Download - Antipsychotic Review

Antipsychotic ReviewAntipsychotic Review

Jena L. Ivey, PharmD, BCPS, CPPJena L. Ivey, PharmD, BCPS, CPP

ObjectivesObjectives

1.1. Review different antipsychotic agents with Review different antipsychotic agents with regard to efficacy and safetyregard to efficacy and safety

2.2. Discuss adverse effect profiles of Discuss adverse effect profiles of antipsychotic agents and learn how to antipsychotic agents and learn how to pick the “best” one for your patient if pick the “best” one for your patient if neededneeded

Antipsychotic Use in Older AdultsAntipsychotic Use in Older Adults

o Decreased metabolism can lead to increased blood levels Decreased metabolism can lead to increased blood levels and increased side effectsand increased side effects

o Decreased absorption can lead to decreased blood levels Decreased absorption can lead to decreased blood levels and reduced effectiveness and reduced effectiveness

o Brain changes with aging can lead to heightened sensitivity Brain changes with aging can lead to heightened sensitivity to side effects (e.g. EPS) and reduced effectivenessto side effects (e.g. EPS) and reduced effectiveness

o Cognitive impairment can lead to nonadherenceCognitive impairment can lead to nonadherence

AntipsychoticsAntipsychoticso Choice of traditional vs. new generation drugsChoice of traditional vs. new generation drugs

o Side effect profiles often direct selectionSide effect profiles often direct selection

o EPS, TD, NMS less likely with newer agentsEPS, TD, NMS less likely with newer agents

o Efficacy against negative symptoms (when relevant) is higher Efficacy against negative symptoms (when relevant) is higher with the new drugs (probably related to 5HT-2 antagonism)with the new drugs (probably related to 5HT-2 antagonism)

o 22% of Nursing home patients 22% of Nursing home patients

Traditional AntipsychoticsTraditional Antipsychotics

o All have tendency to produce EPS/TDAll have tendency to produce EPS/TD

o Low potency drugs are usually highly sedating, Low potency drugs are usually highly sedating, highly anticholinergic and promote orthostasishighly anticholinergic and promote orthostasis

o Orthostatic hypotension is related to Orthostatic hypotension is related to alpha-1 alpha-1 blocking blocking effects and correlates highly with hip FXeffects and correlates highly with hip FX

o Low cost is an advantageLow cost is an advantage

Typical Antipsychotics Typical Antipsychotics

ChlorpromazineChlorpromazine– Prototype typical antipsychoticPrototype typical antipsychotic

– Only able to substantially improve positive Only able to substantially improve positive symptoms, little effect on negative symptoms symptoms, little effect on negative symptoms and many adverse effectsand many adverse effects

– Equivalent doses of other typical Equivalent doses of other typical antipsychotics based on 100 mg of antipsychotics based on 100 mg of chlorpromazinechlorpromazine

Typical AntipsychoticsTypical Antipsychotics

Low potencyLow potency– ChlorpromazineChlorpromazine– ThioridazineThioridazine– MesoridazineMesoridazine

Mid potencyMid potency

– MolindoneMolindone– LoxapineLoxapine– PerphenazinePerphenazine

High potencyHigh potency– HaloperidolHaloperidol– FluphenazineFluphenazine– ThiothixeneThiothixene– TrifluoperazineTrifluoperazine

Pharmacological Profile for Pharmacological Profile for HaloperidolHaloperidol

Affects alpha, dopamine-2 receptors Affects alpha, dopamine-2 receptors

Oral, depot formulationsOral, depot formulations

OralOral– Start 0.5 mg daily, increase to 30 mg Start 0.5 mg daily, increase to 30 mg

maximum per day in divided dosesmaximum per day in divided doses

Depot (haloperidol decanoate)Depot (haloperidol decanoate)– Given usually once monthlyGiven usually once monthly– Must been stable on oral dose firstMust been stable on oral dose first

Why Use Depot?Why Use Depot?

ComplianceCompliance– Once weekly dosingOnce weekly dosing

ConvenienceConvenience

Side effectsSide effects

– Lacks peak concentrationsLacks peak concentrations

– Gives lower but steady concentrationsGives lower but steady concentrations

PerphenazinePerphenazine

Mid potency typical antipsychoticMid potency typical antipsychotic– Less EPS over high potencyLess EPS over high potency– Less affinity for muscarinic, alpha, and Less affinity for muscarinic, alpha, and

histaminic receptors over low potencyhistaminic receptors over low potency

Max dose= 64 mgMax dose= 64 mg

Average dose in chronic schizophrenicsAverage dose in chronic schizophrenics– 32 mg/day32 mg/day

Traditional AntipschoticsTraditional AntipschoticsTypeType SedationSedation EPSEPS AnticholinergicAnticholinergic CardiovascularCardiovascular

Low PotencyLow Potency

ChlorpromazineChlorpromazine HighHigh ModMod ModMod HighHigh

Mid PotencyMid Potency

PerphenazinePerphenazine ModMod Mod-HighMod-High ModMod LowLow

High PotencyHigh Potency

HaloperidolHaloperidol Very LowVery Low Very HighVery High Very LowVery Low Very LowVery Low

Efficacy of Typical Efficacy of Typical AntipsychoticsAntipsychotics

Most benefit seen with positive symptomsMost benefit seen with positive symptoms

Limited benefit with negative symptomsLimited benefit with negative symptoms

May worsen negative or cognitive May worsen negative or cognitive symptoms, especially in high dosessymptoms, especially in high doses

Have fallen out of favor as first-line agentsHave fallen out of favor as first-line agents

Atypical Antipsychotics Atypical Antipsychotics

Improve psychotic Improve psychotic symptomssymptomsImprove or not Improve or not worsen negative worsen negative symptomssymptomsMay improve May improve cognitioncognition

Cause less or no EPSCause less or no EPS

Cause less or no Cause less or no tardive dyskinesiatardive dyskinesia

Effective in refractory Effective in refractory patientspatients

Decision of AntipsychoticDecision of AntipsychoticAtypical agents are now accepted to be first-line treatmentAtypical agents are now accepted to be first-line treatment

Considered ‘first-line’ now, but anticholinergic effects, Considered ‘first-line’ now, but anticholinergic effects, orthostasis and COST are important factors in older orthostasis and COST are important factors in older adultsadults

Treatment choice based on:Treatment choice based on:– Past response or past side effects to individual agents and Past response or past side effects to individual agents and

number of treatment failuresnumber of treatment failures– Patient or practitioner preferencePatient or practitioner preference– Problems with EPS or tardive dyskinesiaProblems with EPS or tardive dyskinesia– Other concomitant disease statesOther concomitant disease states– Compliance issuesCompliance issues

Available Atypical AntipsychoticsAvailable Atypical Antipsychotics

ClozapineClozapine

RisperidoneRisperidone

PaliperidonePaliperidone

OlanzapineOlanzapine

QuetiapineQuetiapine

ZiprasidoneZiprasidone

AripiprazoleAripiprazole

ClozapineClozapine

NotNot a first-line agent a first-line agentMust have failed at least two other trials of antipsychoticsMust have failed at least two other trials of antipsychoticsDifficult to tolerate due to adverse drug effectsDifficult to tolerate due to adverse drug effects

Baseline work-upBaseline work-upCBC with diff (WBC, ANC)CBC with diff (WBC, ANC)Cardiac historyCardiac history– EKGEKG

FLPFLPWeight/BMIWeight/BMIFPG and/or HgbA1cFPG and/or HgbA1c

Clozapine – Adverse EffectsClozapine – Adverse Effects

Black Box WarningsBlack Box Warnings– HypotensionHypotension– SeizureSeizure– Agranulocytosis Agranulocytosis – MyocarditisMyocarditis– Risk of death in elderly demented patients with Risk of death in elderly demented patients with

psychosispsychosis

Significant potential for metabolic dysregulationsSignificant potential for metabolic dysregulations

Others: sedation, constipation, tachycardiaOthers: sedation, constipation, tachycardia

Clozapine AgranulocytosisClozapine Agranulocytosis1% incidence1% incidence

More frequently occurs early in therapyMore frequently occurs early in therapy

Monitor CBC weekly for first 6 months, every two weeks Monitor CBC weekly for first 6 months, every two weeks for next 6 months, then every 4 weeks thereafterfor next 6 months, then every 4 weeks thereafter

Must be registered to receive clozapineMust be registered to receive clozapine

Do Do notnot rechallenge if patient has experienced rechallenge if patient has experienced agranulocytosis to clozapine in the pastagranulocytosis to clozapine in the past– ANC<1000ANC<1000

Risperidone (RisperdalRisperidone (Risperdal))

Mixed serotonin-dopamine antagonist activityMixed serotonin-dopamine antagonist activityAlso antagonizes alpha-2, histamine receptorsAlso antagonizes alpha-2, histamine receptors

Baseline work-upBaseline work-upCardiac historyCardiac history– EKGEKG

FLPFLPWeight/BMIWeight/BMIFPG and/or HgbA1cFPG and/or HgbA1c

Black BoxBlack Box– risk of death in elderly demented patients with psychosisrisk of death in elderly demented patients with psychosis

Risperidone – Adverse EffectsRisperidone – Adverse Effects

Lower EPS than with typical antipsychotics Lower EPS than with typical antipsychotics like haloperidol like haloperidol – Risk of EPS higher with doses greater than 6 Risk of EPS higher with doses greater than 6

mg/daymg/day

Prolactin elevationProlactin elevation

OrthostasisOrthostasis

TachycardiaTachycardia

Risperidone DecanoateRisperidone Decanoate

Only long-acting atypical antipsychotic Only long-acting atypical antipsychotic injectioninjection– ComplianceCompliance

Gluteal injectionGluteal injection

Polymeric microspheresPolymeric microspheres

Main release at 3 weeksMain release at 3 weeks– Single dose maintained for 4-6 weeksSingle dose maintained for 4-6 weeks

Paliperidone (InvegaPaliperidone (Invega))

Major metabolite (9-OH) of risperidoneMajor metabolite (9-OH) of risperidoneInnovative delivery system Innovative delivery system – Delivers smooth plasma levels over 24 hrsDelivers smooth plasma levels over 24 hrs

Baseline work-upBaseline work-upSimilar to RisperidoneSimilar to Risperidone

Black BoxBlack Box– risk of death in elderly demented patients with risk of death in elderly demented patients with

psychosispsychosis

PaliperidonePaliperidone

Comparison to risperidoneComparison to risperidone– Less peak/trough fluctuations, possibly less Less peak/trough fluctuations, possibly less

side effects due to fluctuationsside effects due to fluctuations– ““Once-daily” dosingOnce-daily” dosing– No CYP 2D6 interactions (e.g. paroxetine, No CYP 2D6 interactions (e.g. paroxetine,

fluoxetine, poor metabolizers)fluoxetine, poor metabolizers)– Better choice for patients w/liver dysfunctionBetter choice for patients w/liver dysfunction

Phase II metabolismPhase II metabolism

Olanzapine (ZyprexaOlanzapine (Zyprexa))

Potent antagonist of several serotonin receptors, Potent antagonist of several serotonin receptors, dopaminergic, muscarinic, histaminergic, and dopaminergic, muscarinic, histaminergic, and alphaalpha

Baseline work-upBaseline work-upSimilar to risperidone Similar to risperidone PLUS PLUS – LFTSLFTS

Black BoxBlack Box– risk of death in elderly demented patients with risk of death in elderly demented patients with

psychosispsychosis

Olanzapine – Adverse Effects Olanzapine – Adverse Effects

Significant potential for metabolic Significant potential for metabolic dysregulationsdysregulations

SedationSedation

Anticholinergic effectsAnticholinergic effects


EPS less than with risperidoneEPS less than with risperidone– monitor for akathisia at higher doses (>15mg)monitor for akathisia at higher doses (>15mg)

Olanzapine – IM Olanzapine – IM

For control of acute agitation in For control of acute agitation in schizophrenic and bipolar patientsschizophrenic and bipolar patients

Calming without oversedationCalming without oversedation

Can give Q 2-4 hoursCan give Q 2-4 hours

Risk of bradycardia and orthostasisRisk of bradycardia and orthostasis– Do not give within 1 hour of IM/IV lorazepamDo not give within 1 hour of IM/IV lorazepam

Quetiapine (SeroquelQuetiapine (Seroquel))Antagonist of serotonin, dopamine receptors, Antagonist of serotonin, dopamine receptors,

some effect on histamine/alpha receptorssome effect on histamine/alpha receptors

Baseline work-upBaseline work-upSimilar to risperidone Similar to risperidone PLUS:PLUS:

– CBC in pre-existing low WBC or h/o drug-induced CBC in pre-existing low WBC or h/o drug-induced neutropenianeutropenia

Black BoxBlack Box– Risk of death in elderly demented patients with Risk of death in elderly demented patients with

psychosispsychosis

Quetiapine – Adverse EffectsQuetiapine – Adverse Effects

EPS appears to be less due to less effect on dopamine EPS appears to be less due to less effect on dopamine (loose and transient binding to dopamine receptors)(loose and transient binding to dopamine receptors)

Sedation/fatigue Sedation/fatigue

OrthostasisOrthostasis

Anticholinergic effects at doses >300-400mgAnticholinergic effects at doses >300-400mg


Increased LFTs (transient)Increased LFTs (transient)

Ziprasidone (GeodonZiprasidone (Geodon))

High affinity for serotonin receptors, moderate dopamine/histamine, High affinity for serotonin receptors, moderate dopamine/histamine, no affinity for alpha/betano affinity for alpha/beta

Baseline work-upBaseline work-up Similar to risperidone Similar to risperidone PLUSPLUS

– ElectrolytesElectrolytes

Black BoxBlack Box– Risk of death in elderly demented patients with psychosisRisk of death in elderly demented patients with psychosis

ContraindicatedContraindicated– H/O arrhythmias or QTc prolongationH/O arrhythmias or QTc prolongation– Uncompensated heart failureUncompensated heart failure– Acute or recent myocardial infarctionAcute or recent myocardial infarction

Ziprasidone – Adverse Effects Ziprasidone – Adverse Effects

EPS versus “activation”EPS versus “activation”

Minimal effects on metabolic profileMinimal effects on metabolic profile

EKG changesEKG changes– QTc prolongationQTc prolongation

Ziprasidone – IntramuscularZiprasidone – Intramuscular

For acute psychotic agitationFor acute psychotic agitation


Can give Q 2-4 hoursCan give Q 2-4 hours

Can give with IM/IV lorazepamCan give with IM/IV lorazepam

Aripiprazole (AbilifyAripiprazole (Abilify))Dopamine-2 partial agonist, pDopamine-2 partial agonist, partial serotonin-1A artial serotonin-1A

agonistagonist

Baseline work-upBaseline work-upSimilar to risperidoneSimilar to risperidone

Black BoxBlack Box– Risk of death in elderly demented patients with Risk of death in elderly demented patients with

psychosispsychosis– Risk of increased suicidal behavior similar to Risk of increased suicidal behavior similar to

antidepressants labelingantidepressants labelingFDA approval for adjunct therapy in MDDFDA approval for adjunct therapy in MDD

Aripiprazole – Adverse Effects Aripiprazole – Adverse Effects

EPS initially presumed minimalEPS initially presumed minimal– Akathisia versus anxiety, restlessnessAkathisia versus anxiety, restlessness

Minimal effects on metabolic profileMinimal effects on metabolic profile

NauseaNausea

HeadacheHeadache

Aripiprazole – IM Aripiprazole – IM

For acute agitation in patients with For acute agitation in patients with schizophrenia or bipolar d/oschizophrenia or bipolar d/o


Can give Q 2 hoursCan give Q 2 hours

Can give with IV/IM lorazepamCan give with IV/IM lorazepam

DosingDosingDrug Initial Doses in

Dementia PtsUsual Ranges for Psychotic D/O

Clozapine 25mg* Initial dosing BID-TID minimizes side effects

300-450mg Max: 900mg

Olanzapine Oral2.5-5mg (start Qday dosing at HS)

Oral 10-30mg Max 20mgIM (short-acting) 5-10mg Max: 30mg/24 hrs

Quetiapine 12.5-25mg (start Qday dosing at HS)

300-800mg Max: 800mg



Risperidone Oral0.25-0.5mg

IM (long-acting)12.5-25mg

Oral 2-6mg Max 16mg^IM (long-acting) 25-50mg Max: 50mgAdminister 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



Aripiprazole Oral2-5mg

Oral 10-20mg Max: 30mgIM (short-acting) 9.75mg Max: 30mg/24hrs

Ziprasidone Oral20mg

* Absorption increased with food

Oral 120-200mg Max: 200mgIM (short-acting) 10-20mg Max: 40 mg/24hrs

Antipsychotic Adverse EffectsAntipsychotic Adverse Effects

Orthostatic HypotensionOrthostatic Hypotensiono Vulnerability in older adults isVulnerability in older adults is increased increased because of because of

decreased sensitivity of baroreceptors in the carotid and BP decreased sensitivity of baroreceptors in the carotid and BP regulatory centers in the hypothalamus regulatory centers in the hypothalamus PLUSPLUS decreased decreased alpha-1 adrenergic receptorsalpha-1 adrenergic receptors

o 30+% of institutionalized older adults display symptomatic 30+% of institutionalized older adults display symptomatic orthostatic hypotensionorthostatic hypotension

o Drugs cause this primarily by blocking alpha-1 receptorsDrugs cause this primarily by blocking alpha-1 receptorso TCAs, MAOIs, antipsychoticsTCAs, MAOIs, antipsychotics (including many of the new (including many of the new

generation drugs) andgeneration drugs) and lithium lithium are all offenders are all offenders

o Benzodiazepines can cause falls by producing Benzodiazepines can cause falls by producing dysequilibrium rather than orthostasisdysequilibrium rather than orthostasis

Falls/Hip FracturesFalls/Hip Fractures

o 250,000 yearly250,000 yearlyo Most occur in women over age 65Most occur in women over age 65o 90% are due to a fall from standing height!90% are due to a fall from standing height!o 50-60% of FXs in this age group require Nursing 50-60% of FXs in this age group require Nursing

Home placement and about Home placement and about 1/2 never leave1/2 never leaveo Mortality rate at the end of 1 year is 20%Mortality rate at the end of 1 year is 20%o Most falls are due to a combination of orthostasis, Most falls are due to a combination of orthostasis,

dizziness, EPS, sedation, decreased vision and dizziness, EPS, sedation, decreased vision and dysequilibrium all of which can be caused or dysequilibrium all of which can be caused or exacerbated by psychotropicsexacerbated by psychotropics

Tardive DyskinesiaTardive Dyskinesia

o Risk Risk much higher much higher in older adultsin older adultso Incidence may be as high as 25% per year (versus Incidence may be as high as 25% per year (versus

5% per year in younger patients)5% per year in younger patients)o Older adults have increased severity and lower Older adults have increased severity and lower

spontaneous remission ratesspontaneous remission rateso Risk factorsRisk factors: : AGE, F>M, early-onset EPS, length AGE, F>M, early-onset EPS, length

of neuroleptic exposureof neuroleptic exposureo TXTX:: empiric. ?branched-chain amino acids, vitamin empiric. ?branched-chain amino acids, vitamin

E, benzosE, benzos

Antipsychotic ComparisonAntipsychotic Comparison

Haloperidol Clozapine Risperidone Olanzapine Ziprasidone

Antichol. + +++ +/- ++ 0

EPS +++ 0 + +/- + (esp IM)

Ortho. + +++ ++ ++ ++

Sedation + +++ ++ ++ ++

Prolactin ++ 0 ++ + (transient)

+ (transient)

Lower Sz Threshold

+ +++ + + +

Comparative Side Effects Of Atypical Agents

Rel

ativ

e P

ote

ncy Sedation

EPS

Antichol

Ortho

Atypicals and Weight Gain Lots of ways to look at this issue (total average wt gain, number of 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, patients with >10% initial body weight gain, length of weight gain, types of weight gain)types of weight gain)

Risk of significant weight gain:Risk of significant weight gain:– Clozapine, olanzapine and quetiapine, highClozapine, olanzapine and quetiapine, high– Risperidone, moderateRisperidone, moderate– Ziprasidone, aripiprazole, lowZiprasidone, aripiprazole, low

Generally, thinner people gain more weight (lower BMI)Generally, thinner people gain more weight (lower BMI)• weight gain seems to plateau at 3 yrs or so, but average weight gain is in weight gain seems to plateau at 3 yrs or so, but average weight gain is in

the 15 lb rangethe 15 lb range• weight gain may be less of a problem in the elderlyweight gain may be less of a problem in the elderly

However, even in low risk drugs like ziprasidone and aripiprazole, However, even in low risk drugs like ziprasidone and aripiprazole, certain individuals gained large amounts of weight according to certain individuals gained large amounts of weight according to package insert date (7-8%)package insert date (7-8%)

How Do Atypicals Cause Weight Gain?How Do Atypicals Cause Weight Gain?o Antihistamine effects (H1) : clozapine, olanzapine, Antihistamine effects (H1) : clozapine, olanzapine,

quetiapine are strong inhibitorsquetiapine are strong inhibitors

o 5HT5HT2c2c blocking effects – Mice with this receptor ‘knocked blocking effects – Mice with this receptor ‘knocked out’ are all obese – all atypicals are 5HTout’ are all obese – all atypicals are 5HT2c2c blockers blockers except aripiprazoleexcept aripiprazole

o Endocrine effects such as hyperprolactinemia may Endocrine effects such as hyperprolactinemia may contributecontribute

o Genetic susceptibility (receptor polymorphisms)Genetic susceptibility (receptor polymorphisms)

Atypical Antipsychotics: HyperglycemiaAtypical Antipsychotics: Hyperglycemia

o Hyperglycemia has been seen with olanzapine & Hyperglycemia has been seen with olanzapine & clozapineclozapine

• Good prospective studies are lacking; DM in Good prospective studies are lacking; DM in schizophrenics increased dramatically after schizophrenics increased dramatically after neuroleptics introduced in 1950’sneuroleptics introduced in 1950’s

• Schizophrenics may have impaired glucose Schizophrenics may have impaired glucose tolerancetolerance

• Insulin resistance may be the mechanismInsulin resistance may be the mechanism

• Monitor Monitor Hgb A1cHgb A1c every 3 months; every 3 months; Chol & TGsChol & TGs every 6 monthsevery 6 months

Monitoring ProtocolMonitoring Protocolabab

VariableVariable BaselineBaseline 4 weeks4 weeks 8 weeks8 weeks 12 weeks12 weeks QuarterlyQuarterly AnnuallyAnnually

WeightWeight

(BMI)(BMI)

xx xx xx xx xx

Waist Waist circumfer.circumfer.

xx xx

Blood Blood PressurePressure

xx xx xx

Fasting Fasting GlucoseGlucose

xx xx xx

Fasting Fasting LipidsLipids

xx xx

aBased on American Diabetes Association Consensus statetment

bMore frequent assessments may be necessary based on clinical status

Managing Side EffectsManaging Side Effects

o Anticholinergic EffectsAnticholinergic Effectso fluids, sugarless gum, bowel regimenfluids, sugarless gum, bowel regimen

o EPSEPSo lower dose of drug (esp. risperidone)lower dose of drug (esp. risperidone)o drug holidaydrug holiday

o HypotensionHypotensiono rise slowly fromrise slowly from bed, divide doses, increase salt intake, bed, divide doses, increase salt intake,

TED hose, fludrocortisone in refractory casesTED hose, fludrocortisone in refractory cases

o Sedation:Sedation: lower dose, modafanil (Provigil), methylphenidate lower dose, modafanil (Provigil), methylphenidate (Ritalin)(Ritalin)

Prolongation of QTc intervalProlongation of QTc intervalo QTc interval is time it takes the heart to repolarize, QTc interval is time it takes the heart to repolarize,

ccorrected for heart rateorrected for heart rate 440 msec upper limits of nomal; >480 definitely prolonged440 msec upper limits of nomal; >480 definitely prolonged

o Tricyclics widen QRS & QTc intervalsTricyclics widen QRS & QTc intervals

o Drugs which may significantly prolong QTc include: Drugs which may significantly prolong QTc include: thioridazine , mesoridazine, ziprasidone, droperidol, thioridazine , mesoridazine, ziprasidone, droperidol, pimozide & ketoconozolepimozide & ketoconozole - often metabolized by - often metabolized by P450-P450-3A43A4

o Drugs which interfere with metabolism of these QTc Drugs which interfere with metabolism of these QTc prolongers such as: Nefazodone (prolongers such as: Nefazodone (SERZONESERZONE), ), fluvoxamine (fluvoxamine (LUVOXLUVOX), cimetidine, erythromycin, ), cimetidine, erythromycin, ketoconazole, norfluoxetine can cause problemsketoconazole, norfluoxetine can cause problems

