Suggested Minimal Effective Dose of Risperidone Based on PET-Measured D<sub>2</sub> and 5-HT<sub>2A</sub> Receptor Occupancy in Schizophrenic Patients

Nyberg, Sigrid; Eriksson, Bo; Oxenstierna, Gabriel; Halldin, Christer; Farde, Lars

doi:10.1176/ajp.156.6.869

Cited by 227 publications

(143 citation statements)

References 29 publications

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“…As reported by Schotte et al (1996), these agents, including clozapine, risperidone, 9-hydroxyrisperidone (paliperidone), olanzapine, pipamperone, quetiapine, sertindole, ziprasidone, and zotepine, also have higher occupancy in the rat cortex and striatum of 5-HT 2A than D 2 receptors, respectively, at all but the highest doses studied. 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).…”

Section: Da Effluxsupporting

confidence: 69%

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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Section: Da Effluxsupporting

confidence: 69%

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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“…Third, our patients were scheduled to receive a target dose of 4 mg/day of risperidone rather than a standard dose of 6 mg/day. A low risk of EPS was observed among these subjects, as was suggested by several other studies (Nyberg et al, 1999;Williams, 2001). Consequently, we were able to maintain a uniform dosage schedule for most patients.…”

Section: Discussionsupporting

confidence: 83%

Effects of the Dopamine D3 Receptor (DRD3) Gene Polymorphisms on Risperidone Response: A Pharmacogenetic Study

Xuan

Zhao

et al. 2007

Neuropsychopharmacol

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Previous observations of the anatomical distribution and pharmacological profile of the dopamine D 3 receptor (DRD3) have indicated its potential role in antipsychotic drug action. Risperidone, an effective first-line atypical antipsychotic agent, exhibits a relatively high affinity for this receptor. Recent studies have reported an association of the Ser9Gly polymorphism in the DRD3 gene with therapeutic response to risperidone, but the results were inconsistent. We therefore postulated that the Ser9Gly polymorphism might be in linkage disequilibrium with an undetected variant that exerts a direct influence on risperidone efficacy. The present study genotyped eight single nucleotide polymorphisms (SNPs) distributed throughout the DRD3 gene and examined five of these for association with treatment outcome, following an 8-week period of risperidone monotherapy in 130 schizophrenic patients from mainland China. Clinical symptoms were assessed before and after the treatment period, using the Brief Psychiatry Rating Scale (BPRS). The confounding effects of nongenetic factors were estimated and the baseline symptom score was included as a covariate for adjustment. Neither was any association observed between the five polymorphisms and improvement in total BPRS scores nor was any combined effect of these variants detected in the haplotype analysis. The current results indicate that genetic variations within the DRD3 gene may not contribute significantly to interindividual differences in the therapeutic efficacy of risperidone.

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“…In line with the in vivo data (see above), most of the atypical drugs display higher 5-HT 2A than D 2 occupancy rates when dual-tracer approaches are used (Kapur et al, 1998;Nyberg et al, 1999;Gefvert et al, 2001;Mamo et al, 2004). But although it was suggested that the predominant 5-HT 2A receptor antagonism of atypical drugs protects against EPS (Meltzer, 1999), even atypical substances such as olanzapine or risperidone cause EPS when given in higher doses that lead to D 2 receptor occupancy of more than 80% (Kapur et al, 1998;Nyberg et al, 1999).…”

Section: Antipsychotic Drug Action and Serotonin Receptor Occupancymentioning

confidence: 61%

“…But although it was suggested that the predominant 5-HT 2A receptor antagonism of atypical drugs protects against EPS (Meltzer, 1999), even atypical substances such as olanzapine or risperidone cause EPS when given in higher doses that lead to D 2 receptor occupancy of more than 80% (Kapur et al, 1998;Nyberg et al, 1999). receptors (-2-44%) at doses between 10 to 30 mg in schizophrenia patients.…”

Section: Antipsychotic Drug Action and Serotonin Receptor Occupancymentioning

confidence: 99%

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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Suggested Minimal Effective Dose of Risperidone Based on PET-Measured D₂ and 5-HT_2A Receptor Occupancy in Schizophrenic Patients

Cited by 227 publications

References 29 publications

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

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

Effects of the Dopamine D3 Receptor (DRD3) Gene Polymorphisms on Risperidone Response: A Pharmacogenetic Study

Serotonin and Schizophrenia

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Suggested Minimal Effective Dose of Risperidone Based on PET-Measured D2 and 5-HT2A Receptor Occupancy in Schizophrenic Patients

Cited by 227 publications

References 29 publications

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

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

Effects of the Dopamine D3 Receptor (DRD3) Gene Polymorphisms on Risperidone Response: A Pharmacogenetic Study

Serotonin and Schizophrenia

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Product

Resources

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Suggested Minimal Effective Dose of Risperidone Based on PET-Measured D₂ and 5-HT_2A Receptor Occupancy in Schizophrenic Patients