Psychosis Flashcards
what is psychosis?
presence of gross impairment of reality testing (e.g., lose touch with reality) as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganised and agitated behaviour without apparent awareness on the part of the patient of the incomprehensibility of their behaviour
what is considered treatment resistant schizophrenia?
no significant improvement in symptoms despite treatment with 2 or more APs from 2 different classes at optimal dose for 6-8 weeks
what is schizophreniform disorder?
1-6 months, same symptoms of schizophrenia, social/occupation function impairment not required
what is schizoaffective disorder?
2 or more weeks of delusions, or hallucinations without mood symptoms + uninterrupted period of illness containing either major depressive or manic episodes with concurrent symptoms diagnostic of schizophrenia
social/occupation functional impairment not required
what is brief psychotic disorder?
1 day to 1 month of 1 or more delusions, hallucinations, disorganised speech
return to premorbid function
what is delusional disorder?
1 or more months of delusions
hallucinations not prominent
function only mildly impaired, behaviour not blatantly bizarre
what is substance induced psychosis?
hallucinations or delusions development during or within 1 month of substance use/withdrawal
what is the duration of untreated psychosis?
time from the manifestation of the first psychotic symptom to initiation of adequate treatment
how does being untreated effect mortality?
risk of death doubles if never treated with AP
what is the medication nonadherence rates of schizophrenia?
50-60%
what are some factors associated with nonadherence?
decreased motivational drive from AP
adverse effects
poor insight into illness
personal attitudes towards treatment
stigma
financial constraints
homelessness
substance use
lack of support
ethnic minority
weak therapeutic alliance
what is the key therapy underlying the pathophysiology of schizophrenia?
dopamine dysregulation
how does serotonin dysregulation contribute to schizophrenia?
serotonin modulates dopamine
where is the origin of the nigrostriatal tract?
substantia nigra
what innervates the nirgrostriatal dopamine tract?
basal ganglia
what is the function of the nigrostriatal dopamine tract?
motor coordination, posture control
what does blocking the nigrostriatal dopamine tract cause?
movement disorders (EPS)
where does the mesolimbic dopamine tract originate from?
midbrain
what innervates the mesolimbic dopamine tract?
limbic areas
what is the function of the mesolimbic dopamine tract?
pleasure, reward, desire, response to stimuli, motivational behaviour
what dopamine tract causes positive symptoms of schizophrenia?
mesolimbic
what is the effect of blocking the mesolimbic dopamine tract?
relief of psychosis
where does the mesocortical dopamine tract originate from?
midbrain
what innervates the mesocortical dopamine tract?
frontal and prefrontal cortex
what is the function of the mesocortical dopamine tract?
cognition, motivation, communication, social functioning, emotional response, problem solving
what are the effects of blocking the mesocortical dopamine tract?
akathisia?
treatment of negative symptoms and depression
what dopamine tract is responsible for the negative symptoms of schizophrenia?
mesocortical
where does the tuberoinfunbular dopamine tract originate from?
hypothalamus
what innervates the tuberoinfunbular dopamine tract?
anterior pituitary gland
what is the function of the tuberoinfunbular dopamine tract?
regulate prolactin release
what is the effect of blocking the tuberoinfunbular dopamine tract?
hyperprolactinemia: gynecomastia, galactorrhea, amenorrhea, hirsutism, weight gain, osteoporosis, sexual dysfunction, ED
what are prodromal features of schizophrenia?
often recognised retrospectively after the diagnosis has been made
reclusive adolescence without close friends
not functioning well in occupational, social and personal activities
markedly peculiar behaviour, abnormal affects, unusual speech, bizarre ideas and strange perceptual experiences
what are the 4 symptom clusters in schizophrenia?
positive symptoms (psychosis)
negative symptoms
cognitive symptoms
mood symptoms
what are the positive symptoms of schizophrenia?
hallucinations
suspiciousness/paranoia
delusions
disturbed thought content
bizarre or disorganised behaviour
thought disorder
what are the negative symptoms of schizophrenia?
apathy, social indifference, loss of emotional connectedness
loss of motivation (avolition)
alogia (poverty of speech)
flat affect
poor self care
psychomotor retardation
what are the cognitive symptoms of schizophrenia?
