The Experts below are selected from a list of 32262 Experts worldwide ranked by ideXlab platform
Gitte M Knudsen - One of the best experts on this subject based on the ideXlab platform.
-
brain Serotonin 2A Receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans
Journal of Psychopharmacology, 2020Co-Authors: Dea Siggaard Stenbaek, Gitte M Knudsen, Martin K Madsen, Brice Ozenne, Sara Kristiansen, Daniel Burmester, David ErritzoeAbstract:Background:Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by Serotonin 2A Receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness...
-
Common HTR2A variants and 5-HTTLPR are not associated with human in vivo Serotonin 2A Receptor levels
Human brain mapping, 2020Co-Authors: Marie Spies, Gitte M Knudsen, Brice Ozenne, Arafat Nasser, Peter S. Jensen, Patrick M. FisherAbstract:The Serotonin 2A Receptor (5-HT2AR) is implicated in the pathophysiology and treatment of various psychiatric disorders. [18 F]altanserin and [11 C]Cimbi-36 positron emission tomography (PET) allow for high-resolution imaging of 5-HT2AR in the living human brain. Cerebral 5-HT2AR binding is strongly genetically determined, though the impact of specific variants is poorly understood. Candidate gene studies suggest that HTR2A single nucleotide polymorphisms including rs6311/rs6313, rs6314, and rs7997012 may influence risk for psychiatric disorders and mediate treatment response. Although known to impact in vitro expression of 5-HT2AR or other Serotonin (5-HT) proteins, their effect on human in vivo brain 5-HT2AR binding has as of yet been insufficiently studied. We thus assessed the extent to which these variants and the commonly studied 5-HTTLPR predict neocortex in vivo 5-HT2AR binding in healthy adult humans. We used linear regression analyses and likelihood ratio tests in 197 subjects scanned with [18 F]altanserin or [11 C]Cimbi-36 PET. Although we observed genotype group differences in 5-HT2AR binding of up to ~10%, no genetic variants were statistically significantly predictive of 5-HT2AR binding in what is the largest human in vivo 5-HT2AR imaging genetics study to date. Thus, in vitro and post mortem results suggesting effects on 5-HT2AR expression did not carry over to the in vivo setting. To any extent these variants might affect clinical risk, our findings do not support that 5-HT2AR binding mediates such effects. Our observations indicate that these individual variants do not significantly contribute to genetic load on human in vivo 5-HT2AR binding.
-
identification of a Serotonin 2A Receptor subtype of schizophrenia spectrum disorders with pimavanserin the sub sero proof of concept trial protocol
Frontiers in Pharmacology, 2020Co-Authors: Olga B Baltzersen, Vibe Gedsoe Frokjaer, Jayachandra Mitta Raghava, Lone Baandrup, Christian H Fibiger, Birte Glenthøj, Birgitte Fagerlund, Henrik Larsson, Herbert Y. Meltzer, Gitte M KnudsenAbstract:Background: All current approved antipsychotic drugs against schizophrenia spectrum disorders share affinity for the dopamine Receptor (D2R). However, up to one-third of these patients respond insufficiently, and in some cases, side-effects outweigh symptom reduction. Previous data have suggested that a subgroup of antipsychotic-naive patients will respond to Serotonin 2A Receptor (2AR) blockade. Aims: This investigator-initiated, translational, proof-of-concept study has overall two aims; 1) To test the clinical effectiveness of monotherapy with the newly approved drug against Parkinson's disease psychosis, pimavanserin, in antipsychotic-free patients with first-episode schizophrenia spectrum disorders; 2) To characterize the neurobiological profile of responders to pimavaserin. Materials and Equipment: Forty patients will be enrolled in this 6-week open label, one-armed trial with the selective Serotonin 2AR antagonist (pimavanserin 34 mg/day). At baseline, patients will undergo: positron emission tomography (PET) imaging of the Serotonin 2AR using the radioligand [¹¹C]Cimbi-36; structural magnetic resonance imaging (MRI); MR spectroscopy of cerebral glutamate levels and diffusion tensor imaging; cognitive and psychopathological examinations; electrocardiogram, and blood sampling for genetic- and metabolic analyses. Outcome Measures: The primary clinical endpoint will be reduction in the Positive and Negative Syndrome Scale (PANSS) positive score. Secondary clinical endpoints comprise multiple clinical ratings (positive and negative symptoms, depressive-, obsessive-compulsive symptoms, quality of life, social functioning, sexual functioning, and side-effects). PET, MRI, and cognitive parameters will be used for in-depth neuropsychiatric characterization of pimavanserin response. Anticipated Results: Clinically, we expect pimavanserin to reduce psychotic symptoms with similar effect as observed with conventional antipsychotics, for which we have comparable historical data. We expect pimavanserin to induce minimal side-effects. Neurobiologically, we expect psychotic symptom reduction to be most prominent in patients with low frontal Serotonin 2AR binding potential at baseline. Potential pro-cognitive and brain structural effects of pimavanserin will be explored. Perspectives: Sub-Sero will provide unique information about the role Serotonin 2AR in antipsychotic-free, first-episode psychosis. If successful, Sub-Sero will aid identification of a "serotonergic subtype" of schizophrenia spectrum patients, thereby promoting development of precision medicine in clinical psychiatry. Clinical Trial Registration: ClinicalTrials, identifier NCT03994965.
