), disorganised Too much DA in the mesolimbic s
behaviour + speech (repetitive), catatonia Leading to presence of problemati
Positive
Alogia, affective blunting, asociality, anhedonia, Too little DA in mesocortical pa
avolition Leading to absence of healthy
Negative
Impaired attention & memory, problems in Too little DA in mesocortical pa
prioritising, difficulty in problem solving
Cognitive
Young people more likely to present positive symptoms
Negative and cognitive more difficult to treat
Test for Schizophrenia: the Stroop test (measuring defective selective attention). But slower times could also m
Causes of Schizophrenia
Exact causes remain unclear
Due to variety of ways Schizophrenia presents its symptoms
Also many of these are difficult to track in animal models
Current animal studies: modulating DA/NMDAR functions (not mutually exclusive)
But we do know there are clear genetic and environmental causes, implicated in the disease
Genetic Cause How it leads to Schizophrenia
1st degree relative (Onstad et al, 1991) mentioned schizophrenic and
who is schizotypal personality disorders being significantly
Schizophrenic more frequent in people with relatives
Schizophrenic twin Studies show 41-61% of identical twins both being
Schizophrenic when one is
So clear correlations seen in twin occurence of the
disease
Neuregulin-1 gene Underexpression of this gene is linked to abnormal
synaptic plasticity and development
Dysbindin Abnormalities in this gene lead to abnrmal NMDAR
tethering at post-synaptic densities
DISC-1 Mutations can lead to irregular cytoskeletal
machinery, and neurite outgrowth
, DISC-1
Generally, these genetic implications tell us that Schizophrenia is a neurodevelopmental condition, over neurod
You aren't born Schizophrenic, just predisposed to it potentially
Although there is a neurodegenerative component to it - progressive nature, worsening response to drugs over
This degeneration is possibly linked to glutamatergic signalling malfunctions, and excitotoxicity
We don't know the extent to which these two factors cause Schizophrenia, and how they interact
Aetiology
While the original causes remain up to debate, we know more about the aetiology
Technique Finding
Brain Imaging Thinner sub-cortical GABAergic regions in early This is likely a defect in developm
Studies Schizophrenia It causes hyperactive dopaminerg
Post-mortem brain Misplaced or ectopic clusters of neurones in Abnormal neuronal migration con
studies on Schiz neocortex
patients
There are two areas implicated in Schizophrenia aetiology
Dopaminergic, and Glutamatergic dysfunction (not mutually exclusive)
Dopaminergic is known, whereas glutamatergic has had more debate
Pathway Symptoms
Dopaminergic Overactive dopaminergic activity in mesolimbic Amphetamines (increases DA
dysfunction pathway --> positive symptoms behaviour in humans
Decreased dopaminergic activity in mesocortical In animals, increased DA relea
pathway --> negative/cognitive symptoms behaviour, like the repetitive b
humans
Nigrostriatal and tuberoinfundibular pathways seem Levodopa and DA-receptor ago
unaffected. can be hallucinogenic
DA receptor antagonists can b
symptoms - strong correlation
IC50, and dose of drug require
GWAS's have shown clear imp
Schizophrenia, e.g. D2 recepto
Glutamatergic NMDAR hypofunction could cause decreased Humans taking NMDAR antago
dysfunction activity of mesocortical DA neurones --> negative 3 sets of symptoms
(the symptoms GWAS's have shown decreased
hypogulatamatergi NMDAR hypofunction in cortex could alter cognitive patients, as well as NMDAR ge
c hypothesis) programming, leading to cognitive symptoms. These validate the idea the glu
Decreased NMDAR function on GABAergic Schizophrenia (heavily contest
neurones leads to decreased inhibition of excitatory
input to VTA --> enhanced mesolimbic DA output,
and so positive symptoms.
, and so positive symptoms.
Schizophrenia Therapy
There are two classes: typical and atypical
Type of Drug Example
Typical Chlorpromazine - first major antipsychotic drug
discovered.
