schizophrenia/psychotic disorders Flashcards
gene-environment interaction in developing schizophrenia
CMOT-marijuana
schizophrenia symptoms
positive: respond well to drug therapy; ex: hallucinations, delusions, bizarre behavior, thought disorders
negative: little response to drug therapy, newer agents are better; ex: blunted emotion, poor self care, social withdrawal, poverty in speech
cognitive: decrease in cognitive fxn, involves D1 receptors and glutamate receptors
receptors involved in schizophrenia
serotonin, dopamine, glutatamte
presynaptic agonists ___ NT concentration
decrease synthesis and release
cell tells itself that it’s releasing too much
presynaptic antagonists ___ NT conc
increase synthesis and release
dopamine antagonist use in schizophrenia
block presynaptic receptors - increase synthesis and release - also bock post synaptic receptors - dopamine cannot be used
dopamine originally increases, but basal levels change and the conc returns to normal
actions of D2 antagonists in CNS
basal ganglia: motor effects, extrapyramidal symptoms (EPS)
mesolimbic (best): therapeutic and decrease in cognition
mesocortical: hypofunction in schizophrenia, antagonists may exacerbate cognitive deficits
hypothalamus and endocrine systems: D2 receptor blockade in endocrine system
medulla: chemoreceptor trigger zone; D2 antagonists are anti-emetics
when we occupy __% of the dopamine receptors, we occupy __% of ___
50;10 90;50 histamine receptors sedation and weight gain we need 70% occupancy to see therapeutic efficacy
EPS Sx and drug therapy
dystonia, pseudoparkinsonism, tremor, akathisia
benztropine, trihexyphenidyl, akineton - anticholenergic
diphenhydramine - antihistamine
amantadine - dopamine releasing agent
tardive dyskinesia
SE of antipsychotics
occur late, IRREVERSIBLE
Sxs: rhyhmic involuntary movements of the mouth, choreiform (irregular purposelessness), athetoid (worm-like), axial hyperkinesias (to and fro movements)
unkown MOA
monitor with AIMS q6mo
treatment: prevention, use least risky agent at lowest dose possibe and monitor (reduce dose, change to a different drug, eliminate anticholinergic drugs)
neuroleptic malignant syndrome (NMS)
serious and rapid; 10% fatality
symptoms: EPS symptoms with fever, impaired cognition
treatment: restore dopamine balance; d/c drug, DA agonists, diazepam or dantrolene
antipsychotic AEs
autonomic: loss of accomidation, dry mouth, difficulty urinating, constipation
CNS: parkinsons, akathisia, dystonia, tadrive dyskinesia, toxic confusional state, sedation
endocrine: amenorrhea-galactorrhea, infertility, impotence
other: weight gain
antipsychotic precautions and CIS
CV: increased QT prolongation
parkinsons
epilepsy (clozapine lowers seizure threshold)
diabetes (newer agents)
high D/5HT2a ratio leads to
EPS
aliphatic phenothiazines
1st generation antipsychotic
chlorpromazine, promezine, triflupromazine
used for H1 antagonist properties: promethazine, trimeprazine
piperidine phenothiazines
1st generation antipsychotic
mesoridazine, thioridazine (sedation, hypotension, anticholinergic, many SE)
fluphenazine, trifluoperazine, prochlorperazine, triethylperazine, perphenazine
thioxanthines
1st generation antipsychotic
thiothixene (modest EPS), chlorprothixene
butyrophenones
1st generation antipsychotic
haloperidol (EPS), droperidol (sedative), droperidol with fentayl
misc 1st generation antipsychotics
molindone - moderate EPS
pimozide
atypical/second generation antipsychotics
reduced EPS, efficacy for negative symptoms, similar or enhanced 5HT2A receptor antagonism vs D2
more metabolic problems - diabetes
affect multiple receptors, potency at D2 and 5HT2A, affinity at 2A is responsible for dec EPS
clozapine
atypical/second generation antipsychotics
most effective
2nd or 3rd line be it causes *agranolocytosis
SE: anticholinergic, antihistamine
decreased movement disorders, risk of diabetes
olanzapine
atypical/second generation antipsychotics
weight gain, less like to cause NV and movement disorders, risk of diabetes
loxapine
atypical/second generation antipsychotics
older agent
antidepressant
quetapine
atypical/second generation antipsychotics
antidepressant activity
low EPS, hypotension, sedation, risk of diabetes
risperidone
5HT2A and D2 antagonist
low EPS at 8 mg/day
weight gain/sedation
ziprasidone
atypical/second generation antipsychotics
prolongs QT interval
lurasidone
atypical/second generation antipsychotics
less weight gain and metabolic effects
fast onset
low doses similar effectiveness to high doses
aripiprazole
atypical/second generation antipsychotics/ “third generation”
high affinity for 5HT2A and D2, D2 actions are dopamingeric-state dependent and/or it is functionally selective
brexpiprazole
D2/D3 partial agonist
*less akathisia than aripiprazole
used for schizophrenia and as an adjunct to antidepressants for major depression
cariprazine
**Once daily dosing (long t1/2 – 48 – 96 hours; active metabolite 1 – 3 weeks); moderate risk of weight gain; high risk of akathisia; high receptor binding affinity; P450 3A4 substrate (minimal 2D6, 20% renal elimination); not recommended in severe hepatic impairment or CrCl under 30 mL/min; max dose = 6 mg once daily – higher doses not more effective, but greater risk of akathisia. (brand only
key features of psychotic disorders
delusions, hallucinations, disorganized thinking (speech), disorganized or abnormal motor behavior, negative symptoms
most effective antipsychotic
clozapine - issue: granulocytosis
consideration when choosing an antipsychotic
doses per day
side effects - tolerance, other disease states, risk factors?
