the f t re ofthe future of antipsychotic therapyantipsychotic...

The F t re ofThe F t re ofThe Future ofThe Future ofAntipsychotic TherapyAntipsychotic TherapyAntipsychotic TherapyAntipsychotic Therapy

(page 7 in syllabus)(page 7 in syllabus)

Stephen M. Stahl, MD, PhDStephen M. Stahl, MD, PhDStephen M. Stahl, MD, PhDStephen M. Stahl, MD, PhDp , ,p , ,Adjunct Professor, Department of Psychiatry

University of California, San Diego School of Medicine

p , ,p , ,Adjunct Professor, Department of Psychiatry

University of California, San Diego School of Mediciney gHonorary Visiting Senior Fellow, Cambridge University, UK

y gHonorary Visiting Senior Fellow, Cambridge University, UK

Sponsored by the Neuroscience Education Institute

Copyright © 2011 Neuroscience Education Institute. All rights reserved.

p yAdditionally sponsored by the American Society for the Advancement of Pharmacotherapy

This activity is supported by an educational grant from Sunovion Pharmaceuticals Inc.

Individual Disclosure StatementIndividual Disclosure Statement

Faculty Editor / Presenter yStephen 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, TorrentConsultant/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/TrovisNeuronetics, 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 PfizerSpeakers Bureau: Dainippon Sumitomo, Forest, Lilly, Merck, Pamlab, Pfizer, Sepracor/Sunovion, Servier, Wyeth


Learning ObjectivesLearning Objectivesg jg j

• Differentiate antipsychotic drugs from each other on the basis of their pharmacological mechanisms and their associated therapeutic and side effectsassociated therapeutic and side effects

• Integrate novel treatment approaches into clinical• Integrate novel treatment approaches into clinical practice according to best practices guidelines

• Identify novel therapeutic options currently being researched for the treatment of schizophreniaresearched for the treatment of schizophrenia


Conventional (FirstConventional (First--Generation) Generation) AntipsychoticsAntipsychoticsAntipsychoticsAntipsychotics

Chlorpromazine Perphenazine

D2

ChlorpromazineCyamemazineFlupenthixolFluphenazine

PerphenazinePimozidePipothiazineSulpirideFluphenazine

HaloperidolLoxapineMesoridazine

SulpirideThioridazineThiothixeneTrifluoperazine

• D2 antagonists

Molindone Zuclopenthixol

2 g• Effective for positive symptoms• Side effects

– Extrapyramidal symptoms– Possible worsening of negative, cognitive, and affective symptoms

Copyright © 2011 Neuroscience Education Institute. All rights reserved.Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. Cambridge University Press 2008.

DD22 Receptor Receptor OOccupancy ccupancy IInduced by nduced by ClinicalClinical DDoses of Antipsychoticoses of Antipsychotic DDrugsrugsClinical Clinical DDoses of Antipsychotic oses of Antipsychotic DDrugsrugs

Haloperidol 6Haloperidol 6

ParkinsonismAkathisiaHaloperidol 6

Haloperidol decanoate 50 / 28 d.Haloperidol 6Haloperidol 4Haloperidol 12

ParkinsonismParkinsonismAkathisia, parkinsonismAkathisia

ParkinsonismFlupentixol decanoate 40 / 7 d.Zuclopenthixol decanoate 200 / 24 d.Thioridazine 400Pimozide 8Chlorpromazine 200

ParkinsonismDystonia

AkathisiaChlorpromazine 200Sulpiride 800Perphenazine enanthate 100 / 7 d.Haloperidol 4Trifluoperazine 10

EPSNo EPS

ParkinsonismAkathisia

Thioridazine 300Haloperidol decanoate 70 / 28 d.Remoxipride 400Flupentixol 6Melperone 250

Doses in mg/d

0 20 40 60 80 100

Melperone 250Melperone 300Flupentixol 6


D2 receptor occupancy (%)Courtesy of L. Farde.

