Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Semester 3 > Case 8 - neurobiology of schizophrenia > Flashcards

Case 8 - neurobiology of schizophrenia Flashcards

1
Q

what does the ICD 10 define schizophrenia as

A

a severe and enduring mental disorder, with fundamental and characteristic distortions of thinking and perception, and affects that are inappropriate or blunted. clear consciousness and intellectual capacity are usually maintained although cognitive deficits may evolve in the course of time

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what are the positive symptoms

A

delusions
hallucinations
thought disorder

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what are the negative symptoms

A

flat or blunted affect and emotion
poverty of speech
inability to experience pleasure
lack of desire to form relationships
lack of motivation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what are delusions

A

a fixed false belief, unshakeable by superior evidence to the contrary and out of keeping with a persons cultural norms

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

examples of delusions

A

Examples:
reference
Persecution
Control
Bizarre and impossible
Grandiosity (mania in bipolar disorder)
Hypochondriacal or somatic (various, often depression)
Nihilistic (usually psychotic depression)
Guilt (usually psychotic depression)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what is hallucination

A

a perception, internally generated in the absence of external stimulus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

in any sense modality examples

A

In any sensory modality:
hearing (auditory)
Vision (visual)
Taste (gustatory)
Smell (olfactory)
Somatosensory (tactile)
Kinaesthetic (body position), temperature, pressure

In schizophrenia, hallucinations are characteristically auditory

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

ICD 10 diagnostic criteria

A

At least 1 first-rank symptoms (for at least 1 month):
Thought echo, thought insertion or withdrawal, or thought broadcasting
Delusions of control, influence or passivity, clearly referred to body or limb movements or specific thoughts, actions or sensations
Auditory hallucinations giving a running commentary or discussing the patient between themselves, hallucinatory voice from parts of the body
Persistent delusions that are completely impossible

OR at least 2 second-rank symptoms (at least 1 month):
Other persistent hallucinations in any modality
Thought disorder (neologisms, loosening or breaks in the train of thought resulting in incoherent or irrelevant speech)
Catatonic behaviour (posturing, waxy flexibility, mutism, stupor, catatonic excitement)
Negative symptoms, not due to depression or medications

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

classification of DA receptors

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what are the four dopamine pathways

A

nigrostrital pathway
mesolimbic pathway
mesocortical pathway
tuberoinfundibulnar pathway

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what is the nigrostrital pathway

A

substantia nigra (A9) —> caudate and putamen

1. SNc —> sensorimotor (dorsal) striatum 
- motor (involuntary) control. PD 

2. SNc —> associative (mild) striatum 
- cognition, emotion, volition. PD
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what is the mesolimbic pathway

A

ventral tegmental (A10) area in midbrain to limbic regions associated with reward, motivation, affect and memory
Include ventral striatum (nucleus accumbens) amygdala, hippocampus and medial prefrontal cortex

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what is the mesocortical pathway

A

VTA to frontal cortex, including dorsolateral prefrontal cortex (DLPFC)
Cognitive function, motivation and emotional response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what is the tuberoinfundibulnar pathway

A

puberal region to median eminence
DA acts to inhibit prolactin release from pituitary

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what are the 3 functional divisions of the striatum

A

sensorimotor
Associative: learning, habituation, memory, attention, motivation, emotion and volition. Strong input from DLPFC
Limbic: ventral striatum: reward

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what are the DA abnormalities in schizophrenia

A

Excessive DA release in striatum during acute psychotic episodes
- positively correlated with positive symptoms
- correlated with good treatment response to antipsychotic drugs

Inadequate DA in frontal cortex
- associated with deficits in cognitive function e.g working memory

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

is DA dysregulation thought to be a primary abnormality

A

DA dysregulation is not thought to be a primary abnormality. Secondary to a more proximal abnormality, probably in GABA-glutamate interaction.

18
Q

where is the excessive dopamine release in the striatum

A

increased synaptic DA concentration is associative striatum in untreated schizophrenic patients
VST DA unaffected overall. But associated with severity of negative symptoms in patients with decreased VST DA
Low dopamine in the mesolimbic pathway may contribute to negative symptoms

19
Q

when does increased DA develop

A

DA function elevated on average in people at high risk of developing schizophrenia, though none has yet done so
This elevation approached that seen I patients with established schizophrenia

18F-DOPA uptake is correlated positively with severity of symptoms and negatively with cognitive function

20
Q

DA abnormalities in ARMS II (case group study)

A

DA function elevated at baseline in the ARMS subjects who developed schizophrenia
Elevated DA function in associative, not limbic or sensorimotor subdivision
DA function NOT elevated at baseline in non-transition group

within the psychotic transition group: significant positive relationship between DA function and CAARMS and PANSS
No relationship in the non-transition group

21
Q

pooled data from the 2 studies

A

associative dopamine raised substantially
Sensorimotor dopamine raised slightly
Ventral/limbic dopamine is normal

The associative and sensorimotor are both the nigrostriatal pathway

22
Q

what was the result found:

A

DA synthesis is increased in the nigrostriatal pathway and NOT the mesolimbic pathway as predicted for decades