previous drug therapy - success or failure? family members? what did they take?
cost of therapy - payer source? PO or IM?
concomitant therapy
monitoring - labs? weight? EKG?
smoker? more than 7 cigarettes/day will wipe out anything metabolized by 1A2
Fluphenazine
injection: q2weeks, 10 mg PO = 12.5 mg IM, NO OVERLAP, oil-based (z-track)
haloperidol
injection: q4weeks,
load: 20 times oral dose, maintenance: 10 times oral dose
oil-based, need to z-track
Loxapine
Adasuve®
dosage form: capsule or Oral inhalation powder: 10mg/dose
dosing: Oral inhalation powder:
10mg dose per 24 hour
period
“Atypical Typical”
Adasuve® oral inhalation powder has a REMS – must be given in hospital setting with access to emergency services, contraindicated with history of lung disease; monitor closely for bronchospasm
perphenazine
Increased use in recent years
due to CATIE study
pimozide
3A4 substrate
QTc prolongation limits use; usual clinical use limited to Tourette’s disorder
Thioridazine
**Significant QTc prolongation limits use; not generally initiated as new therapy; informed consent necessary
Thiothixene
1A2 substrate
aripiprazole
**Once daily dosing (long t1/2 – 72 – 96 hours); akathisia/anxiety side effects prominent; low risk of weight gain or metabolic syndrome; high receptor binding affinity; P450 2D6 and 3A4 substrate; LAIs (Abilify Maintena and Aristada) have dosing adjustments when using with strong 2D6 or 3A4 inhibitors or 3A4 inducers; LAI must have 2 (Abilify Maintena) or 3 (Aristada) week oral overlap
asenapine
**Sublingual only; poor oral bioavailability; moderate weight gain; metabolic syndrome; QTc prolongation warning; P450 **1A2 substrate (brand only so expensive); nonadherence a problem due to metallic taste and unit-dose packaging that patients have trouble with; smoking decreases concentration; caffeine can increase; ? Efficacy for negative symptoms – some positive evidence
brexpiprazole
**Once daily dosing (long t1/2 - ~ 91 hours with multiple doses), moderate risk of weight gain (more
than aripiprazole); akathisia (less than aripiprazole); high receptor binding affinity; P450 2D6 and 3A4
substrate – dosing adjustments with strong 2D6/3A4 inhibitors and 3A4 inducers; max dose reduction
to 3 mg daily (usual max 4 mg daily) with moderate to severe hepatic dysfunction or CrCl under 60
mL/min) (brand only – expensive)
clozapine
**MOST EFFECTIVE; significant side effects requiring slow dose titration – agranulocytosis
(required REMS monitoring), *cardiomyopathy, hypersalivation, hypotension, metabolic syndrome,
*dose-related seizures; QTc prolongation, constipation, sedation; P450 1A2 substrate (3A4 minor);
REMS – must monitor ANC weekly x 6 months, biweekly x 6 months, then every 4 weeks
iloperidone
**Boxed warning for QTc prolongation; orthostatic hypotension requiring slow dose titration with necessary twice daily dosing; moderate weight gain; metabolic syndrome; P450 2D6 and 3A4 substrate; (brand only – expensive)
lurasidone
**Once daily dosing (t1/2 – 18 hours); MUST take with food (meal) to improve bioavailability; prominent akathisia; low risk of weight gain/metabolic syndrome; P450 3A4 substrate; Usual max dose = 160 mg; moderate hepatic impairment or CrCl under 50 mL/min – max dose = 80 mg; severe hepatic impairment – max dose = 40 mg
olanzapine
**Once or twice daily dosing; if daily, give at bedtime (high risk of sedation); significant weight gain,
hyperglycemia, hyperlipidemia, metabolic syndrome risk; anticholinergic at higher doses (> 15
mg/day); P450 1A2 substrate; LAI – Zyprexa Relprevv – REMS requiring patient consent to
treatment and monitoring after dose
paliperidone
**9-OH metabolite of risperidone; once daily dosing (t1/2 - 23 hours); ER dosage form – ghost tablet; renal elimination – dose adjustment in renal impairment; higher risk of EPS and hyperprolactinemia;
moderate weight gain/metabolic syndrome; QTc prolongation warning; LAIs – Invega Sustenna – given IM every 4 weeks; Invega Trinza – given IM every 12 weeks