Hypothetical Thresholds for Hypothetical Thresholds for AntipsychoticAntipsychotic DDrugrug EEffectsffects

100

Antipsychotic Antipsychotic DDrug rug EEffectsffects

EPS threshold

100

80%)

Antipsychotic effect threshold60

ocka

de (

40

epto

r blo

20D2

rece

0


Dose; plasma concentration

Antipsychotics at High DosesAntipsychotics at High Dosesp y gp y g

• Although standard doses of all antipsychotics target 60• 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 psychotic illness occurs when patients p y pdo 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

b j tifi d i ll if ff ti i d imay be justified, especially if effective in reducing assaults and if side effects are carefully monitored


Atypical (SecondAtypical (Second--Generation) AntipsychoticsGeneration) Antipsychoticsy (y ( ) y) y

• Potentially effective for treating positive,Potentially effective for treating positive, negative, affective, and cognitive symptom domains due to vast molecular polypharmacydomains due to vast molecular polypharmacy

• Side effects• Side effects– Cardiometabolic

S d ti– Sedation– Various others

Copyright © 2011 Neuroscience Education Institute. All rights reserved.Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. Cambridge University Press 2008.

Common Classes of Atypical AntipsychoticsCommon Classes of Atypical Antipsychotics

SDA DPASPASDA

asenapineiloperidone

amisulpride?low-dose sulpiride?iloperidone

olanzapinepaliperidoneperospirone i id

low dose sulpiride?

cariprazineclozapinequetiapine

risperidone sertindolezotepine

ziprasidone


aripiprazole

Molecular Basis of Side EffectsMolecular Basis of Side Effects

Functional Groups Responsible for Therapeutic Effects


Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008.

Molecular Basis of Side EffectsMolecular Basis of Side Effects

Functional Groups Responsible for Side EffectsCardiometabolic side effects, includingweight gain insulin

EPS

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.

The “The “--pines”: D2pines”: D2pp


The “The “--pines”: 5HT2Apines”: 5HT2App


The “The “--pines”: 5HT1A, 2C, and 6pines”: 5HT1A, 2C, and 6p , ,p , ,


The “The “--pines”: 5HT7pines”: 5HT7pp


The “The “--pines”: Alpha 1pines”: Alpha 1p pp p


The “The “--pines”: Alpha 2pines”: Alpha 2p pp p


The “The “--pines”: H1pines”: H1pp


The “The “--pines”: M1pines”: M1pp


The “The “--donesdones”: D2”: D2


The “The “--donesdones”:5HT2A ”:5HT2A


The “The “--donesdones”: 5HT1A, 2C, and 6”: 5HT1A, 2C, and 6, ,, ,


The “The “--donesdones”: 5HT7”: 5HT7


The “The “--donesdones”: Alpha 1”: Alpha 1pp


The “The “--donesdones”: Alpha 2”: Alpha 2pp


The “The “--donesdones”: H1”: H1


The “The “--donesdones”: M1”: M1


AripiprazoleAripiprazole: D2: D2p pp p


AripiprazoleAripiprazole: 5HT2A: 5HT2Ap pp p


AripiprazoleAripiprazole: 5HT1A : 5HT1A p pp p


AripiprazoleAripiprazole: 5HT7: 5HT7p pp p


R tl A d A ti h tiR tl A d A ti h tiRecently Approved Antipsychotic Recently Approved Antipsychotic TreatmentsTreatmentsTreatmentsTreatments

ILOPERIDONEILOPERIDONE

ASENAPINEASENAPINE

LURASIDONELURASIDONE


IloperidoneIloperidonepp

• Serotonin 5-HT2A / dopamine D2 antagonist (SDA)

• Recently approved for acute treatment of schizophrenia in adults


IloperidoneIloperidone

• Efficacy comparable to other AAPs

• Not approved for mania, but

• Limited registration data and real world clinical experience; follow slow titrationpp

potentially effective

• Has very low placebo-level EPS and little or no akathisia

titration

• Use caution with patients sensitive to orthostasis (young, elderly, patients with CV problems)

• Potent alpha 1 blocking properties suggest potential utility in PTSD

with CV problems)

• In presence of potent 2D6 inhibitors (paroxetine, fluoxetine, duloxetine),

d d b h lf• Binding properties suggest theoretical efficacy in depression

• Long half-life suggests potential for

reduce dose by half

• Weight gain/metabolic profile comparable to that of risperidone


g gg ponce-daily dosing • Dose-dependent QTc prolongation

AsenapineAsenapinepp

• 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


• Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults

AsenapineAsenapine

• Mild metabolic risk; no prolactin elevation

• Not absorbed once swallowed; must be administered sublinguallyelevation

• No dose titration needed

• Long half-life; once-daily dose is

must be administered sublingually

• Common side effect: oral hypoesthesia

g ; ytheoretically possible

• Sublingual tablet good for reliable, compliant patient

• Patients may not eat or drink for 10 minutes after administration to increase bioavailability

compliant patient

• Not approved for depression, but binding profile suggests potential use in treatment-resistant cases

