Schizophrenia Flashcards
what are positive symptoms for schizophrenia?
hallucinations - mainly auditory
thought disorders
steryotyped behaviours
what are negative symptoms for schizophrenia?
poverty of affect (more common in poorer communities)
cognitive impairment
temporal disorientation
what are causes of schizophrenia?
-genetic
-psychosocial
-brain damage
-viral infection
how are genetic risks of schizophrenia and the environmental exposure linked?
genetics can cause an increased number of risk loci for developing schizophrenia. the chance of it being developed can be potentiated by environmental insults that increase its chance of development.
what affects the psychosocial causes of schizophrenia?
-tends to have an adolesent onset.
-stress can precipitate it
-higher rate of relapse in ‘emotionally charged homes
-blunted cortisol response
what effect does schizophrenia have on the limbic system structures?
the limbic structures of the brain. decreased size of temporal lobe, increased activity during auditory hallucination.
what occurs to the dominant cerebral hemisphere in schizophrenia?
left hemisphere in specialised for verbal function in normal individuals. in Schizophrenia this is disrupted during verbal tasks.
How do viral infections affect schizophrenia
Hypotheisis that exposure of mother to virus during second trimester increases the risk of schizophrenia to the child. There is a higher incidence in patients born i late winter or spring
what is the site of action for antipsychotic drugs
Basal ganglia
What is chlorpromazine?
Antipsychotic drug. increases dopamine turnover. a Dopamine receptor antagonist. Leads to increase apperance of metabolites in the CSF (cerebrospinal fluid)
what is the dopamine hypothesis of schizophrenia
that the symptoms are due to excess dopamine neurotransmission in mesolimbic and mesocortical regions of the brain
What does clinical studies think of the dopamine hypothesis?
No evidence for increased dopamine release. confliciting litrature.
how is dopamine synthesised?
From tyrosine. gets converted to DOPA by tyrosine hydroxylase. DOPA to dopamine by DOPA carboxylase.
How is dopamine broken down?
by monoamine oxidase A (MAO A), MAO B and catechol-o-methyltransferase. (COMT)
what is the rate limiting step in dopamine production and where is its expression increased in schizophrenia?
Tyrosine hydroxylase. expression is significantly higher in the substantia nigra of schizophrenia patients compared to normal subjects.
Dysfunction in what dopamine receptor has been linked to the negative symptoms of schizophrenia?
D1. mediates dopaminergic transmission in the prefrontal cortex.
WHERE does the mesolimbic pathway project?
from the venteral tegmental area to the nucleus accumbens in the limbic system.
how does dopamine activity affect psychotic symptoms in the mesolimbic pathway?
hyperactivity of dopamine in the mesolimbic pathway leads to positive psychotic symptoms. it is also the pathway that mediates agression.
the mesolimbic pathway is the site of rewards. what do antipsychotics to that alter this pathway
block the D2 receptors. they reduce pleasure effects. leads to self pleasure hypothesis. schizophrenic patients have higher incidences of smoking as nicotine enhances dopamine release.
Where does the mesocortical pathway project?
from the VTA to the prefrontal cortex.
Has projections to the dorsolateral prefrontal cortex regulating cognition and executive functioning.
Ventromedial prefrontal cortex projections to regulate emotion an affect.
where does the nigrostriatal pathway project and what does it mediate?
projects from the dopaminergic neurons in the substantia nigra to the basal ganglia or striatum.
mediates motor moments.
What are some typical antispychotics (neuroleptics)
Phenothiazines
Thioxanthenes
Butrophenones
what are some of the side affects of typical antipsychotics
weight gain, sedation, postural hypotension, atropine like side affects, hyperprolactinameia, movement disorders like parkinson like syndrome and tardive dyskinesia
what is tardive dyskinesia?
repetitive purposeless movement. it is irreversible
What are some of the benifits of atypical antiphychotics?
less sedation and reportedly low incidence of movement disorders.
what are some classes of atypical antipsychotics?
CLOZAPINE
QUETIAPINE
OLANZIPINE
RISPERIDONE
ARIPIPRAZOLE
ASENAFINE
PALIPERIDONE
Atypicals like chlozapine are reportedly more effective against what symptoms
negative symptoms
What is velocardio facial syndrome (VCFS) and what implications can it bring about?
A deletion in ch22.
- increased incidence of psychiatric disorders including schizophrenia
higher incidence of deletion in ch22 in schizophrenic population
what is catechol O methyl transferase (COMT) and what alleles does it have in humans?
metabolic enzyme for dopamine.