memory impairment
poor concentration
impaired executive functioning: planning, problem solving
what are the mood symptoms of schizophrenia?
dysphoria, depression
excitement, mania
what are delusions?
fixed beliefs that are not amenable to change in light of conflicting evidence
what are some common themes in schizophrenic delusions?
persecutory, referential, somatic, religious, grandiose
what are hallucinations?
perception like experiences that occur without external stimuli
vivid and clear with the full force and impact of normal perceptions and not under voluntary control
what are the most common hallucinations in schizophrenia?
auditory
what is catatonia?
marked decreased in reactivity to the environment
ranges from resistance to instructions (negativism); to maintaining a rigid, inappropriate or bizarre posture; to a complete lack of verbal and motor responses (mutism and stupor)
can also include purposeless and excessive motor activity without obvious cause (catatonic excitement)
what is alogia?
dysfunction of communication
poverty of speech
what is affective blunting?
dysfunction of affect
reduced range of emotions (perception, experience and expression)
what is asociality?
dysfunction of socialisation
reduced social drive and interactions
what is anhedonia?
dysfunction of capacity for pleasure
reduced ability to experience pleasure
what is avolition ?
dysfunction of motivation
reduced desire, motivation, persistence
which enzyme does smoking induce?
CYP1A2
what are the effects of smoking on AP treatment?
affects metabolism of olanzapine and clozapine
may decrease some ADEs of AP through nicotine-dept activation of DA neurons
what are some risk factors of suicide in schizophrenic pts?
depressive symptoms
young age
high socioeconomic status
high premorbid functioning
early onset
chronic deteriorating course
what lab and diagnostic work up is required in schizophrenia diagnosis?
CBC, serum electrolytes, glucose, BUN, SCr, Ca, Mg, P, LFTs, TSH
screen for syphilis, Hep C, HIV (high risk pts)
ECG
urinalysis and urine tox screen
if appropriate:
- CXR
- CT scan/MRI of head
- lumbar puncture
- sleep deprived EEG
what is the diagnostic criteria for schizophrenia?
2 or more of the following each present for a significant period of time during a 1 month period - at least one of these must be 1, 2 or 3
1. delusions
2. hallucinations
3. disorganised speech
4. grossly disorganised or catatonic behaviour
5. negative symptoms
level of social/occupational functioning is markedly below what is was prior to onset
continuous signs of disturbances persist for at least 6 months
which drugs can induced psychosis?
amphetamine and cocaine use and withdrawal
caffeine
bupropion
cannabis
chloroquine
efavirenz
ketamine
steroids
what is the main scale for measuring schizophrenia symptoms?
PANNS (positive and negative syndrome scale)
what is considered a clinical response on the PANNS?
20-25% decrease = minimally improved
40-50% decrease = much improved
70-80% decrease = very much improved
what are the main receptor targets of antipsychotics?
D2
5HT2A
muscarinic
alpha1
H1
which receptors do 1st generation antipsychotics act on?
D2 receptor antagonism
mixed receptor affinity at alpha, muscarinic, histamine receptors
which receptors do 2nd generation antipsychotics act on?
D2 receptor antagonism
5HT 2a/2C antagonism
mixed receptor affinity at alpha, muscarinic, histamine receptors
which receptors do 3rd generation antipsychotics act on?
D2 receptor partial agonism
5HT 2a antagonism
5HT 1a and 1c partial agonism
what are the major ADEs associated with each generation of APs?
1st gen: movement ADEs (EPS)
2nd gen: metabolic ADEs
3rd gen: akathisia
what is the therapeutic effect of D2 antagonism?
antipsychotic effects
improve positive symptoms
what are the ADEs associated with D2 antagonism?
EPS: parkinsonism, akathisia, dystonic reactions, tardive dyskinesia
elevated prolactin: gynecomastia, amenorrhea, impotence, osteoporosis
sexual dysfunction
what is the therapeutic effect of 5HT 2a/2c antagonism and 1a agonism?