quetiapine
**Broad dose range (300 – 800 mg daily); short t1/2 but still give once daily if possible; significant sedation; **QTc prolongation boxed warning; moderate risk of weight gain/metabolic syndrome; P450 **3A4 substrate; abuse potential – used to “come down” from stimulants/cocaine; can be abused for its own effects – similar to benzodiazepines; (XR dosage form - brand)
risperidone
**Often seen as first-line treatment; once daily dosing usual; **higher risk of EPS and hyperprolactinemia; moderate risk of weight gain/metabolic syndrome; P450 **2D6 substrate (produces paliperidone); LAI – Risperdal Consta – given 25 mg IM every 2 weeks; must supplement with oral risperidone/antipsychotic for first few weeks
ziprasidone
**Twice daily (but can be given once daily); MUST be taken with food (meal) to improve
bioavailability; *lower risk of weight gain/metabolic syndrome; low risk of akathisia; no significant
P450 metabolism; QTc prolongation warning; *DRESS warning from post-marketing surveillance
invega sustenna
234mg loading dose on day 1; 156mg booster on day 8; 117mg 5 weeks after loading dose (then every 4 weeks); this strategy followed = no oral overlap required
zyprexa relprevv injection
side effects similar to oral olanzapine
**PDSS (post-dose delirium sedation syndrome): significant sedation, patient may not pick up dose; patient must stay in clinic and have side effect monitoring for 3 hours; must have accompanied ride home
May required oral overlap indefinitely
immediate release antipsychotics
haloperidol*, chlorpromazine, fluphenazide all w lorazepam
ziprasidone, aripiprazole can be given with lorazepam
olanzipine CANNOT be given with lorazepam
EPS etiology and treatments
acute dystonia: young, black, male, treat w IM anticholinergic NOW (benztropine, diphenhydramine)
drug-induced parkinsons: oral anticholinergic (benztopine, diphenhydramine, trihexyphenidyl), amandatine
akathisia: restlessness, inc suicidal thoughts/behaviors, betablocker (**propranolol 20 mg BID), benzodiazepine (lorazepam), oral anticholinergic, lower dose of antipsychotic
tardive dyskinesia - lower dose of antipsychotic or switch
neuroleptic malignant syndrome
Life-threatening = medical emergency
Caused by effects of antipsychotics on dopamine blockade
Hyperpyrexia, tachycardia, labile blood pressure
Treatment: supportive, discontinue antipsychotics, consider dopamine agonists
metabolic adverse effects
hyperglycemia, hyperlipidemia, hypertension, weight gain
Most: clozapine and olanzapine
Moderate: quetiapine, risperidone, paliperidone, asenapine, iloperidone
Low to No Risk: ziprasidone, lurasidone, aripiprazole
Must monitor: weight, waist circumference, **fasting blood glucose, A1C, fasting lipids
metabolic monitoring
personal/family hx - baseline and yearly
weight - baseline, q4 weeks, q 3 mo
waist circumference - baseline and yearly
BP - baseline, 12 weeks, yearly
FPG/A1c - baseline, 12 weeks, yearly
fasting lipids - baseline, 12 weeks, every 5 years
disease course
*men: late teens, early 20s
*women: late 20s, early 30s
aging patients: less psychosis, more negative and cognitive Sxs
“typical” antipsychotic pearls
Haloperidol used most often- PRN and maintenance
More EPS with higher potency typical
Often used after failure of aytpicals
polypharmacy
Must have failed 2 courses of monotherapy and clozapine (unless reason not to take it) before polypharmacy
Common in clinical practice, some patients may require it
other drug related info
- *Aripiprazole: FDA-approved for major depressive disorder in combination with anti-depressant
- *Clozapine: WBC/ANC must be monitored weekly x 6 weeks, every 2 weeks x 6 weeks, then every 4 weeks to maintain ANC >2000
- *Quetiapine: recent boxed warning for QTc prolongation
