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Antipsychotics The Fut ure of Antipsychotic Therapy (page 7 in syllabus) Stepp,,hen M. Stahl, MD, PhD Adjunct Professor, Department of Psychiatry Universityyg of California, San Diego School of Medicine Honorary Visiting Senior Fellow, Cambridge University, UK Sppyonsored by the Neuroscience Education Institute Additionally sponsored by the American Society for the Advancement of Pharmacotherapy This activity is supported by an educational grant from Sunovion Pharmaceuticals Inc. Copyright © 2011 Neuroscience Education Institute. All rights reserved. Individual Disclosure Statement Faculty Editor / Presenter Stephen M. Stahl, MD, PhD, is an adjunct professor in the department of psychiatry at the University of California, San Diego School of Medicine, and an honorary visiting senior fellow at the University of Cambridge in the UK. Grant/Research: AstraZeneca, BioMarin, Dainippon Sumitomo, Dey, Forest, Genomind, Lilly, Merck, Pamlab, Pfizer, PGxHealth/Trovis, Schering-Plough, Sepracor/Sunovion, Servier, Shire, Torrent Consultant/Advisor: Advent, Alkermes, Arena, AstraZeneca, AVANIR, BioMarin, Biovail, Boehringer Ingelheim, Bristol-Myers Squibb, CeNeRx, Cypress, Dainippon Sumitomo, Dey, Forest, Genomind, Janssen, Jazz, Labopharm, Lilly, Lundbeck, Merck, Neuronetics, Novartis, Ono, Orexigen, Otsuka, Pamlab, Pfizer, PGxHealth/Trovis, Rexahn, Roche, Royalty, Schering-Plough, Servier, Shire, Solvay/Abbott, Sunovion/Sepracor, Valeant, VIVUS, Speakers Bureau: Dainippon Sumitomo, Forest, Lilly, Merck, Pamlab, Pfizer, Sepracor/Sunovion, Servier, Wyeth Copyright © 2011 Neuroscience Education Institute. All rights reserved. Learninggj Objectives • Differentiate antipsychotic drugs from each other on the basis of their pharmacological mechanisms and their associated therapeutic and side effects • Integrate novel treatment approaches into clinical practice according to best practices guidelines • Identify novel therapeutic options currently being researched for the treatment of schizophrenia Copyright © 2011 Neuroscience Education Institute. All rights reserved. Conventional (First(First--Generation)Generation) Antipsychotics Chlorpromazine Perphenazine Cyamemazine Pimozide Flupenthixol Pipothiazine D2 Fluphenazine Sulpiride Haloperidol Thioridazine Loxapine Thiothixene Mesoridazine Trifluoperazine Molindone Zuclopenthixol • D2 antagonists • Effective for positive symptoms • Side effects – Extrapyramidal symptoms – Possible worsening of negative, cognitive, and affective symptoms Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. Cambridge University Press 2008. Copyright © 2011 Neuroscience Education Institute. All rights reserved. D2 Receptor OOccupancyccupancy IInducednduced by Clinical Doses of Antipsychotic Drugs Haloperidol 6 Parkinsonism Haloperidol 6 Akathisia Haloperidol decanoate 50 / 28 d. Parkinsonism Haloperidol 6 Parkinsonism Haloperidol 4 Akathisia, parkinsonism Haloperidol 12 Akathisia Flupentixol decanoate 40 / 7 d. Parkinsonism Zuclopenthixol decanoate 200 / 24 d. Dystonia Thioridazine 400 Pimozide 8 Akathisia Chlorpromazine 200 Sulpiride 800 Parkinsonism Perphenazine enanthate 100 / 7 d. EPS Haloperidol 4 Akathisia Trifluoperazine 10 No EPS Thioridazine 300 Haloperidol decanoate 70 / 28 d. Doses in mg/d Remoxipride 400 Flupentixol 6 Melperone 250 Melperone 300 Flupentixol 6 0 20 40 60 80 100 D2 receptor occupancy (%) Courtesy of L. Farde. Copyright © 2011 Neuroscience Education Institute. All rights reserved. Hypothetical Thresholds for Antipsychotic Drug Effects 100 80 EPS threshold %) Antipsychotic effect threshold 60 ckade ( oo 40 ptor bl ee rec 2 20 D 0 Dose; plasma concentration Copyright © 2011 Neuroscience Education Institute. All rights reserved. Antippysychotics at Hig h Doses • Although standard doses of all antipsychotics target 60- 80% occupancy of D2 receptors, this may not be sufficient to quell psychotic symptoms in all patients • Pharmacodynamic treatment failure for aggression associated with ppysychotic illness occurs when patients do not respond despite attaining 80% D2 receptor occupancy with standard doses of antipsychotics • In these cases, clozapine or high doses of antipsychotics targeting more than 80% D2 occupancy may be jus tifie d, espec ia lly if e ffec tive in re duc ing assaults and if side effects are carefully monitored Copyright © 2011 Neuroscience Education Institute. All rights reserved. Atyy(pical (SecondSecond--GenerationGeneration))y Antipsychotics • Potentially effective for treating positive, negative, affective, and cognitive symptom