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MedScape InDiscussion: Schizophrenia
- S2 Episode 6: Is MDMA a Potential Treatment for Negative Symptoms of Schizophrenia? Exploring Stigma and Strategies to Alleviate Symptoms July 20, 2023Drs John M. Kane and Mitchell Arnovitz discuss assessment of patients for negative symptoms of schizophrenia and the potential of MDMA in alleviating these symptoms in supervised treatment settings. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/984490). The topics and discussions are planned, produced, and reviewed independently of advertisers. This […]
- S2 Episode 5: First-Episode Schizophrenia: The Importance of Engaging and Educating Patients and Their Families in Treatment June 21, 2023Drs John M. Kane and Delbert G. Robinson discuss psychoeducation, treatment options, and possible side effects of medication for patients experiencing their first episode of schizophrenia. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/984489). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended […]
New Drug Discovery & Harm Reduction Paradigms Building Toward Reducing Suffering In Schizophrenia
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2023 (1)
Ulotaront: review of preliminary evidence for the efficacy and safety of a TAAR1 agonist in schizophrenia. Achtyes, E. D.; Hopkins, S. C.; Dedic, N.; Dworak, H.; Zeni, C.; and Koblan, K. European Archives of Psychiatry and Clinical Neuroscience. May 2023.
![Ulotaront: review of preliminary evidence for the efficacy and safety of a TAAR1 agonist in schizophrenia [link]](//bibbase.org/img/filetypes/link.svg "Paper")
Paper doi link bibtex abstract
![Ulotaront: review of preliminary evidence for the efficacy and safety of a TAAR1 agonist in schizophrenia [link]](http://bibbase.org/img/filetypes/link.svg "Paper")
Paper doi link bibtex abstract
@article{achtyes_ulotaront_2023,
title = {Ulotaront: review of preliminary evidence for the efficacy and safety of a {TAAR1} agonist in schizophrenia},
issn = {1433-8491},
shorttitle = {Ulotaront},
url = {https://doi.org/10.1007/s00406-023-01580-3},
doi = {10.1007/s00406-023-01580-3},
abstract = {Ulotaront is a trace amine-associated receptor 1 (TAAR1) agonist in Phase 3 clinical development for the treatment of schizophrenia. Ulotaront was discovered through a unique, target-agnostic approach optimized to identify drug candidates lacking D2 and 5-HT2A receptor antagonism, while demonstrating an antipsychotic-like phenotypic profile in vivo. The mechanism of action (MOA) of ulotaront is thought to be mediated by agonism at TAAR1 and serotonin 5-HT1A receptors. Ulotaront has completed two Phase 2 trials (4-week acute study and 26-week open-label extension) which led to Breakthrough Therapy Designation from the US Food and Drug Administration for the treatment of schizophrenia. In the double-blind, placebo-controlled, acute study, ulotaront was associated with significant (p {\textless} 0.001) improvement in Positive and Negative Syndrome Scale (PANSS) total score (effect size [ES]: 0.45), with improvements vs. placebo also observed across secondary endpoints. Post-hoc analyses of the acute trial revealed additional evidence to support the effect of ulotaront on negative symptoms. In the 4-week study, ulotaront was well-tolerated, with an incidence of adverse events (AEs) numerically lower compared to placebo (45.8\% vs. 50.4\%; with a number needed to harm [NNH] for individual ulotaront AEs all {\textgreater} 40). The open-label extension demonstrated further improvement across schizophrenia symptoms and confirmed the tolerability of ulotaront, with a 6-month completion rate of 67\%. Based on current data, ulotaront shows potential to be a first-in-class TAAR1 agonist for the treatment of schizophrenia with a safety and efficacy profile distinct from current antipsychotics.},
language = {en},
urldate = {2023-07-19},
journal = {European Archives of Psychiatry and Clinical Neuroscience},
author = {Achtyes, Eric D. and Hopkins, Seth C. and Dedic, Nina and Dworak, Heather and Zeni, Courtney and Koblan, Kenneth},
month = may,
year = {2023},
keywords = {Schizophrenia, Serotonin 5-HT1A, Trace amine-associated receptor 1},
}
Ulotaront is a trace amine-associated receptor 1 (TAAR1) agonist in Phase 3 clinical development for the treatment of schizophrenia. Ulotaront was discovered through a unique, target-agnostic approach optimized to identify drug candidates lacking D2 and 5-HT2A receptor antagonism, while demonstrating an antipsychotic-like phenotypic profile in vivo. The mechanism of action (MOA) of ulotaront is thought to be mediated by agonism at TAAR1 and serotonin 5-HT1A receptors. Ulotaront has completed two Phase 2 trials (4-week acute study and 26-week open-label extension) which led to Breakthrough Therapy Designation from the US Food and Drug Administration for the treatment of schizophrenia. In the double-blind, placebo-controlled, acute study, ulotaront was associated with significant (p \textless 0.001) improvement in Positive and Negative Syndrome Scale (PANSS) total score (effect size [ES]: 0.45), with improvements vs. placebo also observed across secondary endpoints. Post-hoc analyses of the acute trial revealed additional evidence to support the effect of ulotaront on negative symptoms. In the 4-week study, ulotaront was well-tolerated, with an incidence of adverse events (AEs) numerically lower compared to placebo (45.8% vs. 50.4%; with a number needed to harm [NNH] for individual ulotaront AEs all \textgreater 40). The open-label extension demonstrated further improvement across schizophrenia symptoms and confirmed the tolerability of ulotaront, with a 6-month completion rate of 67%. Based on current data, ulotaront shows potential to be a first-in-class TAAR1 agonist for the treatment of schizophrenia with a safety and efficacy profile distinct from current antipsychotics.
2022 (13)
Schizophrenia and psychedelic state: Dysconnection versus hyper-connection. A perspective on two different models of psychosis stemming from dysfunctional integration processes. Sapienza, J.; Bosia, M.; Spangaro, M.; Martini, F.; Agostoni, G.; Cuoco, F.; Cocchi, F.; and Cavallaro, R. Molecular Psychiatry. August 2022. 1 citations (Semantic Scholar/DOI) [2023-01-12]
doi link bibtex abstract
doi link bibtex abstract
@article{sapienza_schizophrenia_2022,
title = {Schizophrenia and psychedelic state: {Dysconnection} versus hyper-connection. {A} perspective on two different models of psychosis stemming from dysfunctional integration processes},
issn = {1476-5578},
shorttitle = {Schizophrenia and psychedelic state},
doi = {10.1038/s41380-022-01721-5},
abstract = {Psychotic symptoms are a cross-sectional dimension affecting multiple diagnostic categories, despite schizophrenia represents the prototype of psychoses. Initially, dopamine was considered the most involved molecule in the neurobiology of schizophrenia. Over the next years, several biological factors were added to the discussion helping to constitute the concept of schizophrenia as a disease marked by a deficit of functional integration, contributing to the formulation of the Dysconnection Hypothesis in 1995. Nowadays the notion of dysconnection persists in the conceptualization of schizophrenia enriched by neuroimaging findings which corroborate the hypothesis. At the same time, in recent years, psychedelics received a lot of attention by the scientific community and astonishing findings emerged about the rearrangement of brain networks under the effect of these compounds. Specifically, a global decrease in functional connectivity was found, highlighting the disintegration of preserved and functional circuits and an increase of overall connectivity in the brain. The aim of this paper is to compare the biological bases of dysconnection in schizophrenia with the alterations of neuronal cyto-architecture induced by psychedelics and the consequent state of cerebral hyper-connection. These two models of psychosis, despite diametrically opposed, imply a substantial deficit of integration of neural signaling reached through two opposite paths.},
language = {eng},
journal = {Molecular Psychiatry},
author = {Sapienza, Jacopo and Bosia, Marta and Spangaro, Marco and Martini, Francesca and Agostoni, Giulia and Cuoco, Federica and Cocchi, Federica and Cavallaro, Roberto},
month = aug,
year = {2022},
pmid = {35931756},
note = {1 citations (Semantic Scholar/DOI) [2023-01-12]},
}
Psychotic symptoms are a cross-sectional dimension affecting multiple diagnostic categories, despite schizophrenia represents the prototype of psychoses. Initially, dopamine was considered the most involved molecule in the neurobiology of schizophrenia. Over the next years, several biological factors were added to the discussion helping to constitute the concept of schizophrenia as a disease marked by a deficit of functional integration, contributing to the formulation of the Dysconnection Hypothesis in 1995. Nowadays the notion of dysconnection persists in the conceptualization of schizophrenia enriched by neuroimaging findings which corroborate the hypothesis. At the same time, in recent years, psychedelics received a lot of attention by the scientific community and astonishing findings emerged about the rearrangement of brain networks under the effect of these compounds. Specifically, a global decrease in functional connectivity was found, highlighting the disintegration of preserved and functional circuits and an increase of overall connectivity in the brain. The aim of this paper is to compare the biological bases of dysconnection in schizophrenia with the alterations of neuronal cyto-architecture induced by psychedelics and the consequent state of cerebral hyper-connection. These two models of psychosis, despite diametrically opposed, imply a substantial deficit of integration of neural signaling reached through two opposite paths.
Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics. Spark, D. L.; Fornito, A.; Langmead, C. J.; and Stewart, G. D. Translational Psychiatry, 12(1): 1–11. April 2022. Number: 1 Publisher: Nature Publishing Group
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{spark_beyond_2022,
title = {Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics},
volume = {12},
copyright = {2022 The Author(s)},
issn = {2158-3188},
shorttitle = {Beyond antipsychotics},
url = {https://www.nature.com/articles/s41398-022-01904-2},
doi = {10.1038/s41398-022-01904-2},
abstract = {Despite 50+ years of drug discovery, current antipsychotics have limited efficacy against negative and cognitive symptoms of schizophrenia, and are ineffective—with the exception of clozapine—against any symptom domain for patients who are treatment resistant. Novel therapeutics with diverse non-dopamine D2 receptor targets have been explored extensively in clinical trials, yet often fail due to a lack of efficacy despite showing promise in preclinical development. This lack of translation between preclinical and clinical efficacy suggests a systematic failure in current methods that determine efficacy in preclinical rodent models. In this review, we critically evaluate rodent models and behavioural tests used to determine preclinical efficacy, and look to clinical research to provide a roadmap for developing improved translational measures. We highlight the dependence of preclinical models and tests on dopamine-centric theories of dysfunction and how this has contributed towards a self-reinforcing loop away from clinically meaningful predictions of efficacy. We review recent clinical findings of distinct dopamine-mediated dysfunction of corticostriatal circuits in patients with treatment-resistant vs. non-treatment-resistant schizophrenia and suggest criteria for establishing rodent models to reflect such differences, with a focus on objective, translational measures. Finally, we review current schizophrenia drug discovery and propose a framework where preclinical models are validated against objective, clinically informed measures and preclinical tests of efficacy map onto those used clinically.},
language = {en},
number = {1},
urldate = {2022-08-10},
journal = {Translational Psychiatry},
author = {Spark, Daisy L. and Fornito, Alex and Langmead, Christopher J. and Stewart, Gregory D.},
month = apr,
year = {2022},
note = {Number: 1
Publisher: Nature Publishing Group},
keywords = {Molecular neuroscience, Predictive markers},
pages = {1--11},
}
Despite 50+ years of drug discovery, current antipsychotics have limited efficacy against negative and cognitive symptoms of schizophrenia, and are ineffective—with the exception of clozapine—against any symptom domain for patients who are treatment resistant. Novel therapeutics with diverse non-dopamine D2 receptor targets have been explored extensively in clinical trials, yet often fail due to a lack of efficacy despite showing promise in preclinical development. This lack of translation between preclinical and clinical efficacy suggests a systematic failure in current methods that determine efficacy in preclinical rodent models. In this review, we critically evaluate rodent models and behavioural tests used to determine preclinical efficacy, and look to clinical research to provide a roadmap for developing improved translational measures. We highlight the dependence of preclinical models and tests on dopamine-centric theories of dysfunction and how this has contributed towards a self-reinforcing loop away from clinically meaningful predictions of efficacy. We review recent clinical findings of distinct dopamine-mediated dysfunction of corticostriatal circuits in patients with treatment-resistant vs. non-treatment-resistant schizophrenia and suggest criteria for establishing rodent models to reflect such differences, with a focus on objective, translational measures. Finally, we review current schizophrenia drug discovery and propose a framework where preclinical models are validated against objective, clinically informed measures and preclinical tests of efficacy map onto those used clinically.
