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.

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

• A Tale of Serotonin Antagonism • The Dopamine Partial Agonism Story • Pharmacogenetics and the Genes • Once Upon a Glutamate Receptor

D2 Antagonist Actions

5HT2A

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

clozapine risperidone non-US 5HT2A paliperidone

olanzapine

perospirone quetiapine

ziprasidone zotepine low dose loxapine? sertindole D2

low dose cyamemazine?

iloperidone

5HT2A asenapine

SM13493/ lurasidone

blonanserin Y931

NRA0562 D2

nemonapride

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 LSM Change -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

10.5 10.2 11 9.9 9.8 9.6 9.5 9.4

9.0 10 8.9 8.9 8.9 8.9 8.8 8.7 8.6 8.6 8.5 D2 ) i 9 8.0

Affinity (pK 7

6 5.1

A 7 B 6 1 5 1 A B 2 1 T 2C T 2 T T 2 T α 2B D 3 D 4 α α 2A α 2C D 2 T H T 1 T 1 D 1 H M H H -H H -H -H H H 5- 5- 5 5- 5 5 5- 5-

CH 3

CH 3 CH 3 N

= mirtazapine N N

= asenapine CH CH 3 3

• 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

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

• 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

• A Tale of Serotonin Antagonism • The Dopamine Partial Agonism Story • Pharmacogenetics and the Genes • Once Upon a Glutamate Receptor

D2 PA

too cold antipsychotic EPS

too hot psychosis

just right

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

RGH188 3PPP bifeprunox sarizotan SLV313

SSR-181507 SLV314

ACR16

ACP-104

PNU 9639/OSU 6162 D2 CI1007 PA

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 Mean PANSS-T -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

5HT1A 5HT1A PA PA

D2 D2

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

• Effective antipsychotics have inverted U shaped dose response curves – Aripiprazole (20 mg >30 mg) – Bifeprunox – RGH 188

• Agonists that are “too full” are psychotomimetic – OPC 4293 – Aplindore – Lisuride/tergeride

• Augmenting SSRIs/SNRIs for treatment resistant unipolar depression • First line treatment of unipolar or bipolar depression? • Augmenting mood stabilizers for bipolar depression? • Augmenting D2 antagonists to reduce hyperprolactinemia, weight gain and metabolic abnormalities?

30 Antidepressant + Placebo (n=172)

25 Antidepressant + Aripiprazole (n=181)

10 Response Rate

Response Rate (%) Response 5 30

0 25 123456 Week 20

Remission Rate (%) 5

0 123456 Week

• A Tale of Serotonin Antagonism • The Dopamine Partial Agonism Story • Pharmacogenetics and the Genes • Once Upon a Glutamate Receptor

genotype

molecular abnormality

(biological) abnormal information endophenotypes processing

abnormal behavior (with complex functional interactions)

cognition

The Wisconsin Card Sorting Task

temperament Genes: Cells: Systems: Behavior: sequence molecular activity in emotion variants and pathways processing circuitry Clinical phenotype variable gene processing Weinberger. Presented at NEI CME Consulting Meeting 2007. Copyright © 2008 Neuroscience Education Institute. All rights reserved. Genetics Refresher: Vocab

• DNA Nucleic acids that store genetic “blueprints” • Gene Region of DNA sequence; Regulates and/or translates into function; Heritable • Allele One of two copies of a gene • SNP Single nucleotide polymorphism, most common DNA variation • Genotype Set of alleles for a certain trait • Genome Set of genotypes for all genes of a species • Phenotype Observable quality; usually the product of interaction of many genes

AATCGTC Normal gene

AAGCGTC mRNA interactions SNP (occurs in >1% of the population)

AACCGTC structure/function Point mutation (occurs in <1% of DNA proteins the population)

• Candidate genes – Linking one (or several) predetermined SNPs to a function

• GWA (Genome-Wide Association) – Analyzing whole genomes for functional correlations

A gene is said to be associated with a trait (e.g., an illness) when a variant in the gene is found with increased frequency in a population enriched with that trait

A population of BLUE folks AA aA Aa AA AA Aa AA Aa “cases” genotype CC Cc Cc cc cc cC CC cc

male female

A population lacking the “BLUE” trait aa Aa “controls” aa Aa aa aa aA aa Aa AA CC Cc Cc cc cc cC CC cc The A gene is associated with the BLUE trait. The “A” allele is the risk allele.

Frequency Effect on Drugs Prescribed Dose: metabolized by 2D6

Rapid 1%-7% Levels greatly Use higher doses reduced

Normal 75% Normal Normal doses

Intermediate 10%-15% Higher Lower doses

Poor 5%-10% Much higher Very low doses

• Genotype informs individual rate of drug metabolism • Drug metabolism informs effective dose and treatment outcome – Other (genetic and non-genetic) factors need to be identified; CYP450 is one of many

• AmpliChip is FDA-approved as a diagnostic tool • Value of routine screening not confirmed in trials

• HER-2 (Human epidermal growth factor receptor) overexpression previously predictive of poor disease outcome (30%-40% of all breast cancers) • Pertuzumab - humanized monoclonal antibody acts on the HER2/neu (erbB2) receptor to reduce tumor growth rate – FDA highlights that only patients whose tumors are HER2-positive should receive the drug due to the risk of heart disease • Anthracyclines reduce relapse (p < 0.001) and mortality (p < 0.001) in HER2-positive tumors; no health benefits for HER2-negative tumors.

