Draft: 3-27-07 11Antipsychotics andMood Stabilizers:PharmacokineticsAdverse EffectsDrug InteractionsPhilip G. Janicak, MDProfessor of PsychiatryRush University Medical Center2Goals Antipsychotics Diagnostic indications Classification Relevant Pharmacokinetics Serious Adverse Effects Drug Interactions Mood Stabilizers Diagnostic indications Classification Relevant Pharmacokinetics Serious Adverse Effects Drug Interactions2Draft: 3-27-07 23Antipsychotics:Diagnostic IndicationsPsychiatric Schizophrenia Schizoaffective disorder Mood disorders with psychosis Delusional disorderNonpsychiatric Dementia/Delirium Psychosis secondary to a non-psychiatric medical disorder Developmental disability with psychosis and/or aggression Tourette’s disorder Nausea, vomiting34Positivesymptoms:Delusions*Hallucinations*Disorganized speechCatatoniaCognitivesymptoms:AttentionMemoryExecutive functionsMoodsymptoms:DysphoriaSuicidalityHelplessnessNegativesymptoms:Affective flatteningAlogiaAvolitionAnhedoniaSocial inattentivenessOccupationalInterpersonalSelf- careSocialWorkImpact of SchizophrenicSymptoms on OverallFunctioning*Schneiderian First Rank Symptoms4Draft: 3-27-07 35Pharmacokinetics ofAntipsychotics ADME profiles• All are readily absorbed• All are metabolized by the hepatic cytochromeP450 system• prone to drug interactions• T1/2 is generally 20 hours except:• ziprasidone, quetiapine, aripiprazole• Dosing adjustment in elderly renal and/orhepatic impairment56Antipsychotic Agents© Janicak15-225 mg2.5-10 mg (IM)3-50 mg20-250 mgMolindoneDroperidolHaloperidolLoxapine MobanDihydroindolones Haldol InapsineButyrophenones LoxitaneDibenzoxapines10-600 mgChlorprothixene Taractan6-60 mgThiothixene NavaneThioxanthenes15-125 mgTindalProchlorperazineCompazine2-60 mgPerphenazineTrilafon5-40 mgFluphenzineProlixin2-60 mgTrifluoperazineStelazinePiperazines20-160 mgPiperacetazineQuide30-800 mgThioridazineMellaril20-200 mgMesoridazineSerentilPiperidines25-1000 mgPromazineSparine20-150 mgTriflupromazineVesprin100-1000 mgChlorpromazineThorazineAliphatics40-80 mgDosage (average range; PO, qd)Generic NameClass/Trade NameAcetophenazinePhenothiazines6Draft: 3-27-07 47Antipsychotic Agents (con’t)Pimozide 1-10 mg100 mg/wk10-30 mg40-160 mg75-750 mg5-20 mg2-10 mg3-12 mg100-900 mgDosage (average range; PO, qd)PenfluridolAripiprazoleZiprasidoneQuetiapineOlanzapineRisperidonePaliperidoneClozapineGeneric NameOrapSemapDiphenytbutyrylpiperidinesAbilifyGeodonQuinolinonesBenzisothiazolylsSeroquelDibenzothiazepinesZyprexaThienobenzodiazepinesRisperdal InvegaBenzisoxazoleDibenzodiazepinesClozarilClass/Trade Name© Janicak780+++++0/++Cardiovascular++++++/+++++++Sedation00/+0/+0/++++0/+++Prolactin00000+++0Hematological00/+0/++/++0/++++0Anticholinergic0/+0/++++++++++++Weight gain/Endocrine0/+0/+00/++0+++NeurologicalARIPZIPQTPOLZRISPCLOZHPDLEPS*+++++00/++++PALIAdapted from Masand PS et al. Handbook of Psychiatry in Primary Care. 1998.Antipsychotics:Adverse Effect Profiles*At appropriate doses; 0 = none; + = mild; ++ = moderate; +++ = substantialDraft: 3-27-07 59Maximum MinimumHIGH POTENCY RISPERIDONE OLANZAPINE CLOZAPINEFGAs PALIPERIDONE ZIPRASIDONE (DOSE-RELATED) QUETIAPINE ARIPIPRAZOLE*ADVERSE EFFECTS OF ANTIPSYCHOTICSAcute EPS*Based on clinical trial data• Psuedoparkinsonism• Dystonia• Akathisia• Tardive Dyskinesia910Dementia Patients Risks Mortality rate CVA in 4% vs 2% Risks may behigher for all APs Recommendations Avoid in those withvascular dementia Avoid with TIA,hypertension, Afib Use low dosesMonitor forhypotension,sedation, EPS10Draft: 3-27-07 611Weight Gain: Overview General population Increased morbidity and mortality Stigmatization Major mental disorders This adverse effect is more common with some recent antipsychotics Recognized problem since chlorpromazine Polypharmacy may contribute Divalproex sodium Lithium Antidepressants Antipsychotics© Janicak1112The Metabolic Syndrome Insulin resistance Hyperinsulinemia Decreased beta cell function Postprandial hyperglycemia12Draft: 3-27-07 713SGAs and MetabolicAbnormalities+ = increase effect; - = no effect; D = discrepant results.*Newer drugs with limited long-term data.Diabetes Care. 2004.Risk for WorseningDrug Weight Gain Diabetes Lipid ProfileClozapine +++ + +Olanzapine +++ + +Risperidone ++ D DQuetiapine ++ D DAripiprazole* +/- - -Ziprasidone* +/- - -1314Baseline Monitoring History (personal or family) of obesity,diabetes, dyslipidemia, hypertension, CVD BMI Waist circumference Blood pressure Fasting lipid profile Fasting plasma glucose14Draft: 3-27-07 815Anticholinergic EffectsMost common with: Clozapine Olanzapine Quetiapine Low-potency FGAs© Janicak1516Hematological Clozapine-induced agranulocytosis ManagementStop agentReverse isolation; supportive measuresGSCF (filgastrim) Rechallenging strategies© Janicak16Draft: 3-27-07 917 Cardiovascular Related to both alpha1 adrenergic andmuscarinic effects Hypotension Tachycardia Myocarditis Arrhythmogenic potential possible with allantipsychotics1718Royal College of Psychiatrists. 1997.QTc prolongationVentricular fibrillation(sudden death)RarelyRarely(syncope)Torsade de pointes arrhythmiaPotential Consequences ofQTc Interval Prolongation18Draft: 3-27-07 1019QT interval Time between onsetof depolarization andrepolarization Affected by diet,alcohol intake, time ofday, heart rate Usually corrected forheart rate = QTc1920Antipsychotics:Drug Interactions Pharmacodynamic Anticholinergic Hypotension Pharmacokinetic P450 inhibition (quinidine) P450 induction (carbamazepine)20Draft: 3-27-07 1121Bipolar Disorder:Symptom DomainsManiaEuphoriaGrandiosityPressured speechImpulsivityExcessive libidoRecklessnessDiminished need forsleepDepressionDepressionAnxietyIrritabilityHostilityViolence orsuicideManic, depressedor mixedPsychosis•Delusions•Hallucinations•Sensory hyperactivityCognition•Racing thoughts•Distractability•Poor insight•Disorganization•Inattentiveness•Confusion2122Lithium* (A, M)AnticonvulsantsValproate*
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