-
identification of a Serotonin 2A Receptor subtype of schizophrenia spectrum disorders with pimavanserin the sub sero proof of concept trial protocol
Frontiers in Pharmacology, 2020Co-Authors: Olga B Baltzersen, Jayachandra Mitta Raghava, Lone Baandrup, Christian H Fibiger, Birte Glenthøj, Birgitte Fagerlund, Henrik Larsson, Herbert Y. Meltzer, Vibe G. Frokjaer, Gitte M KnudsenAbstract:Background: All current approved antipsychotic drugs against schizophrenia spectrum disorders share affinity for the dopamine Receptor (D2R). However, up to one-third of these patients respond insufficiently, and in some cases, side-effects outweigh symptom reduction. Previous data have suggested that a subgroup of antipsychotic-naive patients will respond to Serotonin 2A Receptor (2AR) blockade. Aims: This investigator-initiated, translational, proof-of-concept study has overall two aims; 1) To test the clinical effectiveness of monotherapy with the newly approved drug against Parkinson's disease psychosis, pimavanserin, in antipsychotic-free patients with first-episode schizophrenia spectrum disorders; 2) To characterize the neurobiological profile of responders to pimavaserin. Materials and Equipment: Forty patients will be enrolled in this 6-week open label, one-armed trial with the selective Serotonin 2AR antagonist (pimavanserin 34 mg/day). At baseline, patients will undergo: positron emission tomography (PET) imaging of the Serotonin 2AR using the radioligand [¹¹C]Cimbi-36; structural magnetic resonance imaging (MRI); MR spectroscopy of cerebral glutamate levels and diffusion tensor imaging; cognitive and psychopathological examinations; electrocardiogram, and blood sampling for genetic- and metabolic analyses. Outcome Measures: The primary clinical endpoint will be reduction in the Positive and Negative Syndrome Scale (PANSS) positive score. Secondary clinical endpoints comprise multiple clinical ratings (positive and negative symptoms, depressive-, obsessive-compulsive symptoms, quality of life, social functioning, sexual functioning, and side-effects). PET, MRI, and cognitive parameters will be used for in-depth neuropsychiatric characterization of pimavanserin response. Anticipated Results: Clinically, we expect pimavanserin to reduce psychotic symptoms with similar effect as observed with conventional antipsychotics, for which we have comparable historical data. We expect pimavanserin to induce minimal side-effects. Neurobiologically, we expect psychotic symptom reduction to be most prominent in patients with low frontal Serotonin 2AR binding potential at baseline. Potential pro-cognitive and brain structural effects of pimavanserin will be explored. Perspectives: Sub-Sero will provide unique information about the role Serotonin 2AR in antipsychotic-free, first-episode psychosis. If successful, Sub-Sero will aid identification of a "serotonergic subtype" of schizophrenia spectrum patients, thereby promoting development of precision medicine in clinical psychiatry. Clinical Trial Registration: ClinicalTrials, identifier NCT03994965.
-
Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain.
