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Optimizing Care for Patients with Schizophrenia

Psychopharmacology Workshop Dr. Stephen M. Stahl (USA)


Symptom, Circuits, and Neurotransmitters and the Antipsychotic Armamentarium
Educational Symposium Psychiatry May 2013

PHEM/PSY/0813/0001 Aug 2013

Psychopharmacology of Schizophrenia: Objectives


Review the circuits and receptors that are currently linked to the symptom dimensions of schizophrenia Review the widely hypothesized mechanism of therapeutic action of antipsychotics as D2 antagonists and partial agonists Introduce the potential glutamate-linked actions of atypical antipsychotic drugs Discuss the multifunctional pharmacologic and clinical properties of serotonin 5-HT2A antagonism and 5-HT1A partial agonism of atypical antipsychotics

D, dopaminergic; 5-HT, serotonergic


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Disclaimer
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Psychotic and Cognitive Symptoms of Schizophrenia

PATHWAYS, CIRCUITS, AND NEUROTRANSMITTERS


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Symptom Dimensions Match Hypothetically Malfunctioning Brain Circuit


Mesolimbic

Mesocortical/ prefrontal cortex Nucleus accumbens reward circuits


Positive symptoms Negative symptoms

Affective symptoms Aggressive symptoms

Cognitive symptoms

Ventromedial prefrontal cortex Orbitofrontal cortex

Dorsolateral prefrontal cortex

Amygdala

Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York

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Dopamine Pathways Project from Neurotransmitter Centers to the Striatum, Prefrontal Cortex, Thalamus, and Hypothalamus
DLPFC

Striatum Thalamus Nucleus Accumbens Substantia Nigra Tegmentum


Pituitary
Hypothalamus

VMPFC

DLPFC, dorsolateral prefrontal cortex; VMPFC, ventromedial prefrontal cortex Adapted from Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York
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The Mesolimbic Dopamine Hypothesis of Positive Symptoms of Schizophrenia Describes the Effects of Excessive DA
D2

HIGH

mesolimbic hyperactivity = excessive dopamine

DA, dopamine; D, dopaminergic

Positive Symptoms
PHEM/PSY/0813/0001 Aug 2013

Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York

D2 Hypoactivity Along the Mesocortical Pathway is Also Related to Negative, Cognitive, and Affective Symptoms

D2

Cognitive symptoms

Negative symptoms

Mesocortical underactivity = negative, cognitive, and affective symptoms of schizophrenia


D, dopaminergic Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York

Affective symptoms
PHEM/PSY/0813/0001 Aug 2013

Which Action Predominates?


D2 ANTAGONISM 5-HT2A ANTAGONISM D2

5-HT2A

D, dopaminergic; 5-HT, serotonergic

The answer depends on the region of the brain


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Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York

Psychotic and Cognitive Symptoms of Schizophrenia

NMDA AND GLUTAMATE

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The NMDA-Glutamate Hypofunction Hypothesis Can Explain Psychotic and Cognitive Symptoms
Implicates dysfunctional NMDA receptors in the prefrontal cortex, especially for the cognitive dysfunction of schizophrenia

NMDA antagonists (like ketamine and PCP) exacerbate psychotic symptoms and cognitive impairment in patients with schizophrenia
NMDA antagonists also induce these symptoms in healthy volunteers Atypical antipsychotics share a common property of augmenting NMDA-evoked responses in pyramidal cells of the prefrontal cortex, implying facilitation of NMDA receptormediated transmission
NMDA, N-methyl-d-aspartate; PCP, phencyclidine Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York
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The PCP-Ketamine Model of Schizophrenia Suggests Ketamine Blocks NMDA Receptors


Ketamine blockade of NMDA
Glutamate neuron GABA interneuron

GABA
Glutamate neuron

NMDA receptor

Ketamine
GABA interneuron

Glutamate

PCP, phencyclidine; NMDA, N-methyl-d-aspartate; GABA, gamma aminobutyric acid Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York
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Glutamate Dysfunction Can Cause Mesolimbic Hyperactivation


1. Normally active glutamate neuron 5. Consequence is hyperactive mesolimbic dopamine neuron 2. Hypoactive NMDA receptors 3. GABA neuron malfunction