Atypical Clozapine D2 receptor antagonism + 5-H
5-HT's role in Schizophrenia ha
but the blockade is still import
reducing side effects
Some are also partial agonists
further 5-HT release too (Gi/o
Further: D-cycloserine can target glycine binding site of NMDARs, and is a partial agonist. This is thought to caus
The fact that glutamatergic antagonists model symptoms of Schizophrenia, strengthens the argument for D-cyc
Clozapine has more rapid dissociation kinetics than Chlorpromazine
So it is hypothesised that rapid dissociation kinetics can enable some DA signalling
This DA surge could still then overcome the blockade
So partial agonists at D2 receptor are being researched and developed
These would reduce DA signalling in mesolimbic pathway (reduce positive symptoms)
And produce some stimulation at the mesocortical pathway (reduce negative symptoms)
We need new drug targets in Schizophrenic therapy
The current drugs aren't efficacious enough in treating symptoms
Definitely not for negative and cognitive too
We should look further into glutamate signalling
And try to target components here, e.g. metabotropic glutamate receptors
Since all current drugs target DA siganlling
And glutamate is upstream of DA, so could be what is causing DA irregularities
Delusions, Hallucinations (auditory), disorganised Too much DA in the mesolimbic s
behaviour + speech (repetitive), catatonia Leading to presence of problemati
Positive
Alogia, affective blunting, asociality, anhedonia, Too little DA in mesocortical pa
avolition Leading to absence of healthy
Negative
Impaired attention & memory, problems in Too little DA in mesocortical pa
prioritising, difficulty in problem solving
Cognitive
Young people more likely to present positive symptoms
Negative and cognitive more difficult to treat
Test for Schizophrenia: the Stroop test (measuring defective selective attention). But slower times could also m
Causes of Schizophrenia
Exact causes remain unclear
Due to variety of ways Schizophrenia presents its symptoms
Also many of these are difficult to track in animal models
Current animal studies: modulating DA/NMDAR functions (not mutually exclusive)
But we do know there are clear genetic and environmental causes, implicated in the disease
Genetic Cause How it leads to Schizophrenia
1st degree relative (Onstad et al, 1991) mentioned schizophrenic and
who is schizotypal personality disorders being significantly
Schizophrenic more frequent in people with relatives
Schizophrenic twin Studies show 41-61% of identical twins both being
Schizophrenic when one is
So clear correlations seen in twin occurence of the
disease
Neuregulin-1 gene Underexpression of this gene is linked to abnormal
synaptic plasticity and development
Dysbindin Abnormalities in this gene lead to abnrmal NMDAR
tethering at post-synaptic densities
DISC-1 Mutations can lead to irregular cytoskeletal
machinery, and neurite outgrowth
, DISC-1
Generally, these genetic implications tell us that Schizophrenia is a neurodevelopmental condition, over neurod
You aren't born Schizophrenic, just predisposed to it potentially
Although there is a neurodegenerative component to it - progressive nature, worsening response to drugs over
This degeneration is possibly linked to glutamatergic signalling malfunctions, and excitotoxicity
We don't know the extent to which these two factors cause Schizophrenia, and how they interact
Aetiology
While the original causes remain up to debate, we know more about the aetiology
Technique Finding
Brain Imaging Thinner sub-cortical GABAergic regions in early This is likely a defect in developm
Studies Schizophrenia It causes hyperactive dopaminerg
Post-mortem brain Misplaced or ectopic clusters of neurones in Abnormal neuronal migration con
studies on Schiz neocortex
patients
There are two areas implicated in Schizophrenia aetiology
Dopaminergic, and Glutamatergic dysfunction (not mutually exclusive)
Dopaminergic is known, whereas glutamatergic has had more debate
Pathway Symptoms
Dopaminergic Overactive dopaminergic activity in mesolimbic Amphetamines (increases DA
dysfunction pathway --> positive symptoms behaviour in humans
Decreased dopaminergic activity in mesocortical In animals, increased DA relea
pathway --> negative/cognitive symptoms behaviour, like the repetitive b
humans
Nigrostriatal and tuberoinfundibular pathways seem Levodopa and DA-receptor ago
unaffected. can be hallucinogenic
DA receptor antagonists can b
symptoms - strong correlation
IC50, and dose of drug require
GWAS's have shown clear imp
Schizophrenia, e.g. D2 recepto
Glutamatergic NMDAR hypofunction could cause decreased Humans taking NMDAR antago
dysfunction activity of mesocortical DA neurones --> negative 3 sets of symptoms
(the symptoms GWAS's have shown decreased
hypogulatamatergi NMDAR hypofunction in cortex could alter cognitive patients, as well as NMDAR ge
c hypothesis) programming, leading to cognitive symptoms. These validate the idea the glu
Decreased NMDAR function on GABAergic Schizophrenia (heavily contest
neurones leads to decreased inhibition of excitatory
input to VTA --> enhanced mesolimbic DA output,
and so positive symptoms.
, and so positive symptoms.
Schizophrenia Therapy
There are two classes: typical and atypical
Type of Drug Example
Typical Chlorpromazine - first major antipsychotic drug
discovered.
Atypical Clozapine D2 receptor antagonism + 5-H
5-HT's role in Schizophrenia ha
but the blockade is still import
reducing side effects
Some are also partial agonists
further 5-HT release too (Gi/o
Further: D-cycloserine can target glycine binding site of NMDARs, and is a partial agonist. This is thought to caus
The fact that glutamatergic antagonists model symptoms of Schizophrenia, strengthens the argument for D-cyc
Clozapine has more rapid dissociation kinetics than Chlorpromazine
So it is hypothesised that rapid dissociation kinetics can enable some DA signalling
This DA surge could still then overcome the blockade
So partial agonists at D2 receptor are being researched and developed
These would reduce DA signalling in mesolimbic pathway (reduce positive symptoms)
And produce some stimulation at the mesocortical pathway (reduce negative symptoms)
We need new drug targets in Schizophrenic therapy
The current drugs aren't efficacious enough in treating symptoms
Definitely not for negative and cognitive too
We should look further into glutamate signalling
And try to target components here, e.g. metabotropic glutamate receptors
Since all current drugs target DA siganlling
And glutamate is upstream of DA, so could be what is causing DA irregularities