MDMA for the Treatment of Negative Symptoms in Schizophrenia. Arnovitz, M. D.; Spitzberg, A. J.; Davani, A. J.; Vadhan, N. P.; Holland, J.; Kane, J. M.; and Michaels, T. I. Journal of Clinical Medicine, 11(12): 3255. January 2022. Number: 12 Publisher: Multidisciplinary Digital Publishing Institute
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{arnovitz_mdma_2022,
title = {{MDMA} for the {Treatment} of {Negative} {Symptoms} in {Schizophrenia}},
volume = {11},
copyright = {http://creativecommons.org/licenses/by/3.0/},
issn = {2077-0383},
url = {https://www.mdpi.com/2077-0383/11/12/3255},
doi = {10.3390/jcm11123255},
abstract = {The profound economic burden of schizophrenia is due, in part, to the negative symptoms of the disease, which can severely limit daily functioning. There is much debate in the field regarding their measurement and classification and there are no FDA-approved treatments for negative symptoms despite an abundance of research. 3,4-Methylenedioxy methamphetamine (MDMA) is a schedule I substance that has emerged as a novel therapeutic given its ability to enhance social interactions, generate empathy, and induce a state of metaplasticity in the brain. This review provides a rationale for the use of MDMA in the treatment of negative symptoms by reviewing the literature on negative symptoms, their treatment, MDMA, and MDMA-assisted therapy. It reviews recent evidence that supports the safe and potentially effective use of MDMA to treat negative symptoms and concludes with considerations regarding safety and possible mechanisms of action.},
language = {en},
number = {12},
urldate = {2022-08-10},
journal = {Journal of Clinical Medicine},
author = {Arnovitz, Mitchell D. and Spitzberg, Andrew J. and Davani, Ashkhan J. and Vadhan, Nehal P. and Holland, Julie and Kane, John M. and Michaels, Timothy I.},
month = jan,
year = {2022},
note = {Number: 12
Publisher: Multidisciplinary Digital Publishing Institute},
keywords = {MDMA, negative symptoms, psychedelic-assisted therapy, psychosis, schizophrenia},
pages = {3255},
}
The profound economic burden of schizophrenia is due, in part, to the negative symptoms of the disease, which can severely limit daily functioning. There is much debate in the field regarding their measurement and classification and there are no FDA-approved treatments for negative symptoms despite an abundance of research. 3,4-Methylenedioxy methamphetamine (MDMA) is a schedule I substance that has emerged as a novel therapeutic given its ability to enhance social interactions, generate empathy, and induce a state of metaplasticity in the brain. This review provides a rationale for the use of MDMA in the treatment of negative symptoms by reviewing the literature on negative symptoms, their treatment, MDMA, and MDMA-assisted therapy. It reviews recent evidence that supports the safe and potentially effective use of MDMA to treat negative symptoms and concludes with considerations regarding safety and possible mechanisms of action.
Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics. Spark, D. L.; Fornito, A.; Langmead, C. J.; and Stewart, G. D. Translational Psychiatry, 12(1): 1–11. April 2022. Number: 1 Publisher: Nature Publishing Group
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{spark_beyond_2022-1,
title = {Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics},
volume = {12},
copyright = {2022 The Author(s)},
issn = {2158-3188},
shorttitle = {Beyond antipsychotics},
url = {https://www.nature.com/articles/s41398-022-01904-2},
doi = {10.1038/s41398-022-01904-2},
abstract = {Despite 50+ years of drug discovery, current antipsychotics have limited efficacy against negative and cognitive symptoms of schizophrenia, and are ineffective—with the exception of clozapine—against any symptom domain for patients who are treatment resistant. Novel therapeutics with diverse non-dopamine D2 receptor targets have been explored extensively in clinical trials, yet often fail due to a lack of efficacy despite showing promise in preclinical development. This lack of translation between preclinical and clinical efficacy suggests a systematic failure in current methods that determine efficacy in preclinical rodent models. In this review, we critically evaluate rodent models and behavioural tests used to determine preclinical efficacy, and look to clinical research to provide a roadmap for developing improved translational measures. We highlight the dependence of preclinical models and tests on dopamine-centric theories of dysfunction and how this has contributed towards a self-reinforcing loop away from clinically meaningful predictions of efficacy. We review recent clinical findings of distinct dopamine-mediated dysfunction of corticostriatal circuits in patients with treatment-resistant vs. non-treatment-resistant schizophrenia and suggest criteria for establishing rodent models to reflect such differences, with a focus on objective, translational measures. Finally, we review current schizophrenia drug discovery and propose a framework where preclinical models are validated against objective, clinically informed measures and preclinical tests of efficacy map onto those used clinically.},
language = {en},
number = {1},
urldate = {2022-07-24},
journal = {Translational Psychiatry},
author = {Spark, Daisy L. and Fornito, Alex and Langmead, Christopher J. and Stewart, Gregory D.},
month = apr,
year = {2022},
note = {Number: 1
Publisher: Nature Publishing Group},
keywords = {Molecular neuroscience, Predictive markers},
pages = {1--11},
}
Despite 50+ years of drug discovery, current antipsychotics have limited efficacy against negative and cognitive symptoms of schizophrenia, and are ineffective—with the exception of clozapine—against any symptom domain for patients who are treatment resistant. Novel therapeutics with diverse non-dopamine D2 receptor targets have been explored extensively in clinical trials, yet often fail due to a lack of efficacy despite showing promise in preclinical development. This lack of translation between preclinical and clinical efficacy suggests a systematic failure in current methods that determine efficacy in preclinical rodent models. In this review, we critically evaluate rodent models and behavioural tests used to determine preclinical efficacy, and look to clinical research to provide a roadmap for developing improved translational measures. We highlight the dependence of preclinical models and tests on dopamine-centric theories of dysfunction and how this has contributed towards a self-reinforcing loop away from clinically meaningful predictions of efficacy. We review recent clinical findings of distinct dopamine-mediated dysfunction of corticostriatal circuits in patients with treatment-resistant vs. non-treatment-resistant schizophrenia and suggest criteria for establishing rodent models to reflect such differences, with a focus on objective, translational measures. Finally, we review current schizophrenia drug discovery and propose a framework where preclinical models are validated against objective, clinically informed measures and preclinical tests of efficacy map onto those used clinically.
MDMA for the Treatment of Negative Symptoms in Schizophrenia. Arnovitz, M. D.; Spitzberg, A. J.; Davani, A. J.; Vadhan, N. P.; Holland, J.; Kane, J. M.; and Michaels, T. I. Journal of Clinical Medicine, 11(12): 3255. January 2022.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{arnovitz_mdma_2022-1,
title = {{MDMA} for the {Treatment} of {Negative} {Symptoms} in {Schizophrenia}},
volume = {11},
copyright = {http://creativecommons.org/licenses/by/3.0/},
issn = {2077-0383},
url = {https://www.mdpi.com/2077-0383/11/12/3255},
doi = {10.3390/jcm11123255},
abstract = {The profound economic burden of schizophrenia is due, in part, to the negative symptoms of the disease, which can severely limit daily functioning. There is much debate in the field regarding their measurement and classification and there are no FDA-approved treatments for negative symptoms despite an abundance of research. 3,4-Methylenedioxy methamphetamine (MDMA) is a schedule I substance that has emerged as a novel therapeutic given its ability to enhance social interactions, generate empathy, and induce a state of metaplasticity in the brain. This review provides a rationale for the use of MDMA in the treatment of negative symptoms by reviewing the literature on negative symptoms, their treatment, MDMA, and MDMA-assisted therapy. It reviews recent evidence that supports the safe and potentially effective use of MDMA to treat negative symptoms and concludes with considerations regarding safety and possible mechanisms of action.},
language = {en},
number = {12},
urldate = {2022-07-12},
journal = {Journal of Clinical Medicine},
author = {Arnovitz, Mitchell D. and Spitzberg, Andrew J. and Davani, Ashkhan J. and Vadhan, Nehal P. and Holland, Julie and Kane, John M. and Michaels, Timothy I.},
month = jan,
year = {2022},
keywords = {MDMA, negative symptoms, psychedelic-assisted therapy, psychosis, schizophrenia},
pages = {3255},
}
The profound economic burden of schizophrenia is due, in part, to the negative symptoms of the disease, which can severely limit daily functioning. There is much debate in the field regarding their measurement and classification and there are no FDA-approved treatments for negative symptoms despite an abundance of research. 3,4-Methylenedioxy methamphetamine (MDMA) is a schedule I substance that has emerged as a novel therapeutic given its ability to enhance social interactions, generate empathy, and induce a state of metaplasticity in the brain. This review provides a rationale for the use of MDMA in the treatment of negative symptoms by reviewing the literature on negative symptoms, their treatment, MDMA, and MDMA-assisted therapy. It reviews recent evidence that supports the safe and potentially effective use of MDMA to treat negative symptoms and concludes with considerations regarding safety and possible mechanisms of action.
Trace Amine-Associated Receptor 1 (TAAR1): Molecular and Clinical Insights for the Treatment of Schizophrenia and Related Comorbidities. Nair, P. C.; Chalker, J. M.; McKinnon, R. A.; Langmead, C. J; Gregory, K. J.; and Bastiampillai, T. ACS Pharmacology & Translational Science, 5(3): 183–188. March 2022. Publisher: American Chemical Society
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{nair_trace_2022,
title = {Trace {Amine}-{Associated} {Receptor} 1 ({TAAR1}): {Molecular} and {Clinical} {Insights} for the {Treatment} of {Schizophrenia} and {Related} {Comorbidities}},
volume = {5},
shorttitle = {Trace {Amine}-{Associated} {Receptor} 1 ({TAAR1})},
url = {https://doi.org/10.1021/acsptsci.2c00016},
doi = {10.1021/acsptsci.2c00016},
abstract = {Schizophrenia is a complex and severe mental illness. Current treatments for schizophrenia typically modulate dopaminergic neurotransmission by D2-receptor blockade. While reducing positive symptoms of schizophrenia, current antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairments. For the last few decades, discovery efforts have sought nondopaminergic compounds with the aim to effectively treat the broad symptoms of schizophrenia. In this viewpoint, we provide an overview on trace-amine associated receptor-1 (TAAR1), which presents a clinically validated nondopaminergic target for treating schizophrenia and related disorders, with significantly less overall side-effect burden. TAAR1 agonists may also be specifically beneficial for the substance abuse comorbidity and metabolic syndrome that is often present in patients with schizophrenia.},
number = {3},
urldate = {2022-07-11},
journal = {ACS Pharmacology \& Translational Science},
author = {Nair, Pramod C. and Chalker, Justin M. and McKinnon, Ross A. and Langmead, Christopher J and Gregory, Karen J. and Bastiampillai, Tarun},
month = mar,
year = {2022},
note = {Publisher: American Chemical Society},
pages = {183--188},
}
Schizophrenia is a complex and severe mental illness. Current treatments for schizophrenia typically modulate dopaminergic neurotransmission by D2-receptor blockade. While reducing positive symptoms of schizophrenia, current antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairments. For the last few decades, discovery efforts have sought nondopaminergic compounds with the aim to effectively treat the broad symptoms of schizophrenia. In this viewpoint, we provide an overview on trace-amine associated receptor-1 (TAAR1), which presents a clinically validated nondopaminergic target for treating schizophrenia and related disorders, with significantly less overall side-effect burden. TAAR1 agonists may also be specifically beneficial for the substance abuse comorbidity and metabolic syndrome that is often present in patients with schizophrenia.