4. Hyperactive glutamate neuron

NMDA, N-methyl-d-aspartate; GABA, gamma aminobutyric acid Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York
PHEM/PSY/0813/0001 Aug 2013

Glutamate, Serotonin, and Antipsychotic Actions


Hypothetically, overactive glutamate neurons in the prefrontal cortex may accompany psychosis and mania These neurons project to the ventral tegmental area and drive DA neurons there into a state of hyperactivity Serotonin regulates the cortical glutamate neurons via 5-HT2A receptors

Blocking 5-HT2A receptors on prefrontal glutamate neurons may reduce overactivity and lead to normalization of DA, and thus a reduction of psychosis and mania
DA, dopamine; 5-HT, serotonergic Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York
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CURRENT TREATMENT OPTIONS: ANTIPSYCHOTIC MEDICATIONS


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Learning Objectives
Review the dopamine D2 and serotonin 5-HT2A antagonist properties of all atypical antipsychotics
Demonstrate that all atypical antipsychotics have numerous additional binding properties, but no two agents are identical Propose that these differences in binding properties comprise the most rational hypothesis to explain differences in efficacy and tolerability of atypical antipsychotics in individual patients

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Conventional Antipsychotics have D2 Antagonist Actions D2 Relative Receptor Binding Affinity for the -pines
Clozapine

D2
Antipsychotic Actions

Olanzapine

Quetiapine

Asenapine

D, dopaminergic
Leponex EU SmPC November 2002; Zyprexa EU SmPC August 2013; Seroquel EU SmPC May 2012; Saphris PI 2013; Farah. Prim Care Comp J Clin Psych 2005;7:268274
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Conventional Antipsychotics have D2 Antagonist Actions D2 Relative Receptor Binding Affinity for the -dones
Risperidone

D2

Paliperidone

Antipsychotic Actions

Ziprasidone

Iloperidone

Lurasidone

D, dopaminergic
Risperdal EU SmPC November 2012; Invega EU SmPC November 2012; Geodon PI 2013; Fanapt PI 2012; Latuda PI 2012; Farah. Prim Care Comp J Clin Psych 2005;7:268274
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D2 Receptor Binding Affinity: Partial Agonist D2


Aripiprazole Antipsychotic Actions

D, dopaminergic Abilify EU SmPC February 2013


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Outline
Conventional antipsychotic: D2 Atypical antipsychotic: D2 + 5-HT2A Some mediators of therapeutic actions: 5-HT1A, 2C, 7 Some mediators of side effects: H1 and M1

D, dopaminergic; 5-HT, serotonergic; H, histaminergic; M, muscarinic


PHEM/PSY/0813/0001 Aug 2013

5-HT2A Relative Receptor Binding Affinity for the -pines


Clozapine
5-HT2A

D2
Low EPS
5-HT2A

Olanzapine Quetiapine
5-HT2A

Low prolactin

5-HT2A

Asenapine
More Potent than D2
5-HT, serotonergic; D, dopaminergic; EPS, Extrapyramidal Symptoms
Leponex EU SmPC November 2002; Zyprexa EU SmPC August 2013; Seroquel EU SmPC May 2012; Saphris PI 2013; Farah. Prim Care Comp J Clin Psych 2005;7:268274
PHEM/PSY/0813/0001 Aug 2013

Less Potent than D2

5-HT2A Receptor Binding Affinity: Partial Agonist

D2
Low EPS
5-HT2A

Aripiprazole Low prolactin

5-HT, serotonergic; D, dopaminergic; EPS, Extrapyramidal Symptoms Abilify EU SmPC February 2013

More Potent than D2

Less Potent than D2


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Outline
Conventional antipsychotic: D2 Atypical antipsychotic: D2 + 5-HT2A Some mediators of therapeutic actions: 5-HT1A, 2C, 7 Some mediators of side effects: H1 and M1

D, dopaminergic; 5-HT, serotonergic; H, histaminergic; M, muscarinic


PHEM/PSY/0813/0001 Aug 2013

Additional Antipsychotic Binding Properties Hypothetical Mediators of Therapeutic Actions

