Transcript Secondary Stroke Prevention: Implications of the MATCH Trial

Antipsychotic Review
Jena L. Ivey, PharmD, BCPS, CPP
Objectives
1. Review different antipsychotic agents with
regard to efficacy and safety
2. Discuss adverse effect profiles of
antipsychotic agents and learn how to
pick the “best” one for your patient if
needed
Antipsychotic Use in Older Adults
o Decreased metabolism can lead to increased blood levels
and increased side effects
o Decreased absorption can lead to decreased blood levels
and reduced effectiveness
o Brain changes with aging can lead to heightened sensitivity
to side effects (e.g. EPS) and reduced effectiveness
o Cognitive impairment can lead to nonadherence
Antipsychotics
o Choice of traditional vs. new generation drugs
o Side effect profiles often direct selection
o EPS, TD, NMS less likely with newer agents
o Efficacy against negative symptoms (when relevant) is
higher with the new drugs (probably related to 5HT-2
antagonism)
o 22% of Nursing home patients
Traditional Antipsychotics
o All have tendency to produce EPS/TD
o Low potency drugs are usually highly
sedating, highly anticholinergic and promote
orthostasis
o Orthostatic hypotension is related to alpha-1
blocking effects and correlates highly with hip FX
o Low cost is an advantage
Typical Antipsychotics
Chlorpromazine
– Prototype typical antipsychotic
– Only able to substantially improve positive
symptoms, little effect on negative symptoms
and many adverse effects
– Equivalent doses of other typical
antipsychotics based on 100 mg of
chlorpromazine
Typical Antipsychotics
Low potency
– Chlorpromazine
– Thioridazine
– Mesoridazine
Mid potency
– Molindone
– Loxapine
– Perphenazine
High potency
–
–
–
–
Haloperidol
Fluphenazine
Thiothixene
Trifluoperazine
Pharmacological Profile for
Haloperidol
Affects alpha, dopamine-2 receptors
Oral, depot formulations
Oral
– Start 0.5 mg daily, increase to 30 mg
maximum per day in divided doses
Depot (haloperidol decanoate)
– Given usually once monthly
– Must been stable on oral dose first
Why Use Depot?
Compliance
– Once weekly dosing
Convenience
Side effects
– Lacks peak concentrations
– Gives lower but steady concentrations
Perphenazine
Mid potency typical antipsychotic
– Less EPS over high potency
– Less affinity for muscarinic, alpha, and
histaminic receptors over low potency
Max dose= 64 mg
Average dose in chronic schizophrenics
– 32 mg/day
Traditional Antipschotics
Type
Sedation
EPS
Anticholinergic
Cardiovascular
High
Mod
Mod
High
Mod
Mod-High
Mod
Low
Very Low
Very High
Very Low
Very Low
Low Potency
Chlorpromazine
Mid Potency
Perphenazine
High Potency
Haloperidol
Efficacy of Typical
Antipsychotics
Most benefit seen with positive symptoms
Limited benefit with negative symptoms
May worsen negative or cognitive
symptoms, especially in high doses
Have fallen out of favor as first-line agents
Atypical Antipsychotics
Improve psychotic
symptoms
Improve or not
worsen negative
symptoms
May improve
cognition
Cause less or no EPS
Cause less or no
tardive dyskinesia
Effective in refractory
patients
Decision of Antipsychotic
Atypical agents are now accepted to be first-line treatment
Considered ‘first-line’ now, but anticholinergic effects,
orthostasis and COST are important factors in older
adults
Treatment choice based on:
– Past response or past side effects to individual agents and
number of treatment failures
– Patient or practitioner preference
– Problems with EPS or tardive dyskinesia
– Other concomitant disease states
– Compliance issues
Available Atypical Antipsychotics
Clozapine
Risperidone
Paliperidone
Olanzapine
Quetiapine
Ziprasidone
Aripiprazole
Clozapine
Not a first-line agent
Must have failed at least two other trials of antipsychotics
Difficult to tolerate due to adverse drug effects
Baseline work-up
CBC with diff (WBC, ANC)
Cardiac history
– EKG
FLP
Weight/BMI
FPG and/or HgbA1c
Clozapine – Adverse Effects
