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Scizophrenia Flashcards

1
Q

Schizophrenia stats

A

1% of population affected
Suicide no. 1 cause of premature death of those with it

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2
Q

Antipsychotics

A

Old name: neuroleptics

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3
Q

Schizophrenia

A

Fragmentation of cognitive processes and personality
Onset in adolescence, complex array of symptoms

Paranoia, hallucinations, incoherent communication, depression, triggered by stress, episodic

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4
Q

Positive symptoms of schizophrenia

A

Overt
Hallucinations - mainly auditory for to problem of inner speech (neurones in cingulate in process of self monitoring) (increase in activity in Broca’s area during hallucinations)
Thought disorders
Stereotyped behaviour

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5
Q

Negative symptoms

A

Symptoms affecting mood
Cognitive impairment
Temporal disorientation

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6
Q

Time course of schizophrenia

A

Positive to negative symptoms

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7
Q

Causes of schizophrenia

A

Genetic risk factors predispose individuals
Identical twins - 60% risk so not just genetics

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8
Q

Environmental factor

A

Normal and normal = same as general population
Scizophrenic and normal = 8% risk factor (genotype and not just environment)

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9
Q

Genetics of schizophrenia

A

Multiple polymorphisms in a number of different genes. Each low level risk but together major risk
Lots of risk factors + bad environment = more likely to have
Low genomic risk + bad environment = not hugely likely
Neuro developmental disorder

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10
Q

Psychosocial cause of schizophrenia

A

Adolescent onset
Strsss can cause illness
Higher rate of relapse in emotionally charged home environment
Blunted cortisol response in those who suffer with it

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11
Q

Structural brain damage in schizophrenia

A

Ventricular size in patients
Increase ventricular size in those who suffer
Decreased volume of temporal lobe
Increased dendritic pruning

But no gliosis so not neuro degenerative

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12
Q

Fun fact

A

Left hadidness more common in schizophrenia
Early birth trauma?

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13
Q

Cytoarchitectural abnormalities in cortex

A

Decreased number of small neurones in superficial layers
Increased numbers of large neurones in deeper layers

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14
Q

Development of migration pathway of neurones in cortex

A

Embryonic neurone progenitor cells occur at sun ventricular zone. Born there and migrate through brain to get to correct area
Mechanism: migrate along radial glial cell provide tract from ventricular zone to cortical zone and make synapses

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15
Q

Viral infection as cause of schizophrenia

A

Exposure of mother to virus in late winter or spring during second trimester increases risk of schizophrenia
Cytokine response causes it not the disease itself

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16
Q

Sites of brain dysfunction: Limbic structures

A

Decreased size of temporal lobe
Increased activity during auditory hallucinations
So greater ventricles

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17
Q

Sites of brain dysfunction: dysfunction of dominant cerebral hemisphere

A

Left hemisphere is specialised for verbal function
Normal individuals - increased brain activity to left side of brain during verbal task
Lateralisation disrupted in schizophrenia
DTI - abnormalities in corpus collosal (connectivity)

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18
Q

Site of brain dysfunction: Hopi functionality of dorsal lateral prefrontal cortex

A

Wisconsin card sorting test
Poorly performed by schizophrenics
Impaired cognitive performance - lower activity of dorsal lateral prefrontal cortex
Thinning and thickening around certain parts of cortex compared to controls

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19
Q

Site of brain dysfunction: basal ganglia

A

Nuclei: striatum
Disruption of signalling in basal ganglia = psychosis, focus of epilepsy seizures (observations but studies inconclusive)
Site of drugs action to treat

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20
Q

Current understanding

A

Genetic susceptibility involved but environmental factors can modulate expression
Positive symptoms: temporal lobe
Negative symptoms: prefrontal cortex

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21
Q

Neuro chemical basis of schizophrenia : reserpine is an antipsychotic

A

Blocks the vesicular monoamine transporter
5HT, dopamine, noradrenergic synapses, NTs stored in vesicles. Monoamine transporters (vmat) NTs into vesicles so depletes monoamenergic transmission in brain

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22
Q

Neurochemical basis of schizophrenia

A

Indirect evidence to implicate dopamine

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23
Q

Neurochemical basis of schizophrenia: amphetamine causes toxic psychosis in susceptible individuals

A

Amphetamine- reverse transport so increases release of noradrenaline and dopamine
Clinicians can’t tell apart toxic psychosis and schizophrenia

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24
Q

Neurochemical basis of schizophrenia: L-DOPA can trigger psychotic episodes

A

L-DOPA is precursor for L-dopamine
Used to treat Parkinson’s (neurones project from substantia nigra to striatum degenerate so loss of dopamine signalling in basal ganglia)

