L12 - schizophrenia and antipsychotics Flashcards
describe the pathology of schizophrenia
- reduction in cortical grey matter - supporting degeneration within cortex
- post mortem analysis shows that cortical pyramidal cells had reduced dendritic length and spine density
- reduced synapses especially in pre-frontal cortex
describe the pathology of schizophrenia
- reduction in cortical grey matter - supporting degeneration within cortex
- post mortem analysis shows that cortical pyramidal cells had reduced dendritic length and spine density
- reduced synapses especially in pre-frontal cortex
how was reduced synapses in schizophrenia identiifed?
PET scanning using tracer that binds to synaptic protein SV2A
does loss of synapses correlate with intensity of schizophrenia symptoms? what can be concluded from this
no
suggests synapse loss occurs at early stage of disease
supports the neurodevelopmental hypothesis for schizophrenia
it doesnt worsen with the progression of loss of synapses
list possible causes of schizophrenia
genetic
environmental
neurodevelopmental
expand on genetic cause for schizophrenia
50% risk of schizophrenia if individual has affected twin
many gene association studies concluded that singular genes have little impact on schizophrenia developmeny, but a combination of several of these genes may do
expand on environmental causeof schizophrenia
- cannabis exposure
- maternal factors (events during pregnancy eg malnutrition / infection)
- urban living and stress of adolescence
expand on neurodevelopmental hypothesis for schizophrenia
suggests the cause could either be
- a trigger in the gestational period that leads to schizophrenia development (possibly infection or malnutrition)
evidence is that individuals with schizophrenia have abnormal fingerprint ( which is developed in the 14th - 22 week gestational period) - in adolecence fine tuning of synapses could be affected (by genetics/environmental disturbance) that leads to the impairment of this fine tuning and development of schizophrenia
evidence that supports this is reduced no. of synapses
what are the 3 categories of Schizophrenia symptoms and define them
positive -> exaggeration of normal behaviour
negative -> suppression of normal behaviour
different patients will experience different symptoms
cognitive symptoms
give some examples of positive symotoms of schizophrenia
- delusions -> fixed inaccurate self belief such as delusions of grandeur
- hallucinations
- delusions
- thought disorders (irrational thoughts)
- abnormal behaviour (agression, repetitive, purposless
give some examples of negative symptoms of schizophrenia
- social withdrawal
- Flattened emotions
- Lack of drive
- Disorganised speech (alogia)
give some examples of cognitive symptoms of schizophrenia
- attention deficits
- Learning and memory issues
- Decision making
what is the dopamine hypothesis of schizophrenia
DA hyperactivity is responsible for positive symptoms of schizophrenia
list evidence that supports the DA hypothesis of schizophrenia
- Amphetamine (which increases [DA]) induces stereotypical psychotic like symptoms in patients (paranoia, visual&auditory hallucinations)
- L-DOPA can induce psychosis in patients with Parkinson’s
- Genetic associations between genes of dopaminergic system and schizophrenia
- D2/D3 receptor genes
- BDNF (brain derived neurotrophic factor) which supports growth and survival of dopaminergic neurones
- COMT (catecho-O-methyl transferase) enzyme involved in dopamine metabolism
- Increased numbers of D2 dopamine receptors in brain post mortem (more receptors indicates more firing and over activity)However some have argued that this could be as a result of treatment - blocking receptors may cause the brain to upregulate their expression
- Effective anti-psychotic drugs block brain dopamine D2 receptors
- Affinity of drug for D2 receptors directly correlates with clinical potency of drugs
describe the genetic evidence that supports the DA hypothesis of schizophrenia
Genetic associations between genes of dopaminergic system and schizophrenia
- D2/D3 receptor genes - BDNF (brain derived neurotrophic factor) which supports growth and survival of dopaminergic neurones - COMT (catecho-O-methyl transferase) enzyme involved in dopamine metabolism
polymmorphisms in these associated with schizophrenia
what could the increased numbers of D2 DA receptors in schizophrenia patients be due to rather than the disease itself?
