Antipyschotics

Antipsychotics: New agents and new perspectives on older agentsTed D. WilliamsPharmD, PGY1 ResidentSyracuse VAMCJune 9, 2010OutlinePsychotic DisordersPathophysiology & PharmacologyTypical vs. Atypical AntipsychoticsSide Effect ManagementTherapy ManagementA closer look at select agentsPsychosis vs. NeurosisPsychosisInappropriate processing of sensory informationDisturbed views of reality and selfNot recognized by suffererNeurosisAbnormal reactionsRecognized by sufferer by abnormalDisorders with Psychotic Symptoms PossibleBig ThreeSchizophreniaBipolar DisorderDelirium in DementiaOther CausesDepressionMajor Depressive DisorderSecondary DepressionPost Traumatic Stress DisorderDrug InducedSchizophrenia SymptomsPositive SymptomsDisordered thoughtsDelusionsParanoiaHallucinationsLoose ideationNegative SymptomsFlat AffectAnhedonialoss of emotional responseModels of PsychosisCurrent models suggest psychotic symptoms to be a disregulation in dopaminergic pathwaysThese models primary built on efficacy of dopamine antagonist in schizophreniaDopamine Receptor ResponseD2 receptor occupancy of 65%70% correlates with maximal antipsychotic efficacyunclear if this 65%70% occupancy has to be continuously maintained or intermittently achieved (tight versus loose D2 receptor binding)prolactin elevation appearing beyond 72% D2 occupancyExtrapyramidal Symptoms (EPS) appear beyond 78% D2 occupancy without any increase in benefits at higher rates of occupancyIneffectiveEPSOptimalResponseNasrallah, HA, Dandon, R.Textbook of Psychopharmacology:Chapter 27. Classic Antipsychotic MedicationsDopaminergic PathwaysMesolimbicProject from Ventral tegmental area to the cerebral cortex, including the Nucleus Accumbens (reward pathways)MesocorticalProject from Ventral tegmental area to the limbic structuresTuberoinfundibularD2 receptors in the Hypothalamus inhibit Prolactin secretionNigrostriatal pathway Associated with Parkinsonian SymptomsPathology of SchizophreniaMeso-corticalMesolImbicMesolimbicOveractivity of mesolimbic pathway produce positive symptomsMesocortical Underactivity of mesocortical pathways produces negative symptomsTuberoinfundibular and Nigrostriatal pathways unaffected by SchizophreniaTuberoin-fundibularNigrostriatalTypical vs. AtypicalTypical or First Generation Antipsychotics (FGA) have High affinity for dopamine receptors Low/no affinity for serotonin receptorsAtypical or Second Generation Antipsychotics (SGA) haveModerate affinity for dopamine receptorsIncreased affinity for serotonin ReceptorsRich Pharmacology is beneficialFGA provide a strong dopama-lyticresponseSGA with 5-HT2 antagonism blocks normal vesicular release inhibition, promoting dopamine release into the synapseThis increased dopamine signal is believed to prevent downstream remodeling and development of EPS

Meso-corticalMeso-corticalPharmacologic treatment of SchizophreniaMesolImbicDopamine blockade correct mesolimbic positive symptomsSerotonin corrects mesocortical negative symptomsToo much dopamine blockade causes EPS via nigrostriatalLactation via Tuberoinfundibular The models dont entirely match clinical observationsSerotonin modeled to prevent tuberinfundibular and nigrostriatal symptomsClinical trial show FGA haloperidol to be more effective in improving negative symptoms than quetiapineTuberoin-fundibularNigrostriatalMesolImbic

Other Receptor AffinitiesAlpha 1 Antagonism Hypotension / Reflex Tachycardia Sedation Muscarinic Antagonists Anticholinergic Effects H1 Antagonism Sedation Weight Gain (Appetite) Compilation of Receptor AffinitiesFGA have high D2 affinity and low 5HT affinityNewer SGA have balanced D2 and 5HT affinities

Pharmacology & Pathophysiology SummaryDopamine antagonism is the primary proposed mechanism of psychosisMultiple CNS pathways mediate symptoms and ADRs of agentsSynaptic dopamine levels appear to be modulated by serotoninAchieving the correct level of synaptic dopamine is the key to therapeutic response without ADRsClinical OutcomesEfficacy vs. Tolerability?Both lack of efficacy and intolerability contribute significantly to very high discontinuation ratesEfficacy MeasuresPsychiatric Scores (e.g. PANSS, CGI)Activities of Daily LivingIndependent LivingEmployment statusTolerabilityWeight GainEPSSedation

