10. Schizophrenia Flashcards
(42 cards)
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
- anhedonia
- social withdrawal
- flattened emotional response
- poverty of speech
- lack of initiative
- persistence
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
Schizophrenics and 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
Is schizophrenia heritable?
A
Yes
- schizophrenia is heritable (twin & adoption studies)
- having the genes makes one susceptible to developing schizophrenia, depending on environment
- it is a polygenic condition (not caused by a single gene)
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
When does synaptic pruning occur?
What is different in schizophrenia?
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
What are the two types of antipsychotics?
- '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 is a neurotransmitter in NMDA receptors
- NMDA receptor hypofunction causes schizophrenia
## Footnote
opposite of glutamate is GABA (inhibitory neurotransmitter)
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
39
How do typical antipsychotics work?
They block the D2 receptor
(2nd type of DA receptor)
