10. Schizophrenia Flashcards
1
Q
Definition
A
A disorder causing a ‘break from reality’
2
Q
When do symptoms appear?
A
in adulthood, gradually, over 3-5 years
3
Q
Positive symptoms
(Positive = Presence of abnormal behaviour)
A
- Thought disorders
- Delusions
- Hallucinations
4
Q
Thought disorders include…
A
- disorganised, irrational thinking (most important symptom)
- difficulty arranging thoughts logically
- difficulty sorting out logical thoughts from illogical
- jumping frequently from topic to topic
- saying meaningless words / words chosen because they rhyme
5
Q
What types of delusions are there?
A
- grandeur (being a god, special powers)
- persecution (conspiracies everywhere)
- control (Truman show)
6
Q
What hallucinations are experienced?
A
- sensory
- auditory are most common and can contribute to delusions of persecution (people trying to kill you)
7
Q
Negative symptoms
(Negative = Loss of normal behaviour)
A
- flattened emotional response
- poverty of speech
- lack of initiative
- persistence
- anhedonia
- social withdrawal
8
Q
Cognitive symptoms:
Deficits in…
A
- attention
- learning/memory
- planning
- information processing
- problem solving
- abstract thinking
- psychmotor speed (takes longer to will limbs to move)
9
Q
Cognitive Symptoms:
Poor performance on the following tests
A
- IQ tests
- Stroop test (attention deficit)
- Anti-saccade task
- Wisconsin Card Sorting Test (working memory deficits)
- P50 and PPI tasks (sensory-motor gating deficits)
- Oculomotor function (eye tracking deficit)
10
Q
What causes the cognitive symptoms?
A
Frontal lobe hypofunction (underactivity)
11
Q
What causes negative symptoms?
A
Hypofrontality (decreased activity in frontal lobes) (Weinberger, 1988)
12
Q
Why do schizophrenics have Sensory-Motor Gating Deficits?
A
- Sensory-motor gating deficits are difficulties screening out irrelevant stimuli and focusing on salient ones
- P50 is a test where a stimulus is given and an action potential should fire 50 ms after
- Participants are presented with 2 auditory stimuli (2 clicks) 500ms apart
- Healthy response is Pre-Pulse Inhibition (PPI) so the P50 wave to 2nd click is 80% diminished (person inhibits startle response)
- Schizophrenic patients react to both P50s (they do not inhibit the startle response)
(Freedman et al 1987)
13
Q
What is different about schizophrenic oculomotor function?
A
- Non-schizophrenics show smooth pursuit when tracking a moving stimulus
- Schizophrenics have more jerky eye movements (“catchup” saccades)
14
Q
Structural differences between healthy and schizophrenic brains
A
CT scans showed schizophrenic subjects had:
- > 2x bigger relative ventricle size than control subjects
- reduced brain volume (less grey matter) in temporal, frontal lobes and hippocampus
- faulty cellular arrangement in the cortex and hippocampus
(Weinberger and Wyatt., 1982)
15
Q
What is the heritability of schizophrenia?
A
- schizophrenia is heritable (twin & adoption studies)
- it is a polygenic condition (not caused by a single gene)
- having the genes makes one susceptible to developing schizophrenia, depending on environment
16
Q
Heritability:
What is DISC1?
A
- a gene originally believed to increase likelihood of schizophrenia by 50x
- meta-analysis by Mathieson, Munafo & Flint (2011) showed it isn’t linked to schizophrenia
- it does increase the chances of BD and ASD (Kim et al., 2009)
- it is involved in regulation of neurogenesis, neuronal migration, postsynaptic density (excitatory neurons) and mitochondria function
17
Q
Heritability:
Paternal age
A
- the child of an older father is more likely to develop schizophrenia (Brown et al., 2002; Sipos et al., 2004)
- probably due to mutations in spermatocytes (spermatocytes divide consistently throughout life and are likely to mutate)
18
Q
Monochorionic vs Dichorionic
A
Monochorionic twins - Monozygotic twins that share a placenta
Dichorionic twins - Monozygotic twins with seperate placentas (therefore not the exact same uterine environment)
All dizygotic twins have seperate placentas as they develop seperately
19
Q
What is the concordance rate of monochorionic twins vs dichorionic?
A
- Monochorionic - 60%
- Dichorionic - 32%
(Davis and Phelps, 1995)
20
Q
Theories of schizophrenia:
The ‘early’ neurodevelopmental model
A
- events occur early in life causing deviations from normal development
- events such as infections, obstetric complications, nutritional deficiences
- these changes are ‘dormant’ until the brain is mature
- in adulthood they cause schizophrenia
- evidence: home movies (Walker et al 1994,1996) where the children that became schizophrenic had more negative affect and abnormal movements
21
Q
Theories of schizophrenia:
The ‘late’ neurodevelopmental model
A
Schizophrenia is caused by abnormality in development (excessie synaptic pruning) during adolescence (Feinberg, 1982)
22
Q
Theories of schizophrenia:
The ‘two-hit’ neurodevelopmental model
A
- Both early and late models are correct
- Early abnormalities in neurodevelopment cause later abnormalities in the form of excessive synaptic pruning
(Fatemi & Folsom, 2009; Keshavan and Hogarty, 1999)
23
Q
How does synaptic pruning affect development?