QTc Prolongation In AntipsychoticsQTc Prolongation In Antipsychotics

o 2+ Pimozide, Mesoridazine, Thioridazine, Droperidol2+ Pimozide, Mesoridazine, Thioridazine, Droperidolo 1+ Ziprasidone, Clozapine, Loxapine, Thiothixene, 1+ Ziprasidone, Clozapine, Loxapine, Thiothixene,

…...Chlorpromazine, Trifluoperazine, Risperidone, …...Chlorpromazine, Trifluoperazine, Risperidone,

… …...Quetiapine...Quetiapineo +/- Olanzapine, Haloperidol, Fluphenazine+/- Olanzapine, Haloperidol, Fluphenazine

o RISK FACTORSRISK FACTORS::• Female sexFemale sex• Congenital Long QTCongenital Long QT• Ischemic heart diseaseIschemic heart disease

QTc Prolongation by Other DrugsQTc Prolongation by Other Drugs

o Antidepressants: Antidepressants: Fluoxetine, Sertraline, Citalopram, Doxepin, Desipramine, Fluoxetine, Sertraline, Citalopram, Doxepin, Desipramine, Amitriptyline, MaprotilineAmitriptyline, Maprotiline

o Non-psychiatric*: Non-psychiatric*: Amiodarone, Ibutilide, Procainamide, Amiodarone, Ibutilide, Procainamide, Inadapamide,Clarithromycin, Erythromycin, CisaprideInadapamide,Clarithromycin, Erythromycin, Cisapride

*partial list*partial list

QTc Recommendations*QTc Recommendations*

1.1. Do not use thioridazine, mesoridazine or pimozide for Do not use thioridazine, mesoridazine or pimozide for patients with known heart disease, hx of syncope, FH patients with known heart disease, hx of syncope, FH of sudden death or congenital prolonged QT.of sudden death or congenital prolonged QT.

2.2. If ziprasidone is used for any of these patients, a If ziprasidone is used for any of these patients, a baseline ECG should be obtained before beginning baseline ECG should be obtained before beginning treatment. A subsequent ECG is indicated for treatment. A subsequent ECG is indicated for symptoms suggestive of a prolonged QT interval (e.g. symptoms suggestive of a prolonged QT interval (e.g. syncope)syncope)

* AJP, August 2004, pg 1334. (These are recs for patients with schizophrenia)* AJP, August 2004, pg 1334. (These are recs for patients with schizophrenia)

Stroke Risk - AntipsychoticsStroke Risk - Antipsychotics

Some evidence to suggest increased risk of Some evidence to suggest increased risk of cerebrovascular events and death seen in older patients cerebrovascular events and death seen in older patients treated with antipsychotics for behavioral and treated with antipsychotics for behavioral and psychological symptoms of dementia psychological symptoms of dementia – Risperidone, olanzapine studied the mostRisperidone, olanzapine studied the most

Similar risk noted with atypical and typical agents Similar risk noted with atypical and typical agents

Studies are retrospective and the groups receiving and Studies are retrospective and the groups receiving and not receiving antipsychotics may not be comparable for not receiving antipsychotics may not be comparable for the question being asked the question being asked

Try non-drug modalities firstTry non-drug modalities first

Educate family/patient on risks associated with useEducate family/patient on risks associated with use

Must weigh benefits of use with potential harms on case-Must weigh benefits of use with potential harms on case-by-case basisby-case basis

Pharmacologic choices are limited in this population and Pharmacologic choices are limited in this population and there is no evidence one way or the other whether other there is no evidence one way or the other whether other pharmacologic agents used for these same purposes are pharmacologic agents used for these same purposes are any saferany safer

Stroke Risk - AntipsychoticsStroke Risk - Antipsychotics

Selecting Atypical AntipsychoticsSelecting Atypical AntipsychoticsSpecific 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

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