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Serotonin Dopamine Antagonists) NewNew DevelopmentsDevelopments inin thethe ResearchResearch andand TreatmentTreatment ofof SchizophreniaSchizophrenia StephenStephen M.M. Stahl,Stahl, MD,MD, PhDPhD Adjunct Professor, Department of Psychiatry, University of California, San Diego School of Medicine Sponsored by Neuroscience Education Institute Additionally sponsored by American Society for the Advancement of Pharmacotherapy This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP; Cephalon, Inc.; and Shire Pharmaceuticals Inc. with additional support from Alkermes, Inc.; Eli Lilly and Company; Jazz Pharmaceuticals, Inc.; and Sepracor Inc. Copyright © 2007 Neuroscience Education Institute. All rights reserved. Learning Objectives After completion of this lecture you should be able to: • Evaluate evidence about the function and efficacy of the newest antipsychotics • Describe the rationale and present state of pharmacogenetics research • Discuss goals and challenges of pharmacogenetics in psychiatry Copyright © 2008 Neuroscience Education Institute. All rights reserved. Overview: Four Bedtime Stories • A Tale of Serotonin Antagonism • The Dopamine Partial Agonism Story • Pharmacogenetics and the Genes • Once Upon a Glutamate Receptor Copyright © 2008 Neuroscience Education Institute. All rights reserved. Overview: Four Bedtime Stories • A Tale of Serotonin Antagonism • The Dopamine Partial Agonism Story • Pharmacogenetics and the Genes • Once Upon a Glutamate Receptor Copyright © 2008 Neuroscience Education Institute. All rights reserved. What Makes an Antipsychotic Conventional? D2 Antagonist Actions D2 10-1 Copyright © 2008 Neuroscience Education Institute. All rights reserved. What Makes an Antipsychotic Atypical? Adding 5HT2A Antagonist Actions 5HT2A D2 10-14 Copyright © 2008 Neuroscience Education Institute. All rights reserved. A Tale of Serotonin Antagonism 5HT2A inhibition of stimulation of 5HT1A DA release DA release 5HT DA DA GABA neuron neuron DA 5HT2A 5HT2A antagonist antagonist GABA neuron 5HT2A antagonist 5HT 5HT neuron neuron Stahl’s Essential Psychopharmacology 3rd ed. 2008 Copyright © 2008 Neuroscience Education Institute. All rights reserved. Which Antipsychotics are SDAs? (Serotonin Dopamine Antagonists) clozapine risperidone non-US 5HT2A paliperidone olanzapine perospirone quetiapine ziprasidone zotepine low dose loxapine? sertindole D2 low dose cyamemazine? 10-37 Copyright © 2008 Neuroscience Education Institute. All rights reserved. New SDAs in Development iloperidone 5HT2A asenapine SM13493/ lurasidone blonanserin Y931 NRA0562 D2 nemonapride 10-38 Copyright © 2008 Neuroscience Education Institute. All rights reserved. Preview: Asenapine in Trials Action: Dopamine-serotonin antagonist Change from Baseline in PANSS Total Score 0 • Preliminary trials of -2 0123456 -4 asenapine show good -6 efficacy for the treatment of -8 acute schizophrenia. -10 -12 -14 Asenapine LSM Change From Baseline -16 Risperidone Placebo -18 Mean Weight Gain (6-week trial) Week 1.8 1.6 1.4 1.2 Dosage for this 6-week 1 controlled study was 0.8 0.6 5 mg b.i.d. 0.4 Mean Weight Gain (kg) 0.2 0 Asenapine 5 mg b.i.d. Risperidone 3 mg Placebo b.i.d. Adapted from Potkin et al. J Clin Psychiatry 2007;68:1492-500. Copyright © 2008 Neuroscience Education Institute. All rights reserved. Asenapine: Receptor Binding Profile 11 10.5 10 10.2 ) 9 i 9.9 8 9.8 9.6 Affinity (pK 7 9.5 9.4 6 9.0 5 8.9 8.9 8.9 8.9 5-HT2C 5-HT2A 5-HT7 5-HT2B 8.8 5-HT6 8.7 α2B Shahid M and Wong EHF. 2005. 8.6 8.6 D3 D4 Copyright © 2008 Neuroscience Educatio 8.5 α1 α2A 8.0 α2C D 2 D2 5-HT5 H1 n Institute. All rights reserved. Eur Neuropsychopharmacol. 5-HT1A 5-HT1B D 1 5.1 H2 M1 asenapine CH 3 N CH 3 Copyright © 2008 Neuroscience Education Institute. All rights reserved. mirtazapine N N N CH 3 CH 3 N N = mirtazapine N N = asenapine CH CH 3 3 Copyright © 2008 Neuroscience Education Institute. All rights reserved. Dosing Asenapine • Sublingual b.i.d. – Will not absorb in stomach: no drinking or swallowing after administration • Trials at 5 and 10 mg for schizophrenia, 10 mg for mania – Unclear whether doses > 10 mg are tolerable – Unclear whether 20 mg q.d. is effective – Unclear whether smaller doses are effective • Superior to risperidone in some trials • Inferior to olanzapine in some trials Potkin, et al. J Clin Psychiatry 2007;68:1492-500. Potkin, et al. Poster presented at ACNP 2005. Copyright © 2008 Neuroscience Education Institute. All rights reserved. Preview: Iloperidone Action: Serotonin-Dopamine antagonist • Comparable to ziprasidone tolerability (weight gain, metabolic, sedation) • Placebo rates of EPS, akathisia, hyperprolactinemia • Trials with 7-day fixed titration – Started at 2mg/day, added 2mg each day up to: • Low dose: 12 or 16mg/day • High dose: 20 or 24mg/day • Pharmacogenomic markers of iloperidone’s efficacy in testing • Injectable formulation in development Weiden et al. Poster presented at APA 2007. Copyright © 2008 Neuroscience Education Institute. All rights reserved. Iloperidone, Risperidone, and Akathisia Categorical Change in Barnes Akathisia Scale Iloperidone 12-16 mg/d 80 Iloperidone 20-24 mg/d Risperidone 6-8 mg/d 60 Placebo 40 Patients (%) 20 * * 0 Improvement No Change Worsening * p < 0.05 Weiden, et al. Poster presented at APA 2007. Copyright © 2008 Neuroscience Education Institute. All rights reserved. Dosing Iloperidone • Trials at 12-16 and 20-24 mg/d resulting in similar side effect profile – Unclear whether higher doses are more effective in some patients; however, lower doses generally less effective – Unclear whether faster titration is tolerable in some patients – Not yet tested in mania • QTc prolongation comparable to ziprasidone – Dose dependent – Desensitizes over time Copyright © 2008 Neuroscience Education Institute. All rights reserved. Overview: Four Bedtime Stories • A Tale of Serotonin Antagonism • The Dopamine Partial Agonism Story • Pharmacogenetics and the Genes • Once Upon a Glutamate Receptor Copyright © 2008 Neuroscience Education Institute. All rights reserved. What Makes an Antipsychotic Atypical? D2 Partial Agonist Actions (DPA) D2 PA 10-45 Copyright © 2008 Neuroscience Education Institute. All rights reserved. conventional antipsychotic antagonist: deficiency of agonist too cold antipsychotic EPS 10-46 Copyright © 2008 Neuroscience Education Institute. All rights reserved. dopamine stimulant: excess of full agonist too hot psychosis 10-46 Copyright © 2008 Neuroscience Education Institute. All rights reserved. dopamine partial agonist dopamine stabilizer: balance between agonist and antagonist actions just right antipsychotic without EPS 10-46 Copyright © 2008 Neuroscience Education Institute. All rights reserved. The Dopamine Partial Agonism Story D2 antagonist DPA Mesolimbic pathway: Effective dopamine reduction antipsychotic Nigrostriatal pathway: Nigrostriatal pathway: Excessive dopamine Partial dopamine EPS reduction reduction no EPS Stahl SM. Essential Psychopharmacology 3rd Ed. In press. Copyright © 2008 Neuroscience Education Institute. All rights reserved. Which Antipsychotics are DPAs? aripiprazole amisulpride? bifeprunox D2 low dose sulpiride? PA 10-52 Copyright © 2008 Neuroscience Education Institute. All rights reserved. New DPAs in Development RGH188 3PPP bifeprunox sarizotan SLV313 SSR-181507 SLV314 ACR16 ACP-104 PNU 9639/OSU 6162 D2 CI1007 PA 10-53 Copyright © 2008 Neuroscience Education Institute. All rights reserved. Bifeprunox: Receptor Binding Profile Action: Dopamine-serotonin partial agonist 10 9 8 7 6 Maximum Reported pki 5 1 2 α α D3 D4 H1 M1 D2* 5HT2A 5HT1A 5HT2C* Therapeutic Receptor Action Side-Effect Receptor Action Newman-Tancredi et al. Current Opinion in Investigational Drugs 2007;8(7):539-554. Copyright © 2008 Neuroscience Education Institute. All rights reserved. Preview: Bifeprunox Change from Baseline in PANSS Total Score 12346 0 -2 week • More positive -4 -6 results at lower -8 dose -10 -12 -14 • Low EPS -16 -18 Mean PANSS-T score change -20 0.7 0.7 Bifeprunox (30 mg) 0.5 0.4 0.4 Bifeprunox (40 mg) 0.3 0.2 Risperidone (6 mg) 0.1 0.1 0.1 0.1 0 0 Placebo -0.1 -0.3 -0.3 -0.3 -0.5 -0.4 Change from Baseline Simpson-Angus Barnes Akathisia Abnormal Scale Scale Involuntary Movement Scale Meltzer et al. Intl J Neuropsychopharmacology. In press. Copyright © 2008 Neuroscience Education Institute. All rights reserved. Preview: Bifeprunox • Positive results at low doses (30 mg/day) • Less positive results at high doses (40 mg/day) • Requires titration to avoid vomiting • Inferior to risperidone as monotherapy • Consider combining with risperidone – Lowers nausea from bifeprunox – Lowers prolactin from risperidone Copyright © 2008 Neuroscience Education Institute. All rights reserved. What Makes an Antipsychotic Atypical? Adding 5HT1A Agonist/Partial Agonist Actions 5HT1A 5HT1A PA PA D2 D2 PA 10-55 Copyright © 2008 Neuroscience Education Institute. All rights reserved. Dopamine 2 Receptor Partial Agonist DPA Spectrum antipsychotic psychotomimetic silent bifeprunox OPC aripiprazole 4293 lisuride antagonists terguride sulpiride aplindore amisulpride pramipaxole (DAB452 or ropinirole WAY13592) DA stimulants/ inverse conventionals amantadine full NET inhibitors agonists DAT inhibitors agonists SDAs 10-54 Copyright © 2008 Neuroscience Education Institute. All rights reserved. Do dopamine 2 partial agonists have partial efficacy as antipsychotics? • Effective antipsychotics have inverted U shaped dose response curves – Aripiprazole (20 mg >30 mg) – Bifeprunox – RGH 188 • Agonists that are “too full”
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