SCHIZOPHRENIA

What is schizophrenia as defined in ICD-10? (4)

Severe & enduring mental disorder
Distorted thinking & perception
Blunted or inappropriate affects
May include cognitive deficits
What are the three symptom domains in schizophrenia? (3)
Positive
Negative
Cognitive
What are positive symptoms in schizophrenia?
Psychosis
e.g. Delusions, hallucinations, thought disorder (disorganized thoughts/speech)
What are negative symptoms also known as?
Deficit symptoms
What are examples of negative symptoms in schizophrenia? (5)
Blunted emotions
Alogia (lack of speech)
Anhedonia (lack of pleasure)
Asociality (lack of desire for social relationships)
Avolition (lack of motivation)
What is alogia?
Lack of speech
What is anhedonia?
Lack of pleasure
What is asociality?
Lack of desire for social relationships
What is avolition?
Lack of motivation
What are the cognitive impairments experienced in schizophrenia? (2)
Memory impairments
Executive function impairments

What is a delusion? (3)

A fixed false belief

Unshakeable by superior evidence to the contrary

Out of keeping with a persons cultural norms
What are the four kinds of delusions commonly seen in schizophrenia? (3)
Reference (talking about me)
Persecution (out to get me)
Control (they are controlling me)
Bizarre & impossible (birds are talking to me)
What kind of delusions are seen in bipolar disorder (mania)?
Grandiose delusions (I am the strongest, I am the sexiest, I have superpowers)
In what disorder are grandiose delusions commonly seen?
Mania of bipolar disorder
What is a hypochondriacal or somatic delusion?
e.g. Believe heart has turned to wood or that a body limb has died
What is a nihilistic delusion?
I no longer exist (nothing exists, the world is meaningless)
What is a guilt delusion?
Belief that one is guilty of absurd things (I am responsible for all the tragedy in
the world)
What kinds of delusions are commonly seen in psychotic depression? (3)
Hypochondriacal/somatic
Nihilistic
Guilt
What are the four first rank ICD-10 symptoms for schizophrenia?
1) Thought things (echo, insertion, withdrawal, broadcasting)
2) Delusions (of reference, persecution, control)
3) Auditory hallucinations
4) Persistent impossible delusions (bizarre & impossible delusions)
What are the ICD-10 diagnostic criteria for schizophrenia?
At least 1 first-rank symptom (for at least a month)
OR 2 second-rank symptoms (for at least a month)
What are the four second rank ICD-10 symptoms for schizophrenia?
1) Persistent hallucinations (other than auditory)
2) Thought disorder (disorganized speech/thoughts)
3) Catatonic behavior (motor problem, posturing, waxy flexibility)
4) Negative symptoms

Where is the A9 group of cells?

In the substantia nigra pars compacta
What are the four dopaminergic pathways in the brain?
Nigrostriatal
Mesolimbic
Mesocortical
Tuberoinfundibular
What are the end points of the nigrostriatal pathway?
Substantia nigra (pc; A9 group of cells) -> Striatum (caudate & putamen)
Degradation of dopaminergic neurones in the nigrostriatal pathway is involved
in what disease?
Parkinsons disease
What are the 3 functional subdivisions of the striatum?
Sensorimotor (dorsal)
Associative
Limbic (ventral)
[Insert picture]
Which subdivisions of the striatum are involved in which dopaminergic
pathways? (2)
Sensorimotor & Associative = nigrostriatal pathway
Limbic = mesolimbic pathway
Which functional subdivisions of the striatum are affected in Parkinsons
disease? Which is responsible for which symptoms?
Sensorimotor/dorsal & Associative
Sensorimotor (dorsal) = motor control
Associative = learning, memory, attention, volition, emotion, motivation
What are the end points of the mesolimbic pathway?
Midbrain (ventral tegmental area A10 group of cells) -> Limbic regions
Specifically = nucleus accumbens, amygdala, hippocampus, medial
prefrontal cortex
Where is the A10 group of cells?
In the ventral tegmental area of the midbrain
About the nucleus accumbens:
a) Where is it?
b) What does it form?

c) What is it involved in?