In Vitro ADME and Preclinical Pharmacokinetics of Ulotaront, a TAAR1/5-HT1A Receptor Agonist for the Treatment of Schizophrenia. Xiao, G.; Chen, Y.; Dedic, N.; Xie, L.; Koblan, K. S.; and Galluppi, G. R. Pharmaceutical Research, 39(5): 837–850. May 2022.
doi link bibtex abstract
doi link bibtex abstract
@article{xiao_vitro_2022,
title = {In {Vitro} {ADME} and {Preclinical} {Pharmacokinetics} of {Ulotaront}, a {TAAR1}/5-{HT1A} {Receptor} {Agonist} for the {Treatment} of {Schizophrenia}},
volume = {39},
issn = {1573-904X},
doi = {10.1007/s11095-022-03267-1},
abstract = {PURPOSE: Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT1A agonist activity currently in clinical development for the treatment of schizophrenia. The objectives of the current study were to characterize the in vitro ADME properties, preclinical PK, and to evaluate the DDI potential of ulotaront and its major metabolite SEP-383103.
METHODS: Solubility, permeability, plasma protein binding, CYP inhibition and induction, transporter inhibition and uptake studies were conducted in vitro. Phenotyping studies were conducted using recombinant human CYPs and FMOs, human liver microsomes and human liver homogenates. Preclinical plasma and brain pharmacokinetics were determined after a single intraperitoneal, intravenous, and oral administration of ulotaront.
RESULTS: Ulotaront is a compound of high solubility, high permeability, and low binding to plasma proteins. Ulotaront metabolism is mediated via both NADPH-dependent and NADPH-independent pathways, with CYP2D6 as the major metabolizing enzyme. Ulotaront is an inducer of CYP2B6, and an inhibitor of CYP2D6, OCT1 and OCT2, while SEP-383103 is neither a CYP inducer nor a potent inhibitor of CYPs and human transporters. Ulotaront exhibits rapid absorption, greater than 70\% bioavailability, approximately 3.5 L/kg volume of distribution, 1.5-4 h half-life, 12-43 ml/min/kg clearance, and good penetration across the blood-brain barrier in preclinical species.
CONCLUSIONS: Ulotaront has been designated as a BCS1 compound by US FDA. The ability of ulotaront to penetrate the blood-brain barrier for CNS targeting has been demonstrated in mice and rats. The potential for ulotaront and SEP-383103 to act as perpetrators of CYP and transporter-mediated DDIs is predicted to be remote.},
language = {eng},
number = {5},
journal = {Pharmaceutical Research},
author = {Xiao, Guangqing and Chen, Yu-Luan and Dedic, Nina and Xie, Linghong and Koblan, Kenneth S. and Galluppi, Gerald R.},
month = may,
year = {2022},
pmid = {35484370},
keywords = {Animals, CYP2D6, Cytochrome P-450 CYP2D6, Cytochrome P-450 Enzyme System, Mice, Microsomes, Liver, NADP, Pharmaceutical Preparations, Rats, Receptor, Serotonin, 5-HT1A, Schizophrenia, TAAR1, blood–brain barrier, drug-drug interactions, phenotyping, ulotaront},
pages = {837--850},
}
PURPOSE: Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT1A agonist activity currently in clinical development for the treatment of schizophrenia. The objectives of the current study were to characterize the in vitro ADME properties, preclinical PK, and to evaluate the DDI potential of ulotaront and its major metabolite SEP-383103. METHODS: Solubility, permeability, plasma protein binding, CYP inhibition and induction, transporter inhibition and uptake studies were conducted in vitro. Phenotyping studies were conducted using recombinant human CYPs and FMOs, human liver microsomes and human liver homogenates. Preclinical plasma and brain pharmacokinetics were determined after a single intraperitoneal, intravenous, and oral administration of ulotaront. RESULTS: Ulotaront is a compound of high solubility, high permeability, and low binding to plasma proteins. Ulotaront metabolism is mediated via both NADPH-dependent and NADPH-independent pathways, with CYP2D6 as the major metabolizing enzyme. Ulotaront is an inducer of CYP2B6, and an inhibitor of CYP2D6, OCT1 and OCT2, while SEP-383103 is neither a CYP inducer nor a potent inhibitor of CYPs and human transporters. Ulotaront exhibits rapid absorption, greater than 70% bioavailability, approximately 3.5 L/kg volume of distribution, 1.5-4 h half-life, 12-43 ml/min/kg clearance, and good penetration across the blood-brain barrier in preclinical species. CONCLUSIONS: Ulotaront has been designated as a BCS1 compound by US FDA. The ability of ulotaront to penetrate the blood-brain barrier for CNS targeting has been demonstrated in mice and rats. The potential for ulotaront and SEP-383103 to act as perpetrators of CYP and transporter-mediated DDIs is predicted to be remote.
Candidates for Drug Repurposing to Address the Cognitive Symptoms in Schizophrenia. Koch, E.; Kauppi, K.; and Chen, C. Technical Report Genetics, March 2022.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@techreport{koch_candidates_2022,
type = {preprint},
title = {Candidates for {Drug} {Repurposing} to {Address} the {Cognitive} {Symptoms} in {Schizophrenia}},
url = {http://biorxiv.org/lookup/doi/10.1101/2022.03.07.483231},
abstract = {In the protein-protein interactome, we have previously identified a significant overlap between schizophrenia risk genes and genes associated with cognitive performance. Here, we further studied this overlap to identify potential candidate drugs for repurposing to treat the cognitive symptoms in schizophrenia. We first defined a cognition-related schizophrenia interactome from network propagation analyses, and identified drugs known to target more than one protein within this network. Thereafter, we used gene expression data to further select drugs that could counteract schizophrenia-associated gene expression perturbations. Additionally, we stratified these analyses by sex to identify sex-specific pharmacological treatment options for the cognitive symptoms in schizophrenia. After excluding drugs contraindicated in schizophrenia, we identified eight drug candidates, most of which have anti-inflammatory and neuroprotective effects. Due to gene expression differences in male and female patients, four of those drugs were also selected in our male-specific analyses, and the other four in the female-specific analyses. Based on our bioinformatics analyses of disease genetics, we suggest eight candidate drugs that warrant further examination for repurposing to treat the cognitive symptoms in schizophrenia, and suggest that these symptoms could be addressed by sex-specific pharmacological treatment options.},
language = {en},
urldate = {2022-05-31},
institution = {Genetics},
author = {Koch, Elise and Kauppi, Karolina and Chen, Chi-Hua},
month = mar,
year = {2022},
doi = {10.1101/2022.03.07.483231},
}
In the protein-protein interactome, we have previously identified a significant overlap between schizophrenia risk genes and genes associated with cognitive performance. Here, we further studied this overlap to identify potential candidate drugs for repurposing to treat the cognitive symptoms in schizophrenia. We first defined a cognition-related schizophrenia interactome from network propagation analyses, and identified drugs known to target more than one protein within this network. Thereafter, we used gene expression data to further select drugs that could counteract schizophrenia-associated gene expression perturbations. Additionally, we stratified these analyses by sex to identify sex-specific pharmacological treatment options for the cognitive symptoms in schizophrenia. After excluding drugs contraindicated in schizophrenia, we identified eight drug candidates, most of which have anti-inflammatory and neuroprotective effects. Due to gene expression differences in male and female patients, four of those drugs were also selected in our male-specific analyses, and the other four in the female-specific analyses. Based on our bioinformatics analyses of disease genetics, we suggest eight candidate drugs that warrant further examination for repurposing to treat the cognitive symptoms in schizophrenia, and suggest that these symptoms could be addressed by sex-specific pharmacological treatment options.
Drug Discovery Paradigms: Phenotypic-Based Drug Discovery. Talevi, A.; and Bellera, C. L. In Scotti, M. T.; and Bellera, C. L., editor(s), Drug Target Selection and Validation, of Computer-Aided Drug Discovery and Design, pages 25–40. Springer International Publishing, Cham, 2022.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@incollection{talevi_drug_2022,
address = {Cham},
series = {Computer-{Aided} {Drug} {Discovery} and {Design}},
title = {Drug {Discovery} {Paradigms}: {Phenotypic}-{Based} {Drug} {Discovery}},
isbn = {978-3-030-95895-4},
shorttitle = {Drug {Discovery} {Paradigms}},
url = {https://doi.org/10.1007/978-3-030-95895-4_2},
abstract = {A drug discovery and development project typically starts with the identification of novel active scaffolds, i.e., core chemical structures with a desired biological effect. Beyond serendipitous discoveries and findings based on ethnopharmacology/traditional medicine, drug discovery in the modern age has been guided by two fundamental screening philosophies (implemented whether through in silico, in vitro or less often, in vivo approximations). Occasionally, novel chemotypes can be designed de novo by searching for complementary features to a binding site in a predefined drug target. Historically, systematic screening for new active compounds comprised phenotypic screening assays (e.g., against a collection of microorganisms, animal models of disease, or cellular models). Later, the interest of the pharmaceutical companies experienced a substantial shift toward target-focused approximations in which exquisitely selective compounds were sought, usually through high-throughput screening. There, the test compounds were typically confronted with some biological entity, usually a protein, to identify those which could modulate such biomolecule. Nevertheless, as target-focused approximation failed to deliver the expectations, especially when pursuing therapies for complex disorders, renewed interest in phenotypic screening was observed in the pharmaceutical community, supported by a network pharmacology paradigm, high-content screening, small animal models, and organoids and other advanced cell culture platforms.},
language = {en},
urldate = {2022-05-29},
booktitle = {Drug {Target} {Selection} and {Validation}},
publisher = {Springer International Publishing},
author = {Talevi, Alan and Bellera, Carolina L.},
editor = {Scotti, Marcus T. and Bellera, Carolina L.},
year = {2022},
doi = {10.1007/978-3-030-95895-4_2},
keywords = {Drug discovery, High-content analysis, High-content screening (HCS), High-throughput screening, Hit identification, Phenotypic screening, Target deconvolution, Target-focused approximations},
pages = {25--40},
}
A drug discovery and development project typically starts with the identification of novel active scaffolds, i.e., core chemical structures with a desired biological effect. Beyond serendipitous discoveries and findings based on ethnopharmacology/traditional medicine, drug discovery in the modern age has been guided by two fundamental screening philosophies (implemented whether through in silico, in vitro or less often, in vivo approximations). Occasionally, novel chemotypes can be designed de novo by searching for complementary features to a binding site in a predefined drug target. Historically, systematic screening for new active compounds comprised phenotypic screening assays (e.g., against a collection of microorganisms, animal models of disease, or cellular models). Later, the interest of the pharmaceutical companies experienced a substantial shift toward target-focused approximations in which exquisitely selective compounds were sought, usually through high-throughput screening. There, the test compounds were typically confronted with some biological entity, usually a protein, to identify those which could modulate such biomolecule. Nevertheless, as target-focused approximation failed to deliver the expectations, especially when pursuing therapies for complex disorders, renewed interest in phenotypic screening was observed in the pharmaceutical community, supported by a network pharmacology paradigm, high-content screening, small animal models, and organoids and other advanced cell culture platforms.
