What's New in the World of Antipsychotics?

Transcription

1 Handout for the Neuroscience Education Institute (NEI) online activity: What's New in the World of Antipsychotics? (page 7 in syllabus) Stephen M. Stahl, MD, PhD Adjunct Professor, Department of Psychiatry University of California, San Diego School of Medicine Honorary Visiting Senior Fellow, Cambridge University, UK Sponsored by the Neuroscience Education Institute Additionally sponsored by Fairleigh Dickinson University School of Psychology This activity is supported by an educational grant from Sunovion Pharmaceuticals Inc.

2 Learning Objectives Implement accumulating evidence and clinical experience in the utilization of the most recently approved atypical antipsychotics Investigate several novel antipsychotics with unique mechanisms of action that are currently being investigated

3 Pretest Question 1 Irene is a 27-year-old patient with schizophrenia. She has had limited success with trials of several older atypical antipsychotics and has experienced significant drug-induced weight gain over the past 5 years. You are considering starting her on 1 of the newer atypical antipsychotics (iloperidone, asenapine, or lurasidone). Which of these newer agents carries the highest risk of weight gain? 1. Iloperidone 2. Asenapine 3. Lurasidone

4 Pretest Question 2 Richard is a 42-year-old patient with schizophrenia who is currently not being treated. Genetic testing has revealed that he has a polymorphism in the gene for cytochrome P450 1A2 that results in very poor metabolism by the CYP450 1A2 enzyme. Which of the following antipsychotics may require a dose adjustment due to this CYP450 1A2 polymorphism? 1. Iloperidone 2. Asenapine 3. Lurasidone

5 Pretest Question 3 A promising approach to the novel treatment of schizophrenia is: 1. Glycine reuptake inhibitors 2. Ketamine 3. Both of the above 4. None of the above

6 The Latest Additions to the Clinician's "Toolbox" of Antipsychotics Iloperidone FDA approved May 7, 2009 Asenapine FDA approved August 13, 2009 Lurasidone FDA approved October 28, 2010 Tarazi FI, Stahl SM. Expert Opinion Pharmacother 2012;Epub ahead of print.

7 Indications Iloperidone Acute schizophrenia in adults Lurasidone Acute schizophrenia in adults Asenapine Acute schizophrenia in adults Manic or mixed episodes associated with bipolar I, with or without psychotic features Maintenance treatment of schizophrenia Adjunctive treatment with lithium or valproate for acute manic or mixed episodes associated with bipolar I disorder Tarazi FI, Stahl SM. Expert Opinion Pharmacother 2012;Epub ahead of print.

8 Iloperidone

9 Iloperidone: Pharmacokinetics Metabolized by CYP450 2D6 and 3A4 Inhibitors of 2D6 increase plasma levels of iloperidone e.g., paroxetine, duloxetine, quinidine Inhibitors of 3A4 increase plasma levels of iloperidone e.g., fluoxetine, nefazodone, and ketoconazole Decrease iloperidone by 50% when 2D6 or 3A4 inhibitors are co-administered Tarazi FI, Stahl SM. Expert Opinion Pharmacother 2012;Epub ahead of print.

10 Iloperidone: Dosing Tips and Pearls Slow titration to avoid orthostatic hypotension Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 and beyond 1 mg 2X/day 2 mg 2X/day 4 mg 2X/day 6 mg 2X/ day 8 mg 2X/day 10 mg 2X/day 12 mg 2X/day Can be administered with or without food No dose adjustments needed for patients with renal or hepatic impairment Often used as a switch agent in non-urgent situations A 4-week depot preparation is in clinical testing Tarazi FI, Stahl SM. Expert Opinion Pharmacother 2012;Epub ahead of print; Stahl SM. Stahl's Essential Psychopharmacology: The Prescriber's Guide. 4th ed

11 Iloperidone Efficacy Citrome L et al. Hum Psychopharmacol Clin Exp 2012;27:24-32.

12 Iloperidone: Tolerability Moderate effects on body weight Iloperidone-induced changes in weight are independent from significant changes in glucose or lipid levels Low rate of akathisia Slow titration and careful monitoring of orthostatic hypotension are required Especially in the elderly or when used in combination with other medications that may induce orthostasis (e.g., diuretics, TCAs) Significant risk of QTc prolongation Tarazi FI, Stahl SM. Expert Opinion Pharmacother 2012;Epub ahead of print.