The International Journal of Neuropsychopharmacology, 2017Co-Authors: Kai-chun Yang, Gitte M Knudsen, Anders Ettrup, Vladimir Stepanov, Stefan Martinsson, Akihiro Takano, Christer Halldin, Lars Farde, Sjoerd J. FinnemaAbstract:Background: [11C]Cimbi-36 is a Serotonin 2A Receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the current study, we compared the effect of Serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a Serotonin 2A Receptor antagonist radioligand), and [11C]AZ10419369 (a Serotonin 1B Receptor partial agonist radioligand with established Serotonin sensitivity) in the monkey brain. Methods: Eighteen positron emission tomography measurements, 6 for each radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region. Results: Fenfluramine significantly decreased [11C]Cimbi-36 (26-62%) and [11C]AZ10419369 (35-58%) binding potential values in most regions (P < 0.05). Fenfluramine-induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of Serotonin 2A Receptor in the high-affinity state was estimated as 54% in the neocortex. Conclusions: The Serotonin sensitivity of Serotonin 2A Receptor agonist radioligand [11C]Cimbi-36 was higher than for antagonist radioligand [11C]MDL 100907. The Serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive radioligands. [11C]Cimbi-36 is a promising radioligand to examine Serotonin release in the primate brain.
Christophe P Stove - One of the best experts on this subject based on the ideXlab platform.
-
correction to in vitro structure activity relationship determination of 30 psychedelic new psychoactive substances by means of β arrestin 2 recruitment to the Serotonin 2A Receptor
Archives of Toxicology, 2020Co-Authors: Eline Pottie, Annelies Cannaert, Christophe P StoveAbstract:It has been brought to the authors' attention that Fig. 1 of "In vitro structure-activity relationship determination of 30 psychedelic new psychoactive substances by means of β-arrestin 2 recruitment to the Serotonin 2A Receptor" contained a mistake in the structures for 2C-B-FLY and Bromo-DragonFLY. This has now been corrected. The authors apologize for any inconvenience caused.
-
Correction to: In vitro structure–activity relationship determination of 30 psychedelic new psychoactive substances by means of β-arrestin 2 recruitment to the Serotonin 2A Receptor
Archives of toxicology, 2020Co-Authors: Eline Pottie, Annelies Cannaert, Christophe P StoveAbstract:It has been brought to the authors' attention that Fig. 1 of "In vitro structure-activity relationship determination of 30 psychedelic new psychoactive substances by means of β-arrestin 2 recruitment to the Serotonin 2A Receptor" contained a mistake in the structures for 2C-B-FLY and Bromo-DragonFLY. This has now been corrected. The authors apologize for any inconvenience caused.
-
In vitro structure–activity relationship determination of 30 psychedelic new psychoactive substances by means of β-arrestin 2 recruitment to the Serotonin 2A Receptor
Archives of Toxicology, 2020Co-Authors: Eline Pottie, Annelies Cannaert, Christophe P StoveAbstract:Serotonergic psychedelics, substances exerting their effects primarily through the Serotonin 2A Receptor (5-HT_2AR), continue to comprise a substantial portion of reported new psychoactive substances (NPS). The exact mechanisms of action of psychedelics still remain to be elucidated further, and certain pathways remain largely unexplored on a molecular level for this group of compounds. A systematic comparison of substances belonging to different subclasses, monitoring the Receptor-proximal β-arrestin 2 recruitment, is lacking. Based on a previously reported in vitro bioassay employing functional complementation of a split nanoluciferase to monitor β-arrestin 2 recruitment to the 5-HT_2AR, we here report on the setup of a stable HEK 293 T cell-based bioassay. Following verification of the performance of this new stable cell system as compared to a system based on transient transfection, the stable expression system was deemed suitable for the pharmacological characterization of psychedelic NPS. Subsequently, it was applied for the in vitro assessment of the structure–activity relationship of a set of 30 substances, representing different subclasses of phenylalkylamine psychedelics, among which 12 phenethylamine derivatives (2C-X), 7 phenylisopropylamines (DOx) and 11 N -benzylderivatives (25X-NB). The resulting potency and efficacy values provide insights into the structure–activity relationship of the tested compounds, overall confirm findings observed with other reported in vitro assays, and even show a significant correlation with estimated common doses. This approach, in which a large series of psychedelic NPS belonging to different subclasses is comparatively tested, using a same assay setup, monitoring a Receptor-proximal event, not only gives pharmacological insights, but may also allow prioritization of legal actions related to the most potent -and potentially dangerous- compounds.