2A and 2C: antipsychotic effect
theoretically improve negative symptoms improve negative symptoms through increased dopamine release in mesocortical pathway
1A: anxiolytic
what are the ADEs associated with 5HT antagonism/agonism in APs?
hypotension
sedation
sexual dysfunction
what is the therapeutic effect of alpha1& antagonism?
none
what are the ADEs associated with alpha1&2 antagonism?
a1: postural hypotension, dizziness, reflex tachycardia, sedation, incontinence, drooling
a2: sexual dysfunction
what are the therapeutic effect of muscarinic antagonism?
none
potentiation of drugs with anticholinergic properties
what are the ADEs associated with muscarinic antagonism?
dry mouth
blurred vision
constipation
urinary retention
confusion/memory disturbances
what are the therapeutic effects of H1 antagonism?
none
potentiates the effects of other CNS depressant drugs
what are the ADEs associated with H1 antagonism?
sedation, drowsiness
postural hypotension
weight gain
what are the 1st generation antipsychotics? (10)
chlorpromazine
flupentixol
fluphenazine
haloperidol
loxapine
methotrimeprazine
perphenazine
pimozide
trifluoperazine
zuclopenthixol
what is the difference between higher potency FGAs and lower potency FGAs in regards to ADEs?
high potency = higher risk of movement disorders and weaker anticholinergic effects
low potency = lower risk of movement disorders and stronger anticholinergic effects
which FGAs are more sedating: high potency or low potency?
low potency
what are the signs of pseudoparkinsonism?
stooped posture
shuffling gait
rigidity
bradykinesia
tremors at rest
pill-rolling motion of the hand
what are the signs of akathisia?
restless
trouble standing still
paces on floor
feet in constant motion, rocking back and forth
what are the signs of acute dystonia?
facial grimacing
involuntary upward eye movement
muscle spasms of the tongue, face, neck, and back
laryngeal spasms
what are the signs of tardive dyskinesia?
protrusion and rolling of the tongue
sucking and smacking movements of the lips
chewing motion
facial dyskinesia
involuntary movements of the body and extremities
which FGA has the highest risk of EPS?
haloperidol
what are the second generation antipsychotics? (8)
asenapine
clozapine
lurasidone
olanzapine
paliperidone
quetiapine
risperidone
ziprasidone
what makes an antipsychotic atypical?
adding 5HT2A antagonism/inverse agonist actions
which symptoms do atypicals improve over typical antipsychotics?
negative symptoms due to enhanced D release in mesocortical area of brain
which SGA has the least risk of EPS?
clozapine
which receptors does risperidone bind to?
high affinity for D2, 5HT2 and alpha-adrenergic receptors
low affinity for alpha2 and H1
NO affinity for muscarinic receptors
at which does does risperidone have FGA features?
> 8 mg/d
what is the dosing of PO risperidone?
initial: 1-2mg/d (OD or BID) (0.5 in elderly)
increase to 4-6 mg/d
what is the prominent ADE associated with risperidone?
increased prolactin/sexual dysfunction
which kinds of tablet does paliperidone PO have?
OROS technology like concerta
what is the dosing of PO paliperidone?
3-12 mg
maintenance = 6 mg once daily
why is initial use of olanzapine limited?
due to metabolic ADEs
what is the dosing of olanzapine?
initial: 5-10mg PO OD
usual dose: 10-20 mg PO OD
max: 20-40 mg PO OD
what is the prominent ADE associated with olanzapine?
metabolic
- weight gain (>10 lbs)
- increased risk of T2DM, dyslipidemia
what is an important DI of olanzapine
smoking
what is the max dosing of quetiapine?
800 mg (1200 mg)/day
how does quetiapine dosing in psychosis compare to dosing in other conditions?
much higher
psychosis doses > depression doses > hypnotic doses
what is the prominent ADE associated with quetiapine?
increased risk of T2DM and dyslipidemia
which SGA needs to be taken with >500 calories of food?
ziprasidone
what is the dosing of ziprasidone?
initial: 40mg PO BID (20 mg PO BID in AP naive pts)
titrat4e to 120-160mg/d
what is the prominent ADE associated with ziprasidone?
conditional risk of QT prolongation
what are some CI with ziprasidone?