Burstein, et al. Cancer 2007;110:965-72. Gennari, et al. J Natl Cancer Inst 2008;100:14-20. Copyright © 2008 Neuroscience Education Institute. All rights reserved. Pharmacogenetics in Medicine Now: Warfarin • Warfarin inhibits the enzyme that recycles vitamin K (vitamin K epoxide reductase complex-1) to produce its anticoagulation effect. • Variability in response depends on a patient's variants of the genes CYP2C9 and VKORC1 (combined predict up to 60% response variance). • FDA highlights use of genetic tests to assess reasonable doses of • Currently not clinically warfarin for individual routine patients. Caraco et al. Clin Pharmacol Ther 2007;Epub ahead of print. Copyright © 2008 Neuroscience Education Institute. All rights reserved. Pharmacogenetics in Medicine Now: Imatinib Mesylate (Gleevec) • Imatinib mesylate (Gleevec) targets chronic myelogenous leukemia (CML) by turning off its cancer-causing protein signal (BCR-ABL; also known as the Philadelphia chromosome)

CML

BCR-ABL oncogene imatinib

• Targeting a gene that is only expressed by this particular cancer • FDA recommends drug use only for these patients to avoid risk of cardiac toxicities and unnecessary expense in patients destined not to respond

• Prevent • Diagnose • Understand * Predict • Treat

Genes affect metabolism of psychiatric drugs • Inform individualized drug choice • Inform optimal dose (max efficacy/min side effects)

• Lack of data – Confirm preliminary results – Evaluate usefulness of implementation • Limited catalogue of functional variants • Non-genetic heterogeneity in drug response – Age – Smoking – Compliance

• SNP forms: val/met – Functional variants affect secondary structure of protein Æ alters function of frontal lobe Change in Attention and • Val/Met genotype and clozapine Verbal Fluency Scores with response (frontal lobe effects): Clozapine Treatment – Val alleles: no change; Met alleles: improvement • Val/val: no change • Met/met: most improvement • Val/met and met/val: some improvement

Woodward, et al. Schiz Research 2007;90:86-96.

• CNTF = Ciliary Neurotrophic Factor • CNTF is involved in neuroprotection by promoting neurotransmitter synthesis and neurite outgrowth • A DNA polymorphism (FS63Ter) in the CNTF gene leads to a truncated biologically inactive protein • Those with 0 or 1 copy of the functional protein instead of 2 copies of the functional protein may be predisposed to schizophrenia • Patients with 2 copies of the functional protein responded to iloperidone better; so did patients on ziprasidone, but no difference for risperidone

• Large-scale analyses becoming more accessible – Microarrays/DNA chips – From Illumina: 1 million chip SNPs for $500 – HAPMAP Project goal: Identify all common SNPs • Cover most common variations in genome – Exist in at least 1%-2% of population • Approach in its infancy – No good examples in literature yet – Likely to show more promise than single-candidate genes

Licamele, et al. Poster presented at ASHG 2007.

• A Tale of Serotonin Antagonism • The Dopamine Partial Agonism Story • Pharmacogenetics and the Genes • Once Upon a Glutamate Receptor

signal transduction glutamate B

Na+ glycine

resting but activated blocked by Mg++

depolarization AMPA receptor NMDA receptor

activated activated

depolarization AMPA receptor NMDA receptor long term potentiation 5-43B Copyright © 2008 Neuroscience Education Institute. All rights reserved. Neurodevelopmental Hypothesis of Schizophrenia: Key Susceptibility Genes Causing Abnormal Synaptogenesis

in ind NMDA sb dy

n Glu uli normal eg ur ne AMPA synaptic -1 strengthening SC DI

fl aw NMDA ed g en es

abnormal AMPA synaptic strengthening

Glutamate Release Excitation Inhibition NORMAL

Glutamate GABA Release inter- neuron

Glutamate Dysfunctional Decreased Release Excitation Inhibition HIGH

Glutamate GABA Release inter- neuron

Glutamate Dysfunctional Decreased Release Excitation Inhibition NORMAL

Glutamate GABA Release inter- neuron

mGluR agonist

Glutamate DysfunctionalD-cycloserine Release Excitation Inhibition NORMAL

Glutamate GABA Release inter- neuron

• Novel antipsychotics with serotonin 2A-dopamine 2 antagonism and with dopamine 2 partial agonism are in development • Pharmacogenetics may eventually allow for predicting variation in side effects, dosage, and response to a drug, including antipsychotics, among individuals • Novel antipsychotics with primary actions on the glutamate neurotransmitter system may be the next generation of treatments