13 Iloperidone: Extrapyramidal Side Effects High alpha 1 affinity coupled with 5HT2A receptors may underlie the low risk of EPS Iloperidone shares these features with other low EPS-risk antipsychotics (quetiapine and clozapine) Cutler AJ et al. J Clin Psychopharmacol 2008;28(2)(suppl 1):S20-8; Stahl SM. Stahl's Essential Psychopharmacology: The Prescriber's Guide. 4th ed

14 Cortical 5HT2A striatum raphe nucleus accumbens brainstem neurotransmitter centers substantia nigra Adapted from Stahl s Essential Psychopharmacology, 3 rd edition 2008 and 4 th edition in press.

15 Cortical 5-HT 2A Receptors Decrease Dopamine Decreased DA release Inhibited DA neuron 5-HT Activated glutamatergic pyramidal neuron GABA release from GABA neuron Adapted from Stahl s Essential Psychopharmacology, 3 rd edition 2008 and 4 th edition in press; Ugedo L, et al. Psychopharmacology. 1989; 98:45-50.

16 Cortical 5-HT 2A Receptors Decrease Dopamine Decreased DA release 5-HT neurons 5-HT 2A receptor GABA release from GABA neuron Inhibited DA neuron Glutamate release from glutamate neuron Activated glutamatergic pyramidal neuron Adapted from Stahl s Essential Psychopharmacology, 3 rd edition 2008 and 4 th edition in press; Ugedo L, et al. Psychopharmacology. 1989; 98: HT

17 Blocking Cortical 5-HT 2A Receptors Increases Dopamine Increased DA release Activated DA neuron 5-HT 2A antagonist Inactivate glutamatergic pyramidal neuron Inactive GABA neuron Extrapyramidal symptoms (EPS) Adapted from Stahl s Essential Psychopharmacology, 3 rd edition 2008 and 4 th edition in press; Ugedo L, et al. Psychopharmacology. 1989; 98:45-50.

18 Blocking Cortical 5-HT 2A Receptors Increases Dopamine Increased DA release Extrapyramidal symptoms (EPS) 5-HT 2A antagonist Activated DA neuron Inactive GABA neuron Inactive glutamate neuron Inactivate glutamatergic pyramidal neuron Adapted from Stahl s Essential Psychopharmacology, 3 rd edition 2008 and 4 th edition in press; Ugedo L, et al. Psychopharmacology. 1989; 98:45-50.

19 Nigral and Striatal 5HT2A striatum raphe nucleus accumbens brainstem neurotransmitter centers substantia nigra Adapted from Stahl s Essential Psychopharmacology, 3 rd edition 2008 and 4 th edition in press.

20 Nigral and Striatal 5-HT 2A Receptors Decrease Dopamine Inhibited DA neuron Decreased DA release 5-HT GABA release from GABA neuron 5-HT GABA release from GABA neuron Adapted from Stahl s Essential Psychopharmacology, 3 rd edition 2008 and 4 th edition in press; Kapur S, Remington G. Am J Psychiatry. 1996;153:

21 Nigral and Striatal 5-HT 2A Receptors Decrease Dopamine 5-HT neuron 5-HT 2A receptors 5-HT 2A receptor Adapted from Stahl s Essential Psychopharmacology, 3 rd edition 2008 and 4 th edition in press; Kapur S, Remington G. Am J Psychiatry. 1996;153: ; Jakab RL, Goldman-Rakic PS. PNAS. 1998; 95:

22 Nigral and Striatal 5-HT 2A Receptors Decrease Dopamine Decreased DA release GABA release from GABA neuron 5-HT GABA release from GABA neuron Inhibited DA neuron 5-HT Decreased DA release Adapted from Stahl s Essential Psychopharmacology, 3 rd edition 2008 and 4 th edition in press; Kapur S, Remington G. Am J Psychiatry. 1996;153:

23 Blocking Nigral and Striatal 5-HT 2A Receptors Increases Dopamine Increased DA release Activated DA neuron 5-HT 2A antagonist Inactive GABA neuron Inactive GABA neuron Extrapyramidal symptoms (EPS) Adapted from Stahl s Essential Psychopharmacology, 3 rd edition 2008 and 4 th edition in press.

24 Blocking Nigral and Striatal 5-HT 2A Receptors Increases Dopamine. Increased DA release Extrapyramidal symptoms (EPS) Inactive GABA neuron Increased DA release Inactive GABA neuron 5-HT 2A antagonist Activated DA neuron 5-HT 2A antagonist Adapted from Stahl s Essential Psychopharmacology, 3 rd edition 2008 and 4 th edition in press.

