Schizophrenia
NMDA receptors & Schizophrenia
PCP & MK801 block NMDA receptors (NMDA antagonist)
both produce hallucinations
certain antipsychotics enhance current flow (flux) through NMDA receptors
Huntington's Chorea
genetic disorder
excessive movements
hemibalism
stroke
excessive movements
treated with antipsychotics - dopamine reuptake inhibit/block dopamine transmission
excess of dopamine - positive symptoms
Parkinsons
progressive disorder
slow movement
treated wth L.DOPA
dopamine precursor
not enough dopamine
Schizophrenia
Symptomatology
affects 1% population
been around a long time (1,000s years)
Costs nations more than cancer
symptoms universal across culture
appeasrs gradually over 3-5 years
negative symptoms first
cognitive symptoms later
positive symptoms years later
Positive symptoms
presence/excess
Thought disorder
disorganised, irrational thinking
difficulty arranging thoughts logically
difficulty between plausible and absurd conclusions
jump between associations in conversation
meaningless words chosen for rhyme, rather than meaning
delusions
persecution - plots or conspiracies against self
grandeur - power or importance (special powers, godlike, special knowledge)
control - being controlled, tiny radio in brain
Hallucinations
most common auditory - voices (typically negative)
olfactory - can contribute to persecutary delusions
Negative symptoms
absence or diminuation
- flattened affect
- poverty of speech
- lack of initiative and persistence
- anhedonia
- social withdrawal
cognitive symptoms
- difficulty sustaining attention
- low psychomotor speed
- learning and memory issues
- poor abstract thinking
- poor problem solving
Heritibility & genetics
adpotion and twin studies indicate sizable heritability
not a single gene disorder
having 'schizophrenia gene' increases susceptibility from trauma/stress/environment
Rare mutation of DISC1 gene
regulation of neurogenesis
neuronal migration
postsynaptic density in excitatory neurons
mitochondria function
increase chances of schizophrenia by 50
increases insicence of MDD, autism, bipolar
Paternal age
older fathers more likely to produce schizophrenic children
mutations in spermatocytes
concordance in monochorionic (same placenta) MZ twins higher
60% monochorionic, 11% dichorionic MZ
Neuropathology
Neurodevelopmental theories
Early neurodevelopment model
fixed lesions in early life
lie dormant until age where
damaged areas are used
evidence
(Walker, 1994, 1996)
home movies of schizophrenics as children analysed
more negative affect and abnormal movements
(Schiffman 2004)
blind rated Danish children videos
less sociability & deficient psychomotor function
evidence
minor physical abnormalities (wide or narrow set eyes)
people with schizopherenic relatives ~12%
also with abnormalities ~31%
- head
- two or more hair whorls
- head circumference
- eyes
- skin fold at inner corner of eye
- wide (or narrow) set eyes
- ears
- low-seated
- asymmetrical
- mouth
- high-steeped palate
- furrowed tongue
- hands
- curved 5th finger
- single transverse crease in palm
- feet
- 3rd toe longer than 2nd toe
- partial webbing of two middle toes
late neurodevelopment model
abnormalities in synaptic pruning during adolescence
two-hit model
early developmental insults to specific networks
excessive pruning during adolescence & loss of plasticity
Early
obstetric complications
prenatal infection
nutritional difficency
late
substance abuse
(cannabis 6x risk)
adverse life effects
Structural changes
ventricular englargement
- associated with loss of neurons
- associated with loss of neurons
reduced grey matter in:
- temporal lobes
- frontal lobes
- hippocampus
Faulty cellular arrangement (asymmetry) in:
- cortex
- hippocampus
Weinberger (1982)
80 schiz 66 healthy
lateral ventricles 2x size
Neurocognitive deficits
- all associated with frontal lobe
- lower IQ
- attention deficits
- planning and information processing
- working memory deficits
- sensory motor gating
- antisaccade task
- oculolotor function
hypofrontality
decreased activity
dlPFC esp.
attention to everything
P50 second click not habituated
PPI small pulse doesn't prepare for second
Neurochemistry
Dopamine hypothesis
caused by abnormality in DA system
overactivity in mesolimbic - positive (VTA to NAc)
underactivity in mesocortical - negative (VTA to pFC)
Evidence
Dopamine agonists psychotomimetic
L-DOPA, cocaine, amphetamine
antipsychotics ameliorate effects
CPZ DA antagonist
since CPZ typical antipsychotics
work on positive symptoms (although ~20-30% don't respond)
Block D2 receptors
dose required and D2 receptor affinity closely matched
more evidence
PET experiment
IBZM reversible antagonist - competes with DA for binding site
displacement after amphetamine measured
more DA actiity (IBZM displacement) in striatum associated with positive symptoms
issues
only covers positive not negative symptoms
atypical (low D2 affinity) drugs work better
negative symptoms associated with underactivity in mesocortical DA pathway
obverse of DA overactivity
long term drug treatment
antipsychotics cause parkinson's type symptoms:
- slowness movement
- lack of facial expression
- general weakness
~1/3 patients tardive dyskinesia
unable to stop moving
atypical antipsychotics
Clozapine
first
low affinity for D2 (higher for D3, D4 and 5HT)
only drug which reduces suicide rate
not widely used
lots of side effects:
weight gain, sedation, hypersalivation, tachycardia, hypotension, neutropenia
Glutamate hypothesis
~50% of neurons use glutamate as neurotx
in mammals balanced with GABA
both neurotx influence almost every area and chemical in brain
evidence that NMDA receptor implicated in schiz
NMDA receptor (4 subunits)
ionotropic
mutations in subunits
evidence that mice(!) display schizopherenic symptoms with NMDA receptor subtypes selectively knocked out
Hypothesis
NMDA receptor hypofunction
- why neg symptoms are treatment resistant
- onset in early adulthood
- why disorder has structural changes and cognitive deficits
Evidence
NMDA receptor antagonists (PCP, Ketamine)
cause positive, negative & cognitive symptom similarities
glutamate agonists improve both +ve and -ve symptoms
positive symptoms
in healthy brain, glutamate projected from PFC into VTA
if not function, VTA doesn't get inhibitory singals from PFC
negative symptoms
in healthy brain, glutamtate from PFC to VTA
overstimulate GABA interneuron
from VTA DA projection to dlPFC and dmPFC
disrupted in schiz
less dopamine
Recent developments
Neuroinflamatory hypothesis
brain's immune (microglia) hyperactive in schizo risks
animal study support for pro-inflamatory agents and schiz symptoms
reversed with antipsychotics or antibiotics which reduce microglial activation
not just involved in pathogen control
neuronal death & survival
synaptogenesis
synaptic pruning
microglia action is slow (?)
peaking at adolescence
Estrogen hypothesis
more schiz in men than women
later onset in women than men
women respond better to treatment
2nd peak of schiz in women 40-50yrold (menopause)
estrogen may be protective