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Antipsychotic Review. Jena L. Ivey, PharmD, BCPS, CPP. Objectives. Review different antipsychotic agents with regard to efficacy and safety Discuss adverse effect profiles of antipsychotic agents and learn how to pick the “best” one for your patient if needed. - PowerPoint PPT Presentation

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  • Antipsychotic ReviewJena L. Ivey, PharmD, BCPS, CPP

  • ObjectivesReview different antipsychotic agents with regard to efficacy and safety

    Discuss adverse effect profiles of antipsychotic agents and learn how to pick the best one for your patient if needed

  • Antipsychotic Use in Older AdultsDecreased metabolism can lead to increased blood levels and increased side effects

    Decreased absorption can lead to decreased blood levels and reduced effectiveness

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

    Cognitive impairment can lead to nonadherence

  • AntipsychoticsChoice of traditional vs. new generation drugs

    Side effect profiles often direct selection

    EPS, TD, NMS less likely with newer agents

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

    22% of Nursing home patients

  • Traditional AntipsychoticsAll have tendency to produce EPS/TD

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

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

    Low cost is an advantage

  • Typical Antipsychotics ChlorpromazinePrototype 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 AntipsychoticsLow potencyChlorpromazineThioridazineMesoridazine

    Mid potency MolindoneLoxapinePerphenazine

    High potencyHaloperidolFluphenazineThiothixeneTrifluoperazine

  • Pharmacological Profile for HaloperidolAffects alpha, dopamine-2 receptors Oral, depot formulationsOralStart 0.5 mg daily, increase to 30 mg maximum per day in divided dosesDepot (haloperidol decanoate)Given usually once monthlyMust been stable on oral dose first

  • Why Use Depot?ComplianceOnce weekly dosingConvenience

    Side effectsLacks peak concentrationsGives lower but steady concentrations

  • PerphenazineMid potency typical antipsychoticLess EPS over high potencyLess affinity for muscarinic, alpha, and histaminic receptors over low potencyMax dose= 64 mgAverage dose in chronic schizophrenics32 mg/day

  • Traditional Antipschotics

    TypeSedationEPSAnticholinergicCardiovascularLow PotencyChlorpromazineHighModModHighMid PotencyPerphenazineModMod-HighModLowHigh PotencyHaloperidolVery LowVery HighVery LowVery Low

  • Efficacy of Typical AntipsychoticsMost 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 symptomsImprove or not worsen negative symptomsMay improve cognition

    Cause less or no EPSCause less or no tardive dyskinesiaEffective in refractory patients

  • Decision of AntipsychoticAtypical 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 failuresPatient or practitioner preferenceProblems with EPS or tardive dyskinesiaOther concomitant disease statesCompliance issues

  • Available Atypical AntipsychoticsClozapine

    Risperidone

    Paliperidone

    Olanzapine

    Quetiapine

    Ziprasidone

    Aripiprazole

  • ClozapineNot a first-line agentMust have failed at least two other trials of antipsychoticsDifficult to tolerate due to adverse drug effects

    Baseline work-upCBC with diff (WBC, ANC)Cardiac historyEKGFLPWeight/BMIFPG and/or HgbA1c

  • Clozapine Adverse EffectsBlack Box Warnings Hypotension Seizure Agranulocytosis MyocarditisRisk of death in elderly demented patients with psychosis

    Significant potential for metabolic dysregulations

    Others: sedation, constipation, tachycardia

  • Clozapine Agranulocytosis1% 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 pastANC

  • Risperidone (Risperdal) Mixed serotonin-dopamine antagonist activityAlso antagonizes alpha-2, histamine receptors

    Baseline work-upCardiac historyEKGFLPWeight/BMIFPG and/or HgbA1c

    Black Boxrisk of death in elderly demented patients with psychosis

  • Risperidone Adverse EffectsLower EPS than with typical antipsychotics like haloperidol Risk of EPS higher with doses greater than 6 mg/dayProlactin elevationOrthostasisTachycardia