23
Q

what are the challenges of the current concept of schizphernia

A

biomarker for conversion to schizophrenia: PET expensive and 18f-DOPA uptake is unlikely to provide enough specificity and selectivity to play a significant role in treatment decision in UHR patients
How to selectively reduce firing of the nigrostriatal pathway, especially the associative branch? Perhaps not fully antipsychotic but may reduce conversion from ARMS (at risk mental state) and reduce relapse in patients with schizophrenia
What is dysregulating associative striatum DA function? Most likely explanation is abnormal DLPFC function, possibly secondary to abnormal glutamate NMDA receptors affecting GABA and glutamate function

24
Q

schizophrenia and glutamate relationship

A

glutamate is the most abundant excitatory neurotransmitter in the CNS
Receptors: NMDA, AMPA, kainate, mGluR1-8
NMDA receptor hypofunction is a model for positive and negative and cognitive symptoms of schizophrenia
Decreases NMDA receptor function:
Glu excitotoxicity leads to impaired neuronal development leads to disease progression
DA dysregulation via Glu-DA interactions

25
Q

Glu-DA interaction hypothesis

A

Neurodevelopmentally hypo functional NMDA receptor-mediated synapse with GABA interneurones

GABA release is low and doesn’t adequately suppress cortico-brainstem glutamate outflow

Excessive direct glutamate stimulation of SNc DA Nerone cell bodies leads to increase DA in AST and SMST

Excessive glutamate indirectly (via GABA interneurone) inhibits the mesolimbic and mesocortical DA neurone cell bodies in VTA

Decrease cortical DA release

26
Q

DA abnormalities summary

A

psychosis is strongly associated with overactivity of presynaptic DA function (synthesis and synaptic release) in nigrostrital pathway, particularly associative division

opposite of PD
What would we like? To selectively attenuate this pre-synaptically
What do we have? The ability to block the action of the excess DA post synaptically at D2 receptors

cognitive impairment is associated with decrease DA release in PFC
Negative symptoms less well explained by DA, but some evidence they may be worse if DA release is decreased in ventral striatum (i.e mesolyombic pathway)

27
Q

what is the mechanism of antipsychotic efficacy

A

all known antipsychotic drugs reduce positive symptoms by blocking true D2 receptors in the associate striatum i.e they are D2 receptor antagonists
Many also block the D3 and D4 receptor and the 5HT2A receptors, but that doesn’t reduce antipsychotic symptoms

28
Q

what is the threshold of D2R receptor occupancy

A

antipsychotics are (true) D2 receptor antagonists
Threshold for antipsychotic efficacy >65% D2 receptor occupancy in the associate striatum

29
Q

antipsychotic efficacy summary

A

all current antipsychotics are true D2 receptor antagonists
For antipsychotic efficacy, a drug must block more than 65% of D2 receptors in the associative striatum for an adequate proportion of the time
This threshold is the same for all antipsychotics, but the doses needed to achieve it vary widely between drugs
Occupancy >65% does not need to be continuous. Some APs (e.g clozapine and quetiapine) only achieve this intermittently. The optimum duration is not yet known
Other receptor occupancy is unnecessary for efficacy

30
Q

D2 antagonism adverse effects in nigrostrital pathway: efficacy

A

antipsychotic efficacy mediated by D2 antagonism in nigrostrital associative pathway

31
Q

adverse effects in mesolimbic pathway (VST)

A

excessive D2 blockade leads to worsening of negative symptoms

32
Q

adverse effects in nigrostrital motor pathway (SMST)

A

Parkinsonism and other extrapyramidal side effects (EPSE)

33
Q

adverse effects in mesocortical pathway (DLPFC)

A

May exacerbate low DA, leading to deterioration in cognitive function

34
Q

adverse effets in the tuberoinfundibulnar pathway

A

hyperprolatinaemia secondary to antipsychotics

35
Q

hyperprolactinamyia

A

Sexual dysfunction:
diminished libido
Decreased arousal
Orgasmic dysfunction

Breast pathology:
galactorrhoea
Breast enlargement
Slight increased risk of breast cancer

Reproductive dysfunction:
anovulation
Oligomenorrhoea
Amenorrhoea
Subfetility
False pregnancy tests

Hyopgonadism:
decreased bone mineral density
Hip fracture

Miscellaneous:
acne and hirsutism

36
Q

receptor binding affinities

A

the further up the line the colour goes that means it has higher binding efficacy

37
Q

what receptor binding makes them sedative

A

H1 (histamine)

38
Q

what are the receptor mediated adverse effects

A
39
Q

antipsychotic side effects summary

A

unwanted high levels of D2 receptor antagonism:
Motor nigrostriatal branch —> Parkinsonism and EPSE
Mesolimbic pathway —> worsening negative symptoms
Mesocortical pathway —> worsening cognitive function
Tuberoinfundibulnar pathway —> raised prolactin

unwanted other receptor antagonism —> a range of side effects including anticholinergic, postural hypotension, cardiotoxicity, sedation and weight gain (know the mechanisms behind these)
It is important that Pharma companies develop antipsychotics with better tolerability and efficacy

40
Q

diagnosis criteria screenshot

A

Semester 3 (94 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions