AntipsychoticsSomethingOld,SomethingNew,SomethingUsed toTreattheBlues

Objectives• Toprovideanoverview ofthekeydifferences between firstandsecondgenerationagents

• Toanoverview thenewer secondgenerationantipsychotics• Indications• Dosageregimens anddosage form• Adverse effect profiles• DrugInteractions

FirstGenerationAntipsychotics• Haloperidol, chlorpromazine, fluphenazine, thioridazine,thiothixene, andpimozide

• Highaffinitydopamine D2 receptorantagonism• Effective intreatingpositive symptomsofpsychosis• Negativesymptoms,mood symptoms, andcognitivedeficitsminimally responsive

• Unfavorableadverseeffectprofile• HighratesofEPS,tardivedyskinesia• Adverse effects duetoactionatother receptor sites

• Sedation,drymouth• Weightgain

SecondGenerationAntipsychotics• Keydistinction fromFGAisdecreased riskofextrapyramidalsideeffects.

• Thisispossiblyduetotheir loweraffinity forthedopamine 2,orD2receptor.

• Workmainlyon• Dopamineandserotonin receptors inthecentralnervoussystem• Cholinergic,adrenergic, andhistaminergic receptors.

• Thedegreeandselectivity ofreceptorinhibition varieswhichresults inthediffering sideeffectprofilesthatareobserved.

• SGAsdifferfromtheFGA,astheserotonin5-HT2receptorbindingcanexceed theiraffinityfordopamine D2receptors.

SecondGenerationAntipsychotics• “Older”SGAs• Clozapine• Olanzapine• Quetiapine• Risperidone

• “Newer” SGAs• Asenapine (Saphris)• Aripiprazole (Abilify)• Lurasidone (Latuda)• Paliperidone (Invega)• Ziprasidone (Zeldox)

SecondGenerationAntipsychotics

• Clozapine,olanzapine,quetiapine,risperidone• Improvedefficacyformoodsymptomsorstabilization• MinimalEPS,butmetaboliceffects

• Asenapine,Aripiprazole,Lurasidone,Paliperidone,Ziprasidone• PartialagonistsatD2or5-HTreceptors• Bindtoreceptor, initiatingapartialresponsewithoutfullinhibition

• Potentialforsimilarefficacyasolder secondgenerationantipsychoticswithlesspronouncedmetaboliceffects andsedation

FGAsversusSGAs• AllFGAsandSGAshavesimilar efficacyintreatingthepositive(psychotic)symptomsofschizophrenia andrelateddisorders.• Clozapinemaybemoreefficacious• Clozapine ishasprovenefficacyintreatment resistanceschizophrenia

• Forfirst-episode psychosis,SGAsmaybemoreeffective• Negativesymptoms,mood,cognition• Studieshavehadmixed results, inconsistent

• Majordifferences between theFGAsandSGAs(andamongindividual SGAs)• Sideeffectprofiles, safetyandtolerability

ApprovedIndications

Schizophrenia BipolarDisorder

MajorDepressiveDisorder

Aripiprazole X X X(Adjunctive)

Asenapine X X

Lurasidone X X

Paliperidone X

Ziprasidone X X

Aripiprazole (Abilify)• DosageandIndications(adults)• Schizophrenia

• 10mgto30mgdaily• Bipolardisorder

• Monotherapy:15mgto30mgdaily• Co-therapy:10mgto30mgdaily

• Adjunctive therapyinMDD• 2mgto5mgdaily

• Dosageforms:2,5,10,15,20and30mgtablets• Usually giveninthemorningbecause itcanbeactivatingandcauseinsomnia

• Changes indosageshouldbemadenomorefrequently thanevery14days• Uniquelylonghalf-life

Aripiprazole Injection(Abilify -Maintena)

• Oncemonthly IMinjection• Recommended startingandmaintenance doseof400mg.• Dosetitrationnotrequired.• Tolerability ofaripiprazole shouldbeassessedwithoralformulationpriortouse.

• Afterfirstinjection,treatment shouldbecontinuedwith10mgto20mgoralfor14consecutivedays

• Switchingfromoralantipsychotics• Continuecurrentoralantipsychoticfor14daysfollowingthefirstdose

• 300mgand400mgvialsthatmustbereconstitutedpriortoadministration

Aripiprazole – DrugInteractions• Metabolized viaCYP2D6andCYP3A4transformations• Hasactivemetabolite• 50%dosereductionrecommended ifconcurrentlytakingpotentinhibitorof• CYP2D6(eg, fluoxetine, paroxetine, bupropion)• CYP3A4(eg,clarithromycin)

• Doseincrease recommended ifconcurrently takingpotentinducerofCYP(eg,carbamazepine).

