Neurobiology of Psychosis and Schizophrenia Flashcards
hertability in schizophrenia?
78%
45% lifetime risk if both parents or MZ twin affected
what is heritability?
proportion of observable differences in a trait between individuals in a population that is due to genetic differences
what problems during pregnancy can increase chance of schizophrenia in later life?
2nd trimester viral illness pre-eclampsia fetal hypoxia emergency C section (also childhood viral CNS infection)
which drug is highly associated with schizophrenia?
cannabis
differences in the brain of people with schizophrenia?
reduced frontal lobe volume
reduced frontal lobe grey matter
enlarged lateral ventricle volume
overall reduction in grey matter volume
main points about grey matter changes in schizophrenia?
associated with widely distributed grey matter abnormalities
abnormalities present in early illness and likely before onset of illness
grey matter reductions due to reduced arborisation and not neuron loss
grey matter reductions likely progressive in initial years of illness
how is white matter affected in schizophrenia?
hypothesis of abnormal neural integration in schizophrenia
- white matter connects different brain regions therefore white matter abnormalities hypothesised
how can white matter abnormalities be investigated?
diffusion tensor imaging (DTI) - type of MRI which shows tracts
2 measures most often reported
- fractional anisotropy (FA) - high numbers = healthy white matter
- mean diffusivity (MD) - high numbers = less healthy white matter
what findings on DTI would be most consistent with schizophrenia?
FA reduced and MD increased
- higher FA = more severe psychotic symptoms
describe the neurodevelopmental model for schizophrenia?
environmental risk factors act in utero
children who later develop schizophrenia have identifiable impaired behaviour, motor and intellectual development from infancy
ventricular enlargement is already present at diagnosis and is not progressive
disruption of normal cerebral cortical cytoarchitecture
how is dopamine affected in schizophrenia?
drugs which release dopamine (amphetamines) in the brain or D2 receptor agonists (apomorphine etc) produce a psychotic state
dopamine receptor antagonists are therefore used to treat schizophrenia symptoms
assumed that schizophrenia is related to overactivity of dopamine pathways in the brain
what are the 3 dopaminergic pathways in the brain?
tuberoinfundibular = control of prolactin release mesolimbic/cortical = motivation and reward nigrostriatal = extrapyramidal motor system
how do amphetamines effect dopamine synapse?
increase dopamine transmission
antipsychotics have the opposite effect
components and function of D1 dopamine receptor family?
D1 and D5
stimulate cAMP
components and function of D2 receptor family?
D2, D3 and D4
inhibit adenylyl cyclase
inhibit voltage activated calcium channels
open potassium channels
describe the distribution of dopamine receptors in the brain?
D1 and D2 in both limbic and striatal areas
D1 most abundant
D2 most pharmacologically important in CNS
other subtypes in smaller numbers and more discrete distribution
which abnormalities in dopaminergic system cause which symptoms in schizophrenia?
subcortical dopamine hyperactivity = psychosis
mesocortical dopamine hypoactivity = negative and cognitive symptoms
what other neurotransmitters may be involved in schizophrenia?
glutamate
- altered NMDA receptor subunit expression
serotonin
- abnormalities in serotonin 2A binding potential in frontal cortex index significantly smaller in patients with schizophrenia
what may cause the bran pathology seen in schizophrenia?
gene alterations
- neuregulin (signalling protein that mediates cell interactions and plays critical role in growth and development of multiple organ systems)
- dysbindin (essential for adaptive neural plasticity)
- DISC-1 (involved in neurite overgrowth and cortical development through its interactions with other proteins)
5 examples of typical antipsychotics?
chlorpromazine thioridazine fluphenazine haloperidol zuclopentixol
main feature of typical antipsychotics?
D2 receptor inhibition
what correlation is seen between average dose of antipsychotic required to improve symptoms and D2 receptor binding activity?
larger dose causes reduced binding at D2 receptors
however, a delay in clinical effect is seen which indicates that neuronal adaptation to the D2 blockade is needed before symptoms improve
(i.e same reason that amphetamines affect dopamine transmission immediately but onyl get psychotic symptoms with continued use)
definition of atypical antipsychotics?
high 5-HT2A to D2 ratio (affect both receptors)
less likely to cause extra-pyramidal side effects
better efficacy against negative symptoms
effective in patients unresponsive to typical drugs
examples of atypical antipsychotics?
olazapine risperidone quetiapine clozapine aripiprazole amisulpride
how do antipsychotics cause parkinsons symptoms?
block D2 dopamine receptors in nigrostriatum
parkinsons is also due to loss of dopaminergic neurons here so causes same symptoms
what occurs in an acute dystonic reaction to antipsychotics?
muscle spasms
- takes hours to days
how is an acute dystonic reaction managed?
prochlorperazine
procyclidine
orphphenadrine
(i.e all acetylcholine antagonists)
how long do parkinsonism symptoms take to occur in antipsychotic treatment?
days to months
features of akathesia as a result of antipsychotic treatment?
internal restlessness (fidgeting, wriggling, pacing etc)
features of tardive dyskinesia?
repetitive involuntary purposeless movements
- grimacing, sticking tongue out, lip smacking, pursing lips, blinking etc
usually takes years to develop and continues after stopping medication
endocrine effects of antipsychotics?
dopamine inhibits prolactin production, so D2 blockade cause hyperprolactinaemia
- sexual dysfunction
- galactorrhoea/gynaecomastia
- amenorrhoea
- infertility
- low oestrogen/testosterone which can lead to osteoporosis
how do hallucinogenic drugs cause psychosis?
high affinity for 5-HT2 receptors causing pure 5-HT2 antagonism (antipsychotics dont cause PURE antagonism)
some evidence of reduced 5-HT2A receptor binding in people at risk of schizophrenia
which type of antipsychotic is more likely to cause a netabolic syndrome and how?
atypicals
interactions at specific serotonin receptors may modulate aspects of the immune response and inflammation as well as weight gain
what is metabolic syndrome?
cluster of conditions which occur together to cause increased risk of heart disease, stroke and type 2 diabetes (hypertension etc)
histamine blockade causes which 2 symptoms?
sedation
increased appetite
what are the effects of the alpha adrenergic blockade caused by snatipsychotics?
causes hypotension and interrupts the baroreflex response leading to dizziness, lightheadedness and fainting on rising from lying/sitting (orthostatic hypotension)
effect of antispychotics on muscarinic receptors?
blockade muscarinic receptors are the target of parasympathetic nervous system causes anti-cholinergic effects: - blurred vision - dry mouth - constipation - urinary retention - sedation and confusion
which effect of antisychotics is most likely to cause better sleep?
histamine blockade
which neuroreceptors are involved with muscular stiffness and tremor?
dopamine
which antipsychotic is least likely to cause parkinsonism?
quetiapine
potential dangerous side effect of clozapine?
agranulocytosis
how is clozapine monitored?
FBC weekly for first 6 months, then fortnightly for next 6 months, every 4 weeks thereafter
keep monitoring for 1 month after stopping drug
do FBC immediately in patient taking clozapine with a sore throat
monitor ECG, BP and pulse before starting (myocarditis risk)