The doors of precision: Reenergizing psychiatric drug development with psychedelics and open access computational tools. Barron, D. S.; and Friedman, R. A. Science Advances, 8(11): eabp8283. March 2022.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{barron_doors_2022,
title = {The doors of precision: {Reenergizing} psychiatric drug development with psychedelics and open access computational tools},
volume = {8},
issn = {2375-2548},
shorttitle = {The doors of precision},
url = {https://www.science.org/doi/10.1126/sciadv.abp8283},
doi = {10.1126/sciadv.abp8283},
abstract = {Psychedelics paired with new applications of computational tools might help bypass the imprecision of psychiatric diagnosis and connect measures of behavior to specific physiologic targets.},
language = {en},
number = {11},
urldate = {2022-05-29},
journal = {Science Advances},
author = {Barron, Daniel S. and Friedman, Richard A.},
month = mar,
year = {2022},
pages = {eabp8283},
}
Psychedelics paired with new applications of computational tools might help bypass the imprecision of psychiatric diagnosis and connect measures of behavior to specific physiologic targets.
The druggable schizophrenia genome: from repurposing opportunities to unexplored drug targets. Lago, S. G.; and Bahn, S. npj Genomic Medicine, 7(1): 1–13. March 2022. Number: 1 Publisher: Nature Publishing Group
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{lago_druggable_2022,
title = {The druggable schizophrenia genome: from repurposing opportunities to unexplored drug targets},
volume = {7},
copyright = {2022 The Author(s)},
issn = {2056-7944},
shorttitle = {The druggable schizophrenia genome},
url = {https://www.nature.com/articles/s41525-022-00290-4},
doi = {10.1038/s41525-022-00290-4},
abstract = {There have been no new drugs for the treatment of schizophrenia in several decades and treatment resistance represents a major unmet clinical need. The drugs that exist are based on serendipitous clinical observations rather than an evidence-based understanding of disease pathophysiology. In the present review, we address these bottlenecks by integrating common, rare, and expression-related schizophrenia risk genes with knowledge of the druggability of the human genome as a whole. We highlight novel drug repurposing opportunities, clinical trial candidates which are supported by genetic evidence, and unexplored therapeutic opportunities in the lesser-known regions of the schizophrenia genome. By identifying translational gaps and opportunities across the schizophrenia disease space, we discuss a framework for translating increasingly well-powered genetic association studies into personalized treatments for schizophrenia and initiating the vital task of characterizing clinically relevant drug targets in underexplored regions of the human genome.},
language = {en},
number = {1},
urldate = {2022-05-27},
journal = {npj Genomic Medicine},
author = {Lago, Santiago G. and Bahn, Sabine},
month = mar,
year = {2022},
note = {Number: 1
Publisher: Nature Publishing Group},
keywords = {Genome, Pharmaceutics, Schizophrenia, Target identification},
pages = {1--13},
}
There have been no new drugs for the treatment of schizophrenia in several decades and treatment resistance represents a major unmet clinical need. The drugs that exist are based on serendipitous clinical observations rather than an evidence-based understanding of disease pathophysiology. In the present review, we address these bottlenecks by integrating common, rare, and expression-related schizophrenia risk genes with knowledge of the druggability of the human genome as a whole. We highlight novel drug repurposing opportunities, clinical trial candidates which are supported by genetic evidence, and unexplored therapeutic opportunities in the lesser-known regions of the schizophrenia genome. By identifying translational gaps and opportunities across the schizophrenia disease space, we discuss a framework for translating increasingly well-powered genetic association studies into personalized treatments for schizophrenia and initiating the vital task of characterizing clinically relevant drug targets in underexplored regions of the human genome.
The doors of precision: Reenergizing psychiatric drug development with psychedelics and open access computational tools. Barron, D. S.; and Friedman, R. A. Science Advances, 8(11): eabp8283. March 2022.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{barron_doors_2022-1,
title = {The doors of precision: {Reenergizing} psychiatric drug development with psychedelics and open access computational tools},
volume = {8},
issn = {2375-2548},
shorttitle = {The doors of precision},
url = {https://www.science.org/doi/10.1126/sciadv.abp8283},
doi = {10.1126/sciadv.abp8283},
abstract = {Psychedelics paired with new applications of computational tools might help bypass the imprecision of psychiatric diagnosis and connect measures of behavior to specific physiologic targets.},
language = {en},
number = {11},
urldate = {2022-05-25},
journal = {Science Advances},
author = {Barron, Daniel S. and Friedman, Richard A.},
month = mar,
year = {2022},
pages = {eabp8283},
}
Psychedelics paired with new applications of computational tools might help bypass the imprecision of psychiatric diagnosis and connect measures of behavior to specific physiologic targets.
Two large studies reveal genes and genome regions that influence schizophrenia risk. April 2022. Section: Research News
Paper link bibtex abstract
Paper link bibtex abstract
@misc{noauthor_two_2022,
title = {Two large studies reveal genes and genome regions that influence schizophrenia risk},
url = {https://www.broadinstitute.org/news/two-large-studies-reveal-genes-and-genome-regions-influence-schizophrenia-risk},
abstract = {International collaborations analyze common and rare DNA variants in hundreds of thousands of people, further elucidating genetic roots of psychiatric disorder},
language = {en},
urldate = {2022-04-09},
journal = {Broad Institute},
month = apr,
year = {2022},
note = {Section: Research News},
}
International collaborations analyze common and rare DNA variants in hundreds of thousands of people, further elucidating genetic roots of psychiatric disorder
2021 (12)
The Promise of Psychedelic Science. Olson, D. E. ACS Pharmacology & Translational Science, 4(2): 413–415. April 2021. Publisher: American Chemical Society
Paper doi link bibtex
Paper doi link bibtex
@article{olson_promise_2021,
title = {The {Promise} of {Psychedelic} {Science}},
volume = {4},
url = {https://doi.org/10.1021/acsptsci.1c00071},
doi = {10.1021/acsptsci.1c00071},
number = {2},
journal = {ACS Pharmacology \& Translational Science},
author = {Olson, David E.},
month = apr,
year = {2021},
note = {Publisher: American Chemical Society},
pages = {413--415},
}
Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders. Wu, R.; and Li, J. CNS drugs, 35(12): 1239–1248. December 2021.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{wu_potential_2021,
title = {Potential of {Ligands} for {Trace} {Amine}-{Associated} {Receptor} 1 ({TAAR1}) in the {Management} of {Substance} {Use} {Disorders}},
volume = {35},
issn = {1172-7047},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8787759/},
doi = {10.1007/s40263-021-00871-4},
abstract = {Trace amines, including β-phenylethylamine (β-PEA), p-tyramine (TYR), tryptamine (TRP) and p-octopamine (OCT), represent a group of amines expressed at low levels in the mammalian brain. Given the close structural similarities to traditional monoamines, the links between trace amines and the monoaminergic system have long been established. Trace amine associated receptor 1 (TAAR1), the most well characterized receptor in the TAARs family, has been shown to be potently activated by trace amines like TYR and PEA. Meanwhile, catecholamine metabolites and amphetamine analogs are also potent agonists of TAAR1, implicating its role in mediating the monoaminergic system and substance use disorders. In the central nervous system, TAAR1 is expressed in brain regions involved in dopaminergic, serotonergic and glutamatergic transmission. Genetic animal models and electrophysiological studies have revealed that TAAR1 is a potent modulator of the monoaminergic system, and TAAR1 agonists may be potential pharmacotherapies for the treatment of substance use disorders. Selective and potent engineered TAAR1 ligands, including full (RO5166017 and RO5256390) and partial (RO5203648, RO5263397 and RO5073012) agonists and the antagonist EPPTB (N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide, RO5212773), serve as invaluable tools for the investigation of TAAR1 functions and display high potential for the development of TAAR1-based pharmacotherapies for the treatment of substance use disorders. Despite a number of advances that have been made, more clinical studies are warranted in order to test the potential and efficacy of TAAR1 ligands in the treatment of psychiatric disorders, especially substance use disorders.},
number = {12},
urldate = {2022-07-23},
journal = {CNS drugs},
author = {Wu, Ruyan and Li, Jun-Xu},
month = dec,
year = {2021},
pmid = {34766253},
pmcid = {PMC8787759},
pages = {1239--1248},
}
Trace amines, including β-phenylethylamine (β-PEA), p-tyramine (TYR), tryptamine (TRP) and p-octopamine (OCT), represent a group of amines expressed at low levels in the mammalian brain. Given the close structural similarities to traditional monoamines, the links between trace amines and the monoaminergic system have long been established. Trace amine associated receptor 1 (TAAR1), the most well characterized receptor in the TAARs family, has been shown to be potently activated by trace amines like TYR and PEA. Meanwhile, catecholamine metabolites and amphetamine analogs are also potent agonists of TAAR1, implicating its role in mediating the monoaminergic system and substance use disorders. In the central nervous system, TAAR1 is expressed in brain regions involved in dopaminergic, serotonergic and glutamatergic transmission. Genetic animal models and electrophysiological studies have revealed that TAAR1 is a potent modulator of the monoaminergic system, and TAAR1 agonists may be potential pharmacotherapies for the treatment of substance use disorders. Selective and potent engineered TAAR1 ligands, including full (RO5166017 and RO5256390) and partial (RO5203648, RO5263397 and RO5073012) agonists and the antagonist EPPTB (N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide, RO5212773), serve as invaluable tools for the investigation of TAAR1 functions and display high potential for the development of TAAR1-based pharmacotherapies for the treatment of substance use disorders. Despite a number of advances that have been made, more clinical studies are warranted in order to test the potential and efficacy of TAAR1 ligands in the treatment of psychiatric disorders, especially substance use disorders.
