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Disease in the brain > Schizophrenia (finished) > Flashcards

Schizophrenia (finished) Flashcards

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1
Q

What are the 3 types of symptoms in schizophrenia?

A

1 - Positive

2 - Negative

3 - Cognitive

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2
Q

Give examples of positive SZ symptoms:

A
  • Reality distortion
  • Hallucinations (auditory & visual)
  • Delusions
  • Thought disorder
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3
Q

What are the negative symptoms of SZ?

A
  • Self-neglect
  • Social withdrawal
  • Dec emotion
  • Apathy
  • Poverty of speech
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4
Q

Where do the cognitive dysfunction symptoms come from in SZ?

A

Dementia

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5
Q

Why is SZ so hard to treat?

A

It is a very heterogenous disorder

So able to treat +ive symptoms but not the -ive symptoms

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6
Q

What is the incidence of SZ?

A

About 1%

Approx 24 million ppl (1 in 300, 0.32%) worldwide

Adults –> 1 in 222 (0.45%) affected worldwide

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7
Q

When is SZ generally diagnosed/onset?

A

Typically diagnosed late teens w adolescent onset

Men = 15-25y/o
Women = 25-35y/o

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8
Q

Why is it thought that women are affected later in life w SZ?

A

Due to protective E2 (estrogen)

Oestrogen may have a protective effect = later onset

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9
Q

What is the neuro cause of the positive symptoms of SZ?

A

Hyper-activity of MESOLIMBIC DA neurons

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10
Q

What is the neuro cause of the negative symptoms of SZ?

A

Hypo-activity of MESOCORTICAL DA neurons

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11
Q

How does life expectancy change in SZ patients?

A

Life expectancy dec by 2 decades

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12
Q

How many recover from SZ?

A

Only 1 in 7

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13
Q

What are the 6 general causes of SZ?

A
  • 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)

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14
Q

How strong is the hereditary component of SZ?

A

Strong but not invariable hereditary component

Identical twin 50% risk

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15
Q

When are brain structure abnormalities present in SZ patients?

& what does this suggest

A

Present at ONSET of psychosis –> NOT progressive

Suggests DEVELOPMENTAL rather than degenerative

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16
Q

How does the brain structure differ in SZ patients?

A
  • 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
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17
Q

What is the genetic component to SZ?

A
  • 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
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18
Q

What are the 2 hypotheses of the environmental component to SZ?

A
  • Early lesion hypothesis
  • Late lesion hypothesis
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19
Q

What is the early lesion hypothesis?

A
  • 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)

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20
Q

What is the late lesion hypothesis?

A

Deviation in neuronal maturation during adolescence

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21
Q

Babies born when are more at risk of SZ & why?

A

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

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22
Q

How does maternal immune activation lead to SZ?

A

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

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23
Q

What happens after the maternal immune activation process if foetus has NO genetic susceptibility?

A

5 - Compensation & recovery

6 - Resume normal fetal brain development

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24
Q

What happens after the maternal immune activation process if foetus has genetic susceptibility?

A

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

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25
Q

Which gene has the highest correlation for SZ cause in maternal immune activation theory and where is it found?

A
  • 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.
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26
Q

What does the gene C4 do?

A

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

27
Q

What are the genes other than C4 that are involved in the maternal immune activation theory?

A
  • 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)

28
Q

What have mouse studies shown about the maternal immune activation theory?

A
  • 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
29
Q

What are the main inflammatory insults that can cause SZ, from pregnancy to early childhood?

A

In utero = maternal immune activation and perinatal infection

Birth = perinatal infection & premature birth

Early childhood = Infection, stress, malnutrition, changes in microbiome & caregiver interactions

30
Q

How can inflammatory insults over time lead to SZ?

A

Repeated & cumulative hits over time of the inflammatory insults

This leads to inappropriate cytokine cascade

31
Q

How can cannabis affect the development of SZ?

A

Compared w non-cannabis users, daily use of high-potency, skunk like cannabis is associated w 5x inc of developing psychosis

32
Q

Which DA pathways are altered in SZ?

A

2 - Mesocortical pathways

3 - Mesolimbic (VTA) pathways

33
Q

Where do the mesocortical & mesolimbic pathways run to and from?

A

Mesocortical = VTA –> frontal cortex

Mesolimbic = VTA –> Nuc acc

34
Q

How do the mesocortical & Mesolimbic change in Sz?

A

Mesocortical = reduced

Mesolimbic = enhanced

35
Q

What symptoms does the mesocortical pathway induce?