Black Box Warnings
–
–
–
–
–
Hypotension
Seizure
Agranulocytosis
Myocarditis
Risk of death in elderly demented patients with
psychosis
Significant potential for metabolic dysregulations
Others: sedation, constipation, tachycardia
Clozapine Agranulocytosis
1% incidence
More frequently occurs early in therapy
Monitor CBC weekly for first 6 months, every two weeks
for next 6 months, then every 4 weeks thereafter
Must be registered to receive clozapine
Do not rechallenge if patient has experienced
agranulocytosis to clozapine in the past
– ANC<1000
Risperidone (Risperdal)
Mixed serotonin-dopamine antagonist activity
Also antagonizes alpha-2, histamine receptors
Baseline work-up
Cardiac history
– EKG
FLP
Weight/BMI
FPG and/or HgbA1c
Black Box
– risk of death in elderly demented patients with psychosis
Risperidone – Adverse Effects
Lower EPS than with typical antipsychotics
like haloperidol
– Risk of EPS higher with doses greater than 6
mg/day
Prolactin elevation
Orthostasis
Tachycardia
Risperidone Decanoate
Only long-acting atypical antipsychotic
injection
– Compliance
Gluteal injection
Polymeric microspheres
Main release at 3 weeks
– Single dose maintained for 4-6 weeks
Paliperidone (Invega)
Major metabolite (9-OH) of risperidone
Innovative delivery system
– Delivers smooth plasma levels over 24 hrs
Baseline work-up
Similar to Risperidone
Black Box
– risk of death in elderly demented patients with
psychosis
Paliperidone
Comparison to risperidone
– Less peak/trough fluctuations, possibly less
side effects due to fluctuations
– “Once-daily” dosing
– No CYP 2D6 interactions (e.g. paroxetine,
fluoxetine, poor metabolizers)
– Better choice for patients w/liver dysfunction
Phase II metabolism
Olanzapine (Zyprexa)
Potent antagonist of several serotonin receptors,
dopaminergic, muscarinic, histaminergic, and
alpha
Baseline work-up
Similar to risperidone PLUS
– LFTS
Black Box
– risk of death in elderly demented patients with
psychosis
Olanzapine – Adverse Effects
Significant potential for metabolic
dysregulations
Sedation
Anticholinergic effects
Tachycardia
EPS less than with risperidone
– monitor for akathisia at higher doses (>15mg)
Olanzapine – IM
For control of acute agitation in
schizophrenic and bipolar patients
Calming without oversedation
Can give Q 2-4 hours
Risk of bradycardia and orthostasis
– Do not give within 1 hour of IM/IV lorazepam
Quetiapine (Seroquel)
Antagonist of serotonin, dopamine receptors,
some effect on histamine/alpha receptors
Baseline work-up
Similar to risperidone PLUS:
– CBC in pre-existing low WBC or h/o drug-induced
neutropenia
Black Box
– Risk of death in elderly demented patients with
psychosis
Quetiapine – Adverse Effects
EPS appears to be less due to less effect on dopamine
(loose and transient binding to dopamine receptors)
Sedation/fatigue
Orthostasis
Anticholinergic effects at doses >300-400mg
Tachycardia
Increased LFTs (transient)
Ziprasidone (Geodon)
High affinity for serotonin receptors, moderate dopamine/histamine,
no affinity for alpha/beta
Baseline work-up
Similar to risperidone PLUS
– Electrolytes
Black Box
– Risk of death in elderly demented patients with psychosis
Contraindicated
– H/O arrhythmias or QTc prolongation
– Uncompensated heart failure
– Acute or recent myocardial infarction
Ziprasidone – Adverse Effects
EPS versus “activation”
Minimal effects on metabolic profile
EKG changes
– QTc prolongation
Ziprasidone – Intramuscular
For acute psychotic agitation
Calming without oversedation
Can give Q 2-4 hours
Can give with IM/IV lorazepam
Aripiprazole (Abilify)
Dopamine-2 partial agonist, partial serotonin-1A
agonist
Baseline work-up
Similar to risperidone
Black Box
– Risk of death in elderly demented patients with
psychosis
– Risk of increased suicidal behavior similar to
antidepressants labeling
FDA approval for adjunct therapy in MDD
Aripiprazole – Adverse Effects