QT prolongation
recent MI
uncompensated heart failure
concurrent QT prolonging agents
what is the SGA with the most metabolic risk?
olanzapine
what is the dosing of asenapine?
initial: 5 mg BID
max: 10 mg BID
what is the prominent ADE associated with asenapine?
mouth numbness x 1 hr post dose (hypoesthesia)
which SGA has the least metabolic concerns?
lurasidone
what is the dosing of lurasidone?
40 mg PO with food (350 cal)
titrate prn to 120-160 mg PO OD
which antipsychotics must be taken with food?
ziprasidone (500 cal)
lurasidone (350 cal)
what are the 3rd generation APs? (3)
aripiprazole
brexpiprazole
cariprazine
which 3rd gen AP has the highest risk of akathisia?
aripiprazole
what is the goldilocks principle? which class of AP does it pertain to?
in high levels of dopamine production (positive symptoms) it acts as an antagonist
in low levels of dopamine production (negative symptoms) it acts as an agonist
3rd gen APs (aripiprazole)
what is the dosing of aripiprazole?
10-15 mg PO OD (max = 30mg/d)
what is the half life of aripiprazole? what is its consequences?
t1/2 = 75 h
do not increase dose faster than q2w
what is the prominent ADE associated with aripiprazole?
akathisia
what is the dosing of brexpiprazole?
initial: 1 mg OD
target dose: 2-4 mg/d
what is the half life of brexpiprazole?
91 h
what are the receptor actions of cariprazine?
high affinity partial agonist at D3 + D2
at low doses –> higher affinity for D3 > D2
high affinity partial agonist at 5HT1A
antagonist at 5HT2A, 5HT2B
what is unique about cariprazine receptors actions?
D3 partial agonism
what does D3 antagonism and agonism do?
antagonism: block activity of somatodendritic D3 receptors
partial agonism: antagonist at high levels of DA, agonist at low levels of DA
T or F
cariprazine has little protein binding
false
91-97% protein bound
what is the dosing of cariprazine?
recommended dosing range: 1.5 mg to 6 mg OD
max: 6mg/d
T or F
SGAs are more efficacious than FGAs
false
equal efficacy but more ADEs (EPS) associated with FGAs
when are LAIAs considered?
to improve adherence
may be considered if a patient relapses due to nonadherence or if pt prefers injection
what is important to consider before initiating LAIA therapy?
must establish safety on oral therapy first
what are the benefits of LAIAs?
decreased risk of relapse
decreased hospitalisation
decreased pt/caregiver burden
increased interactions with healthcare team/rapport
increased adherence
which FGAs are available as LAIs and how often are they administered?
flupentixol q4w
haloperidol q4w
zuclopentixol q2w
what 2nd generation APs have LAIs and how often are they administered?
paliperidone
- invega sustenna q4w
- invega trinza q3m
risperidone q2w
which 3rd generation APs are available as LAIs and how often are they administered?
aripiprazole q4w
how long of an oral overlap does ambilify maintena require?
2 weeks
how long of an oral overlap does paliperidone LAI require?
none required
how long of an oral overlap does risperidone LAI require?
3 weeks
what are the general monitoring parameters for APs?
vitals
behaviour (improved psychosis and signs of toxicity: CNS changes, anticholinergic efects, EPSE, sexual dysfunction, hyperprolactinemia sx
CBC at baseline and then prn
LFTs at baseline, 1 mo then q6-12mo
ECG at baseline then prn
why is early detection and treatment of schizophrenia critical?
decreased depression
increased mood/cognitive scores
increased overall function at 10 years
what is the treatment duration of first episode psychosis?
minimum 18 months
indefinite therapy reasonable
what do you do for an acute exacerbation of psychosis?
1: screen for nonadherence, substance use, DIs
2: increase or change AP x 6-8 weeks to determine effect
what is considered an adequate AP trial?
6-8 weeks at optimally tolerated dose
T or F
risk of re-hospitalisation or death increase when duration of AP treatment prior to d/c gets longer
true
may relate to AP-induced neurologic changes
what is first line therapy for treatment resistant schizophrenia?
clozapine
what are the most distinctive receptor interactions with clozapine?
D4
5HT2a
alpha1
M1
what is the response rate of clozapine in TRS?
