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Cognitive symptoms
Amygdala
Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York
Dopamine Pathways Project from Neurotransmitter Centers to the Striatum, Prefrontal Cortex, Thalamus, and Hypothalamus
DLPFC
VMPFC
DLPFC, dorsolateral prefrontal cortex; VMPFC, ventromedial prefrontal cortex Adapted from Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York
PHEM/PSY/0813/0001 Aug 2013
The Mesolimbic Dopamine Hypothesis of Positive Symptoms of Schizophrenia Describes the Effects of Excessive DA
D2
HIGH
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
Affective symptoms
PHEM/PSY/0813/0001 Aug 2013
5-HT2A
Stahl. Stahls Essential Psychopharmacology, 4th edition. 2013. Cambridge University Press, New York
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
PHEM/PSY/0813/0001 Aug 2013
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
PHEM/PSY/0813/0001 Aug 2013
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
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
PHEM/PSY/0813/0001 Aug 2013
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
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
PHEM/PSY/0813/0001 Aug 2013
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
PHEM/PSY/0813/0001 Aug 2013
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
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
D2
Low EPS
5-HT2A
5-HT, serotonergic; D, dopaminergic; EPS, Extrapyramidal Symptoms Abilify EU SmPC February 2013
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
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
D2
Antidepressant
5-HT7
Olanzapine Quetiapine
5-HT7
Good Cognition
5-HT7
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
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
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
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
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
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
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