Differential Effects of Aripiprazole on D 2 , 5-HT 2 , and 5-HT 1A Receptor Occupancy in Patients With Schizophrenia: A Triple Tracer PET Study

Mamo, David C.; Graff, Ariel; Mizrahi, Romina; Shammi, Chekkera; Romeyer, Françoise; Kapur, Shitij

doi:10.1176/appi.ajp.2007.06091479

Cited by 224 publications

(147 citation statements)

References 31 publications

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“…receptors (-2-44%) at doses between 10 to 30 mg in schizophrenia patients. EPS was seen only in two of four subjects with D 2 occupancies exceeding 90% (Mamo et al, 2007). In accordance with the study of Bantick et al (2004), who showed that clozapine did not occupy the 5-HT 1A receptor at clinical doses, these data do not support an important role of the 5-HT 1A receptor regarding antipsychotic activity.…”

Section: Antipsychotic Drug Action and Serotonin Receptor Occupancysupporting

confidence: 86%

Serotonin and Schizophrenia

Quednow

Geyer

Halberstadt

2010

Handbook of Behavioral Neuroscience

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Although the serotonin hypothesis of schizophrenia is one of the oldest neurochemical hypotheses on the pathogenesis of this disease, it is still highly topical. The concept of how the serotonin system is involved in the origin and progress of schizophrenia has considerably changed over the past decades. Therefore, the present work will give an overview about the development and the current directions of the serotonin hypothesis of schizophrenia. In this regard, we will discuss the phenomenology of hallucinogenic drug action, model psychosis and translational research, post-mortem studies on receptors and transporters, imaging studies, antipsychotic drug action, neuroendocrine challenge studies, platelet and cerebrospinal fluid data, genetic association studies, developmental aspects, and the cross-talk between the glutamate and the serotonin system. In sum, there are several lines of evidence suggesting that the serotonin system plays a major role in the pathogenesis of at least a subpopulation of schizophrenia patients. Further studies are needed to better characterize patients whose psychotic symptoms are suspected to have a serotonergic origin. Serotonin and Schizophrenia AbstractAlthough the serotonin hypothesis of schizophrenia is one of the oldest neurochemical hypotheses on the pathogenesis of this disease, it is still highly topical. The concept of how the serotonin system is involved in the origin and progress of schizophrenia has considerably changed over the past decades.Therefore, the present work will give an overview about the development and the current directions of the serotonin hypothesis of schizophrenia. In this regard, we will discuss the phenomenology of hallucinogenic drug action, model psychosis and translational research, post-mortem studies on receptors and transporters, imaging studies, antipsychotic drug action, neuroendocrine challenge studies, platelet and cerebrospinal fluid data, genetic association studies, developmental aspects, and the cross-talk between the glutamate and the serotonin system. In sum, there are several lines of evidence suggesting that the serotonin system plays a major role in the pathogenesis of at least a subpopulation of schizophrenia patients. Further studies are needed to better characterize patients whose psychotic symptoms are suspected to have a serotonergic origin.3

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Section: Antipsychotic Drug Action and Serotonin Receptor Occupancysupporting

confidence: 86%

Serotonin and Schizophrenia

Quednow

Geyer

Halberstadt

2010

Handbook of Behavioral Neuroscience

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“…PET studies are also consistent with the view that at clinically relevant doses, those agents, which are direct acting antagonists of D 2 receptors, have higher occupancy of D 2 than 5-HT 2A receptors (Goyer et al, 1996;Nyberg et al, 1999;Gefvert et al, 2001;Kessler et al, 2005). Aripiprazole, a partial D 2 receptor agonist, has a higher D 2 than 5-HT 2A receptor occupancy at clinical doses, but, nevertheless, has a weak functional effect to inhibit D 2 receptor stimulation (Mamo et al, 2007). As mentioned under Introduction, diminished dopaminergic and noradrenergic function in the cortex and HIP have been implicated in the pathophysiology of cognitive impairment, negative symptoms, and perhaps depression in patients with schizophrenia (Meltzer and McGurk, 1999;Millan, 2006;Juckel et al, 2006).…”

Section: Da Effluxsupporting

confidence: 70%

Asenapine Increases Dopamine, Norepinephrine, and Acetylcholine Efflux in the Rat Medial Prefrontal Cortex and Hippocampus