EPS initially presumed minimal
– Akathisia versus anxiety, restlessness
Minimal effects on metabolic profile
Nausea
Headache
Aripiprazole – IM
For acute agitation in patients with
schizophrenia or bipolar d/o
Calming without oversedation
Can give Q 2 hours
Can give with IV/IM lorazepam
Dosing
Drug
Initial Doses in
Dementia Pts
Clozapine
25mg
* Initial dosing BID-TID
minimizes side effects
Olanzapine
Oral
2.5-5mg (start Qday
dosing at HS)
Quetiapine
12.5-25mg (start
Qday dosing at HS)
Usual Ranges for
Psychotic D/O
300-450mg
Max: 900mg
Oral
10-30mg
Max 20mg
IM (short-acting)
5-10mg
Max: 30mg/24 hrs
300-800mg
Max: 800mg
Dosing
Drug
Initial Doses in
Dementia Pts
Usual Ranges for
Psychotic D/O
Risperidone
Oral
0.25-0.5mg
Oral
2-6mg
Max 16mg^
IM (long-acting)
25-50mg
Max: 50mg
Administer q 2
weeks
IM (long-acting)
12.5-25mg
Paliperidone
3mg
6-12mg
Max: 12mg
* Absorption increased
with high fat meal
^ Max dose per Product Labeling; risk of EPS higher with doses > 6mg
Dosing
Drug
Initial Doses in
Dementia Pts
Usual Ranges for
Psychotic D/O
Aripiprazole
Oral
2-5mg
Oral
10-20mg
Max: 30mg
IM (short-acting)
9.75mg
Max: 30mg/24hrs
Ziprasidone
Oral
20mg
Oral
120-200mg
Max: 200mg
IM (short-acting)
10-20mg
Max: 40 mg/24hrs
* Absorption increased
with food
Antipsychotic Adverse Effects
Orthostatic Hypotension
o Vulnerability in older adults is increased because of
decreased sensitivity of baroreceptors in the carotid and BP
regulatory centers in the hypothalamus PLUS decreased
alpha-1 adrenergic receptors
o 30+% of institutionalized older adults display symptomatic
orthostatic hypotension
o Drugs cause this primarily by blocking alpha-1 receptors
o TCAs, MAOIs, antipsychotics (including many of the new
generation drugs) and lithium are all offenders
o Benzodiazepines can cause falls by producing
dysequilibrium rather than orthostasis
Falls/Hip Fractures
o
o
o
o
250,000 yearly
Most occur in women over age 65
90% are due to a fall from standing height!
50-60% of FXs in this age group require Nursing
Home placement and about 1/2 never leave
o Mortality rate at the end of 1 year is 20%
o Most falls are due to a combination of orthostasis,
dizziness, EPS, sedation, decreased vision and
dysequilibrium all of which can be caused or
exacerbated by psychotropics
Tardive Dyskinesia
o Risk much higher in older adults
o Incidence may be as high as 25% per year (versus
5% per year in younger patients)
o Older adults have increased severity and lower
spontaneous remission rates
o Risk factors: AGE, F>M, early-onset EPS, length
of neuroleptic exposure
o TX: empiric. ?branched-chain amino acids, vitamin
E, benzos
Antipsychotic Comparison
Haloperidol
Clozapine
Risperidone Olanzapine Ziprasidone
Antichol.
+
+++
+/-
++
0
EPS
+++
0
+
+/-
+
(esp IM)
Ortho.
+
+++
++
++
++
Sedation
+
+++
++
++
++
Prolactin
++
0
++
+
(transient)
+
(transient)
Lower Sz
Threshold
+
+++
+
+
+
Cl
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Ri
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O
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Q
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Relative Potency
Comparative Side Effects Of Atypical
Agents
Sedation
EPS
Antichol
Ortho
Atypicals and Weight Gain
 Lots of ways to look at this issue (total average wt gain, number of
patients with >10% initial body weight gain, length of weight gain,
types of weight gain)
 Risk of significant weight gain:
– Clozapine, olanzapine and quetiapine, high
– Risperidone, moderate
– Ziprasidone, aripiprazole, low
 Generally, thinner people gain more weight (lower BMI)
• weight gain seems to plateau at 3 yrs or so, but average weight gain is
in the 15 lb range
• weight gain may be less of a problem in the elderly
 However, even in low risk drugs like ziprasidone and aripiprazole,
certain individuals gained large amounts of weight according to
package insert date (7-8%)
How Do Atypicals Cause Weight Gain?