Lieberman, JA et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. NEJM 2005;353:1209-23.ControversiesFirst vs. Second Generation AntipsychoticsMetabolic Side EffectsFirst vs. Second GenerationLeucht, S, Wahlbeck,K, Hamann,J, Kissling, W. New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. The Lancet, 2003:361;1581-1589Mean doses less than 600 mg/day of chlorpromazine or its equivalent had no higher risk of EPS than new generation drugsRosenheck, R, Perlick, D, Bingham, S. et al. Effectiveness and Cost of olanzapine and haloperidol in the treatment of schizophrenia: A randomized controlled trial. JAMA 2003;290:2693-2702.n=309, 12 months, VA StudyFlexible dose olanzapine+benzotropine vs. flexible dose haloperidolNo significant differences in quality of life, symptoms, or ADR.Olanzapine associated with significant metabolic syndrome and significantly higher costs $3,000-9,000 annuallyHaloperidol associated with significant akathesia and reduced memoryFirst vs. Second GenerationJones, PB, et al. Randomized controlled trial of the effect on quality of life of second vs. first generation antipsychotic drugs in schizophrenia. Archives of General Psychiatry 2006;63:1079-1087CUtLASS 1 trial.n=275, 52 weeks randomized to FGA or SGA for patient who failed antipsychotic therapy (ineffective or ADR)Quality of Life Scale and psychotic symptom scores not significantly different between groupsThe debate rages on, but the pendulum appears to be swinging back towards the re-introductions of FGA19Metabolic side effectsMetabolic AlterationsWeightGlucoseLipidsLipid panel required every 6 months for all antipsychotics per VA/DoD GuidelinesProposed MechanismsH1, serotonin, and alpha-1 antagonism have all been suggestedAppetite stimulationInsulin resistanceClinical Comparison of Weight GainCATIE TrialGreater than 7% increase in body weight (p < 0.001)Olanzapine 30% Quetiapine 16% Risperidone 14% Perphenazine 12% Ziprasidone 7%

Treatment of Metabolic SyndromeExercise!!!!Increase insulin sensitivityControls weightDietWeight gain partially due to appetite stimulationMetforminIncrease insulin sensitivityReduces appetite (GI ADRs)TopiramateTaste perversionHealthBuddy?Ellinger, LK, Ipema, HJ, Stachnik,JM. Efficacy of Metformin and Topiramate in Prevention and Treatment of Second-Generation AntipsychoticInduced Weight Gain. Annals of Pharmacotherapy 2010;44:668-79.Bushe, CJ, Bradley, AJ, Doshi, S, Karagianis, J. Changes in weight and metabolic parameters during treatment with antipsychotics and metformin: do thedata inform as to potential guideline development? A systematic review of clinical studies. The International Journal of Clinical Practice. 2009Wong, R-R, et al. Metformin addition attenuates olanzapine-induced weight gain in drug-nave first-episode schizophrenia aptients: A double-blind, placebo-controlled study. American Journal of Psychiatry 2008; 165:352358

Monitoring of Metabolic Side Effects of AntipsychoticsMorrato, EH et al. Metabolic screening after the American Diabetes Associations consensus statement on antipsychotic drugs and diabetes. Diabetes Care 2009;32:1037-1042EPSExtra Pyramidal Side EffectsGenerated by extra pyramidal cells in the nigrostriatal pathway Range from lip smacking to gross tremorsAbnormal Involuntary Movements Scale (AIMS)12 item clincician administered testFour questions on orofacial movmentsThree questions on extremity and truncal dyskinesia3 questions on global severity, both patient and clinician perspectivesTwo questions about possible dental confoundersShould be re-administered at least every 6 months for antipsychotics to be re-approvedAvailable for download at http://www.cqaimh.org/pdf/tool_aims.pdfTreatment/PreventionAnticholinergicsDiphenhydramineBenztropineADR Management SummaryAntipsychotic therapy has a very high failure rate due to both intolerance and lack of efficacyEPS have classically been associated with FGA, but that may have been a dose-response effectMetabolic side effects are know, but not typically well managed in the communityNothing but opportunity for pharmacist to help manage therapyTherapy ManagementPolypharmacy: Is it good policy?RationalNo studies have been performed demonstrating multiple antipsychotics to be more effective than monotherapyClinically AppropriateAntipsychotics have a high discontinuation rateThere is a documented efficacy hierarchy, with Olanzapine and Clozapine having been demonstrated to be the most efficacious in refractory schizophreniaSafeCurrent models of schizophrenia as a D2 mediated disorder suggest that multiple agents with the same MOA is essentially administering supra-maximal dosesCost EffectivePrinciples of a Sound Drug Formulary System. October 2000Lieberman, JA et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. NEJM 2005;353:1209-23Cross Tapering When polypharmacy make senseComparison of three switching strategiesRR of early discontinuation was 0.77 (CI 0.610.99)Can discontinuation of previous antipsychotic be part of the non-formulary approval process?