  • Risperidone DecanoateOnly long-acting atypical antipsychotic injectionComplianceGluteal injectionPolymeric microspheresMain release at 3 weeksSingle dose maintained for 4-6 weeks

  • Paliperidone (Invega)Major metabolite (9-OH) of risperidoneInnovative delivery system Delivers smooth plasma levels over 24 hrs

    Baseline work-upSimilar to Risperidone

    Black Boxrisk of death in elderly demented patients with psychosis

  • PaliperidoneComparison to risperidoneLess peak/trough fluctuations, possibly less side effects due to fluctuationsOnce-daily dosingNo CYP 2D6 interactions (e.g. paroxetine, fluoxetine, poor metabolizers)Better choice for patients w/liver dysfunctionPhase II metabolism

  • Olanzapine (Zyprexa)Potent antagonist of several serotonin receptors, dopaminergic, muscarinic, histaminergic, and alpha

    Baseline work-upSimilar to risperidone PLUS LFTS

    Black Boxrisk of death in elderly demented patients with psychosis

  • Olanzapine Adverse Effects Significant potential for metabolic dysregulationsSedationAnticholinergic effectsTachycardiaEPS less than with risperidonemonitor 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 orthostasisDo not give within 1 hour of IM/IV lorazepam

  • Quetiapine (Seroquel)Antagonist of serotonin, dopamine receptors, some effect on histamine/alpha receptors

    Baseline work-upSimilar to risperidone PLUS:CBC in pre-existing low WBC or h/o drug-induced neutropenia

    Black BoxRisk of death in elderly demented patients with psychosis

  • Quetiapine Adverse EffectsEPS 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-upSimilar to risperidone PLUSElectrolytes

    Black BoxRisk of death in elderly demented patients with psychosis

    ContraindicatedH/O arrhythmias or QTc prolongationUncompensated heart failureAcute or recent myocardial infarction

  • Ziprasidone Adverse Effects EPS versus activation

    Minimal effects on metabolic profile

    EKG changesQTc prolongation

  • Ziprasidone IntramuscularFor 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-upSimilar to risperidone

    Black BoxRisk of death in elderly demented patients with psychosisRisk of increased suicidal behavior similar to antidepressants labelingFDA approval for adjunct therapy in MDD

  • Aripiprazole Adverse Effects EPS initially presumed minimalAkathisia 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

    DrugInitial Doses in Dementia PtsUsual Ranges for Psychotic D/OClozapine25mg* Initial dosing BID-TID minimizes side effects 300-450mg Max: 900mgOlanzapineOral2.5-5mg (start Qday dosing at HS)Oral 10-30mg Max 20mgIM (short-acting) 5-10mg Max: 30mg/24 hrs

    Quetiapine12.5-25mg (start Qday dosing at HS) 300-800mg Max: 800mg

  • Dosing^ Max dose per Product Labeling; risk of EPS higher with doses > 6mg

    DrugInitial Doses in Dementia PtsUsual Ranges for Psychotic D/ORisperidoneOral0.25-0.5mg

    IM (long-acting)12.5-25mgOral 2-6mg Max 16mg^IM (long-acting) 25-50mg Max: 50mgAdminister q 2 weeksPaliperidone3mg

    * Absorption increased with high fat meal 6-12mg Max: 12mg

  • Dosing

    DrugInitial Doses in Dementia PtsUsual Ranges for Psychotic D/OAripiprazoleOral2-5mg

    Oral 10-20mg Max: 30mgIM (short-acting) 9.75mg Max: 30mg/24hrsZiprasidoneOral20mg

    * Absorption increased with foodOral 120-200mg Max: 200mgIM (short-acting) 10-20mg Max: 40 mg/24hrs

  • Antipsychotic Adverse Effects

  • Orthostatic HypotensionVulnerability 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

    30+% of institutionalized older adults display sympto

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