Trace amine-associated receptor 1 (TAAR1): Potential application in mood disorders: A systematic review. Alnefeesi, Y.; Tamura, J. K.; Lui, L. M. W.; Jawad, M. Y.; Ceban, F.; Ling, S.; Nasri, F.; Rosenblat, J. D.; and McIntyre, R. S. Neuroscience & Biobehavioral Reviews, 131: 192–210. December 2021.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{alnefeesi_trace_2021,
title = {Trace amine-associated receptor 1 ({TAAR1}): {Potential} application in mood disorders: {A} systematic review},
volume = {131},
issn = {0149-7634},
shorttitle = {Trace amine-associated receptor 1 ({TAAR1})},
url = {https://www.sciencedirect.com/science/article/pii/S0149763421004024},
doi = {10.1016/j.neubiorev.2021.09.020},
abstract = {There is a need for innovation with respect to therapeutics in psychiatry. Available evidence indicates that the trace amine-associated receptor 1 (TAAR1) agonist SEP-363856 is promising, as it improves measures of cognitive and reward function in schizophrenia. Hedonic and cognitive impairments are transdiagnostic and constitute major burdens in mood disorders. Herein, we systematically review the behavioural and genetic literature documenting the role of TAAR1 in reward and cognitive function, and propose a mechanistic model of TAAR1’s functions in the brain. Notably, TAAR1 activity confers antidepressant-like effects, enhances attention and response inhibition, and reduces compulsive reward seeking without impairing normal function. Further characterization of the responsible mechanisms suggests ion-homeostatic, metabolic, neurotrophic, and anti-inflammatory enhancements in the limbic system. Multiple lines of evidence establish the viability of TAAR1 as a biological target for the treatment of mood disorders. Furthermore, the evidence suggests a role for TAAR1 in reward and cognitive function, which is attributed to a cascade of events that are relevant to the cellular integrity and function of the central nervous system.},
language = {en},
urldate = {2022-07-21},
journal = {Neuroscience \& Biobehavioral Reviews},
author = {Alnefeesi, Yazen and Tamura, Jocelyn K. and Lui, Leanna M. W. and Jawad, Muhammad Youshay and Ceban, Felicia and Ling, Susan and Nasri, Flora and Rosenblat, Joshua D. and McIntyre, Roger S.},
month = dec,
year = {2021},
keywords = {Arousal, Attention, Bipolar disorder, Brain derived neurotrophic factor (BDNF), Cognitive control, Cognitive function, Depression, Mammalian target of rapamycin (mTOR), Medial prefrontal cortex (mPFC), Reward function, Trace amine-associated receptor 1 (TAAR1), Ventral tegmental area (VTA)},
pages = {192--210},
}
There is a need for innovation with respect to therapeutics in psychiatry. Available evidence indicates that the trace amine-associated receptor 1 (TAAR1) agonist SEP-363856 is promising, as it improves measures of cognitive and reward function in schizophrenia. Hedonic and cognitive impairments are transdiagnostic and constitute major burdens in mood disorders. Herein, we systematically review the behavioural and genetic literature documenting the role of TAAR1 in reward and cognitive function, and propose a mechanistic model of TAAR1’s functions in the brain. Notably, TAAR1 activity confers antidepressant-like effects, enhances attention and response inhibition, and reduces compulsive reward seeking without impairing normal function. Further characterization of the responsible mechanisms suggests ion-homeostatic, metabolic, neurotrophic, and anti-inflammatory enhancements in the limbic system. Multiple lines of evidence establish the viability of TAAR1 as a biological target for the treatment of mood disorders. Furthermore, the evidence suggests a role for TAAR1 in reward and cognitive function, which is attributed to a cascade of events that are relevant to the cellular integrity and function of the central nervous system.
Beyond Dopamine Receptor Antagonism: New Targets for Schizophrenia Treatment and Prevention. Gomes, F. V.; and Grace, A. A. International Journal of Molecular Sciences, 22(9): 4467. April 2021.
doi link bibtex abstract
doi link bibtex abstract
@article{gomes_beyond_2021,
title = {Beyond {Dopamine} {Receptor} {Antagonism}: {New} {Targets} for {Schizophrenia} {Treatment} and {Prevention}},
volume = {22},
issn = {1422-0067},
shorttitle = {Beyond {Dopamine} {Receptor} {Antagonism}},
doi = {10.3390/ijms22094467},
abstract = {Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder.},
language = {eng},
number = {9},
journal = {International Journal of Molecular Sciences},
author = {Gomes, Felipe V. and Grace, Anthony A.},
month = apr,
year = {2021},
pmid = {33922888},
pmcid = {PMC8123139},
keywords = {Animals, Antipsychotic Agents, D-Amino-Acid Oxidase, Dopamine Antagonists, Glutamic Acid, Humans, Molecular Targeted Therapy, Receptors, Cholinergic, Receptors, G-Protein-Coupled, Schizophrenia, Sodium Benzoate, antipsychotics, dopamine, gamma-Aminobutyric Acid, glutamate, hippocampus, parvalbumin, psychosis, stress},
pages = {4467},
}
Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder.
An Early Stage Researcher's Primer on Systems Medicine Terminology. Zanin, M.; Aitya, N. A.; Basilio, J.; Baumbach, J.; Benis, A.; Behera, C. K.; Bucholc, M.; Castiglione, F.; Chouvarda, I.; Comte, B.; Dao, T.; Ding, X.; Pujos-Guillot, E.; Filipovic, N.; Finn, D. P.; Glass, D. H.; Harel, N.; Iesmantas, T.; Ivanoska, I.; Joshi, A.; Boudjeltia, K. Z.; Kaoui, B.; Kaur, D.; Maguire, L. P.; McClean, P. L.; McCombe, N.; de Miranda, J. L.; Moisescu, M. A.; Pappalardo, F.; Polster, A.; Prasad, G.; Rozman, D.; Sacala, I.; Sanchez-Bornot, J. M.; Schmid, J. A.; Sharp, T.; Solé-Casals, J.; Spiwok, V.; Spyrou, G. M.; Stalidzans, E.; Stres, B.; Sustersic, T.; Symeonidis, I.; Tieri, P.; Todd, S.; Van Steen, K.; Veneva, M.; Wang, D.; Wang, H.; Wang, H.; Watterson, S.; Wong-Lin, K.; Yang, S.; Zou, X.; and Schmidt, H. H. Network and Systems Medicine, 4(1): 2–50. March 2021. Publisher: Mary Ann Liebert, Inc., publishers
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{zanin_early_2021,
title = {An {Early} {Stage} {Researcher}'s {Primer} on {Systems} {Medicine} {Terminology}},
volume = {4},
url = {https://www.liebertpub.com/doi/10.1089/nsm.2020.0003},
doi = {10.1089/nsm.2020.0003},
abstract = {Background: Systems Medicine is a novel approach to medicine, that is, an interdisciplinary field that considers the human body as a system, composed of multiple parts and of complex relationships at multiple levels, and further integrated into an environment. Exploring Systems Medicine implies understanding and combining concepts coming from diametral different fields, including medicine, biology, statistics, modeling and simulation, and data science. Such heterogeneity leads to semantic issues, which may slow down implementation and fruitful interaction between these highly diverse fields.
Methods: In this review, we collect and explain more than100 terms related to Systems Medicine. These include both modeling and data science terms and basic systems medicine terms, along with some synthetic definitions, examples of applications, and lists of relevant references.
Results: This glossary aims at being a first aid kit for the Systems Medicine researcher facing an unfamiliar term, where he/she can get a first understanding of them, and, more importantly, examples and references for digging into the topic.},
number = {1},
urldate = {2022-07-18},
journal = {Network and Systems Medicine},
author = {Zanin, Massimiliano and Aitya, Nadim A.A. and Basilio, José and Baumbach, Jan and Benis, Arriel and Behera, Chandan K. and Bucholc, Magda and Castiglione, Filippo and Chouvarda, Ioanna and Comte, Blandine and Dao, Tien-Tuan and Ding, Xuemei and Pujos-Guillot, Estelle and Filipovic, Nenad and Finn, David P. and Glass, David H. and Harel, Nissim and Iesmantas, Tomas and Ivanoska, Ilinka and Joshi, Alok and Boudjeltia, Karim Zouaoui and Kaoui, Badr and Kaur, Daman and Maguire, Liam P. and McClean, Paula L. and McCombe, Niamh and de Miranda, João Luís and Moisescu, Mihnea Alexandru and Pappalardo, Francesco and Polster, Annikka and Prasad, Girijesh and Rozman, Damjana and Sacala, Ioan and Sanchez-Bornot, Jose M. and Schmid, Johannes A. and Sharp, Trevor and Solé-Casals, Jordi and Spiwok, Vojtěch and Spyrou, George M. and Stalidzans, Egils and Stres, Blaž and Sustersic, Tijana and Symeonidis, Ioannis and Tieri, Paolo and Todd, Stephen and Van Steen, Kristel and Veneva, Milena and Wang, Da-Hui and Wang, Haiying and Wang, Hui and Watterson, Steven and Wong-Lin, KongFatt and Yang, Su and Zou, Xin and Schmidt, Harald H.H.W.},
month = mar,
year = {2021},
note = {Publisher: Mary Ann Liebert, Inc., publishers},
keywords = {multiscale data science, multiscale modeling, systems medicine},
pages = {2--50},
}
Background: Systems Medicine is a novel approach to medicine, that is, an interdisciplinary field that considers the human body as a system, composed of multiple parts and of complex relationships at multiple levels, and further integrated into an environment. Exploring Systems Medicine implies understanding and combining concepts coming from diametral different fields, including medicine, biology, statistics, modeling and simulation, and data science. Such heterogeneity leads to semantic issues, which may slow down implementation and fruitful interaction between these highly diverse fields. Methods: In this review, we collect and explain more than100 terms related to Systems Medicine. These include both modeling and data science terms and basic systems medicine terms, along with some synthetic definitions, examples of applications, and lists of relevant references. Results: This glossary aims at being a first aid kit for the Systems Medicine researcher facing an unfamiliar term, where he/she can get a first understanding of them, and, more importantly, examples and references for digging into the topic.
Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics. Lam, M.; Chen, C.; Ge, T.; Xia, Y.; Hill, D. W.; Trampush, J. W.; Yu, J.; Knowles, E.; Davies, G.; Stahl, E. A.; Huckins, L.; Liewald, D. C.; Djurovic, S.; Melle, I.; Christoforou, A.; Reinvang, I.; DeRosse, P.; Lundervold, A. J.; Steen, V. M.; Espeseth, T.; Räikkönen, K.; Widen, E.; Palotie, A.; Eriksson, J. G.; Giegling, I.; Konte, B.; Hartmann, A. M.; Roussos, P.; Giakoumaki, S.; Burdick, K. E.; Payton, A.; Ollier, W.; Chiba-Falek, O.; Koltai, D. C.; Need, A. C.; Cirulli, E. T.; Voineskos, A. N.; Stefanis, N. C.; Avramopoulos, D.; Hatzimanolis, A.; Smyrnis, N.; Bilder, R. M.; Freimer, N. B.; Cannon, T. D.; London, E.; Poldrack, R. A.; Sabb, F. W.; Congdon, E.; Conley, E. D.; Scult, M. A.; Dickinson, D.; Straub, R. E.; Donohoe, G.; Morris, D.; Corvin, A.; Gill, M.; Hariri, A. R.; Weinberger, D. R.; Pendleton, N.; Bitsios, P.; Rujescu, D.; Lahti, J.; Le Hellard, S.; Keller, M. C.; Andreassen, O. A.; Deary, I. J.; Glahn, D. C.; Huang, H.; Liu, C.; Malhotra, A. K.; and Lencz, T. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 46(10): 1788–1801. September 2021.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{lam_identifying_2021,
title = {Identifying nootropic drug targets via large-scale cognitive {GWAS} and transcriptomics.},
volume = {46},
issn = {0893-133X},
url = {https://escholarship.org/uc/item/338966jd},
doi = {10.1038/s41386-021-01023-4},
abstract = {Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.},
language = {en},
number = {10},
urldate = {2022-06-28},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
author = {Lam, Max and Chen, Chia-Yen and Ge, Tian and Xia, Yan and Hill, David W. and Trampush, Joey W. and Yu, Jin and Knowles, Emma and Davies, Gail and Stahl, Eli A. and Huckins, Laura and Liewald, David C. and Djurovic, Srdjan and Melle, Ingrid and Christoforou, Andrea and Reinvang, Ivar and DeRosse, Pamela and Lundervold, Astri J. and Steen, Vidar M. and Espeseth, Thomas and Räikkönen, Katri and Widen, Elisabeth and Palotie, Aarno and Eriksson, Johan G. and Giegling, Ina and Konte, Bettina and Hartmann, Annette M. and Roussos, Panos and Giakoumaki, Stella and Burdick, Katherine E. and Payton, Antony and Ollier, William and Chiba-Falek, Ornit and Koltai, Deborah C. and Need, Anna C. and Cirulli, Elizabeth T. and Voineskos, Aristotle N. and Stefanis, Nikos C. and Avramopoulos, Dimitrios and Hatzimanolis, Alex and Smyrnis, Nikolaos and Bilder, Robert M. and Freimer, Nelson B. and Cannon, Tyrone D. and London, Edythe and Poldrack, Russell A. and Sabb, Fred W. and Congdon, Eliza and Conley, Emily Drabant and Scult, Matthew A. and Dickinson, Dwight and Straub, Richard E. and Donohoe, Gary and Morris, Derek and Corvin, Aiden and Gill, Michael and Hariri, Ahmad R. and Weinberger, Daniel R. and Pendleton, Neil and Bitsios, Panos and Rujescu, Dan and Lahti, Jari and Le Hellard, Stephanie and Keller, Matthew C. and Andreassen, Ole A. and Deary, Ian J. and Glahn, David C. and Huang, Hailiang and Liu, Chunyu and Malhotra, Anil K. and Lencz, Todd},
month = sep,
year = {2021},
pages = {1788--1801},
}
Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
An Early Stage Researcher's Primer on Systems Medicine Terminology. Zanin, M.; Aitya, N. A.; Basilio, J.; Baumbach, J.; Benis, A.; Behera, C. K.; Bucholc, M.; Castiglione, F.; Chouvarda, I.; Comte, B.; Dao, T.; Ding, X.; Pujos-Guillot, E.; Filipovic, N.; Finn, D. P.; Glass, D. H.; Harel, N.; Iesmantas, T.; Ivanoska, I.; Joshi, A.; Boudjeltia, K. Z.; Kaoui, B.; Kaur, D.; Maguire, L. P.; McClean, P. L.; McCombe, N.; de Miranda, J. L.; Moisescu, M. A.; Pappalardo, F.; Polster, A.; Prasad, G.; Rozman, D.; Sacala, I.; Sanchez-Bornot, J. M.; Schmid, J. A.; Sharp, T.; Solé-Casals, J.; Spiwok, V.; Spyrou, G. M.; Stalidzans, E.; Stres, B.; Sustersic, T.; Symeonidis, I.; Tieri, P.; Todd, S.; Van Steen, K.; Veneva, M.; Wang, D.; Wang, H.; Wang, H.; Watterson, S.; Wong-Lin, K.; Yang, S.; Zou, X.; and Schmidt, H. H. Network and Systems Medicine, 4(1): 2–50. March 2021. Publisher: Mary Ann Liebert, Inc., publishers
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{zanin_early_2021-1,
title = {An {Early} {Stage} {Researcher}'s {Primer} on {Systems} {Medicine} {Terminology}},
volume = {4},
url = {https://www.liebertpub.com/doi/10.1089/nsm.2020.0003},
doi = {10.1089/nsm.2020.0003},
abstract = {Background: Systems Medicine is a novel approach to medicine, that is, an interdisciplinary field that considers the human body as a system, composed of multiple parts and of complex relationships at multiple levels, and further integrated into an environment. Exploring Systems Medicine implies understanding and combining concepts coming from diametral different fields, including medicine, biology, statistics, modeling and simulation, and data science. Such heterogeneity leads to semantic issues, which may slow down implementation and fruitful interaction between these highly diverse fields.
Methods: In this review, we collect and explain more than100 terms related to Systems Medicine. These include both modeling and data science terms and basic systems medicine terms, along with some synthetic definitions, examples of applications, and lists of relevant references.
Results: This glossary aims at being a first aid kit for the Systems Medicine researcher facing an unfamiliar term, where he/she can get a first understanding of them, and, more importantly, examples and references for digging into the topic.},
number = {1},
urldate = {2022-06-05},
journal = {Network and Systems Medicine},
author = {Zanin, Massimiliano and Aitya, Nadim A.A. and Basilio, José and Baumbach, Jan and Benis, Arriel and Behera, Chandan K. and Bucholc, Magda and Castiglione, Filippo and Chouvarda, Ioanna and Comte, Blandine and Dao, Tien-Tuan and Ding, Xuemei and Pujos-Guillot, Estelle and Filipovic, Nenad and Finn, David P. and Glass, David H. and Harel, Nissim and Iesmantas, Tomas and Ivanoska, Ilinka and Joshi, Alok and Boudjeltia, Karim Zouaoui and Kaoui, Badr and Kaur, Daman and Maguire, Liam P. and McClean, Paula L. and McCombe, Niamh and de Miranda, João Luís and Moisescu, Mihnea Alexandru and Pappalardo, Francesco and Polster, Annikka and Prasad, Girijesh and Rozman, Damjana and Sacala, Ioan and Sanchez-Bornot, Jose M. and Schmid, Johannes A. and Sharp, Trevor and Solé-Casals, Jordi and Spiwok, Vojtěch and Spyrou, George M. and Stalidzans, Egils and Stres, Blaž and Sustersic, Tijana and Symeonidis, Ioannis and Tieri, Paolo and Todd, Stephen and Van Steen, Kristel and Veneva, Milena and Wang, Da-Hui and Wang, Haiying and Wang, Hui and Watterson, Steven and Wong-Lin, KongFatt and Yang, Su and Zou, Xin and Schmidt, Harald H.H.W.},
month = mar,
year = {2021},
note = {Publisher: Mary Ann Liebert, Inc., publishers},
keywords = {multiscale data science, multiscale modeling, systems medicine},
pages = {2--50},
}
Background: Systems Medicine is a novel approach to medicine, that is, an interdisciplinary field that considers the human body as a system, composed of multiple parts and of complex relationships at multiple levels, and further integrated into an environment. Exploring Systems Medicine implies understanding and combining concepts coming from diametral different fields, including medicine, biology, statistics, modeling and simulation, and data science. Such heterogeneity leads to semantic issues, which may slow down implementation and fruitful interaction between these highly diverse fields. Methods: In this review, we collect and explain more than100 terms related to Systems Medicine. These include both modeling and data science terms and basic systems medicine terms, along with some synthetic definitions, examples of applications, and lists of relevant references. Results: This glossary aims at being a first aid kit for the Systems Medicine researcher facing an unfamiliar term, where he/she can get a first understanding of them, and, more importantly, examples and references for digging into the topic.
Signature-based approaches for informed drug repurposing: targeting CNS disorders. Shukla, R.; Henkel, N. D.; Alganem, K.; Hamoud, A.; Reigle, J.; Alnafisah, R. S.; Eby, H. M.; Imami, A. S.; Creeden, J. F; Miruzzi, S. A.; Meller, J.; and Mccullumsmith, R. E. Neuropsychopharmacology, 46(1): 116–130. January 2021.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{shukla_signature-based_2021,
title = {Signature-based approaches for informed drug repurposing: targeting {CNS} disorders},
volume = {46},
issn = {0893-133X},
shorttitle = {Signature-based approaches for informed drug repurposing},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688959/},
doi = {10.1038/s41386-020-0752-6},
abstract = {CNS disorders, and in particular psychiatric illnesses, lack definitive disease-altering therapeutics. The limited understanding of the mechanisms driving these illnesses with the slow pace and high cost of drug development exacerbates this issue. For these reasons, drug repurposing – both a less expensive and time-efficient practice compared to de novo drug development – has been a promising strategy to overcome the paucity of treatments available for these debilitating disorders. While empirical drug-repurposing has been a routine practice in clinical psychiatry, innovative, informed, and cost-effective repurposing efforts using big data (“omics”) have been designed to characterize drugs by structural and transcriptomic signatures. These strategies, in conjunction with ontological integration, provide an important opportunity to address knowledge-based challenges associated with drug development for CNS disorders. In this review, we discuss various signature-based in silico approaches to drug repurposing, its integration with multiple omics platforms, and how this data can be used for clinically relevant, evidence-based drug repurposing. These tools provide an exciting translational avenue to merge omics-based drug discovery platforms with patient-specific disease signatures, ultimately facilitating the identification of new therapies for numerous psychiatric disorders.},
number = {1},
urldate = {2022-05-29},
journal = {Neuropsychopharmacology},
author = {Shukla, Rammohan and Henkel, Nicholas D. and Alganem, Khaled and Hamoud, Abdul-rizaq and Reigle, James and Alnafisah, Rawan S. and Eby, Hunter M. and Imami, Ali S. and Creeden, Justin F and Miruzzi, Scott A. and Meller, Jaroslaw and Mccullumsmith, Robert E.},
month = jan,
year = {2021},
pmid = {32604402},
pmcid = {PMC7688959},
pages = {116--130},
}
CNS disorders, and in particular psychiatric illnesses, lack definitive disease-altering therapeutics. The limited understanding of the mechanisms driving these illnesses with the slow pace and high cost of drug development exacerbates this issue. For these reasons, drug repurposing – both a less expensive and time-efficient practice compared to de novo drug development – has been a promising strategy to overcome the paucity of treatments available for these debilitating disorders. While empirical drug-repurposing has been a routine practice in clinical psychiatry, innovative, informed, and cost-effective repurposing efforts using big data (“omics”) have been designed to characterize drugs by structural and transcriptomic signatures. These strategies, in conjunction with ontological integration, provide an important opportunity to address knowledge-based challenges associated with drug development for CNS disorders. In this review, we discuss various signature-based in silico approaches to drug repurposing, its integration with multiple omics platforms, and how this data can be used for clinically relevant, evidence-based drug repurposing. These tools provide an exciting translational avenue to merge omics-based drug discovery platforms with patient-specific disease signatures, ultimately facilitating the identification of new therapies for numerous psychiatric disorders.