Ganguli, R. et al. Assessment of strategies for switching patients from olanzapine to risperidone: A randomized, open-label, rater-blinded study. Medicine 2008, 6:17Formulary RecommendationsEach agent should undergo a 6 week trial for efficacyAIMS testing and lipid screening is required with ALL SGA at initiation and every 6 months. Risperidone QuetiapineAripiprazoleZiprasidoneCandidate for ClozapineNoClozapineOlanzapinePaliperidoneYesEquipotent DosingMedicationChlorpromazine 100mg/day equivalents (mg)Typical dosage range (mg)VA cost based on maximum daily doseClozapine50250-500$3Quetiapine75300-800$6Olanzapine515-30$22Ziprasidone6080-160$8Risperidone22-6$1Aripiprazole7.510-30$6Haloperidol3*~15$0.37Woods, Chlorpromazine equivalent doses for the newer atypical antipsychotics.Journal of Clinical Psychiatry. 2003;64:663-667Atkins, M, Burgess, A, Bottmley, C, Riccio, M. Chlorpromazine equivalents: a consensus of opinion for both clinical and research applications. Psychiatric Bulletin 1997;21:224-226Pricing from VISN 2 CPRS. Retrieved 6/8/2010*Haloperidol equivalent dose is 3 mg at20 mg/d

ClozapineWidely regarded as the most effective SGAAvoided because of agranulocytosisOccurs in less than 2% of patientsTypically within the first 6 monthsRequires weekly monitoringWBC >2000/mm3 ANC >1000/mm3Also has significant, dose-response weight gain, approximately one pound per weekProviders at the Syracuse VA recognize it can be tremendously effective, but are reluctant to use it due to intensive monitoring and workload constraintsWhat a great opportunity for pharmacy!!!Agid, O. et al. Early Use of Clozapine for Poorly Responding First-Episode Psychosis Journal of Clinical Psychopharmacology 2007;27:369-373Clozapine Underutilization and Discontinuation in African Americans Due to Leucopenia Schizophrenia Bulletin 2007;33:12211224deLeon, J. et al. Weight Gain During a Double-Blind Multidosage Clozapine Study Journal of Clinical Psychopharmacology 2007;27:22-27McEvoy et al. Effectiveness of Clozapine Versus Olanzapine,Quetiapine, and Risperidone in Patients With Chronic Schizophrenia Who Did Not Respond to Prior Atypical\Antipsychotic Treatment Am J Psychiatry 2006; 163:600610Alvir, JMJ, et al. Clozapine-Induced Agranulocytosis -- Incidence and Risk Factors in the United States. NEJM 1993;329:162-167

Non-Traditional UsesPTSDOlanzapine and Risperidone have been demonstrated no more effective than placebo in controlling symptomsDepressionAntipsychotics as add on therapy, not as monotherapy in PSYCHOTIC depression vs. Major Depressive Disorder may be appropriate. Monotherapy is less effective than SSRI based therapyInsomniaPrimarily due to anticholinergic effectsCan you say hydroxyzine?Per VISN 2 formulary: Please try to deter providers from using low-dose quetiapine 25mg QHS for sleep.AgitationSome have FDA indication for this useOlanzapine IMAripiprazole IMZiprasidone IMStein, DJ, Ipser, JC, Seedat, S. Pharmacotherapy for post traumatic stress disorder (PTSD). The Cochrane Collaborative. 2009Wijkstra, J, Lijmer, J, Blak, F, Geeddes, J, Nlen, WA. Pharmacological treatment for psychotic depression. The Cochrane Collaborative. 2009Agitation & Behavioral EmergenciesThe Expert Consensus Guideline Series. Treatment of Behavioral Emergencies 2005. J Psychiatr Pract. 2005;11 Suppl 1:5-108 No SGA emerges as a non-specific replacement for haloperidol. If using haloperidol, use with benzodiazepines For oral treatment for agitation related to schizophrenia or mania first line isHaloperidol plus Benzodiazepines Risperidone +/- Benzodiazepines Olanzapine +/- Benzodiazepines Second line therapyZiprasidoneQuetiapineNew AgentsAsenapine (Saphris)Dibenzamine, similar to olanzapine and clozapineLow Muscarinic receptor affinityHigh Dopamine and serotonin affinitiesAvailable only as a sublingual formulationIloperidone(Fanapt)Structurally similar to risperidone and aripiprazoleLow muscarinic receptor affinityHigh affinity for dopamine and serotonin receptorsAlso as norepinephrine receptor affinityAvailable as standard tabletsNo significantly compelling reasons to add to the formulary

Descriptive information from Clinical Pharmacology Online DatabaseStructures downloaded from wikipedia.orgTherapy Management SummaryPolypharmacy is not justified byMechanistic benefitsEvidence based medicineCostTreatment resistant patient should work through the formulary, giving serious consideration to pharmacist-assisted use of clozapineGradual cross titration of antipsychotics is appropriate, but pharmacist should monitor carefully to prevent inadvertent polypharmacySGA not demonstrated superior to haloperidol + BNZ for agitationNewest agents are, in essence, me-too agents and are not easily justified clinically or economicallyConclusionsAntipsychotic therapy is a moving target, with a shifting debate on optimal therapyTherapy management consists of carefully, continuous, and deliberately balancing efficacy and side effectsTo date, poly-pharmacy (2+antipsychotics) is not rational, safe, cost-effective The formulary actually does a good job of balancing efficacy and ADRsThe opportunities for pharmacist to optimize therapy are HUGE