Schizophrenia Flashcards
psychosis
syndrome associated with a variety of illnesses
set of sx in which a person’s mental capacity, affective response, capacity to recognize reality, communicate, and relate to others is impaired.
DSM dx Schizophrenia 6 main sx
Delusions
hallucinations
disorganized speech
grossly disorganized or catatonic behavior
negative symptoms
signs of disturbance for at least 6 months
positive symptoms
delusions
hallucinations
agitation
disorganization
negative symptoms
asociality
affective flattening
alogia
avolition
anhedionia
affective sx
depressed mood
inappropriate
blunted
cognitive sx
poor attention
problems with learning
impaired fluency
5 As
asociality
affective flattening
alogia
avolition
anhedionia
avolition
lack of motivation
kinda looks like depression which is why some dx with depression first
alogia
poverty of speech
4 pathways
mesocortical pathway
mesolimbic pathway
nigrostriatal pathway
tuberoinfundibular pathway
dopamine hypothesis
mesocortical dec D2
mesolimbic inc D2
Nigrostriatal and tuberoinfundibular not affected
mesocortical pathway
Innervates the prefrontal cortex
Which is responsible for personality, executive function
Dec dopamine means behavioral deficits like impaired cognition
this is whats affected in prodromal phase before psychosis
mesolimbic pathway
Brain tries to compensate with excess in mesolimbic
this leads to Psychosis: Hallucinations, delusions, misinterpret our environment
Nigrostriatal pathway
Responsible for movement
normal function but untreated you see tardive dyskinesia etc
But for simplicity we will say its normal
Tuberoinfundibular pathway
Controls hypothalamus, adrenal, pituitary
We know dysregulation including temp and psychogenic polydipsia
But for simplicity we say its kind of normal there
Glutamate
Involved in mult dx and is a key target for rx (esp newer rx) in schizophrenia and depression
Works tandem with dopamine
glutamate requires what to function
Co-transmitter
Needs glycine and D-serine
required on the NMDA receptor for glutamate to function
key glutamate pathways
Prefrontal cortex
Nucleus accumbens
Glutamate hypothesis
Glutamate activity at NMDA receptors is hypofunctional
so you get:
Neurodevelopmental abnormalities
GABA interneurons in the PFC
Glutamate becomes hyperactive
Also glutamate regulates dopamine in the mesolimbic and mesocortical pathways
It innervates the pathways differently
typical antipsychotics started when and with that
1950s
with thorazine
caused neurolepsis but was originally an antihistamine
neurolepsis
Slowness, absence of motor movements, affective indifference
Neuroleptics AKA antipsychotics
typical antipsychotics aka
1st gen
conventional
typical antipsychotic binding sites
- M1 antag
a. muscarinic - H1 antag
a. histamine - Alpha 1 antag
- D2 antag
a. Block the activity of a ligand, stays resting
typical antipsychotic changes to pathways
dec mesocortical pathway MORE
dec mesolimbic which was elevated
dec nigrostriatal and tuberoinfundibular which were unaffected
1st gen effect on pos and neg sx
Treats our positive sx (mesolimbic)
Worsens our negative sx (mesocortical)
when a patient stops their 1st gen
their neg sx improve
they can navigate the world better
Motivation, organization, processing etc are a prob for these pt and so coming off those may improve and we have to be cautious about worsening these sx
1st gen effect on nigrostriatal pathway
movement dec
pseudoparkinsonism is an AE
1st gen effect on tuberoinfundibular pathway
dec leads to hyperprolactinemia
1st gen AE beyond dopamine changes
anticholinergic effects (M1)
sedation (H1)
orthostatic hypotension (alpha)
EPS and hyperprolactinemia (D2)
threshold for EPS and hyperprolactinemia in 1st gen
close/narrow
low vs high potency 1st gen
Low: More anticholinergic, antihistamine, more alpha 1, but less EPS
High: Less anticholinergic and antihistamine but more EPS
What makes atypical antipsychotics different
5HT2A receptor
helps mitigate dopamine antagonism
What aytpical antipsychotics do to pathways
mesocortical: less of a decrease and some actually increase
mesolimbic: still dec pos sx
Nigra and tubero: does not affect much which mitigates EPS and hyperprolactinemia
EPS and hyperprolactinemia threshold in 2nd gen
not as narrow/close due to 5HT2A mitigating by producing more endogenous dopamine