However some have argued that this could be as a result of treatment - blocking receptors may cause the brain to upregulate their expression
what are the two classes of antipsychotics
typical
atypical / 2nd generation
what is a feature of both typical and atypical antipsychotics that make them a good treatment option for schizophrenia patients
long half lives (15-30h) so only have to be given 1-2 times a day
I.M injections can be given every 2-4 weeks
give example of typical antipsychotic
chlorpromazine
describe mechanism of typical antipsychotics
antagonists at D2 receptors reduce DA hyperactivity and treat POSITIVE schizophrenia symptoms
where else do typical antipsychotics act as antagonists
a adrenoreceptors
D1 receptors
5-HT2 & mACh
histamine H1
how were typical antipsychotics initially used to treat schizophrenia
initally used to sedate patients
later found to reduce positive symptoms
why is there a delay in effectiveness of antipsychotics (up to 3 weeks)
the initial blockade of DA receptors may cause compensative increase in DA firing - this subsides after ~3 weeks
off target side effects of typical antipsychotics (and via what receptor)
- sedation (H1)
- hypotension (a adrenoreceptor block)
- ## anticholinergic effects (mACh block) incuding dry mouth, constipation, blurred vision
what other brain pathways involve D2 receptors and what is their normal function
- tuberoinfundibular pathway (from hthalamus to pituitary) controls prolactin secretion from pituitary. DA acts on D2 receptors here to inhibit prolactin release #
- nigrostriatal pathway (from substantia nigra to striatum) important for motor movement functions
based on the other locations of D2 receptors, what ‘on target’ side effects are there
- increased prolactin secretion from pituitary - can cause gynaecomastia
- impaired motor functions (extra-pyramidal side effects
list symptoms of extra-pyramidal side effects of typical antipsychotics
- pseudoparkinsonism
- rigidity
- stooped posture
- tremors
- bradykinesia - acute dystonias - muscle spasms of face,neck,back
- akathisia
- restlessness
- feet rocking back and forth
what pathway in the brain is involved/impacts positive symptoms of schizophrenia
mesolimbic neurones which originate in VTA (ventral tegmental area) and span to regions such as amygdala, NA, septum
what can happen due to chronic use of typical antipsychotics
upregulation of D2 receptors resulting in tardive dyskinesia (irreversible if not treated early)
symptoms of tardive dyskinesia
protruding tongue
lip smacking
facial dyskinesia
involuntary limb movement
are the extra-pyramidal (motor) side effects of typical antipsychotics reversible
yes upon removal of the drug
give examples of atypical antipsychotics
clozapine
olanzapine
respiridone
where do atypical antipsychotics act as antagonists
same as typical, but have highest affinity for 5-HT2 receptors
also have a higher affinity for D4 receptors over D2 receptors
describe mechanism of action of atypical antipsychotics treating positive symptoms of schizophrenia
- block of D2 and D4 receptors in mesolimbic pathway combats positive symptoms of schizophrenia
why is primarily targeting the D4 receptor rather than the D2 receptor a better treatment of positive symptoms of schizophrenia
D4 receptor blockade relieves positive symptoms but D4 receptors are not found in the nigrostriatal pathway and so reduces extrapyramidal side effects
explain mechanism of atypical psychotics in treatment of negative symptoms of schizophrenia
believed to be due to 5-HT2A receptor blockade but mechanism not fully understood
why are atypical antipsychotics preferred over typical antipsychotics in schizophrenia treatment
less side effects via D2 receptors - still effective at treating positive symptoms via D4
provide some relief of negative symptoms via 5-HT2
side effects of atypical antipsychotics (and what receptors mediate them)
- sedation (h1)
- anticholinergic effects (mACh) - dry mouth, blurred vision, constipation
- hypotension (a1 adrenoreceptor)
- weight gain (5-HT2 blockade causes craving)
- impaired glycaemic control (via 5-HT2 blockade) causing insulin resistance, impaired glucose tolerance (type 2 diabetes)
what side effects of atypical antipsychotics are meidated via blockade of 5-HT2
weight gain (5-HT2 blockade causes food cravings)
impaired glycaemic control, causing
- insulin resistance
- impaired glucose tolerance
- T2D
describe the clozopine only (atypical antipsychotic) side effect, and how its now prevented
clozapine caused leucopenia / agranulocytosis
-> reversible, but potentially fatal loss of neutrophils basophils, eosinophils
rare but patients have regular blood tests to monitor this
weaknesses of current antipsychotic schizophrenia symptoms
- still have many side effects
- many patients experience no benefit from treatment
- treatments provide no benefit to cognitive symptoms
why is glutamate now a drug target of interest for schizophrenia
there is evidence for glutamate hypOactivity in schizophrenia
list the evidence for glutamte HypOactivity in schizophrenia
(all genetic)
- Genetic associations with schizophrenia and gluaminergic system
- GRIN1 (which encodes NMDAR1 subunit) required for functional NMDA receptors
- NGR1 (neuregulin, which controls expression of glutamate receptor subunits)
mutations in these genes associated with S
- NMDA-R knockout mice show stereotypical schizophrenia behaviour (repetitive behaviour) which is reversible with antipsychotics
- NMDA-type receptor antagonists (eg phencyclidine - PCP, ketamine) induce hallucinations, thought disorder and flattened emotional responses in humans (mimics positive and negative symptoms plus cognitive decline)