Huang

Dai

et al. 2008

Neuropsychopharmacol

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Atypical antipsychotic drugs, which are more potent direct acting antagonists of brain serotonin (5-HT) 2A than dopamine (DA) D 2 receptors, preferentially enhance DA and acetylcholine (ACh) efflux in the rat medial prefrontal cortex (mPFC) and hippocampus (HIP), compared with the nucleus accumbens (NAc). These effects may contribute to their ability, albeit limited, to improve cognitive function and negative symptoms in patients with schizophrenia. Asenapine (ASE), a new multireceptor antagonist currently in development for the treatment of schizophrenia and bipolar disorder, has complex serotonergic properties based upon relatively high affinity for multiple serotonin (5-HT) receptors, particularly 5-HT 2A and 5-HT 2C receptors. In the current study, the effects of ASE on DA, norepinephrine (NE), 5-HT, ACh, glutamate, and g-aminobutyric acid (GABA) efflux in rat mPFC, HIP, and NAc were investigated with microdialysis in awake, freely moving rats. ASE at 0.05, 0.1, and 0.5 mg/kg (s.c.), but not 0.01 mg/kg, significantly increased DA efflux in the mPFC and HIP. Only the 0.5 mg/kg dose enhanced DA efflux in the NAc. ASE, at 0.1 and 0.5 mg/kg, significantly increased ACh efflux in the mPFC, but only the 0.5 mg/kg dose of ASE increased HIP ACh efflux. ASE did not increase ACh efflux in the NAc at any of the doses tested. The effect of ASE (0.1 mg/kg) on DA and ACh efflux was blocked by pretreatment with WAY100635, a 5-HT 1A antagonist/D 4 agonist, suggesting involvement of indirect 5-HT 1A agonism in both the actions. ASE, at 0.1 mg/kg, increased NE, but not 5-HT, efflux in the mPFC and HIP. ASE, at 0.1 mg/kg (s.c.), had no effect on glutamate and GABA efflux in either the mPFC or NAc. These findings indicate that ASE is similar to clozapine and other atypical antipsychotic drugs in preferentially increasing the efflux of DA, NE, and ACh in the mPFC and HIP compared with the NAC, and suggests that, like these agents, it may also improve cognitive function and negative symptoms in patients with schizophrenia.

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“…To elucidate this, further studies based on the same design using a selective antagonist for dopamine D 2 receptors, such as sulpiride, should be considered. In addition, a new antipsychotic drug aripiprazole that is a partial agonist to dopamine D 2 receptors has recently been used for treatment of schizophrenia (Mamo et al, 2007). Further studies to investigate the effects of aripiprazole on dopamine synthesis capacity should also be considered.…”

Section: Discussionmentioning

confidence: 99%

Effects of the Antipsychotic Risperidone on Dopamine Synthesis in Human Brain Measured by Positron Emission Tomography with l-[β-¹¹C]DOPA: A Stabilizing Effect for Dopaminergic Neurotransmission?

Ito¹,

Takano²,

Takahashi³

et al. 2009

J. Neurosci.

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receptors corresponding dose of risperidone was observed, the changes in dopamine synthesis capacity by the administration of risperidone were not significant, nor was the relation between the occupancy of dopamine D 2 receptors and these changes. A significant negative correlation was observed between the baseline dopamine synthesis capacity and the changes in dopamine synthesis capacity by risperidone, indicating that this antipsychotic can be assumed to stabilize the dopamine synthesis capacity. The therapeutic effects of risperidone in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity.

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Differential Effects of Aripiprazole on D ₂ , 5-HT ₂ , and 5-HT _1A Receptor Occupancy in Patients With Schizophrenia: A Triple Tracer PET Study

Cited by 224 publications

References 31 publications

Serotonin and Schizophrenia

Serotonin and Schizophrenia

Asenapine Increases Dopamine, Norepinephrine, and Acetylcholine Efflux in the Rat Medial Prefrontal Cortex and Hippocampus

Effects of the Antipsychotic Risperidone on Dopamine Synthesis in Human Brain Measured by Positron Emission Tomography with l-[β-¹¹C]DOPA: A Stabilizing Effect for Dopaminergic Neurotransmission?

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Differential Effects of Aripiprazole on D 2 , 5-HT 2 , and 5-HT 1A Receptor Occupancy in Patients With Schizophrenia: A Triple Tracer PET Study

Cited by 224 publications

References 31 publications

Serotonin and Schizophrenia

Serotonin and Schizophrenia

Asenapine Increases Dopamine, Norepinephrine, and Acetylcholine Efflux in the Rat Medial Prefrontal Cortex and Hippocampus

Effects of the Antipsychotic Risperidone on Dopamine Synthesis in Human Brain Measured by Positron Emission Tomography with l-[β-11C]DOPA: A Stabilizing Effect for Dopaminergic Neurotransmission?

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Differential Effects of Aripiprazole on D ₂ , 5-HT ₂ , and 5-HT _1A Receptor Occupancy in Patients With Schizophrenia: A Triple Tracer PET Study

Effects of the Antipsychotic Risperidone on Dopamine Synthesis in Human Brain Measured by Positron Emission Tomography with l-[β-¹¹C]DOPA: A Stabilizing Effect for Dopaminergic Neurotransmission?