Schizophrenia (finished) Flashcards
What are the 3 types of symptoms in schizophrenia?
1 - Positive
2 - Negative
3 - Cognitive
Give examples of positive SZ symptoms:
- Reality distortion
- Hallucinations (auditory & visual)
- Delusions
- Thought disorder
What are the negative symptoms of SZ?
- Self-neglect
- Social withdrawal
- Dec emotion
- Apathy
- Poverty of speech
Where do the cognitive dysfunction symptoms come from in SZ?
Dementia
Why is SZ so hard to treat?
It is a very heterogenous disorder
So able to treat +ive symptoms but not the -ive symptoms
What is the incidence of SZ?
About 1%
Approx 24 million ppl (1 in 300, 0.32%) worldwide
Adults –> 1 in 222 (0.45%) affected worldwide
When is SZ generally diagnosed/onset?
Typically diagnosed late teens w adolescent onset
Men = 15-25y/o
Women = 25-35y/o
Why is it thought that women are affected later in life w SZ?
Due to protective E2 (estrogen)
Oestrogen may have a protective effect = later onset
What is the neuro cause of the positive symptoms of SZ?
Hyper-activity of MESOLIMBIC DA neurons
What is the neuro cause of the negative symptoms of SZ?
Hypo-activity of MESOCORTICAL DA neurons
How does life expectancy change in SZ patients?
Life expectancy dec by 2 decades
How many recover from SZ?
Only 1 in 7
What are the 6 general causes of SZ?
- Early environmental risk factors important
- Hyper-activity of mesolimbic DA neurons (+ive symps)
- Hypo-activity of mesocortiyal DA neurons (-ive symps)
- Changes in post-synaptic DA D2 & D3 receptors (genetics/drugs)
- Cortical glutamate hypo-function & loss of GABAergic interneurons in striatum (cog effects)
- Dysfunctional development of frontal cortex
(Also a hereditary component)
How strong is the hereditary component of SZ?
Strong but not invariable hereditary component
Identical twin 50% risk
When are brain structure abnormalities present in SZ patients?
& what does this suggest
Present at ONSET of psychosis –> NOT progressive
Suggests DEVELOPMENTAL rather than degenerative
How does the brain structure differ in SZ patients?
- Volume 6-10% reduced (particularly hippocampus) in brain mass
- Enlarged ventricles which translates into reduced temporal lobe
- Identical twins - showed one w SZ has larger ventricles
What is the genetic component to SZ?
- Family high risk (1 parent: 12% risk) & 50% risk in identical twins
- Genome wide study found: 8 rare copy number variants of strong effect (risk inc 4-20fold)
e.g. Deletion syndrome (associated but not disease specific) - 16p11.2 & 22q11.21
What are the 2 hypotheses of the environmental component to SZ?
- Early lesion hypothesis
- Late lesion hypothesis
What is the early lesion hypothesis?
- Foetal or perinatal event (e.g. maternal virus, hypoxia or premature birth interacting w normal development - synapse formation)
- Altered by early life stress: development (e.g. maternal neglect)
(An environmental cause of SZ)
What is the late lesion hypothesis?
Deviation in neuronal maturation during adolescence
Babies born when are more at risk of SZ & why?
Two-fold inc risk SZ for babies born in winter
Possibly due to maternal infection during pregnancy as diseases and viruses are more common in the winter
How does maternal immune activation lead to SZ?
1 - Prenatal infection causes maternal immune activation
2 - This produces lots of cytokines/chemokines
3 - Circulates & crosses placenta –> affects foetal meninges (become leaky) –> can affect BBB & activate fatal brain blood vessels
4 - Temporarily halted fetal brain development
DIVIDES - if genetically susceptible, carries on –> if not then baby recovers
What happens after the maternal immune activation process if foetus has NO genetic susceptibility?
5 - Compensation & recovery
6 - Resume normal fetal brain development
What happens after the maternal immune activation process if foetus has genetic susceptibility?
5 - Immune hyperresponse
6 - Chronic expression & neurochemical changes
7 - Altered developmental trajectory & connectivity
8 - Inc synaptic pruning
9 - Disrupted info processing
10 - Altered behaviour, cognition, emotion
Which gene has the highest correlation for SZ cause in maternal immune activation theory and where is it found?
- The C4 gene –> involved in immune system component- has more than 100 chromosomal sites harbouring genetic risk
- Found SNP most significantly associated schizophrenia lies within the major histocompatibility complex locus on chromosome 6 near the complement component 4 (C4) genes. Encoded C4A expression is higher in brains from schizophrenia patients.
What does the gene C4 do?
C4 promotes activation of complement component 3 (C3)
Experiments in mice brains with C4 knockout showed altered synaptic pruning –> gene therefore responsible for SYNAPTIC CIRCUITRIES
What are the genes other than C4 that are involved in the maternal immune activation theory?
- Neuregulin
- Dysbindin
- D-amino acid oxidase
- Proline dehydrogenase
- Catechol-O-methyltransferase
- Regulator of G protein signalling (RGS-4)
- 5HT2A
- Dopamine D3 receptor (D3)
(Probs don’t need to remember all of these but should have a good idea)
What have mouse studies shown about the maternal immune activation theory?
- U can correlate some of the phenotypes of SZ to the age of embryo & impact of development
- Neurogenesis happens midterm –> this is where +ive symptoms of SZ are induced if impacted (E10 in mice)
- Synpatogenesis happens later in pregnancy –> this is where -vie symptoms of SZ are induced
What are the main inflammatory insults that can cause SZ, from pregnancy to early childhood?
In utero = maternal immune activation and perinatal infection
Birth = perinatal infection & premature birth
Early childhood = Infection, stress, malnutrition, changes in microbiome & caregiver interactions
How can inflammatory insults over time lead to SZ?