• Somnolence/sedation, EPS

• Inhibits 2D6 and is a substrate for 1A2


in treatment resistant cases 1A2

Asenapine and MirtazapineAsenapine and Mirtazapinep pp p

N

N3CH

N

CH 3

N

3CH 3

= mirtazapine


= asenapine

LurasidoneLurasidone

• Recently approved for schizophrenia in adults

• Lack of H1 epitope suggests reduced risk of metabolic sideLack of H1 epitope suggests reduced risk of metabolic side effects and sedation

• 5-HT7 antagonism may be beneficial for cognitive and


5 HT7 antagonism may be beneficial for cognitive and negative symptoms

LurasidoneLurasidone

??

• Lack of affinity at H1 and M1receptors allows treatment to

• EPS and akathisia, but seems to be reduced if taken at nightp

begin at therapeutically effective dose; rapid onset of action

• 40-80 mg/day effective for acute

g

• Will require confirmation from real world clinical experience

40 80 mg/day effective for acute exacerbation of schizophrenia

• Appears to have benign metabolic profile withoutmetabolic profile without affecting QTc prolongation; low EPS


• Once-daily administration is possible

TandospironeTandospirone andand LurasidoneLurasidonepp

N

N N

N

OH

N

OH

N NOHN S

NN


OH

5-HT7 Receptor Distribution in Rat Brain7

• Involved in numerous processes, including learning andInvolved in numerous processes, including learning and memory

• Many atypical antipsychotics and antidepressants act at y yp p y p5-HT7 receptors

• Receptor levels are decreased in post-mortem


p pschizophrenia cortex

Dean et al. Schizophr Res 2006,88:265-74.

55--HTHT77 ReceptorsReceptors77 pp

5 HT5-HTDepressive symptoms

125-HT7

t

9 3receptor

Circadian dysfunction

6Fsxfsg

gdfgfgdfgdfgsdfsdfsggdghdgdgdgddfgdfgdsfsfsfsfsfsfsfsfsfsfsfsfsfssfsfsfsfdsngjhdgiukhdvukdhvkudvnhiduvnhkdjvnkdjvnjkdvnkdjvnkjdvnkjdnvnkjdnvkdjnvnkdjnvknvkdjbvkdjvnkjvnsku

Cognitive deficits

kdvnkdjvnkjdvnkjdnvnkjdnvkdjnvnkdjnvknvkdjbvkdjvnkjvnskunhvskdjvnkjsvnkjsvnkjsnvkjnvkjnvkjxnhvkjnvkjxnvksjnvsudbvkujdhfvukhsruifhsfukcvnhsiodrhfcuhiwernhciurnhtv uikhriuahrfuihfkhsdfkj hsuif khsukfhs ukfhskudjfhsiukfhsuhfksuhfukhdfuksh fiushfkshdfkshdkfhskdfhksu hfiushfukshfksu hfoisajdukshfkuhfughsf ujshfghsfhsdfjhskfhaiukfhakufhukahfkahfkahfksauhfa

ukjhfkah fkahfkaufhka ufh kahfkahfkuahdk had khadkahdkhad khadkha ukahfkauhfkuahdkuahdkahdkuahdkuahdlaiuhdaufgajlgjfgajghfayjdgajkldgajkdbgakgdkuahdkuahdkahdkabfkjbskfabksjbhfkajshfkajhfkjabfkjbadjkbadkjabdkjabdkhakfhas fkafhugwuyrbgcbyrbujrgwbeuirbhywcuicrhuiwhebrhe uwchrwuecrhywuechruiwcebriueehrfuwehcrcufhuchsufhsufh


uwchrwuecrhywuechruiwcebriueehrfuwehcrcufhuchsufhsufhsfhfkhSduhsukfgsfhgsuifgsfgy

Udghsidfgsfuislukhdfkhskjfhnkuas

skhfksahfkhsnhkcfjn

Possible Effects of 5Possible Effects of 5--HTHT77 Receptor Receptor AntagonismAntagonismAntagonismAntagonism

ReducedDepressive symptoms

5-HT7

Reduced?

125-HT7

t

5 HT7antag

Reduced

9 3receptor

Circadian dysfunction?

