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

  • 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