Valine 108 and methionine 108 (less stable enzyme) are the two alleles.
what if the hypothesised difference between alleles of Catechol O methyl transferase?
hypotheisis that metionine 108 gives rise to higher synaptic dopamine.
Val108 is the allele that shows linkage with schizophrenia and impared cognitive function however.
WHat is DISC1? where was it identified
DISC1 (disrupted in schizophrenia 1) was identified in a family that has chromosomal translocation.
has increased expression during neuronal development.
expressed in cortical neurones and interacts with several proteins e.g NuDEL, LIS1
How does DISC1 interact with GSK3beta?
DISC1 inhibits GSK3beta via its N terminal domain.
stabalises Beta catenin and activates downstream transcription factors.
leads to neuronal progenitor cell proliferation.
GSK3beta activity can be affected by DISC1. what else can affect its activity?
Phosprylation of ser9 residue by receptor tyrosine kinase pathway.
Antipsychotic drugs like lithium
What is Neuregulin?
a growth factor that interacts with a ErbB (epidermal growth factor like receptor tyrosine kinase) that regulates neuronal differentiation and migration
What chromosome consists a risk factor for schizophrenia and encodes for Neuregulin?
chromosome 8.
What do post mortem analysis hypothesise about Neuregulin and schizophrenia?
post mortem analysis show schizophrenics have increased mRNA levels for neuregulin.
hypothesis that increase in neuregulin signalling is a risk factor for schizophrenia.
what are some of the cytoarchitectural abnormalities of the cortex in schizophrenia?
-decreased number of small neurones in superficial layers
-increased number of large neurones in deeper layers
why is schizophernia not considered neurodegenerate?
there is no gliosis.
what changes occur in the limbic system in schizophereina
decreased size of the temporal lobe.
increased activity in the temoral lobe during auditory hallucinations.
enlarged ventricles.
what is the winconsin card sorting test and what did it tell us about schizophernic individuals?
Wisconsin card sorting test – ask patient to sort the cards according to number of shapes, colours of shapes or the shapes themselves.
Schizophrenic individuals have reduced cognitive function shown by lower activity levels in their dorsal-lateral PFC (fMRI)
what region of the brain is positive symtpoms incolved in
Temporal lobe
what part of the brain are negative symptoms inolved in?
Pre frontal cortex
what is reserpine and what does it do to the brain?
an antipsychotic and depletes Nadr and DA in the brain, suggests DA is involved in schizophrenia
What can L dopa do that affects the brain and psychosis?
L dopa can trigger pyschotic episodes.
usedx ot treat parkinsons, increases dopamine in the nigrostiatal pathway.
what is chlorpromazine?
antispychotic. DA receptor antagonist.
has sedative affects during physcotic episodes.
what does the dopamine hypothesis state?
states that symptoms of schizophrenia are due to excess dopamine neurotransmision in mesolimbic and decreased dopamine neurtransmission in the mesocortial regions of the brain.
what do prolactin levels indicate about antispychotics?
weather antipsyhcotics are blocking dopamine receptors or not. there are elevated prolactin levels in people administered antispychotics.
what is the deoplarising block?
mesostriatal/mesolimbic neurones have autoreceptors and become silent upon antisphycotics.
mesocortical neurones dont have autoreceptors and release more dopamine.
net overall change is balancing of the DA pathways. with reelatice increase in the mesocoritical.
what are typical antipsychotics.
phenothiazines
chlorprozamine.
what are side effects of anitpsychotics?
Weight gain and sedation (antihistamine effects)
Postural hypotension (alpha adrenoreceptor effects)
Hyperprolactinaemia (due to blockage of D2)
Neuroleptic malignant syndrome
Acute dystonia (Parkinson-like)
Tardive dyskinesia – repetitive, purposeless movement. Irreversible but disappears when individual is asleep. Due to nigrostriatal pathway. Seems to be toxicity to GABA interneurons in the striatum, which are involved in motor control
what are some atypical antispychotics?
clozapine, olanzapine, risperidone
what is a potentially lethal side affect of clozapine?
Agranulocytosis. decrease of granulocytes in the blood which increases vunerability to infection
what receptors is haloperidol most effective against?
D2 and D3 but not agaisnt 5-HT receptors.
what is clozapine more effective recptor targets?
5-HT and muscarnic receptors.
waht condition is DISC1 and mutations linked with
Lissencephaly (smooth brain)