6Fsxfsg

gdfgfgdfgdfgsdfsdfsggdghdgdgdgddfgdfgdsfsfsfsfsfsfsfsfsfsfsfsfsfssfsfsfsfdsngjhdgiukhdvukdhvkudvnhiduvnhkdjvnkdjvnjkdvnkdjvnkjdvnkjdnvnkjdnvkdjnvnkdjnvknvkdjbvkdjvnkjvnsku R d d

Cognitive deficits

kdvnkdjvnkjdvnkjdnvnkjdnvkdjnvnkdjnvknvkdjbvkdjvnkjvnskunhvskdjvnkjsvnkjsvnkjsnvkjnvkjnvkjxnhvkjnvkjxnvksjnvsudbvkujdhfvukhsruifhsfukcvnhsiodrhfcuhiwernhciurnhtv uikhriuahrfuihfkhsdfkj hsuif khsukfhs ukfhskudjfhsiukfhsuhfksuhfukhdfuksh fiushfkshdfkshdkfhskdfhksu hfiushfukshfksu hfoisajdukshfkuhfughsf ujshfghsfhsdfjhskfhaiukfhakufhukahfkahfkahfksauhfa

ukjhfkah fkahfkaufhka ufh kahfkahfkuahdk had khadkahdkhad khadkha ukahfkauhfkuahdkuahdkahdkuahdkuahdlaiuhdaufgajlgjfgajghfayjdgajkldgajkdbgakgdkuahdkuahdkahdkabfkjbskfabksjbhfkajshfkajhfkjabfkjbadjkbadkjabdkjabdkhakfhas fkafhugwuyrbgcbyrbujrgwbeuirbhywcuicrhuiwhebrhe uwchrwuecrhywuechruiwcebriueehrfuwehcrcufhuchsufhsufh

Reduced?


uwchrwuecrhywuechruiwcebriueehrfuwehcrcufhuchsufhsufhsfhfkhSduhsukfgsfhgsuifgsfgy

Udghsidfgsfuislukhdfkhskjfhnkuas

skhfksahfkhsnhkcfjn

55--HTHT7777


Median Change From DoubleMedian Change From Double--Blind Baseline Blind Baseline in Metabolic Parametersin Metabolic Parametersin Metabolic Parametersin Metabolic Parameters

Copyright © 2011 Neuroscience Education Institute. All rights reserved.Stahl et al. APA 2011, Abstract NR6-58.

HighHigh--Dose Lurasidone: Dose Lurasidone: PANSS Total ScorePANSS Total ScorePANSS Total ScorePANSS Total Score

Copyright © 2011 Neuroscience Education Institute. All rights reserved.Loebel et al. APA 2011, Abstract NR6-38.

HighHigh--Dose Lurasidone: Dose Lurasidone: MADRSMADRSMADRSMADRS


HighHigh--Dose Lurasidone: Dose Lurasidone: Weight Increased byWeight Increased by ≥≥ 7%7%Weight Increased by Weight Increased by ≥ ≥ 7%7%


HighHigh--Dose Lurasidone: Dose Lurasidone: Cholesterol and TriglyceridesCholesterol and TriglyceridesCholesterol and TriglyceridesCholesterol and Triglycerides

Cholesterol

TriglyceridesTriglycerides


EmergingEmerging Antipsychotics andAntipsychotics andEmerging Emerging Antipsychotics andAntipsychotics andNovelNovel MechanismsMechanisms of Actionof ActionNovel Novel Mechanisms Mechanisms of Actionof Action

Under Under InvestigationInvestigation


Investigational Mechanisms and Agents Investigational Mechanisms and Agents for Schizophreniafor Schizophreniafor Schizophreniafor Schizophrenia

Molecular Target Clinical Target Drug Development PhaseDopamine 2/serotonin 2A Positive, negative, and cognitive symptoms sertindole Phase IVDopamine 3 antagonism Positive, negative, and cognitive symptoms cariprazine Phase IIIGlycine transport inhibition Positive, negative, and cognitive symptoms RG1678

ORG25935AMG 747

Phase IIIPhase IIPhase IAMG 747 Phase I

Metabotropic 2/3 agonism Positive, negative, and cognitive symptoms LY2140023AZD8529

Phase IIPhase II

Alpha 7 nicotinic agonism Positive, negative, and cognitive symptoms RG3487TC 5619