domains due to vast molecular polypharmacy • Side effects – Cardiometabolic – SdtiSedation – Various others Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. Cambridge University Press 2008. Copyright © 2011 Neuroscience Education Institute. All rights reserved. Common Classes of Atypical Antipsychotics SDA SPA DPA asenapine amisulpride? iloperidone low-dose sulpiride? olanzapine paliperidone clozapine perospirone quetiapine cariprazine riidisperidone ziprasidone sertindole zotepine aripiprazole Copyright © 2011 Neuroscience Education Institute. All rights reserved. Molecular Basis of Side Effects Functional Groups Responsible for Therapeutic Effects Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008. Copyright © 2011 Neuroscience Education Institute. All rights reserved. Molecular Basis of Side Effects Functional Groups Responsible for Side Effects Cardiometabolic side EPS effects, including weight gain, insulin resistance, and increased fasting triglycerides Tardive Dyskinesia Sedation Increased Prolactin Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008. Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--pines”: D2 Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--pines”: 5HT2A Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--pp,,ines”: 5HT1A, 2C, and 6 Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--pines”: 5HT7 Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--pppines”: Alpha 1 Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--pppines”: Alpha 2 Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--pines”: H1 Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--pines”: M1 Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--donesdones”:”: D2 Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--donesdones”:5HT2A”:5HT2A Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--donesdones”:”: 5HT1A,,, 2C, and 6 Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--donesdones”:”: 5HT7 Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--donesdones”:”: Alpha 1 Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--donesdones”:”: Alpha 2 Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--donesdones”:”: H1 Copyright © 2011 Neuroscience Education Institute. All rights reserved. The ““--donesdones”:”: M1 Copyright © 2011 Neuroscience Education Institute. All rights reserved. Aripppiprazolerazole:: D2 Copyright © 2011 Neuroscience Education Institute. All rights reserved. Aripppiprazolerazole:: 5HT2A Copyright © 2011 Neuroscience Education Institute. All rights reserved. Aripppiprazolerazole:: 5HT1A Copyright © 2011 Neuroscience Education Institute. All rights reserved. Aripppiprazolerazole:: 5HT7 Copyright © 2011 Neuroscience Education Institute. All rights reserved. RtlAdAtihtiRecently Approved Antipsychotic Treatments ILOPERIDONE ASENAPINE LURASIDONE Copyright © 2011 Neuroscience Education Institute. All rights reserved. Iloperidone • Serotonin 5-HT2A / dopamine D2 antagonist (SDA) • Recently approved for acute treatment of schizophrenia in adults Copyright © 2011 Neuroscience Education Institute. All rights reserved. Iloperidone • Efficacy comparable to other AAPs • Limited registration data and real world clinical experience; follow slow • Not approved for mania, but titration potentially effective • Use caution with patients sensitive to • Has very low placebo-level EPS orthostasis (young, elderly, patients and little or no akathisia with CV problems) • Potent alpha 1 blocking properties • In presence of potent 2D6 inhibitors suggest potential utility in PTSD (paroxetine, fluoxetine, duloxetine), • Binding properties suggest theoretical reddbhlfduce dose by half efficacy in depression • Weight gain/metabolic profile • Long half-life suggests potential for comparable to that of risperidone once-daily dosing • Dose-dependent QTc prolongation Copyright © 2011 Neuroscience Education Institute. All rights reserved. Asenapine • Serotonin 5-HT2A / dopamine D2 antagonist (SDA) • Currently approved for • Acute and maintenance treatment of schizophrenia in adults • Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults Copyright © 2011 Neuroscience Education Institute. All rights reserved. Asenapine • Mild metabolic risk; no prolactin • Not absorbed once swallowed; elevation must be administered sublingually • No dose titration needed • Common side effect: oral hypoesthesia • Long half-life; once-daily dose is theoretically possible • Patients may not eat or drink for 10 minutes after administration to • Sublingual tablet good for reliable,
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