Signature-based approaches for informed drug repurposing: targeting CNS disorders. Shukla, R.; Henkel, N. D.; Alganem, K.; Hamoud, A.; Reigle, J.; Alnafisah, R. S.; Eby, H. M.; Imami, A. S.; Creeden, J. F; Miruzzi, S. A.; Meller, J.; and Mccullumsmith, R. E. Neuropsychopharmacology, 46(1): 116–130. January 2021.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{shukla_signature-based_2021-1,
title = {Signature-based approaches for informed drug repurposing: targeting {CNS} disorders},
volume = {46},
issn = {0893-133X},
shorttitle = {Signature-based approaches for informed drug repurposing},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688959/},
doi = {10.1038/s41386-020-0752-6},
abstract = {CNS disorders, and in particular psychiatric illnesses, lack definitive disease-altering therapeutics. The limited understanding of the mechanisms driving these illnesses with the slow pace and high cost of drug development exacerbates this issue. For these reasons, drug repurposing – both a less expensive and time-efficient practice compared to de novo drug development – has been a promising strategy to overcome the paucity of treatments available for these debilitating disorders. While empirical drug-repurposing has been a routine practice in clinical psychiatry, innovative, informed, and cost-effective repurposing efforts using big data (“omics”) have been designed to characterize drugs by structural and transcriptomic signatures. These strategies, in conjunction with ontological integration, provide an important opportunity to address knowledge-based challenges associated with drug development for CNS disorders. In this review, we discuss various signature-based in silico approaches to drug repurposing, its integration with multiple omics platforms, and how this data can be used for clinically relevant, evidence-based drug repurposing. These tools provide an exciting translational avenue to merge omics-based drug discovery platforms with patient-specific disease signatures, ultimately facilitating the identification of new therapies for numerous psychiatric disorders.},
number = {1},
urldate = {2022-05-27},
journal = {Neuropsychopharmacology},
author = {Shukla, Rammohan and Henkel, Nicholas D. and Alganem, Khaled and Hamoud, Abdul-rizaq and Reigle, James and Alnafisah, Rawan S. and Eby, Hunter M. and Imami, Ali S. and Creeden, Justin F and Miruzzi, Scott A. and Meller, Jaroslaw and Mccullumsmith, Robert E.},
month = jan,
year = {2021},
pmid = {32604402},
pmcid = {PMC7688959},
pages = {116--130},
}
CNS disorders, and in particular psychiatric illnesses, lack definitive disease-altering therapeutics. The limited understanding of the mechanisms driving these illnesses with the slow pace and high cost of drug development exacerbates this issue. For these reasons, drug repurposing – both a less expensive and time-efficient practice compared to de novo drug development – has been a promising strategy to overcome the paucity of treatments available for these debilitating disorders. While empirical drug-repurposing has been a routine practice in clinical psychiatry, innovative, informed, and cost-effective repurposing efforts using big data (“omics”) have been designed to characterize drugs by structural and transcriptomic signatures. These strategies, in conjunction with ontological integration, provide an important opportunity to address knowledge-based challenges associated with drug development for CNS disorders. In this review, we discuss various signature-based in silico approaches to drug repurposing, its integration with multiple omics platforms, and how this data can be used for clinically relevant, evidence-based drug repurposing. These tools provide an exciting translational avenue to merge omics-based drug discovery platforms with patient-specific disease signatures, ultimately facilitating the identification of new therapies for numerous psychiatric disorders.
In Silico Repositioning of Dopamine Modulators with Possible Application to Schizophrenia: Pharmacophore Mapping, Molecular Docking and Molecular Dynamics Analysis. Mejia-Gutierrez, M.; Vásquez-Paz, B. D.; Fierro, L.; and Maza, J. R. ACS Omega, 6(23): 14748–14764. June 2021. Publisher: American Chemical Society
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{mejia-gutierrez_silico_2021,
title = {In {Silico} {Repositioning} of {Dopamine} {Modulators} with {Possible} {Application} to {Schizophrenia}: {Pharmacophore} {Mapping}, {Molecular} {Docking} and {Molecular} {Dynamics} {Analysis}},
volume = {6},
shorttitle = {In {Silico} {Repositioning} of {Dopamine} {Modulators} with {Possible} {Application} to {Schizophrenia}},
url = {https://doi.org/10.1021/acsomega.0c05984},
doi = {10.1021/acsomega.0c05984},
abstract = {We have performed theoretical calculations with 70 drugs that have been considered in 231 clinical trials as possible candidates to repurpose drugs for schizophrenia based on their interactions with the dopaminergic system. A hypothesis of shared pharmacophore features was formulated to support our calculations. To do so, we have used the crystal structure of the D2-like dopamine receptor in complex with risperidone, eticlopride, and nemonapride. Linagliptin, citalopram, flunarizine, sildenafil, minocycline, and duloxetine were the drugs that best fit with our model. Molecular docking calculations, molecular dynamics outcomes, blood-brain barrier penetration, and human intestinal absorption were studied and compared with the results. From the six drugs selected in the shared pharmacophore features input, flunarizine showed the best docking score with D2, D3, and D4 dopamine receptors and had high stability during molecular dynamics simulations. Flunarizine is a frequently used medication to treat migraines and vertigo. However, its antipsychotic properties have been previously hypothesized, particularly because of its possible ability to block the D2 dopamine receptors.},
number = {23},
urldate = {2022-05-25},
journal = {ACS Omega},
author = {Mejia-Gutierrez, Melissa and Vásquez-Paz, Bryan D. and Fierro, Leonardo and Maza, Julio R.},
month = jun,
year = {2021},
note = {Publisher: American Chemical Society},
pages = {14748--14764},
}
We have performed theoretical calculations with 70 drugs that have been considered in 231 clinical trials as possible candidates to repurpose drugs for schizophrenia based on their interactions with the dopaminergic system. A hypothesis of shared pharmacophore features was formulated to support our calculations. To do so, we have used the crystal structure of the D2-like dopamine receptor in complex with risperidone, eticlopride, and nemonapride. Linagliptin, citalopram, flunarizine, sildenafil, minocycline, and duloxetine were the drugs that best fit with our model. Molecular docking calculations, molecular dynamics outcomes, blood-brain barrier penetration, and human intestinal absorption were studied and compared with the results. From the six drugs selected in the shared pharmacophore features input, flunarizine showed the best docking score with D2, D3, and D4 dopamine receptors and had high stability during molecular dynamics simulations. Flunarizine is a frequently used medication to treat migraines and vertigo. However, its antipsychotic properties have been previously hypothesized, particularly because of its possible ability to block the D2 dopamine receptors.
Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics. Lam, M.; Chen, C.; Ge, T.; Xia, Y.; Hill, D. W.; Trampush, J. W.; Yu, J.; Knowles, E.; Davies, G.; Stahl, E. A.; Huckins, L.; Liewald, D. C.; Djurovic, S.; Melle, I.; Christoforou, A.; Reinvang, I.; DeRosse, P.; Lundervold, A. J.; Steen, V. M.; Espeseth, T.; Räikkönen, K.; Widen, E.; Palotie, A.; Eriksson, J. G.; Giegling, I.; Konte, B.; Hartmann, A. M.; Roussos, P.; Giakoumaki, S.; Burdick, K. E.; Payton, A.; Ollier, W.; Chiba-Falek, O.; Koltai, D. C.; Need, A. C.; Cirulli, E. T.; Voineskos, A. N.; Stefanis, N. C.; Avramopoulos, D.; Hatzimanolis, A.; Smyrnis, N.; Bilder, R. M.; Freimer, N. B.; Cannon, T. D.; London, E.; Poldrack, R. A.; Sabb, F. W.; Congdon, E.; Conley, E. D.; Scult, M. A.; Dickinson, D.; Straub, R. E.; Donohoe, G.; Morris, D.; Corvin, A.; Gill, M.; Hariri, A. R.; Weinberger, D. R.; Pendleton, N.; Bitsios, P.; Rujescu, D.; Lahti, J.; Le Hellard, S.; Keller, M. C.; Andreassen, O. A.; Deary, I. J.; Glahn, D. C.; Huang, H.; Liu, C.; Malhotra, A. K.; and Lencz, T. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 46(10): 1788–1801. September 2021.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{lam_identifying_2021-1,
title = {Identifying nootropic drug targets via large-scale cognitive {GWAS} and transcriptomics.},
volume = {46},
issn = {0893-133X},
url = {https://escholarship.org/uc/item/338966jd},
doi = {10.1038/s41386-021-01023-4},
abstract = {Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.},
language = {en},
number = {10},
urldate = {2022-05-08},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
author = {Lam, Max and Chen, Chia-Yen and Ge, Tian and Xia, Yan and Hill, David W. and Trampush, Joey W. and Yu, Jin and Knowles, Emma and Davies, Gail and Stahl, Eli A. and Huckins, Laura and Liewald, David C. and Djurovic, Srdjan and Melle, Ingrid and Christoforou, Andrea and Reinvang, Ivar and DeRosse, Pamela and Lundervold, Astri J. and Steen, Vidar M. and Espeseth, Thomas and Räikkönen, Katri and Widen, Elisabeth and Palotie, Aarno and Eriksson, Johan G. and Giegling, Ina and Konte, Bettina and Hartmann, Annette M. and Roussos, Panos and Giakoumaki, Stella and Burdick, Katherine E. and Payton, Antony and Ollier, William and Chiba-Falek, Ornit and Koltai, Deborah C. and Need, Anna C. and Cirulli, Elizabeth T. and Voineskos, Aristotle N. and Stefanis, Nikos C. and Avramopoulos, Dimitrios and Hatzimanolis, Alex and Smyrnis, Nikolaos and Bilder, Robert M. and Freimer, Nelson B. and Cannon, Tyrone D. and London, Edythe and Poldrack, Russell A. and Sabb, Fred W. and Congdon, Eliza and Conley, Emily Drabant and Scult, Matthew A. and Dickinson, Dwight and Straub, Richard E. and Donohoe, Gary and Morris, Derek and Corvin, Aiden and Gill, Michael and Hariri, Ahmad R. and Weinberger, Daniel R. and Pendleton, Neil and Bitsios, Panos and Rujescu, Dan and Lahti, Jari and Le Hellard, Stephanie and Keller, Matthew C. and Andreassen, Ole A. and Deary, Ian J. and Glahn, David C. and Huang, Hailiang and Liu, Chunyu and Malhotra, Anil K. and Lencz, Todd},
month = sep,
year = {2021},
pages = {1788--1801},
}
Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia. Heffernan, M. L. R.; Herman, L. W.; Brown, S.; Jones, P. G.; Shao, L.; Hewitt, M. C.; Campbell, J. E.; Dedic, N.; Hopkins, S. C.; Koblan, K. S.; and Xie, L. ACS Medicinal Chemistry Letters. December 2021. Publisher: American Chemical Society
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{heffernan_ulotaront_2021,
title = {Ulotaront: {A} {TAAR1} {Agonist} for the {Treatment} of {Schizophrenia}},
shorttitle = {Ulotaront},
url = {https://doi.org/10.1021/acsmedchemlett.1c00527},
doi = {10.1021/acsmedchemlett.1c00527},
abstract = {Ulotaront (SEP-363856) is a trace-amine associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity in Phase 3 clinical development, with FDA Breakthrough Therapy Designation, for the treatment of schizophrenia. TAAR1 is a G-protein-coupled receptor (GPCR) that is expressed in cortical, limbic, and midbrain monoaminergic regions. It is activated by endogenous trace amines, and is believed to play an important role in modulating dopaminergic, serotonergic, and glutamatergic circuitry. TAAR1 agonism data are reported herein for ulotaront and its analogues in comparison to endogenous TAAR1 agonists. In addition, a human TAAR1 homology model was built around ulotaront to identify key interactions and attempt to better understand the scaffold-specific TAAR1 agonism structure–activity relationships.},
urldate = {2021-12-27},
journal = {ACS Medicinal Chemistry Letters},
author = {Heffernan, Michele L. R. and Herman, Lee W. and Brown, Scott and Jones, Philip G. and Shao, Liming and Hewitt, Michael C. and Campbell, John E. and Dedic, Nina and Hopkins, Seth C. and Koblan, Kenneth S. and Xie, Linghong},
month = dec,
year = {2021},
note = {Publisher: American Chemical Society},
}
Ulotaront (SEP-363856) is a trace-amine associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity in Phase 3 clinical development, with FDA Breakthrough Therapy Designation, for the treatment of schizophrenia. TAAR1 is a G-protein-coupled receptor (GPCR) that is expressed in cortical, limbic, and midbrain monoaminergic regions. It is activated by endogenous trace amines, and is believed to play an important role in modulating dopaminergic, serotonergic, and glutamatergic circuitry. TAAR1 agonism data are reported herein for ulotaront and its analogues in comparison to endogenous TAAR1 agonists. In addition, a human TAAR1 homology model was built around ulotaront to identify key interactions and attempt to better understand the scaffold-specific TAAR1 agonism structure–activity relationships.