-
Setup of a Serotonin 2A Receptor (5-HT2AR) Bioassay: Demonstration of Its Applicability To Functionally Characterize Hallucinogenic New Psychoactive Substances and an Explanation Why 5-HT2AR Bioassays Are Not Suited for Universal Activity-Based Scree
Analytical chemistry, 2019Co-Authors: Eline Pottie, Annelies Cannaert, Katleen Van Uytfanghe, Christophe P StoveAbstract:Classic or serotonergic hallucinogens comprise the third largest number of reported new psychoactive substances (NPS), according to the United Nations Office on Drugs and Crime. While being structurally very divergent, they share activation of the Serotonin 2A Receptor (5-HT2AR), a G protein-coupled Receptor, as their main pharmacological mechanism. Here, we report on the development of a 5-HT2AR bioassay, which monitors β-arrestin2 recruitment to the Receptor via a split-luciferase system, as a measure of Receptor activation. Possible applications of the bioassay would lie in the characterization of serotonergic hallucinogens and the screening of these compounds in biofluids based on their serotonergic activity, rather than on their specific structures. The developed bioassay allowed the determination of the potency and efficacy of representatives of different classes of hallucinogens (LSD, 5-MeO-DALT, mescaline) and of a selected group of 2C hallucinogens and their corresponding NBOMes, with EC50 values from the subnanomolar (NBOMes) to micromolar (mescaline) range. When implementing the bioassay for the screening of plasma, a pronounced Receptor activation was already observed in blank samples, which could be ascribed to endogenous Serotonin, as suggested by annihilation of this activity by a 5-HT2AR antagonist or after incubation with MAO-A (monoamine oxidase-A). The presence and degradability by MAO-A of Serotonin in plasma extracts were confirmed by LC-HRMS. Due to the possible metabolism of certain hallucinogens by MAO-A, which would cause a bias in the detectability of compounds in biofluids, the main application potential of this bioassay lies in the characterization of these scarcely characterized serotonergic hallucinogens.
Sylvain Houle - One of the best experts on this subject based on the ideXlab platform.
-
The Relationship Between Serotonin-2A Receptor and Cognitive Functions in Nondemented Parkinson's Disease Patients with Visual Hallucinations.
Movement disorders clinical practice, 2017Co-Authors: Sang Soo Cho, Mateusz Zurowski, Pablo Rusjan, Antonio P. Strafella, Sarah Duff-canning, Anne-catherine Vijverman, Veronica Bruno, Camila C. Aquino, Marion Criaud, Sylvain HouleAbstract:Background There is growing evidence that the serotonergic system, in particular Serotonin 2A Receptors, is involved in neuropsychiatric symptoms in Parkinson's disease (PD), including cognitive processing and visual hallucinations. However, the relationship between Serotonin 2A Receptor availability, visual hallucinations, and cognitive profile is unknown. The objective of this study was to investigate the level of Serotonin 2A Receptor availability in brain regions affected by visual hallucinations and to test the association with cognitive/behavioral changes in patients who have PD with visual hallucinations. Methods Nondemented patients who had PD with (n = 11) and without (n = 8) visual hallucinations and age-matched controls (n = 10) were recruited. All participants completed neuropsychological testing, which consisted of visuoperceptual, executive, memory, language, and frontal-behavioral function. Positron emission tomography scans using [18F]setoperone, a Serotonin 2A antagonist radioligand, were acquired in patients with PD, and a parametric binding potential map of [18F]setoperone was calculated with the simplified reference tissue model using the cerebellum as a reference. Results Patients who had PD with visual hallucinations exhibited significantly lower scores on measures of executive and visuoperceptual functions compared with age-matched controls. These changes were paralleled by decreased [18F]setoperone binding in the right insula, bilateral dorsolateral prefrontal cortex, right orbitofrontal cortex, right middle temporal gyrus, and right fusiform gyrus. The psychometric correlation analysis revealed significant relationships among tests associated with visuoperceptual function, memory and learning, and Serotonin 2A binding in different prefrontal and ventral visual stream regions. There was also reduced Serotonin 2A Receptor binding in patients who had PD with depression. Conclusions These findings support a complex interaction between Serotonin 2A Receptor function and cognitive processing in patients who have PD with visual hallucinations.