Phase IIPhase IITC-5619 Phase II

Phosphodiesterase 10A enzyme Positive, negative, and cognitive symptoms PF-02545920 Phase IICyclooxygenase-2 inhibition Positive and negative symptoms (adjunct) celecoxib Phase IISerotonin 6 antagonism Cognitive symptoms (adjunct) SB-742457

PF-05212365Phase IIPhase IIPF 05212365

AE58054Phase IIPhase II

Histamine 3 antagonism Cognitive symptoms (adjunct) PF-03654746GSK239512

Phase IIPhase II

Dopamine 2 partial agonism Positive, negative, and cognitive symptoms bifeprunox Ceased in Phase IIIDopamine 2 partial agonism Positive, negative, and cognitive symptoms bifeprunox Ceased in Phase IIISerotonin 1A agonism Positive, negative, and cognitive symptoms PF-217830 Ceased in Phase IISerotonin 2C agonism Positive, negative, and cognitive symptoms vabicaserin Ceased in Phase IIPositive allosteric modulation of glutamatergic AMPA receptors

Cognitive symptoms (adjunct) farampatorCX516

Ceased in Phase IICeased in Phase II


CariprazineCariprazinepp

• In Phase III clinical trials for schizophrenia and bipolar disorder• Stronger affinity for D3 over D2 receptors• Higher doses for schizophrenia and mania (antagonist actions)

L d f d i ( i t ti )• Lower doses for depression (agonist actions)• Few metabolic side effects identified thus far

Long lasting metabolites have potential for long acting


• Long-lasting metabolites have potential for long-acting formulations

Modulation ofModulation of GlutamatergicGlutamatergicModulation of Modulation of GlutamatergicGlutamatergicTransmissionTransmission

• Direct-acting glycine agonistsg g y g• mGluR 2/3 presynaptic agonist• GlyT1 inhibitors (GRIs)• GlyT1 inhibitors (GRIs)

T b d i l t t l tCopyright © 2011 Neuroscience Education Institute. All rights reserved.

To be covered in glutamate lecture

PhosphodiesterasePhosphodiesterase 10A10App

• Phosphodiesterases (PDEs) degrade cAMP and cGMP– Involved in many second messenger systems

• PDE10A is concentrated in striatumPDE10A is concentrated in striatum

• PDE 10A inhibitors lead to– Increased D1 receptor functioning– Decreased D2 receptor functioning

• Effective for positive, negative, and cognitive symptoms?


symptoms?Kehler j, Nielsen J. Curr Pharm Des 2011;17:137-50.

PDE 10A InhibitorsPDE 10A Inhibitors

PDE 10A

DAD1R

PDE 10A

cAMP DAD2RPositive symptoms

cAMP


cAMPcAMP

PDE 10A InhibitorsPDE 10A Inhibitors

Improvement incAMP

PDE 10A

DAD1RImprovement in

negative and cognitive

symptoms?PDE 10A symptoms?

Reduced?

cAMP DAD2Rpositive symptoms

cAMP

cAMP


cAMPcAMP

Nicotinic Alpha 7 AgonistsNicotinic Alpha 7 Agonistsp gp g

• Reduced levels of alpha 7 receptors in schizophrenia• Reduced levels of alpha 7 receptors in schizophrenia

• Patients with schizophrenia often have diminished auditory sensory gating – May contribute to attentional impairment and perceptual

disturbancesdisturbances

• Autosomal dominant polymorphism of the alpha 7 gene on 15q14 linked to cognitive impairments in schizophrenia

• Alpha 7 agonists increase cortical DA and may improve cognitive and negative symptoms


Freedman R et al. Am J Psychiatry 2008;165:1040-7; Smith RC et al. Schizophr Res 2009;110:149-55; Martin LF et al. Psychopharmacol 2004;174:54-64.

Nicotinic Alpha 7 AgonistsNicotinic Alpha 7 Agonistsp gp g

**

* *

*


Freedman R et al. Am J Psychiatry 2008;165:1040-7.

SummarySummaryyy

• Conventional antipsychotics exert therapeutic andConventional antipsychotics exert therapeutic and adverse actions via dopamine D2 receptor antagonismg

• Atypical antipsychotics exert their therapeutic and adverse effects by binding to a variety of receptorsadverse effects by binding to a variety of receptors, including dopamine D2

• Asenapine, iloperidone, and lurasidone are the most recently approved antipsychotics

• Several novel mechanisms of action that go beyond D2 receptor antagonism are under active


2 p ginvestigation

the f t re ofthe future of antipsychotic therapyantipsychotic...

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