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25
Neurochemical basis of schizophrenia: chlorpromazine
1st antipsychotic potential discovered Observed chlorpromazine had calming effect and reduced hallucinations. Tested on people with schizophrenia and showed calming “Chemical straight jacket” “major tranquillisers” “Thorazine”
26
Mechanisms of chlorpromazine
Increases DA turnover Blocks postsynaptic receptors and presynaptic receptors. Blocks inhibition of release so more dopamine metabolised in cleft (seen in CSF) Non selective DA receptor antagonist DA release from synapse but can inhibit release through autonreceptors (negative feedback pathway)
27
Chlorpromazine led to further research for antipsychotic
Rotor rod assay Good motor control - say on rod long time Compound impairing motor control - fall off Extra pyramidal system (dopamine D2 receptors and basal ganglia) control that ability Grid elevated Mouse hangs on as elevated Impaired fall off - catalepsy (D2 receptors cause this) Side effect extra pyramidal motor effects Opiates receptors also cause catalepsy
28
Meta analysis and dopamine receptor blockade as antipsychotic
Dose and affinity Good correlation Highest affinity lowest dose Low affinity high dose
29
Dopamine hypothesis if schizophrenia
Symptoms of schizophrenia are due to excess dopamine neurotransmission in Mesolimbic and mesocortical regions of the brain
30
VTA gives rise to what pathways
Mesolimbic and mesocortical
31
Where does the Mesolimbic pathway give projections to?
Limbic regions eg nucleus accumbens
32
Where does the mesocortical give projections to?
Cortical regions eg frontal cortex
33
Is there increased dopermenergic transmission in schizophrenia
Dopamine release? No consistency evidence Dopamine receptors? Post mortem show increase in D2 but could be due to treatment Measurements in drug naive patients using PET do not show consistent increases levels of D2
34
Drug free for 6 months
Still takes a while to reequilivbriate the dopamine receptors
35
Patients drug free
4/5 showed no/ little increase in dopamine receptors so increase in dopamine receptor numbers is not an underlying pathophysiology of the condition so maybe difference in pharmacology or affinity of receptor
36
Discrepancies with DA hypothesis
Delay between onset of treatment and full benefit Test prolactin in blood indicator of dopamine receptor blockade- anterior pituitary, lactotrophs release prolactin, under inhibitory control of D2 dopamine receptors. Antipsychotics block D2 receptors so elevation of prolactin. Happens within days but symptom improvements of schizophrenia take 3+ weeks
37
Hypothesis based on discrepancies if DA hypothesis
Long term changes in dopaminergic signalling and neural circuits caused by acute blockade of dopamine receptors So not blockade of dopamine receptors but consequence of it causes benefit
38
Compound x is an antagonist of presynaptic auto receptors at dopaminergic sunshades. What is the consequence of compound x on synaptic levels of dopamine?
Increase Blocks negative feedback
39
Which dopaminergic pathway has auto receptors on their presynaptic terminals
Mesolimbic and mesostriatal
40
Which pathway releases more dopamine/is more active
Mesocortical as no auto receptors so less regulation
41
Research on mesostriatal/Mesolimbic vs mesocortical pathways
Mesostriatal and Mesolimbic become silent over time due to depolarising block after it overcomes synaptic block of chlorpromazine on auto receptor feedback. (Increased signalling so depolarises membrane so sodium gated ion channels go to inactivated state- hyperpolarising agent over comes this) Net effect - relative increase in mesocortical pathway
42
Antipsychotics “neuroleptics”: typical
“Typical” class - sedative effects Phenothiazine’s - eg chlorpromazine Thioxanthenez - eg flupenthixol Butyrophenones - eg haloperidol But not effective in all patients and only against positive symptoms
43
Side effects of typical antipsychotics
Weight gain Sedation - chlorpromazine also an antihistamine Postural hypotension - alpha adrenoceptor blockage Atropine like side affects - block muscarinic receptors urine retention Hyperprolactinaemia - D2 Life limiting side effects - neuroleptic malignant syndrome, movement disorders eg chronic traduce dyskinesia and acute Parkinson’s like syndrome as d2 receptors key in extra pyramidal system (substantia nigra to striatum that has dopamine receptors)
44
Chronic - tardive dyskinesia
Can be irreversible Repetive purposeless movement (usually face) Disappears when asleep Long term antipsychotics can lead to hypersensitivity in the extra pyramidal system due to altered dopamine receptor expression (plastic change) I’m striatum reduction in enzyme GAD (synthetic enzymes for GABA) so indicates loss of gabanergic neurones needed for regulation - similar to huntingtons correo and diskinesia
45
Atypical antipsychotics