-
Serotonin 2A Receptors and Visual Hallucinations in Parkinson Disease
Archives of neurology, 2010Co-Authors: Benedicte Ballanger, Thilo Van Eimeren, Mateusz Zurowski, Pablo Rusjan, Sylvain Houle, Antonio P. Strafella, Susan H. FoxAbstract:Background Complex visual hallucinations (VHs) occur in several pathologic conditions; however, the neural mechanisms underlying these symptoms remain unclear. Although dopamine may have a role, indirect evidence indicates that Serotonin may also contribute to the pathogenesis of complex VHs, probably via involvement of the Serotonin 2 Receptor. Objective To examine for the first time in vivo changes in Serotonin 2A Receptor neurotransmission among patients having Parkinson disease (PD) with VHs. Design Case-control study. Setting Academic research. Patients Seven patients having PD with VHs and 7 age-matched patients having PD without VHs were recruited. Main Outcome Measures We used the selective Serotonin 2A Receptor ligand setoperone F 18 during positron emission tomography among nondemented patients having PD with VHs. Results Patients having PD with VHs demonstrate increased Serotonin 2A Receptor binding in the ventral visual pathway (including the bilateral inferooccipital gyrus, right fusiform gyrus, and inferotemporal cortex) as well as the bilateral dorsolateral prefrontal cortex, medial orbitofrontal cortex, and insula. Conclusions This pilot study provides the first in vivo evidence suggesting a role for Serotonin 2A Receptors in mediating VHs via the ventral visual pathway in PD. Treatment studies should be performed using selective Serotonin 2A Receptor antagonists, which have important implications for the clinical management of VHs and psychosis in PD.
-
Serotonin 2A Receptors and Visual Hallucinations in Parkinson Disease
Archives of Neurology -Chigago-, 2010Co-Authors: Benedicte Ballanger, Antonio Strafella, Thilo Van Eimeren, Mateusz Zurowski, Pablo Rusjan, Sylvain Houle, Susan FoxAbstract:Background Complex visual hallucinations (VHs) occur in several pathologic conditions; however, the neural mechanisms underlying these symptoms remain unclear. Although dopamine may have a role, indirect evidence indicates that Serotonin may also contribute to the pathogenesis of complex VHs, probably via involvement of the Serotonin 2 Receptor. Objective To examine for the first time in vivo changes in Serotonin 2A Receptor neurotransmission among patients having Parkinson disease (PD) with VHs. Design Case-control study. Setting Academic research. Patients Seven patients having PD with VHs and 7 age-matched patients having PD without VHs were recruited. Main Outcome Measures We used the selective Serotonin 2A Receptor ligand setoperone F 18 during positron emission tomography among nondemented patients having PD with VHs. Results Patients having PD with VHs demonstrate increased Serotonin 2A Receptor binding in the ventral visual pathway (including the bilateral inferooccipital gyrus, right fusiform gyrus, and inferotemporal cortex) as well as the bilateral dorsolateral prefrontal cortex, medial orbitofrontal cortex, and insula. Conclusions This pilot study provides the first in vivo evidence suggesting a role for Serotonin 2A Receptors in mediating VHs via the ventral visual pathway in PD. Treatment studies should be performed using selective Serotonin 2A Receptor antagonists, which have important implications for the clinical management of VHs and psychosis in PD. Visual hallucinations (VHs) are abnormal perceptions in the absence of an adequate visual stimulus. Complex well-formed VHs have been described in several pathologic conditions, including peduncular hallucinosis, schizophrenia, cortical Lewy body dementia, and Parkinson disease (PD). A potential common substrate for complex VHs in all of these conditions is suppression of normal inhibitory cortical inputs over the visual association cortex, leading to complex VHs as a “release phenomenon.”1 However, the neural mechanisms underlying VHs remain unclear. Although dopamine may have a role,2 indirect evidence indicates that Serotonin may also contribute to the pathogenesis of complex VHs, probably via involvement of the Serotonin 2 Receptor. In fact, hallucinogenic lysergic acid diethylamide acts via Serotonin 2A Receptors,3 and atypical antipsychotics (eg, clozapine and quetiapine fumarate) that effectively reduce VHs, as well as dopamine Receptor antagonists, are Serotonin 2A and 2C Receptor antagonists.4 In PD, this antipsychotic effect on VHs occurs at low dosages (approximately 10-fold less than in schizophrenia); at such dosages, there is high occupancy of Serotonin 2A Receptors and low occupancy of dopamine Receptors.5 Together, these observations suggest that Serotonin 2A Receptors may be involved in VHs in PD; however, the pathogenesis underlying these phenomena and the potential action site of Serotonin 2A ligands in reducing such symptoms is unknown to date. Therefore, the specific objective of this pilot study was to measure for the first time in vivo changes in Serotonin 2A Receptor binding using the selective Serotonin 2A Receptor ligand setoperone F 186 during positron emission tomography (PET) among age-matched nondemented patients having PD with well-formed VHs vs patients having PD without VHs.