A

The cognitive deficits (-ve symptoms)

Due to it acting on frontal cortex

36
Q

What symptoms does the mesolimbic pathway induce?

A

The positive symptoms

Due to overactivity of the Nuc acc

37
Q

What is the evidence for dopamine & SZ?

A
  • Amphetamine induces dopamine signalling = produces psychosis (positive-like symptoms) in SZ
  • Effects of amphetamine antagonised by anti-SZ drugs called antipsychotics or neuroleptic drugs
38
Q

What action do antipsychotic drugs have?

A

They are dopamine (D2) receptor antagonists

they block the action of DA at D2 receptors (dec DA signalling)

39
Q

Describe a PET scan study that shows dopamine signalling in the brain.

A

Give raclopride and will bind to D2 receptors = strong signal
Add amphetamines = reduced signal as dopamine released and displaces raclopride

40
Q

How do amphetamines work to increase dopamine?

A

Block DAT transporter
Block VMAT
= release of dopamine into synaptic cleft

41
Q

What happens if patients are given alpha-MPT (drug)

A

alpha-MPT = inhibits dopamine synthesis = reduces dopaminergic signalling

42
Q

Compare what happens when controls and patients with Sz are given alpha-MPT and what does this show?

A

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

43
Q

What are the 2 typical drugs that target D2 receptors?

A
  • 𝛼-Flupenthixol
  • ꞵ-Flupenthixol
44
Q

How does 𝛼-Flupenthixol work to treat SZ?

A

Blocks only D2 receptors

Clinically effective

45
Q

How does ꞵ-Flupenthixol work?

A

Not active clinically & not a D2 antagonist

46
Q

What type of drugs are 𝛼-Flupenthixol & ꞵ-Flupenthixol

A

Typical antipsychotics –> D2 receptor antagonism essential for antipsychotic effects

Able to antagonise psychosis effects

47
Q

What is this showing about different antipsychotics?

A

= 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

48
Q

What are the 2 specific drugs used to treat SZ?

A
  • Chlorpromazine
  • Clozapine
49
Q

What are the benefits of chlorpromazine?

A
  • Apathy reduced = more interaction with environment- no social withdrawal
  • reduced emotion
  • reduced aggression- due to effect on mesolimbic system
50
Q

What are some problems associated with chlorpromazine?

A
  • 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
51
Q

Name and define some of the extrapyramidial side effects of blocking D2 receptors

A

shows timeline- with top symptom short-term and gets progressively more long term

52
Q

Put these extrapyramidal effects in a timeline and how many days/months do they take to appear?

A
  1. Acute dystonia- 1 – 5 days
  2. Parkinsonism- 5 – 30 days
  3. Akathisia- 5 – 60 days
  4. Tardive Dyskinesia- Months – Years
53
Q

Where are D2 receptors blocked to induce each extrapyrimidial symptom?

A
  1. Acute dystonia- basal ganglia
  2. Parkinsonism- lack of dopamine in striatum
  3. Akathisia- basal ganglia
  4. Tardive Dyskinesia- long-tern dopamine excess in striatum
54
Q

If D2 receptors are blocked by drugs, what happens?

A

= compensatatory response from neurons which try to counteract the blockage = more dopamine receptors and more dopamine presynaptically = reduces effciency of treatment

= counteracts treatment effects

55
Q

Name a drug that targets other receptors other than D2 and how is it different to chlorpromazine?

A

Clozapine = atypical treatment and targets D3 and D4 receptors- only recommended if patient is resistant to other anti-psychotics

56
Q

What is a benefit and a problem associated with clozapine use?

A

Low extra-pyramidal side effects as low affinity for D2 but muscarinic and alpha-adrenoceptors antagonist

57
Q

What type of Sz symptoms is each neurotransmitter related to?

A
58
Q

What is the predominant neurotransmitter involved with Sz?

A

Dopamine

59
Q

What is the 2nd most important neurotransmitter in Sz?

A

Glutamate

60
Q

What is the evidence that glutamate is involved in Sz?

A
  • 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
61
Q

Give 2 examples of NMDA receptor antagonists

A

ketamine
Phencylidine

62
Q

Describe a direct link to glutamate and dopamine activity

A

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

62
Q

Describe some post-mortem evidence that glutamate is linked with Sz

A

= reduction in D-serine = less NMDA receptor function
= Reduced CSF levels of glutamate in patients

Disease in the brain (22 decks)

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