A
- synaptic pruning occurs after birth
- it is excessive in schizophrenics
(Thompson et al 2001)
24
Q
What environmenal causes influence schizophrenia development after birth?
A
- obstetric complications
- infection (prenatal)
- nutritional deficiency
25
What environmenal causes influence schizophrenia development in adolescence?
- adverse life events (trauma)
- substance abuse (esp. cannabis - 6x risk)
26
Neurochemistry of Schizophrenia:
the Dopamine (DA) Hypothesis
- Schizophrenia caused by abnormal DA function
- Overactivity of DA in mesolimbic system causes positive symptoms
- Underactivity of DA in mesocortical system causes negative and cognitive symptoms
27
Evidence for the Dopamine Hypothesis
- Dopamine agonists (increase dopamine) can cause positive schizophrenic symptoms (psychosis)
- Drugs: amphetamine, cocaine, methylphenidate and L-DOPA
- Symptoms produced can be blocked by antipsychotic drugs (∴ antipsychotics block DA receptors)
27
Evidence for the Dopamine Hypothesis
- Dopamine agonists (increase DA levels) cause positive schizophrenic symptoms
- Drugs: amphetamine, cocaine, methylphenidate, L-DOPA
- They can be relieved by antipsychotics (∴ antipsychotics work through blocking DA receptors)
28
First ever antipsychotic
chlorpromazine (CPZ)
DA antagonist
28
The first antipsychotic
Chlorpromazine (CPZ)
(a DA antagonist)
29
Antipsychotics today
Two types:
- 'typical antipsychotics' - block the D2 receptor (type 2 of the DA receptor)
- 'atypical antipsychotics'
29
What do typical antipsychotics do?
- antipsychotics reduce positive symptoms in 70-80% of patients
- long-term treatment leads to Parkinson's-like symtpoms: slowness in movement, lack of facial expression, and general weakness
- ~1/3 of patients develop tardive dyskinesia (cannot stop moving)
30
What do atypical antipsychotics do?
* Atypical antipsychotics work in treatment-resistant patients
* Atypicals do not have the Parkinsonian side-effects due to the fact that they have lower affinity for the D2 receptors
* Improve both positive and negative symptoms of schizophrenia
* Also improve the performance in neuropsychological tests which is not the case with typical antipsychotics
31
Atypical antipsychotic drugs include:
- Clozapine (lower affinity for D2 and higher affinity for other DA receptors (D3, D4 and even 5HT))
- It's the only one to reduce suicide rates
- Side effects: weight gain, sedation, hypersalivation, tachycardia (increased heart rate), hypotension (low blood pressure), neutropenia etc.
32
Neurochemistry of Schizophrenia:
the Glutamate Hypothesis
- glutamate (excitatory neurotransmitter)
- opposite of glutamate is GABA (inhibitory neurotransmitter)
- NMDA receptors are implicated in schizophrenia
33
How are NMDA receptors relevant to schizophrenia?
They are involved in developmental processes:
- development of neural pathways
- neural migration, survival, plasticity, pruning of cortical connections and apoptosis
34
Neurochemistry of Schizophrenia:
Glutamate Hypo-functioning Hypothesis
| (Olney and Farber, 1995)
Schizophrenia is due to NMDA receptor hypofunction which may explain:
- Why there are so many treatment-resistant negative symptoms
- Why the onset is in early adulthood
- Why the disorder is associated with structural changes and cognitive deficits
- the drugs Phencyclidine (PCP) and ketamine are NMDA receptor antagonists and cause positive, negative, and cognitive symptoms of schizophrenia
- glutamate agonists seem to improve both positive and negative symptoms of schizophrenia
- evidence in support from animal genetic studies with NMDA receptor subunits as well as GWAS
35
PFC
- the negative and cognitive symptoms produced by ketamine and PCP are caused by a decrease in the metabolic activity of the frontal lobes.
- evidence: Jentsch et al. (1997) gave PCP to monkeys and it damaged their PFC, causing deficits (in line with schizophrenia)
36
Neuroinflammatory hypothesis of schizophrenia:
Microglial activation and schizophrenia
- brain's immune cells are hyperactive in people at risk of developing schizophrenia
- animals studies show a link between pro-inflammatory agents and schizophrenia symptoms
- symptoms are reversed upon treatment with antipsychotics or antibiotics that reduce microglial activation
- supports evidence for prenatal infection increasing risk for schizophrenia
37
Microglial activation and schizophrenia in animal studies
- microglial activation is not instantaneous in response to infectious agents
- it grows steadily throughout the lifespan, reaching a peak in late adolescence / early adulthood
- a pre- or perinatal infection primes microglia and this priming may interact with cells in the developing nervous system
- can lead to rearrangement of synaptic circuitry resulting in behavioral impairment in adolescence
38
Oestrogen Hypothesis of Schizophrenia
oestrogen seems to play a protective role against the development of schizophrenia (buffer)
women:
- less severe course & symptoms
- later onset = better prognosis
- better response to antipsychotics
- fewer hospitalisations
