the f t re ofthe future of antipsychotic therapyantipsychotic...
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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
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
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
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
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
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
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
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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
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
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
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aripiprazole
Molecular Basis of Side EffectsMolecular Basis of Side Effects
Functional Groups Responsible for Therapeutic Effects
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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
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008.
The “The “--pines”: D2pines”: D2pp
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The “The “--pines”: 5HT2Apines”: 5HT2App
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The “The “--pines”: 5HT1A, 2C, and 6pines”: 5HT1A, 2C, and 6p , ,p , ,
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The “The “--pines”: 5HT7pines”: 5HT7pp
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The “The “--pines”: Alpha 1pines”: Alpha 1p pp p
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The “The “--pines”: Alpha 2pines”: Alpha 2p pp p
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The “The “--pines”: H1pines”: H1pp
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The “The “--pines”: M1pines”: M1pp
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The “The “--donesdones”: D2”: D2
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The “The “--donesdones”:5HT2A ”:5HT2A
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The “The “--donesdones”: 5HT1A, 2C, and 6”: 5HT1A, 2C, and 6, ,, ,
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The “The “--donesdones”: 5HT7”: 5HT7
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The “The “--donesdones”: Alpha 1”: Alpha 1pp
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The “The “--donesdones”: Alpha 2”: Alpha 2pp
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The “The “--donesdones”: H1”: H1
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The “The “--donesdones”: M1”: M1
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AripiprazoleAripiprazole: D2: D2p pp p
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AripiprazoleAripiprazole: 5HT2A: 5HT2Ap pp p
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AripiprazoleAripiprazole: 5HT1A : 5HT1A p pp p
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AripiprazoleAripiprazole: 5HT7: 5HT7p pp p
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R tl A d A ti h tiR tl A d A ti h tiRecently Approved Antipsychotic Recently Approved Antipsychotic TreatmentsTreatmentsTreatmentsTreatments
ILOPERIDONEILOPERIDONE
ASENAPINEASENAPINE
LURASIDONELURASIDONE
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IloperidoneIloperidonepp
• Serotonin 5-HT2A / dopamine D2 antagonist (SDA)
• Recently approved for acute treatment of schizophrenia in adults
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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
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
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
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
• 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
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in treatment resistant cases 1A2
Asenapine and MirtazapineAsenapine and Mirtazapinep pp p
N
N3CH
N
CH 3
N
3CH 3
= mirtazapine
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= 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
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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
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• Once-daily administration is possible
TandospironeTandospirone andand LurasidoneLurasidonepp
N
N N
N
OH
N
OH
N NOHN S
NN
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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
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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
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Cognitive deficits
kdvnkdjvnkjdvnkjdnvnkjdnvkdjnvnkdjnvknvkdjbvkdjvnkjvnskunhvskdjvnkjsvnkjsvnkjsnvkjnvkjnvkjxnhvkjnvkjxnvksjnvsudbvkujdhfvukhsruifhsfukcvnhsiodrhfcuhiwernhciurnhtv uikhriuahrfuihfkhsdfkj hsuif khsukfhs ukfhskudjfhsiukfhsuhfksuhfukhdfuksh fiushfkshdfkshdkfhskdfhksu hfiushfukshfksu hfoisajdukshfkuhfughsf ujshfghsfhsdfjhskfhaiukfhakufhukahfkahfkahfksauhfa
ukjhfkah fkahfkaufhka ufh kahfkahfkuahdk had khadkahdkhad khadkha ukahfkauhfkuahdkuahdkahdkuahdkuahdlaiuhdaufgajlgjfgajghfayjdgajkldgajkdbgakgdkuahdkuahdkahdkabfkjbskfabksjbhfkajshfkajhfkjabfkjbadjkbadkjabdkjabdkhakfhas fkafhugwuyrbgcbyrbujrgwbeuirbhywcuicrhuiwhebrhe uwchrwuecrhywuechruiwcebriueehrfuwehcrcufhuchsufhsufh
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
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?
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uwchrwuecrhywuechruiwcebriueehrfuwehcrcufhuchsufhsufhsfhfkhSduhsukfgsfhgsuifgsfgy
Udghsidfgsfuislukhdfkhskjfhnkuas
skhfksahfkhsnhkcfjn
55--HTHT7777
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55--HTHT7777
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55--HTHT7777
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Weight Change From DoubleWeight Change From Double--Blind BaselineBlind Baselineg gg g
Copyright © 2011 Neuroscience Education Institute. All rights reserved.Stahl et al. APA 2011, Abstract NR6-58.
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
Copyright © 2011 Neuroscience Education Institute. All rights reserved.Loebel et al. APA 2011, Abstract NR6-38.
HighHigh--Dose Lurasidone: Dose Lurasidone: Weight Increased byWeight Increased by ≥≥ 7%7%Weight Increased by Weight Increased by ≥ ≥ 7%7%
Copyright © 2011 Neuroscience Education Institute. All rights reserved.Loebel et al. APA 2011, Abstract NR6-38.
HighHigh--Dose Lurasidone: Dose Lurasidone: Cholesterol and TriglyceridesCholesterol and TriglyceridesCholesterol and TriglyceridesCholesterol and Triglycerides
Cholesterol
TriglyceridesTriglycerides
Copyright © 2011 Neuroscience Education Institute. All rights reserved.Loebel et al. APA 2011, Abstract NR6-38.
EmergingEmerging Antipsychotics andAntipsychotics andEmerging Emerging Antipsychotics andAntipsychotics andNovelNovel MechanismsMechanisms of Actionof ActionNovel Novel Mechanisms Mechanisms of Actionof Action
Under Under InvestigationInvestigation
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
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
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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
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• 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?
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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
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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
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
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
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
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
**
* *
*
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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
Copyright © 2011 Neuroscience Education Institute. All rights reserved.
2 p ginvestigation