o Antihistamine effects (H1) : clozapine, olanzapine,
quetiapine are strong inhibitors
o 5HT2c blocking effects – Mice with this receptor ‘knocked
out’ are all obese – all atypicals are 5HT2c blockers
except aripiprazole
o Endocrine effects such as hyperprolactinemia may
contribute
o Genetic susceptibility (receptor polymorphisms)
Atypical Antipsychotics: Hyperglycemia
o Hyperglycemia has been seen with olanzapine &
clozapine
• Good prospective studies are lacking; DM in
schizophrenics increased dramatically after
neuroleptics introduced in 1950’s
• Schizophrenics may have impaired glucose
tolerance
• Insulin resistance may be the mechanism
• Monitor Hgb A1c every 3 months; Chol & TGs
every 6 months
Monitoring Protocolab
Variable
Baseline
4 weeks
12 weeks
x
Annually
x
Waist
circumfer.
x
Blood
Pressure
x
x
x
Fasting
Glucose
x
x
x
Fasting
Lipids
x
x
bMore
x
Quarterly
Weight
(BMI)
aBased
x
8 weeks
x
x
on American Diabetes Association Consensus statetment
frequent assessments may be necessary based on clinical status
Managing Side Effects
o Anticholinergic Effects
o fluids, sugarless gum, bowel regimen
o EPS
o lower dose of drug (esp. risperidone)
o drug holiday
o Hypotension
o rise slowly from bed, divide doses, increase salt intake,
TED hose, fludrocortisone in refractory cases
o Sedation: lower dose, modafanil (Provigil),
methylphenidate (Ritalin)
Prolongation of QTc interval
o QTc interval is time it takes the heart to repolarize,
corrected for heart rate
 440 msec upper limits of nomal; >480 definitely prolonged
o Tricyclics widen QRS & QTc intervals
o Drugs which may significantly prolong QTc include:
thioridazine , mesoridazine, ziprasidone, droperidol,
pimozide & ketoconozole - often metabolized by P4503A4
o Drugs which interfere with metabolism of these QTc
prolongers such as: Nefazodone (SERZONE),
fluvoxamine (LUVOX), cimetidine, erythromycin,
ketoconazole, norfluoxetine can cause problems
QTc Prolongation In Antipsychotics
o 2+ Pimozide, Mesoridazine, Thioridazine, Droperidol
o 1+ Ziprasidone, Clozapine, Loxapine, Thiothixene,
…...Chlorpromazine, Trifluoperazine, Risperidone,
…...Quetiapine
o +/- Olanzapine, Haloperidol, Fluphenazine
o RISK FACTORS:
• Female sex
• Congenital Long QT
• Ischemic heart disease
QTc Prolongation by Other Drugs
o Antidepressants:
Fluoxetine, Sertraline, Citalopram, Doxepin,
Desipramine, Amitriptyline, Maprotiline
o Non-psychiatric*:
Amiodarone, Ibutilide, Procainamide,
Inadapamide,Clarithromycin, Erythromycin, Cisapride
*partial list
QTc Recommendations*
1.
2.
Do not use thioridazine, mesoridazine or pimozide for
patients with known heart disease, hx of syncope, FH
of sudden death or congenital prolonged QT.
If ziprasidone is used for any of these patients, a
baseline ECG should be obtained before beginning
treatment. A subsequent ECG is indicated for
symptoms suggestive of a prolonged QT interval (e.g.
syncope)
* AJP, August 2004, pg 1334. (These are recs for patients with schizophrenia)
Stroke Risk - Antipsychotics
Some evidence to suggest increased risk of
cerebrovascular events and death seen in older patients
treated with antipsychotics for behavioral and
psychological symptoms of dementia
– Risperidone, olanzapine studied the most
Similar risk noted with atypical and typical agents
Studies are retrospective and the groups receiving and
not receiving antipsychotics may not be comparable for
the question being asked
Stroke Risk - Antipsychotics
Try non-drug modalities first
Educate family/patient on risks associated with use
Must weigh benefits of use with potential harms on caseby-case basis
Pharmacologic choices are limited in this population and
there is no evidence one way or the other whether other
pharmacologic agents used for these same purposes are
any safer
Selecting Atypical Antipsychotics
Specific Side Effect
Best Medication Choices to Avoid Specific Side
Effects
Sedation
ziprasidone, aripiprazole, risperidone/paliperidone
Weight gain/metabolic
side effects
aripiprazole, ziprasidone
EPS/tardive dyskinesia
clozapine>quetiapine>ziprasidone/aripiprazole>
olanzapine
Sexual/reproductive
All except risperidone/paliperidone
Anticholinergic effects
risperidone>ziprasidone>aripiprazole, quetiapine
(at low to medium doses)
J Clinical Psychiatry 1999;60:3-80