James L. Kennedy - One of the best experts on this subject based on the ideXlab platform.
-
Serotonin 2A Receptor gene is associated with personality traits, but not to disorder, in patients with borderline personality disorder.
Neuroscience letters, 2006Co-Authors: Ramprasad Bismil, Kirsten Chan, Tricia Sicard, Natalie Bulgin, Shelley Mcmain, James L. KennedyAbstract:Abstract Borderline personality disorder (BPD) is a chronic, disabling, and high-risk mental disorder characterized by a pervasive pattern of instability in regulation of emotion, interpersonal relationships, self-image, and impulse control beginning in early adulthood. BPD affects about 1%–2% of the general population and has a high mortality rate as a result of suicide and impulsive behaviour. The Serotonin 2A Receptor gene (HTR2A) is considered a candidate gene for BPD because multiple lines of evidence suggest that it plays an important role in suicide, impulsivity and emotional liability. To test for an association between HTR2A and BPD, we genotyped four polymorphisms, rs6313 (T102C), rs4941573, rs2296972 and rs6314 (His452Tyr), in 111 Caucasian patients with BPD and 287 Caucasian healthy controls. The program UNPHASED was used to compare allele and haplotype frequencies between cases and controls. We did not find a significant association between HTR2A and BPD based on allele, genotype or haplotype analyses. However, there were significant associations between HTR2A and personality traits in the BPD patients. The C allele of rs6313 and the A allele of rs4941573 associated with a higher Extraversion score. Our results suggest that the Serotonin 2A Receptor gene may not play a major role in the aetiology of borderline personality disorder, but may have a role in personality traits.
-
Family-based association study of the Serotonin-2A Receptor gene (5-HT2A) and bipolar disorder
NeuroMolecular Medicine, 2002Co-Authors: Xingqun Ni, Emanuela Mundo, Joseph Trakalo, Sagar Parikh, James L. KennedyAbstract:Objectives: The Serotonin 2A Receptor gene ( 5-HT2A ) is of great interest for research in neuropsychiatric disorders based on the observation that various neuroleptic agents and antidepressants bind with relatively high affinity at 5-HT2A Receptors, and the fact that the Receptor density in platelets tends to increase in depression. To test for the presence of association between 5-HT2A and bipolar disorder (BP), we studied a large number of triad families having probands affected with DSM-IV bipolar I (BPI), bipolar II (BPII) or schizoaffective disorder, bipolar type. Methods: Two polymorphisms of 5-HT2A , 102T/C, and His452Tyr were analyzed in the 274 bipolar triad families. Both the transmission disequilibrium test (TDT) and haplotype TDT were performed on the genotype data. We also calculated the maternal transmission and paternal transmission for each allele and compared the mean ages of onset across probands grouped by genotype at each of the two markers. Results: No significant transmission disequilibrium between the alleles of 5-HT2A and BP was found. Separate studies of the sub-phenotypes also failed to demonstrate significant association. However, we found a trend towards transmission disequilibrium with the haplotype 102C.His452 ( p =0.0504). This trend may become more significant with a larger sample size. Significance: At present, results of this study suggest that the 5-HT2A is unlikely to play a major role in the genetic susceptibility to BP. Future studies will be directed towards increasing sample size, focusing on subtypes of BP or biochemical measures as phenotypes, and investigating other polymorphisms of 5-HT2A to provide more information at the DNA level.
-
Family-based association study of the Serotonin-2A Receptor gene (5-HT2A) and bipolar disorder.
Neuromolecular medicine, 2002Co-Authors: Joseph Trakalo, Emanuela Mundo, Lisa Lee, Sagar V. Parikh, James L. KennedyAbstract:Objectives: The Serotonin 2A Receptor gene (5-HT2A) is of great interest for research in neuropsychiatric disorders based on the observation that various neuroleptic agents and antidepressants bind with relatively high affinity at 5-HT2A Receptors, and the fact that the Receptor density in platelets tends to increase in depression. To test for the presence of association between 5-HT2A and bipolar disorder (BP), we studied a large number of triad families having probands affected with DSM-IV bipolar I (BPI), bipolar II (BPII) or schizoaffective disorder, bipolar type.