Less sedation Low incidence of movement disorders More effective against negative symptoms Clozapine - but lethal form of anaemia (agranulocytosis) LAST OPTION Quetiapine Olanzipine Risperdinone Ariprazole Assnafine Paliperidone
46
Receptor profile of haloperidol
Selective drug. Lower affinity for most other receptors other than D2, D3, D4 and slightly alpha 1
47
What is an acute side effect of haloperidol treatment caused by dopamine D2 receptor blockade
Parkinson’s like syndrome Block of nigra striata pathway
48
Receptor profile of clozapine
Not as selective. D4, 5-HT2 receptors (antagonist for 5HT2 receptor so new antipsychotic respiridone mix of 5HT and dopamine receptor blocks), alpha 1, muscarinic and m1 blocked Efficacy of clozapine likely due to mixed pharmacological profile Weight gains, increased lipids
49
Which area in the brain is most implicated in the negative symptoms of schizophrenia
Dorsolateral prefrontal cortex
50
Genetic basis for schizophrenia
Linkage analysis implies cortical dysfunction DISC-1 Neuregulin Catacho-o-methyl-transferase But there’s more
51
Insight into genetic basis of schizophrenia
Association with chromosomal microdeletion syndrome Rate familial variants of schizophrenia
52
Velocardio facial syndrome (VCFS)
Deletion on chromosome 22 1.5 to 3 Mb Learning and developmental disorders eg cleft pallet, cardiac dysfunction Not usually heredity - spontaneous deletion Increased incidence of psychiatric disorders Higher incidence of deletion of chr 22 in schizophrenic population Encodes Catechol-p-methyl-transferase which is highly expressed in prefrontal cortex Metabolic enzyme for dopamine Mutations in COMT might be risk factor for schizophrenia (decreased metabolism of dopamine so higher levels)
53
2 COMT
Valine 108 Methionine 108 (less stable) Hypothesis met 108 gives rise to higher synaptic dopamine but actually opposite. Val108 shows link with schizophrenia and impaired cognitive function. So risk factor = lower levels of dopamine in prefrontal cortex DA Important in cognitive processing via D1 receptors in cortex and involved in working memory Lower level D1 in drug naive through PET scans my
54
Family trees
Chromosomal translocation between chromosomes 1 and 11 Break in chromosome and fragmented ends of ends reattach to other chromosome Disrupted in schizophrenia = DISC 1
55
DISC1
Increased expression during neuronal development Expressed in cortical neurones Interacts with several proteins eg NuDEL, LIS1 DISC1 interactive - neuronal proliferation, migration, regulators of key signalling pathways, spine regulation and synapse maintenance Highly expressed in cortex
56
DISC 1 “scaffolding protein”
Number of different proteins interact Lies in pathway connecting growth factor signalling (tyrosine kinase) via GSK3B to transcriptional regulation involved in proliferation of neural progenitor cells
57
LIs 1
Gene mutated in lissencephaly So link between DISC1 and mutations in lissencephaly Absence of gyri in brain Typically spontaneous not inherited
58
Linkage for other genes involved in neural migration in schizophrenia
Neuregulin Genes important for development - mutated = risk for schizophrenia
59
Neuregulin
Linkage analysis and fine genetic mapping Locus on chr 8 = risk factor (encodes neuregulin) Growth factor in Tera ting with receptor regulating neuronal differentiation and migration Post mortem analysis - increased mRNA for Neuregulin Current hypothesis- increased Neuregulin signalling is risk factor for schizophrenia by reducing the function of glutamate receptor NMDA
60
Hypothesis for schizophrenia
Cortex exerts inhibition on subcortical systems Excessive activity if subcortical systems due to hypo functionality of cortex in schizophrenia This may underpin psychosis
61
evidence of involvement of PFC and subcortical dopamine in negative and positive symptoms of schizophrenia so may be neuro developmental defects that cause abnormality in organisation of cortical neurones
Hypo functionality in brain imagining Altered cytiarchitectural in PM brain Decreased D1 in PM brain Lesions in primates = negative symptoms DISC 1 and COMT highly expressed in cortex DISC 1 implicated in neuronal migration and interacts with proteins which are muted in lissencephaly Lesion prefrontal cortex in rats and measure activity of subcortical dopamine systems = elevated So connectivity
62
Antipsychotics block dopamine receptors
Antipsychotic potential But chlozapine not D2 receptor antagonist so wildly oversimplification Typical don’t address hypofunctionality of cortex Atypical - chlozapine, 5HT2 antagonist, may be able to address negative symptoms
63
What we need to improve schizophrenia research
Increase understanding of genetic basis and underlying mechanisms New models to facilitate improved therapies Understand complex interaction between environment and genetics for expression of disorders Aim for early and accurate diagnosis so treatment prevent worsening of symptoms

Neuropharma Of CNS disorders (5 decks)

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