25 Blocking Cortical Alpha 1 Receptors May Increase Dopamine Release Stahl SM. Stahl's Essential Psychopharmacology: The Prescriber's Guide. 4th ed

26 Asenapine

27 Asenapine: Pharmacokinetics Metabolized by CYP450 1A2 Inhibitors of 1A2 increase plasma levels of asenapine e.g., fluvoxamine, verapamil, ciprofloxacin Asenapine is a weak inhibitor of 2D6 Use caution when co-administering with drugs that are substrates for 2D6 or other inhibitors of 2D6 2D6 substrates Tarazi FI, Stahl SM. Expert Opinion Pharmacother 2012;Epub ahead of print.

28 Asenapine: Dosing Tips and Pearls Sublingual formulation Bioavailability when swallowed is very low Avoid eating or drinking for 10 min after administration Typical dose Schizophrenia: 5 mg 2X/day Bipolar mania: 10 mg 2X/day May be useful as a rapid-acting PRN antipsychotic No dose adjustment necessary in patients with moderate hepatic or renal impairment Use caution in patients with severe hepatic impairment Tarazi FI, Stahl SM. Expert Opinion Pharmacother 2012;Epub ahead of print.

29 Asenapine Efficacy: Schizophrenia Potkin SG et al. J Clin Psychiatry 2007;68:

30 Asenapine Efficacy: Schizophrenia Negative Symptoms Buchanan RW et al. J Clin Psychopharmacol 2012;32(1):36-45.

31 Asenapine Efficacy: Acute Mania McIntyre RS et al. Biol Psychiatry 2010;122(1-2):27-38.

32 Asenapine Efficacy: Adjunctive Treatment for Mania Core Study Extension Szegedi A et al. J Clin Psychopharmacol 2012;32:46-55.

33 Asenapine Efficacy: Adjunctive Treatment for Mania Szegedi A et al. J Clin Psychopharmacol 2012;32:46-55.

34 Asenapine Efficacy: Acute Mania McIntyre RS et al. Bipolar Disord 2009;11(8):

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38 Asenapine: Tolerability Limited effects on weight Small, non-significant effects on fasting glucose levels have been observed No clinically significant effects on total cholesterol or fasting triglycerides have been observed Slightly elevated risk of akathisia and other EPS Oral hypoesthesia and somnolence are not uncommon May induce orthostatic hypotension and syncope Marginal effects on QTc interval Benign effects on prolactin Tarazi FI, Stahl SM. Expert Opinion Pharmacother 2012;Epub ahead of print.

39 % of Patients With Clinically Significant Weight Gain Asenapine: Metabolic Side Effects Potkin SG et al. J Clin Psychiatry 2007;68: ; McIntyre RS et al. Bipolar Disord 2009;11(8):

40 Lurasidone

41 Lurasidone: Pharmacokinetics Metabolized by CYP450 3A4 When co-administered with a 3A4 inhibitor (e.g., diltiazem) Do not exceed 40 mg/day of lurasidone Do NOT co-administer lurasidone: With strong 3A4 inhibitors (e.g., ketoconazole) With strong 3A4 inducers (e.g., rifampin) Lurasidone may increase the effects of antihypertensive agents Tarazi FI, Stahl SM. Expert Opinion Pharmacother 2012;Epub ahead of print.

42 Lurasidone: Dosing Tips and Pearls Recommended starting dose: 40 mg/day Maximum recommended dose was originally 80 mg/day In May 2012, the FDA approved an expanded dose range of mg/day for schizophrenia 120-mg tablet currently in development No titration required Should be taken with food (at least 350 calories) Dose should not exceed 40 mg/day in patients with moderate to severe renal or hepatic impairment Tarazi FI, Stahl SM. Expert Opinion Pharmacother 2012;Epub ahead of print.

43 LS Mean Change From Baseline (PANSS Total) Lurasidone Efficacy: PANSS Total Baseline Day 4 Wk 1 Wk 2 Wk 3 Wk 4 Wk * *** * *p<0.05 **p<0.01 ***p<0.001 *** *** *** *** *** *** *** *** *** *** *** Placebo (n=120) 80 mg/d Lurasidone (n=125) 160 mg/d Lurasidone (n=121) 600 mg/d Quetiapine XR (n=116) *** *** *** *** Wk 6 Endpoint *** *** ***

44 LS Mean Change From Baseline Lurasidone Efficacy: NSA-16 Total Score *** -8.9 *** Placebo LUR 80 mg/d LUR 160 mg/d n=109 n=114 n= *** QXR 600 mg/d n=109 Baseline ***p<0.001

45 LS Mean Change From Baseline Lurasidone Efficacy: MADRS Placebo (n=116) Lurasidone 80 mg/d (n=116) Lurasidone 160 mg/d (n=112) Quetiapine XR 600 mg/d (n=110) *p<0.05 **p<0.01 ***p< *** *** ***

46 Probability of Not Relapsing Time to Relapse for Lurasidone vs. Quetiapine XR Hazard ratio (relapse risk) 2 : LUR vs. QXR = (95% CI: ) Number of Days on Treatment Treatment Group LUR - LUR (n=139) QXR - QXR (n=79) 1 Kaplan-Meier Survival Curve up to 365 Days 2 Derived from the Cox Proportional Hazards Model

47 Lurasidone: Tolerability Benign metabolic profile Minimal changes in body weight No significant changes in total cholesterol, triglycerides, LDLs, HDLs, or fasting blood glucose Risk of akathisia and EPS, especially at higher doses No QTc prolongation Small but significant increase in prolactin levels Administering lurasidone at night may reduce side effects Tarazi FI, Stahl SM. Expert Opinion Pharmacother 2012;Epub ahead of print.

48 Patients (%) Adverse Reactions (ARs) Occurring in 5% of Patients (by Treatment Group) lurasidone to lurasidone* (n=115) olanzapine to lurasidone (n=69) placebo to lurasidone (n=62) *Lurasidone-treated patients who completed the core 6-week study and continued on lurasidone in the 26-week extension Olanzapine-treated patients who completed the core 6-week study and continued on lurasidone in the 26-week extension Placebo-treated patients who completed the core 6-week study and started on lurasidone in the 26-week extension LATUDA Prescribing Information. Sunovion Pharmaceuticals Inc. April 2012.

49 Median Change From OL Baseline (mg/dl) Metabolic Changes at Month 8* PBO to LUR n= Total Cholesterol OLZ to LUR n=31 LUR to LUR n= All LUR n=114 PBO to LUR n= Triglycerides OLZ to LUR n=31 LUR to LUR n= All LUR n= Open-label baseline mean total cholesterol (mg/dl): PBO/LUR=197.4; OLZ/LUR=191.3; LUR/LUR=196.7; All LUR= Open-label baseline mean triglycerides (mg/dl): PBO/LUR=133.4; OLZ/LUR=186.0; LUR/LUR=158.1; All LUR=159.6 PBO=placebo; OLZ=olanzapine; LUR=lurasidone Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. *8 months includes the beginning of the double-blind period to the end of the open-label extension phase. Data on file. Sunovion Pharmaceuticals Inc.

50 Mean Change From Double-Blind Baseline (kg) 6-week fixed-dose core study Weight Changes From Baseline Through Month 8 Double-Blind Baseline 5.0 Wk 6 Mean weight change from open-label baseline to month 8 Wk 8 Month 3 Month 4 placebo to lurasidone: olanzapine to lurasidone: lurasidone to lurasidone: Month 5 Month 6 Month kg kg 0.41 kg Month olanzapine to lurasidone placebo to lurasidone lurasidone to lurasidone 0.0 Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Data on file. Sunovion Pharmaceuticals Inc.

51 LS Mean Change From Baseline Lurasidone Tolerability: Barnes Akathisia Rating Scale (BAS) Placebo (n=120) Lurasidone 80 mg/d (n=125) Lurasidone 160 mg/d (n=121) Quetiapine XR 600 mg/d (n=116) BAS scored 0-5 on Global Clinical Assessment of Akathisia item (maximum possible score = 5)

52 Median Change From OL Baseline (ng/ml) Prolactin Changes at Month 8* placebo to lurasidone n= olanzapine to lurasidone n=30 lurasidone to lurasidone n= all lurasidone n= Open-label baseline mean prolactin (ng/ml): PBO/LUR=9.68; OLZ/LUR=15.55; LUR/LUR=14.18; All LUR=13.43 PBO=placebo; OLZ=olanzapine; LUR=lurasidone As with other drugs that antagonize dopamine D2 receptors, lurasidone elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and sexual dysfunction have been reported in patients receiving prolactin-elevating compounds. *8 months includes the beginning of the double-blind period to the end of the open-label extension phase. Data on file. Sunovion Pharmaceuticals Inc.