atypical antipsychotics pharmacodynamics
complex profiles with many receptors
2nd gen rx blocking one or more of 3 receptors responsible for causing sedation
What 3 receptors
M1
H1
a1
2nd gen that inc sedation (3)
clozapine
olanzapine
quetiapine
pine is high
2nd gen that dont inc sedation (3)
aripiprazole
cariprazine
lurasidone
done pip and rip and low
cardiometabolic effects of 2nd gen
1+ of 2 receptors
which receptors
H1
5HT2C
cardiometabolic effects associated with what sx
wt gain
insulin resistance
not as common as 1st gen
2nd gen that inc cardiometabolic effect (2)
clozapine
olanzapine
pines make worse
2nd gen that dont inc cardiometabolic effect (2)
aripiprazole
cariprazine
lurasidone
ziprasidone
pip rip and done are low (they can but less common)
anticholinergic effect of 2nd gen at what receptor and what are the sx
M1
urinary retention
constipation
blurry vision/dry eyes
2nd gen that inc anticholinergic effect (3)
clozapine
olanzapine
quetiapine
so PINE is high
All others do not effect
Note bowel prophylaxis common with clozapine
EPS and hyperprolactinemia sx for 2nd gen at what receptor
D2 antagonism
How to remember which 2nd gen affect EPS/hyperprolactinemia
DONE are high
PINE are low
Risperidone, paliperidone, ziprasidone
Clozapine, quetiapine, olanzapine
opposite of others
Hypotension effect of 2nd gen at what receptor
a1 antagonism
Hypotension effect for 2nd gen
Which rx do and dont effect
harder to remember
inc sx: clozapine, quetiapine, risperidone, Iloperidone
dec: Brexiprazole, cariprazine, lurasidone
QTC prolongation for 2nd gen activity where
HERG potassium channels
QTC prolongation for 2nd gen activity rx make worse or not
inc: ziprasidone, quetiapine, risperidone, clozapine
dec: aripiprazole, cariprazine, brexpiprazole, lurasidone
Note concern if mult rx are positive
2 pips and rip are D2 partial agonists so
so there is a ceiling affect. High affinity for receptor but doesnt impact as much
so you can add aripiprazole to risperidone when patients have hyperprolactinemia
Quetiapine is a NE reuptake inhibitor so
good use in mood disorders
ziprasidone and lurasidone need
to be taken with food
the only SL 2nd gen
asenapine
Pimavanserin
5HT-SA inverse agonist
no direct dopamine receptor activity
approved for parkinsons dz psychosis because it doesnt affect underlying dz
research in alzheimers
Lumateperone
D2 and 5HT-2A antagonist
D1 receptor activity so inc glutamatergic transmission
clozapine pros
Gold standard in terms of efficacy
Proven to reduce suicidality
Associated with lowest risk of all cause mortality
DOC for side effects caused by D2 blockade
AKA people with risk for parkinsonism and NMS
Glutamatergic activity
clozapine cons
Hits many receptors so big AE profile
Agranulocytosis
Needs blood monitoring
Seizures
DKA
Myocarditis/ Cardiomyopathy
Needs baseline lab
Constipation
Abrupt withdrawal has been associated with psychosis and cholinergic rebound
APA guidelines
Tx with antipsychotic and monitor for effect and AE
Continue if sx improve
Clozapine for tx resistant (2 failed mono)
Also if suicidality remains despite other rx
Tx acute dystonia with anticholinergic
Tx mod to sev tardive dyskinesia with VMAT2 inhibitor
canadian guideline differences
1st episode use low dose and titrate
trial 2-4 wks and switch if no response
cont for at least 18 mo if pos sx resolution
canadian guidelines for Acute exacerbation/relapse prevention
inc or change rx
reassess at 4-8 wks
maintenance:
300-400mg CPZ equivalents
4-6 mg risperidone
Duration 2-5 yrs
LA injection if poss
Australia/NZ guideline differences
a. Start low go slow
b. Consider diff dx
c. Specific rx and dosing
d. CBT should be offered
e. Monitor for metabolic syndrome
f. Recc for combining antipsychotic meds
Note US asks for 3 mono before polypharmacy
CATIE
Clinical Antipsychotic Trials of Intervention Effectiveness
CATIE Efficacy vs effectiveness
Efficacy looks at outcome measured on scale (ex: PAN scale)
Effectiveness trial: Real world outcomes
CATIE FGA vs SGA conclusions
This was 2005 when 2nd gen coming out
No significant diff in effectiveness
Poss small sway toward olanzapine but lots of wt gain
No significant diff for neg sx or cognitive impairment
High rate tx d/c
Diff is more in AE rather than therapeutic effects so good to figure out patient preference