-
Lack of association between Serotonin-2A Receptor gene (HTR2A) polymorphisms and tardive dyskinesia in schizophrenia.
Molecular psychiatry, 2001Co-Authors: Vincenzo S. Basile, Herbert Y. Meltzer, Vural Ozdemir, Mario Masellis, J.a. Lieberman, Steven G. Potkin, Fabio Macciardi, A. Petronis, James L. KennedyAbstract:Lack of association between Serotonin-2A Receptor gene ( HTR2A ) polymorphisms and tardive dyskinesia in schizophrenia
Herbert Y. Meltzer - One of the best experts on this subject based on the ideXlab platform.
-
identification of a Serotonin 2A Receptor subtype of schizophrenia spectrum disorders with pimavanserin the sub sero proof of concept trial protocol
Frontiers in Pharmacology, 2020Co-Authors: Olga B Baltzersen, Vibe Gedsoe Frokjaer, Jayachandra Mitta Raghava, Lone Baandrup, Christian H Fibiger, Birte Glenthøj, Birgitte Fagerlund, Henrik Larsson, Herbert Y. Meltzer, Gitte M KnudsenAbstract:Background: All current approved antipsychotic drugs against schizophrenia spectrum disorders share affinity for the dopamine Receptor (D2R). However, up to one-third of these patients respond insufficiently, and in some cases, side-effects outweigh symptom reduction. Previous data have suggested that a subgroup of antipsychotic-naive patients will respond to Serotonin 2A Receptor (2AR) blockade. Aims: This investigator-initiated, translational, proof-of-concept study has overall two aims; 1) To test the clinical effectiveness of monotherapy with the newly approved drug against Parkinson's disease psychosis, pimavanserin, in antipsychotic-free patients with first-episode schizophrenia spectrum disorders; 2) To characterize the neurobiological profile of responders to pimavaserin. Materials and Equipment: Forty patients will be enrolled in this 6-week open label, one-armed trial with the selective Serotonin 2AR antagonist (pimavanserin 34 mg/day). At baseline, patients will undergo: positron emission tomography (PET) imaging of the Serotonin 2AR using the radioligand [¹¹C]Cimbi-36; structural magnetic resonance imaging (MRI); MR spectroscopy of cerebral glutamate levels and diffusion tensor imaging; cognitive and psychopathological examinations; electrocardiogram, and blood sampling for genetic- and metabolic analyses. Outcome Measures: The primary clinical endpoint will be reduction in the Positive and Negative Syndrome Scale (PANSS) positive score. Secondary clinical endpoints comprise multiple clinical ratings (positive and negative symptoms, depressive-, obsessive-compulsive symptoms, quality of life, social functioning, sexual functioning, and side-effects). PET, MRI, and cognitive parameters will be used for in-depth neuropsychiatric characterization of pimavanserin response. Anticipated Results: Clinically, we expect pimavanserin to reduce psychotic symptoms with similar effect as observed with conventional antipsychotics, for which we have comparable historical data. We expect pimavanserin to induce minimal side-effects. Neurobiologically, we expect psychotic symptom reduction to be most prominent in patients with low frontal Serotonin 2AR binding potential at baseline. Potential pro-cognitive and brain structural effects of pimavanserin will be explored. Perspectives: Sub-Sero will provide unique information about the role Serotonin 2AR in antipsychotic-free, first-episode psychosis. If successful, Sub-Sero will aid identification of a "serotonergic subtype" of schizophrenia spectrum patients, thereby promoting development of precision medicine in clinical psychiatry. Clinical Trial Registration: ClinicalTrials, identifier NCT03994965.