Repeated & cumulative hits over time of the inflammatory insults
This leads to inappropriate cytokine cascade
How can cannabis affect the development of SZ?
Compared w non-cannabis users, daily use of high-potency, skunk like cannabis is associated w 5x inc of developing psychosis
Which DA pathways are altered in SZ?
2 - Mesocortical pathways
3 - Mesolimbic (VTA) pathways
Where do the mesocortical & mesolimbic pathways run to and from?
Mesocortical = VTA –> frontal cortex
Mesolimbic = VTA –> Nuc acc
How do the mesocortical & Mesolimbic change in Sz?
Mesocortical = reduced
Mesolimbic = enhanced
What symptoms does the mesocortical pathway induce?
The cognitive deficits (-ve symptoms)
Due to it acting on frontal cortex
What symptoms does the mesolimbic pathway induce?
The positive symptoms
Due to overactivity of the Nuc acc
What is the evidence for dopamine & SZ?
- Amphetamine induces dopamine signalling = produces psychosis (positive-like symptoms) in SZ
- Effects of amphetamine antagonised by anti-SZ drugs called antipsychotics or neuroleptic drugs
What action do antipsychotic drugs have?
They are dopamine (D2) receptor antagonists
they block the action of DA at D2 receptors (dec DA signalling)
Describe a PET scan study that shows dopamine signalling in the brain.
Give raclopride and will bind to D2 receptors = strong signal
Add amphetamines = reduced signal as dopamine released and displaces raclopride
How do amphetamines work to increase dopamine?
Block DAT transporter
Block VMAT
= release of dopamine into synaptic cleft
What happens if patients are given alpha-MPT (drug)
alpha-MPT = inhibits dopamine synthesis = reduces dopaminergic signalling
Compare what happens when controls and patients with Sz are given alpha-MPT and what does this show?
Controls = certain increase in signal as less dopamine
Sz patients = increase in signal is 2 fold higher when dopamine synthesis is blocked as more receptor able to bind to raclopride = stronger signal
= direct evidence suggesting that Sz patients have more D2 receptors
What are the 2 typical drugs that target D2 receptors?
- 𝛼-Flupenthixol
- ꞵ-Flupenthixol
How does 𝛼-Flupenthixol work to treat SZ?
Blocks only D2 receptors
Clinically effective
How does ꞵ-Flupenthixol work?
Not active clinically & not a D2 antagonist
What type of drugs are 𝛼-Flupenthixol & ꞵ-Flupenthixol
Typical antipsychotics –> D2 receptor antagonism essential for antipsychotic effects
Able to antagonise psychosis effects
What is this showing about different antipsychotics?
= many commonely used drugs to antagonise Dopamine receptor signalling in SZ patients
All have different dose required to act as have different affinity to receptors- higher affinity drugs preferred
Optimum depending on patient and side effects experienced
What are the 2 specific drugs used to treat SZ?
- Chlorpromazine
- Clozapine
What are the benefits of chlorpromazine?
- Apathy reduced = more interaction with environment- no social withdrawal
- reduced emotion
- reduced aggression- due to effect on mesolimbic system
What are some problems associated with chlorpromazine?
- neuroendocrine effects- hyper-prolactin
- extrapyramidal effects = parkinson-like symptoms and long-term tardive dyskinesia
- Anti-emetic drugs = as acts in the chemoreceptor trigger zone
- Also interferes with serotonergic receptors = weight gain
Name and define some of the extrapyramidial side effects of blocking D2 receptors
shows timeline- with top symptom short-term and gets progressively more long term
Put these extrapyramidal effects in a timeline and how many days/months do they take to appear?
- Acute dystonia- 1 – 5 days
- Parkinsonism- 5 – 30 days
- Akathisia- 5 – 60 days
- Tardive Dyskinesia- Months – Years
Where are D2 receptors blocked to induce each extrapyrimidial symptom?
- Acute dystonia- basal ganglia
- Parkinsonism- lack of dopamine in striatum
- Akathisia- basal ganglia
- Tardive Dyskinesia- long-tern dopamine excess in striatum
If D2 receptors are blocked by drugs, what happens?
= compensatatory response from neurons which try to counteract the blockage = more dopamine receptors and more dopamine presynaptically = reduces effciency of treatment
= counteracts treatment effects
Name a drug that targets other receptors other than D2 and how is it different to chlorpromazine?
Clozapine = atypical treatment and targets D3 and D4 receptors- only recommended if patient is resistant to other anti-psychotics
What is a benefit and a problem associated with clozapine use?
Low extra-pyramidal side effects as low affinity for D2 but muscarinic and alpha-adrenoceptors antagonist
What type of Sz symptoms is each neurotransmitter related to?
What is the predominant neurotransmitter involved with Sz?
Dopamine
What is the 2nd most important neurotransmitter in Sz?
Glutamate
What is the evidence that glutamate is involved in Sz?
- NMDA receptor antagonists (=glutametergic receptors) induce psychosis and excerbate Sz + cause negative symptoms and cognitive impairments in animal models
- Several gene mutations positively associated with schizophrenia involve glutamate transmission
(e.g. D-amino acid oxidase, mGluR3 and neuregulin = 3 main mutated proteins associated with schizophrenia
Give 2 examples of NMDA receptor antagonists
ketamine
Phencylidine
Describe a direct link to glutamate and dopamine activity
NMDA receptor hypo-function results in decreased glutamate activation of the GABA inhibitory output onto dopamine neurones in the VTA resulting in DA hyperactivity = positive symptom of Sz
Describe some post-mortem evidence that glutamate is linked with Sz
= reduction in D-serine = less NMDA receptor function
= Reduced CSF levels of glutamate in patients