53 Potential Additional Indications Depression Anxiety Insomnia Mechanism 2 5HT7 5HT2C 5HT1B/D 5HT1A 1 H1 Iloperidone Asenapine Lurasidone Stahl SM. Stahl's Essential Psychopharmacology: The Prescriber's Guide. 4th ed

54 Potentiating Effects From Serotonin Reuptake Blockade Potentiate elevation in serotonin levels in the presence of serotonin reuptake inhibitors (SSRIs/SNRIs) 5HT7 and 5HT1B/D antagonism 5HT1A partial agonism 5HT7 receptors Involved in numerous processes, including learning and memory Many atypical antipsychotics (including iloperidone, asenapine, and lurasidone) and antidepressants act at 5HT7 receptors Receptor levels are decreased in postmortem schizophrenia cortex Stahl SM. Stahl's Essential Psychopharmacology: The Prescriber's Guide. 4th ed

55 5HT7

56 5HT7

57 5HT7

58 Emerging Antipsychotics and Novel Mechanisms of Action Under Investigation

59 Investigational Mechanisms and Agents for Schizophrenia Molecular Target Clinical Target Drug Development Phase Dopamine 2/serotonin 2A Positive, negative, and cognitive symptoms sertindole Phase IV Dopamine 3 antagonism Positive, negative, and cognitive symptoms cariprazine Phase III Glycine transport inhibition Positive, negative, and cognitive symptoms RG1678 ORG25935 AMG 747 Metabotropic 2/3 agonism Positive, negative, and cognitive symptoms LY AZD8529 Alpha 7 nicotinic agonism Positive, negative, and cognitive symptoms RG3487 TC-5619 Phase III Phase II Phase I Ceased in Phase II Phase II Phase II Phase II Phosphodiesterase 10A enzyme Positive, negative, and cognitive symptoms PF Phase II Cyclooxygenase-2 inhibition Positive and negative symptoms (adjunct) celecoxib Phase II Serotonin 6 antagonism Cognitive symptoms (adjunct) SB PF AE58054 Histamine 3 antagonism Cognitive symptoms (adjunct) PF GSK Phase II Phase II Phase II Phase II Phase II Dopamine 2 partial agonism Positive, negative, and cognitive symptoms bifeprunox Ceased in Phase III Serotonin 1A agonism Positive, negative, and cognitive symptoms PF Ceased in Phase II Serotonin 2C agonism Positive, negative, and cognitive symptoms vabicaserin Ceased in Phase II Positive allosteric modulation of glutamatergic AMPA receptors Cognitive symptoms (adjunct) farampator CX516 Ceased in Phase II Ceased in Phase II

60 Cariprazine D2 partial agonist More of an antagonist than aripiprazole In late-stage clinical testing for schizophrenia, acute bipolar mania, bipolar depression, and treatment-resistant depression Higher doses for schizophrenia and mania (antagonist actions) Lower doses for depression (agonist actions) Stronger affinity for D3 than D2 receptors Few metabolic side effects and low risk of EPS identified thus far Long-lasting metabolites have potential for long-acting formulations Stahl SM. Stahl's Essential Psychopharmacology: The Prescriber's Guide. 4th ed

61 Brexpiprazole D2 partial agonist More of an antagonist than aripiprazole Very low risk of EPS and rare akathisia identified so far despite strong affinity for D2 receptors Possibly due to potent 5HT2A antagonism, 5HT1A agonism, and 1 antagonism Potential treatment for agitation and psychosis in dementia Stahl SM. Stahl's Essential Psychopharmacology: The Prescriber's Guide. 4th ed

62 Glutamate and Schizophrenia NMDA hypofunction hypothesis of schizophrenia Neurodevelopmentally abnormal glutamate synapses Hypofunctional NMDA receptors Overstimulation of downstream glutamate receptors Modulation of glutamatergic transmission as a potential treatment strategy Direct-acting glycine agonists mglur 2/3 presynaptic agonist GlyT1 inhibitors (SGRIs)

63 Novel Glutamatergic Treatments for Schizophrenia: Direct-Acting Glycine Site Agonists Glutamate neuron Direct-acting glycine site agonists d-cycloserine Glutamate d-serine Glycine NMDA currents enhanced

64 Novel Glutamatergic Treatments for Schizophrenia: Glycine Transporter 1 Inhibitors (e.g., bitropertin RGH1678) Glutamate neuron Glutamate Glycine GlyT1 inhibitor NMDA currents enhanced

65 Summary Treating schizophrenia is not a "one size fits all" strategy; having options may make all the difference for the individual patient The 3 most recently approved antipsychotics (iloperidone, asenapine, and lurasidone) have unique properties, adding options to the clinician's "toolbox" As clinical data accumulate, we are gaining a better understanding of the efficacy and tolerability of these newer agents as well as their potential use in nonpsychotic disorders There are also several new antipsychotic agents with novel mechanisms of action currently being investigated