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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