d) How many of them are there?
a) In the basal ganglia, between caudate & putamen, below the preoptic area of
the hypothalamus
b) Involves reward, motivation, affect & memory
c) Forms the ventral striatum with the olfactory tubercle
d) One in each hemisphere
[Insert picture]
Where is the amygdala?
Within the temporal lobe
[Insert picture]
Where is the hippocampus?
Under the frontal cortex
[insert picture]
What are the end points of the mesocortical pathway?
Midbrain (ventral tegmental area; A10 group of cells) -> Frontal cortex
(dorsolateral prefrontal cortex)
What is DLPFC?
Dorsolateral pre-frontal cortex
What is VTA?
Ventral tegmental area
What is SNc?
Substantia nigra pars compacta
What are the end points of the tuberoinfundibular pathway?
Tuberal region (arcuate nuclei of the hypothalamus) -> infundibular region
(median eminence of the hypothalamus)
What is the function of the tuberoinfundibular pathway?
Dopamine inhibits prolactin release from the pituitary
The arcuate nuclei of the hypothalamus are in which region?
The tuberal region
The median eminence of the hypothalamus is in which region?
The infundibular region
About dopamine receptors:
a) What are the two main receptor families?

b) What are the 5 subdivisions (grand children)?

a) D1 & D2 receptor families
b) D1 family = D1 + D5
D2 family = D2 (long & short) + D3 + D4
What are D2 long & short receptors?
D2 long = postsynaptic
D2 short = presynaptic autoreceptor
What is the region specificity of dopamine receptors?
D1 & D2 = all 3 parts of the striatum (sensorimotor, associative & limbic)
D5 = hippocampus & hypothalamus
D3 = mainly limbic (limbic striatum, hippocampus & amygdala)
D4 = frontal cortex
What kind of dopamine receptors are found in the frontal cortex?
D4
D3 dopamine receptors are only found where?
In the limbic system
What are autoreceptors?
A site on a neurone that binds neurotransmitter released by that neurone
Regulates the neurones activity when activated
What is the function of D2(short) autoreceptors?
Regulate dopamine synthesis, metabolism & release
What is the function of D3 autoreceptors?
Regulates dopamine release
Which dopamine receptors are autoreceptors?
D2(short) & D3
What are the dopaminergic abnormalities in schizophrenia?
XS (hyperdopaminergic) in striatum
LR (hypodopaminergic) in frontal cortex
How are the dopamine abnormalities in schizophrenia related to the pathways &
symptoms?
XS dopamine in striatum = XS nigrostriatal pathway = positive symptoms
LR dopamine in frontal cortex = LR mesocortical pathway = cognitive deficits
Are dopaminergic abnormalities the primary cause of schizophrenia?
No, they are knock-on effects

Hypothesis = GABA or gluatamate is the primary abnormality

Antipsychotic drugs principally target which receptors? How is this correlated with
treatment response & symptoms?
Antipsychotics = D2 receptors antagonist = striatum = nigrostriatal pathway =
positive symptoms = correlated with good treatment response
Lots of XS dopamine in the striatum is a sign of good treatment response
Where in the striatum is there XS dopamine in schizophrenia? (textbooks VS
2010 papers)
Textbooks say = mesolimbic pathway = limbic striatum
Papers say = nigrostriatal pathway = associative striatum
What dopamine abnormality is associated with negative symptoms?
Decreased dopamine in the limbic pathway (limbic striatum = ventral striatum)
What is the glutamate abnormality in schizophrenia (hypothesis)?
NMDA receptor hypofunction
Causes excessive glutamate release
XS glutamate impairs neuronal development & causes dopamine dysregulation
What would be the ideal schizophrenic antipsychotic?
Reduce associative striatum dopamine release
Without affecting mesocortical, sensorimotor striatum or limbic striatum
What is the threshold of D2 receptor occupancy to achieve an antipsychotic
effect?
>65% D2 receptor occupancy (not necessarily over 24 hours)
Antipsychotics work by blocking D2 receptors where?
In the striatum (and nowhere else)
What are the thresholds of D2 receptor occupancy for efficacy & common sideeffects to antipsychotics?
65% = efficacy
72% = hyperprolactinaemia
75% = extrapyramidal side effects (EPS)
What is the relationship between Ki & affinity?
Small Ki = high affinity
Why do different antipsychotics have different side-effects?
They have different receptor affinities

Receptor affinity is proportional to distinct side-effects