Antipsychotic Review Jena L. Ivey, PharmD, BCPS, CPP Objectives 1. Review different antipsychotic agents with regard to efficacy and safety 2.
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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 High potency – Haloperidol – Fluphenazine – Thiothixene – Trifluoperazine Mid potency – Molindone – Loxapine – Perphenazine
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
Type
Low Potency
Traditional Antipschotics
Sedation EPS Anticholinergic Cardiovascular Chlorpromazine High
Mid Potency
Perphenazine
High Potency
Mod Mod Mod Mod-High Mod High Low Haloperidol Very Low Very High Very Low Very Low
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 neutropenia
PLUS:
– CBC in pre-existing low WBC or h/o drug-induced
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
Drug Clozapine Olanzapine Quetiapine
Dosing
Initial Doses in Dementia Pts Usual Ranges for Psychotic D/O 25mg
* Initial dosing BID-TID minimizes side effects
Oral 2.5-5mg (start Qday dosing at HS) 300-450mg Max: 900mg Oral 10-30mg Max 20mg IM (short-acting) 5-10mg Max: 30mg/24 hrs 12.5-25mg (start Qday dosing at HS) 300-800mg Max: 800mg
Drug Risperidone
Dosing
Initial Doses in Dementia Pts Oral 0.25-0.5mg
IM (long-acting) 12.5-25mg Usual Ranges for Psychotic D/O Oral 2-6mg Max 16mg^ IM (long-acting) 25-50mg Max: 50mg
Administer q 2 weeks
Paliperidone 3mg
* Absorption increased with high fat meal
6-12mg Max: 12mg
^ Max dose per Product Labeling; risk of EPS higher with doses > 6mg
Drug Aripiprazole Ziprasidone
Dosing
Initial Doses in Dementia Pts Oral 2-5mg Usual Ranges for Psychotic D/O Oral 10-20mg Max: 30mg IM (short-acting) 9.75mg
Max: 30mg/24hrs Oral 20mg
* Absorption increased with food
Oral 120-200mg Max: 200mg IM (short-acting) 10-20mg Max: 40 mg/24hrs
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 generation drugs) and lithium (including many of the new are all offenders o Benzodiazepines can cause falls by producing dysequilibrium rather than orthostasis
Falls/Hip Fractures
o 250,000 yearly o o o o o 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 Mortality rate at the end of 1 year is 20% 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 o o o Risk much higher in older adults Incidence may be as high as 25% per year (versus 5% per year in younger patients) Older adults have increased severity and lower spontaneous remission rates
Risk factors
: AGE, F>M, early-onset EPS, length of neuroleptic exposure o
TX
: empiric. ?branched-chain amino acids, vitamin E, benzos
Antipsychotic Comparison
Antichol. Haloperidol Clozapine Risperidone Olanzapine Ziprasidone
+ +++ +/- ++ 0
EPS Ortho. Sedation Prolactin Lower Sz Threshold
+++ + + ++ + 0 +++ +++ 0 +++ + ++ ++ ++ + +/- ++ ++ + (esp IM) ++ ++ + (transient) + + (transient) +
Comparative Side Effects Of Atypical Agents
Sedation EPS Antichol Ortho C lo za pi ne R is pe rid on e O la nz ap in e Q ue tia pi ne Zi pr as id on e
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 5HT 2c blocking effects – Mice with this receptor ‘knocked out’ are all obese – all atypicals are 5HT 2c 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
Variable Weight (BMI) Waist circumfer.
Blood Pressure Fasting Glucose Fasting Lipids Baseline
Monitoring Protocol
ab 4 weeks 8 weeks 12 weeks Quarterly Annually x x x x x x x x x x x x x x x a Based on American Diabetes Association Consensus statetment b More frequent assessments may be necessary based on clinical status
Managing Side Effects
o o o
Anticholinergic Effects
o fluids, sugarless gum, bowel regimen
EPS
o lower dose of drug (esp. risperidone) o drug holiday
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,
c
orrected 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
P450 3A4
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 o o 2+ Pimozide, Mesoridazine, Thioridazine, Droperidol 1+ Ziprasidone, Clozapine, Loxapine, Thiothixene, …...Chlorpromazine, Trifluoperazine, Risperidone, …...Quetiapine
+/- 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 case by-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 ziprasidone, aripiprazole, risperidone/paliperidone Sedation 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