30%
what is the most effective antipsychotics for treatment resistant schizophrenia?
clozapine
what are the common side effects with clozapine?
constipation
blurred vision
dizziness
drooling
drowsiness
weight gain
increased cholesterol and/or blood sugar
tachycardia and orthostatic hypotension
what are some serious side effects of clozapine?
agranulocytosis
myocarditis
cardiomyopathy
constipation
seizures
neuroleptic malignant syndrome
at what WBC count does neutropenia occur?
< 1.5 x 10^9/L
what is the mortality rate of clozapine-induced myocarditis?
10-23%
when is agranulocytosis most likely to occur in clozapine treatment?
first 6 months
when is myocarditis most likely to occur in clozapine treatment?
4-8 weeks
when is cardiomyopathy most likely to occur in clozapine treatment?
months to years of treatment
what is myocarditis?
allergic like reaction causing inflammation of the heart muscle
what is cardiomyopathy?
disease of the heart muscle that makes it harder for the heart to pump blood to the rest of the body
what are we monitoring for to detect myocarditis and cardiomyopathy in clozapine treatment?
orthostatic BP changes
fatigue and decreased exercise tolerance
chest pain/discomfort/pressure
palpitations with increased HR
SOB
peripheral edema
fever
high sensitivity troponin T
CRP
what does high levels of troponin indicate?
the higher the level there is the more damage there is to the heart
what does a high CRP indicate?
inflammation somewhere in the body
what specific blood level is being measured in clozapine therapy?
absolute neutrophil count (ANC)
T or F
agranulocytosis caused by clozapine in not reversible
false
reversible upon d/c
why do pts on clozapine need to be registered with a clozapine registry before beginning therapy?
due to agranulocytosis
how often are blood tests needed with clozapine therapy?
weekly for first 6 months
change to every 2 weeks if green light has been maintained during first 6 months of therapy and pt is clinically stable
change to every 4 weeks if green light for another 6 months
every 4 weeks for as long as on therapy and for 4 weeks after stopping
how many missed doses of clozapine warrants a re-titration?
> 48 hours missed
if clozapine therapy is missed for more than 3 days, how does this effect blood testing?
resume weekly testing for additional 6 weeks
what is a green clozapine level and what does it mean?
ANC ≥2.0 x 10^9/L
continue to dispense
what is a yellow alert clozapine level and what does it mean?
1.5 x 10^9/L ≤ ANC <2.0 x 10^9/L
blood monitoring at least twice a week until stabilised
continue to dispense
what is a red alert clozapine level and what does it mean?
ANC < 1.5 x 10^9/L
immediately withhold and monitor patient closely
at what ANC level should protective isolation be considered?
ANC < 0.5 x 10^9/L
when is clozapine considered non-rechallengable?
total WBC <2.0 x 10^9 or ANC <1.5 x 10^9 from clozapine therapy
what is the dosing of clozapine?
initial: 12.5-25 mg/d
increase by 12.5-25 mg on 2nd day then 25-50mg daily
usual: 300-600 mg PO/d - after 2 weeks
max: 900 mg/d
divided in 1-3 doses/d
T or F
clozapine brands are interchangable?
false
T or F
smoking cessation is recommended with somebody on clozapine?
false
smoking lowers the effect of clozapine and cessation can cause toxicity
T or F
clozapine reduces suicidality in schizophrenia?
true
what is considered clozapine-resistant (ultra-resistant) schizophrenia?
8-12 weeks at doses of ≥400mg/d and trough level ≥350ng/mL for once daily dosing or ≥250 ng/mL for BID dosing
what is the treatment of clozapine resistant schizophrenia?
no consensus on best
aripiprazole, fluoxetine, valproate for total psychosis, memantine for negative symptoms
ECT
what are some examples of pyramidal movement syndromes?
paralysis, paresis, hyperreflexia, and spasticity
what is the difference between pyramidal and extrapyramidal symptoms?
pyramidal is precisely demarcated pathways and are voluntary
extrapyramidal is hypothesized pathways and involuntary
what is the difference between acute extrapyrimidal effects and tardive syndromes?
tardive syndromes appear late in treatment