-
identification of a Serotonin 2A Receptor subtype of schizophrenia spectrum disorders with pimavanserin the sub sero proof of concept trial protocol
Frontiers in Pharmacology, 2020Co-Authors: Olga B Baltzersen, Jayachandra Mitta Raghava, Lone Baandrup, Christian H Fibiger, Birte Glenthøj, Birgitte Fagerlund, Henrik Larsson, Herbert Y. Meltzer, Vibe G. Frokjaer, Gitte M KnudsenAbstract:Background: All current approved antipsychotic drugs against schizophrenia spectrum disorders share affinity for the dopamine Receptor (D2R). However, up to one-third of these patients respond insufficiently, and in some cases, side-effects outweigh symptom reduction. Previous data have suggested that a subgroup of antipsychotic-naive patients will respond to Serotonin 2A Receptor (2AR) blockade. Aims: This investigator-initiated, translational, proof-of-concept study has overall two aims; 1) To test the clinical effectiveness of monotherapy with the newly approved drug against Parkinson's disease psychosis, pimavanserin, in antipsychotic-free patients with first-episode schizophrenia spectrum disorders; 2) To characterize the neurobiological profile of responders to pimavaserin. Materials and Equipment: Forty patients will be enrolled in this 6-week open label, one-armed trial with the selective Serotonin 2AR antagonist (pimavanserin 34 mg/day). At baseline, patients will undergo: positron emission tomography (PET) imaging of the Serotonin 2AR using the radioligand [¹¹C]Cimbi-36; structural magnetic resonance imaging (MRI); MR spectroscopy of cerebral glutamate levels and diffusion tensor imaging; cognitive and psychopathological examinations; electrocardiogram, and blood sampling for genetic- and metabolic analyses. Outcome Measures: The primary clinical endpoint will be reduction in the Positive and Negative Syndrome Scale (PANSS) positive score. Secondary clinical endpoints comprise multiple clinical ratings (positive and negative symptoms, depressive-, obsessive-compulsive symptoms, quality of life, social functioning, sexual functioning, and side-effects). PET, MRI, and cognitive parameters will be used for in-depth neuropsychiatric characterization of pimavanserin response. Anticipated Results: Clinically, we expect pimavanserin to reduce psychotic symptoms with similar effect as observed with conventional antipsychotics, for which we have comparable historical data. We expect pimavanserin to induce minimal side-effects. Neurobiologically, we expect psychotic symptom reduction to be most prominent in patients with low frontal Serotonin 2AR binding potential at baseline. Potential pro-cognitive and brain structural effects of pimavanserin will be explored. Perspectives: Sub-Sero will provide unique information about the role Serotonin 2AR in antipsychotic-free, first-episode psychosis. If successful, Sub-Sero will aid identification of a "serotonergic subtype" of schizophrenia spectrum patients, thereby promoting development of precision medicine in clinical psychiatry. Clinical Trial Registration: ClinicalTrials, identifier NCT03994965.
-
pimavanserin a Serotonin 2A Receptor inverse agonist for the treatment of parkinson s disease psychosis
Neuropsychopharmacology, 2010Co-Authors: Herbert Y. Meltzer, Roger Mills, Hilde Williams, Stephen Revell, Daun Bahr, Ann Johnson, Joseph H. FriedmanAbstract:Pimavanserin, a Serotonin 2A Receptor Inverse Agonist, for the Treatment of Parkinson's Disease Psychosis
-
Psychosis of Parkinson's disease: Serotonin 2A Receptor inverse agonists as potential therapeutics.
Current opinion in investigational drugs (London England : 2000), 2003Co-Authors: David M. Weiner, Herbert Y. Meltzer, Kimberly E. Vanover, Mark R. Brann, Robert E. DavisAbstract:Parkinson's disease (PD) is a movement disorder characterized by progressive degeneration of central dopaminergic systems. Current therapies designed to augment dopaminergic neurotransmission effectively treat the motoric aspects of the disease, however, with prolonged use, they produce a range of treatment-limiting side effects. Of these, neuropsychiatric abnormalities including hallucinosis and psychosis are common, disabling and refractory to most current therapies. This review describes the clinical syndrome of psychosis in PD and data regarding the efficacy and tolerability of existing antipsychotic agents, and presents the scientific rationale for the development of Serotonin 2A Receptor inverse agonists as potential therapeutic agents for treatment-induced psychosis of PD.
-
Lack of association between Serotonin-2A Receptor gene (HTR2A) polymorphisms and tardive dyskinesia in schizophrenia.
Molecular psychiatry, 2001Co-Authors: Vincenzo S. Basile, Herbert Y. Meltzer, Vural Ozdemir, Mario Masellis, J.a. Lieberman, Steven G. Potkin, Fabio Macciardi, A. Petronis, James L. KennedyAbstract:Lack of association between Serotonin-2A Receptor gene ( HTR2A ) polymorphisms and tardive dyskinesia in schizophrenia