Antidepressant

Good Cognition

D, dopaminergic; 5-HT, serotonergic; H, histaminergic; M, muscarinic; , alpha-adrenergic; SRI, serotonin reuptake inhibitors; NRI, noradrenaline reuptake inhibitor Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York
PHEM/PSY/0813/0001 Aug 2013

5-HT7 Relative Receptor Binding Affinity for the -pines


Clozapine
5-HT7

D2
Antidepressant
5-HT7

Olanzapine Quetiapine
5-HT7

Good Cognition

5-HT7

Asenapine More Potent than D2


5-HT, serotonergic; D, dopaminergic Leponex EU SmPC November 2002; Zyprexa EU SmPC August 2013; Seroquel EU SmPC May 2012; Saphris PI 2013; Farah. Prim Care Comp J Clin Psych 2005;7:268274; Gray & Roth. Mol Psychiatry 2007;12:904922; Stahl. Stahls Essential Psychopharmacology, PHEM/PSY/0813/0001 Aug 2013 4th edition. 2013. Cambridge University Press, New York; Shahid et al. J Psychopharmacol. 2009;23:6573

Less Potent than D2

Additional Antipsychotic Binding Properties Hypothetical Mediators of Side Effects


Dry mouth

Sedation

Weight gain

D, dopaminergic; 5-HT, serotonergic; H, histaminergic; M, muscarinic; , alpha-adrenergic; SRI, serotonin reuptake inhibitors; NRI, noradrenaline reuptake inhibitor Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York
PHEM/PSY/0813/0001 Aug 2013

Summary: Atypical Antipsychotics as a Class


All atypical antipsychotics have dopamine D2 and 5-HT2A antagonist properties

All atypicals have numerous other binding properties and are linked to various clinical effects, but no two agents are identical Differences in binding properties are the most rational explanation for differences in efficacy and tolerability in individual patients

D, dopaminergic; 5-HT, serotonergic Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York
PHEM/PSY/0813/0001 Aug 2013

Additional Antipsychotic Binding Properties Hypothetical Mediators of Therapeutic Actions

Antidepressant

Good Cognition

D, dopaminergic; 5-HT, serotonergic; H, histaminergic; M, muscarinic; , alpha-adrenergic; SRI, serotonin reuptake inhibitors; NRI, noradrenaline reuptake inhibitor Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York
PHEM/PSY/0813/0001 Aug 2013

5-HT1A and 2C Relative Receptor Binding Affinity for the -dones

D2
5-HT2C 5-HT1A

Risperidone
5-HT2C

Antidepressant
5-HT1A

Paliperidone
5-HT2C 5-HT1A

Ziprasidone
5-HT1A 5-HT2C

Iloperidone
5-HT1A 5-HT2C

Lurasidone More Potent than D2


5-HT, serotonergic; D, dopaminergic Risperdal EU SmPC November 2012; Invega EU SmPC November 2012; Geodon PI 2013; Fanapt PI 2012; Latuda PI 2012
PHEM/PSY/0813/0001 Aug 2013

Less Potent than D2

H1 Relative Receptor Binding Affinity for the -dones D2


H1

Risperidone
H1

Weight gain

Paliperidone
H1

Ziprasidone
H1

Sedation

Iloperidone No affinity

Lurasidone
More Potent than D2
H, histaminergic; D, dopaminergic Risperidal EU SmPC November 2012; Invega EU SmPC November 2012; Geodon PI 2013; Fanapt PI 2012; Latuda PI 2012
PHEM/PSY/0813/0001 Aug 2013

Less Potent than D2

M1 Relative Receptor Binding Affinity for the -dones D2


Risperidone Paliperidone No affinity No affinity No affinity Ziprasidone No affinity

Dry mouth

Sedation

Iloperidone
No affinity Lurasidone More Potent than D2
M, muscarinic; D, dopaminergic Risperidal EU SmPC November 2012; Invega EU SmPC November 2012; Geodon PI 2013; Fanapt PI 2012; Latuda PI 2012
PHEM/PSY/0813/0001 Aug 2013

Less Potent than D2

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