• Half-life prolongedinCYP2D6slowmetabolizers.• Unpredictableeffect incombinationwithotherantipsychotics.

Asenapine (Saphris)• DosageandIndications• Schizophrenia

• 5mgto10mgbid• Noclearbenefitof10mgdoseover5mg

• Bipolardisorder• Monotherapy:5mgto10mgbid• Co-therapy: 5mgto10mgbid

• Dosageforms• 5and10mgsublingualtablet

• Cannoteatordrinkwithin10minsofadministration

Asenapine – DrugInteractions• Hepatically metabolized byCYP1A2andglucuronidation(UGT1A4)

• Fluvoxamine (CYP1A2inhibitor) shouldbecoadministeredwithcautionoravoidedwhenpossible

• Asenapine weakly inhibitsCYP2D6• Cautionrecommended ifcoadminister withdrugs thatarebothmetabolizedbyCYP2D6andcaninhibitthisenzyme• E.g.paroxetine,dextromethorphan

• Pharmacodynamic considerations• AdditiveQTc prolongation• Alpha-1antagonism

• Potentiation ofalphablockers– hypotension,dizziness

Lurasidone (Latuda)• DosageandIndications• Schizophrenia

• 40mgto80mgdaily• Bipolardisorder (depressive episodes)

• Usualdoseof20mg-60mg/dayasmonotherapyoradjunctivetherapywithlithium orvalproate

• Dosageforms:• 40,80and120mgtablets

• Shouldbeadministered withfood• Atleast350calories independent offatcontent

• Dosageadjustment requiredforrenal impairment

Latuda –DrugInteractions• Hepaticmetabolism includesCYP3A4transformationandactivemetabolites

• Coadministration withstrongCYP3A4inhibitors(eg,oralketoconazole) orinducers(eg,rifampin) iscontraindicated

• Maximum recommended dosewithmoderateCYP3A4inhibitors(eg,diltiazem) is80mgperday.

• Grapefruit interactions

Paliperidone (Invega)• Schizophrenia• Extended-release tablet:3to12mgoncedaily• Mustbeswallowedwholeandmustnotbechewed, divided,orcrushed.

• Dosageforms• 3,6,and9mgextended release tablets• Foodincreases absorption;however, clinicaltrialdosingwascarriedoutwithoutregards tomeals• Taken inthemorning,withoutregardtofood• Change inabsorptionwithfoodnotconsideredclinicallymeaningful

Paliperidone (Invega Sustena)• Schizophrenia• Prolonged-release injection:150mgonday1,100mgonday8,then25–150mgoncemonthly• usualmaintenance dose is75mgmonthly

• Dosageforms• 50mg,75mg,100mg,and150mgprolongedrelease injection(Invega Sustenna)

Paliperidone –Druginteractions• Minimalhepaticmetabolism• Paliperidone isexcretedprimarilyunchanged inurinenecessitatingdosereduction inrenalinsufficiency.

• Pharmacodynamic considerations• AdditiveQTc prolongation• Alpha-1antagonism

• Potentiation ofalphablockers

Ziprasidone (Zeldox)• Schizophrenia• 20mgtwicedailyto100mg

• Bipolardisorder• 40mgtwicedailyto80mg

• Dosageforms• 20,40,60,and80mgcapsules

• Shouldbeadministered withameal• Absorption increased upto2-fold

Ziprasidone – DrugInteractions• Hepaticmetabolism includesCYP3A4andothertransformations• Dosageadjustmentsmayberequired inpresence ofinducersandinhibitorsofCYP3A4,butclinicalsignificance ofsuchdruginteractions remainsunknown.

• Pharmacodynamic considerations• AdditiveQTc prolongation• Alpha-1antagonism

• Potentiation ofalphablockers

ComparativeAdverseEffects

ReceptorBindingandAdverseEffects

SelectedAdverseEffects

Weightgain/DM ↑Chol EPS/

TDProlactinelevation Sedation Anti-chol

SE

Ortho-statichypo-tension

QTcprolongation

Aripiprazole – – + – + – – –

Asenapine + – + ++ ++ – + +

Lurasidone – – + + ++ – + –

Paliperidone ++ + ++ +++ + – ++ +

Ziprasidone – – + + + – + ++

MetabolicMonitoringforPatientsTakingAntipsychotics

Summary• Anumberofnewer atypicalantipsychoticshaveenteredthemarketoverthepastfewyears

• Providealternatives tothosepatientsnotadequatelymanagedonsecondgenerationatypicals orwhoareintolerant

• Within theneweragentstherearedifferences in• Dosageform• Approved indications• QTc intervalprolongation• Use inrenalimpairment

• Selectionamongstagentsmaybeinfluencedbyanumberoffactors