2020 (3)
TAAR Agonists. Xu, Z.; and Li, Q. Cellular and Molecular Neurobiology, 40(2): 257–272. March 2020.
doi link bibtex abstract
doi link bibtex abstract
@article{xu_taar_2020,
title = {{TAAR} {Agonists}},
volume = {40},
issn = {1573-6830},
doi = {10.1007/s10571-019-00774-5},
abstract = {Trace amine-associated receptors (TAARs) are a family of G protein-coupled receptors (GPCRs) that are evolutionarily conserved in vertebrates. The first discovered TAAR1 is mainly expressed in the brain, and is able to detect low abundant trace amines. TAAR1 is also activated by several synthetic compounds and psychostimulant drugs like amphetamine. Activation of TAAR1 by specific agonists can regulate the classical monoaminergic systems in the brain. Further studies have revealed that other TAAR family members are highly expressed in the olfactory system which are termed olfactory TAARs. In vertebrates, olfactory TAARs can specifically recognize volatile or water-soluble amines. Some of these TAAR agonists are produced by decarboxylation of amino acids. In addition, some TAAR agonists are ethological odors that mediate animal innate behaviors. In this study, we provide a comprehensive review of TAAR agonists, including their structures, biosynthesis pathways, and functions.},
language = {eng},
number = {2},
journal = {Cellular and Molecular Neurobiology},
author = {Xu, Zhengrong and Li, Qian},
month = mar,
year = {2020},
pmid = {31848873},
keywords = {Agonist, Animals, Biogenic Amines, Central Nervous System Stimulants, G protein-coupled receptor (GPCR), Humans, Olfactory receptor, Receptors, G-Protein-Coupled, Signal Transduction, Trace amine-associated receptor (TAAR), Trace amines, Volatile amines},
pages = {257--272},
}
Trace amine-associated receptors (TAARs) are a family of G protein-coupled receptors (GPCRs) that are evolutionarily conserved in vertebrates. The first discovered TAAR1 is mainly expressed in the brain, and is able to detect low abundant trace amines. TAAR1 is also activated by several synthetic compounds and psychostimulant drugs like amphetamine. Activation of TAAR1 by specific agonists can regulate the classical monoaminergic systems in the brain. Further studies have revealed that other TAAR family members are highly expressed in the olfactory system which are termed olfactory TAARs. In vertebrates, olfactory TAARs can specifically recognize volatile or water-soluble amines. Some of these TAAR agonists are produced by decarboxylation of amino acids. In addition, some TAAR agonists are ethological odors that mediate animal innate behaviors. In this study, we provide a comprehensive review of TAAR agonists, including their structures, biosynthesis pathways, and functions.
Molecular Variants in Human Trace Amine-Associated Receptors and Their Implications in Mental and Metabolic Disorders. Rutigliano, G.; and Zucchi, R. Cellular and Molecular Neurobiology, 40(2): 239–255. March 2020.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{rutigliano_molecular_2020,
title = {Molecular {Variants} in {Human} {Trace} {Amine}-{Associated} {Receptors} and {Their} {Implications} in {Mental} and {Metabolic} {Disorders}},
volume = {40},
issn = {1573-6830},
url = {https://doi.org/10.1007/s10571-019-00743-y},
doi = {10.1007/s10571-019-00743-y},
abstract = {We provide a comprehensive review of the available evidence on the pathophysiological implications of genetic variants in the human trace amine-associated receptor (TAAR) superfamily. Genes coding for trace amine-associated receptors (taars) represent a multigene family of G-protein-coupled receptors, clustered to a small genomic region of 108 kb located in chromosome 6q23, which has been consistently identified by linkage analyses as a susceptibility locus for schizophrenia and affective disorders. Most TAARs are expressed in brain areas involved in emotions, reward and cognition. TAARs are activated by endogenous trace amines and thyronamines, and evidence for a modulatory action on other monaminergic systems has been reported. Therefore, linkage analyses were followed by fine mapping association studies in schizophrenia and affective disorders. However, none of these reports has received sufficient universal replication, so their status remains uncertain. Single nucleotide polymorphisms in taars have emerged as susceptibility loci from genome-wide association studies investigating migraine and brain development, but none of the detected variants reached the threshold for genome-wide significance. In the last decade, technological advances enabled single-gene or whole-exome sequencing, thus allowing the detection of rare genetic variants, which may have a greater impact on the risk of complex disorders. Using these approaches, several taars (especially taar1) variants have been detected in patients with mental and metabolic disorders, and in some cases, defective receptor function has been demonstrated in vitro. Finally, with the use of transcriptomic and peptidomic techniques, dysregulations of TAARs (especially TAAR6) have been identified in brain disorders characterized by cognitive impairment.},
language = {en},
number = {2},
urldate = {2022-06-29},
journal = {Cellular and Molecular Neurobiology},
author = {Rutigliano, Grazia and Zucchi, Riccardo},
month = mar,
year = {2020},
keywords = {Bipolar disorder, Genetics, Schizophrenia, Single nucletide polymorphism, Trace amine-associated receptors},
pages = {239--255},
}
We provide a comprehensive review of the available evidence on the pathophysiological implications of genetic variants in the human trace amine-associated receptor (TAAR) superfamily. Genes coding for trace amine-associated receptors (taars) represent a multigene family of G-protein-coupled receptors, clustered to a small genomic region of 108 kb located in chromosome 6q23, which has been consistently identified by linkage analyses as a susceptibility locus for schizophrenia and affective disorders. Most TAARs are expressed in brain areas involved in emotions, reward and cognition. TAARs are activated by endogenous trace amines and thyronamines, and evidence for a modulatory action on other monaminergic systems has been reported. Therefore, linkage analyses were followed by fine mapping association studies in schizophrenia and affective disorders. However, none of these reports has received sufficient universal replication, so their status remains uncertain. Single nucleotide polymorphisms in taars have emerged as susceptibility loci from genome-wide association studies investigating migraine and brain development, but none of the detected variants reached the threshold for genome-wide significance. In the last decade, technological advances enabled single-gene or whole-exome sequencing, thus allowing the detection of rare genetic variants, which may have a greater impact on the risk of complex disorders. Using these approaches, several taars (especially taar1) variants have been detected in patients with mental and metabolic disorders, and in some cases, defective receptor function has been demonstrated in vitro. Finally, with the use of transcriptomic and peptidomic techniques, dysregulations of TAARs (especially TAAR6) have been identified in brain disorders characterized by cognitive impairment.
Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia. Singh, T.; Neale, B. M.; Daly, M. J.; and Consortium, o. b. o. t. S. E. M. (. Technical Report medRxiv, September 2020. Type: article
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@techreport{singh_exome_2020,
title = {Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia},
copyright = {© 2020, Posted by Cold Spring Harbor Laboratory. This pre-print is available under a Creative Commons License (Attribution 4.0 International), CC BY 4.0, as described at http://creativecommons.org/licenses/by/4.0/},
url = {https://www.medrxiv.org/content/10.1101/2020.09.18.20192815v1},
abstract = {By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 - 50, P {\textless} 2.14 × 10-6), and 32 genes at a FDR {\textless} 5\%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse. The associations of NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We find significant evidence for an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD), and severe neurodevelopmental disorders (DD/ID), supporting a neurodevelopmental etiology for schizophrenia. We show that protein-truncating variants in GRIN2A, TRIO, and CACNA1G confer risk for schizophrenia whereas specific missense mutations in these genes confer risk for DD/ID. Nevertheless, few of the strongly associated schizophrenia genes appear to confer risk for DD/ID. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk, suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, implying that more schizophrenia risk genes await discovery using this approach.},
language = {en},
urldate = {2022-05-05},
institution = {medRxiv},
author = {Singh, Tarjinder and Neale, Benjamin M. and Daly, Mark J. and Consortium, on behalf of the Schizophrenia Exome Meta-Analysis (SCHEMA)},
month = sep,
year = {2020},
doi = {10.1101/2020.09.18.20192815},
note = {Type: article},
pages = {2020.09.18.20192815},
}
By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 - 50, P \textless 2.14 × 10-6), and 32 genes at a FDR \textless 5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse. The associations of NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We find significant evidence for an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD), and severe neurodevelopmental disorders (DD/ID), supporting a neurodevelopmental etiology for schizophrenia. We show that protein-truncating variants in GRIN2A, TRIO, and CACNA1G confer risk for schizophrenia whereas specific missense mutations in these genes confer risk for DD/ID. Nevertheless, few of the strongly associated schizophrenia genes appear to confer risk for DD/ID. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk, suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, implying that more schizophrenia risk genes await discovery using this approach.
2019 (2)
Hallucinations and Strong Priors. Corlett, P. R.; Horga, G.; Fletcher, P. C.; Alderson-Day, B.; Schmack, K.; and Powers, A. R. Trends in Cognitive Sciences, 23(2): 114–127. February 2019.
doi link bibtex abstract
doi link bibtex abstract
@article{corlett_hallucinations_2019,
title = {Hallucinations and {Strong} {Priors}},
volume = {23},
issn = {1879-307X},
doi = {10.1016/j.tics.2018.12.001},
abstract = {Hallucinations, perceptions in the absence of objectively identifiable stimuli, illustrate the constructive nature of perception. Here, we highlight the role of prior beliefs as a critical elicitor of hallucinations. Recent empirical work from independent laboratories shows strong, overly precise priors can engender hallucinations in healthy subjects and that individuals who hallucinate in the real world are more susceptible to these laboratory phenomena. We consider these observations in light of work demonstrating apparently weak, or imprecise, priors in psychosis. Appreciating the interactions within and between hierarchies of inference can reconcile this apparent disconnect. Data from neural networks, human behavior, and neuroimaging support this contention. This work underlines the continuum from normal to aberrant perception, encouraging a more empathic approach to clinical hallucinations.},
language = {eng},
number = {2},
journal = {Trends in Cognitive Sciences},
author = {Corlett, Philip R. and Horga, Guillermo and Fletcher, Paul C. and Alderson-Day, Ben and Schmack, Katharina and Powers, Albert R.},
month = feb,
year = {2019},
pmid = {30583945},
pmcid = {PMC6368358},
keywords = {Hallucinations, Humans, Illusions, Nerve Net, Speech Perception, auditory verbal hallucinations, hallucinations, predictive coding, prior beliefs, psychosis},
pages = {114--127},
}
Hallucinations, perceptions in the absence of objectively identifiable stimuli, illustrate the constructive nature of perception. Here, we highlight the role of prior beliefs as a critical elicitor of hallucinations. Recent empirical work from independent laboratories shows strong, overly precise priors can engender hallucinations in healthy subjects and that individuals who hallucinate in the real world are more susceptible to these laboratory phenomena. We consider these observations in light of work demonstrating apparently weak, or imprecise, priors in psychosis. Appreciating the interactions within and between hierarchies of inference can reconcile this apparent disconnect. Data from neural networks, human behavior, and neuroimaging support this contention. This work underlines the continuum from normal to aberrant perception, encouraging a more empathic approach to clinical hallucinations.
Schizophrenia. Marder, S. R.; and Cannon, T. D. New England Journal of Medicine, 381(18): 1753–1761. October 2019.
Paper doi link bibtex
Paper doi link bibtex
@article{ropper_schizophrenia_2019,
title = {Schizophrenia},
volume = {381},
issn = {0028-4793, 1533-4406},
url = {http://www.nejm.org/doi/10.1056/NEJMra1808803},
doi = {10.1056/NEJMra1808803},
language = {en},
number = {18},
urldate = {2022-05-29},
journal = {New England Journal of Medicine},
author = {Marder, Stephen R. and Cannon, Tyrone D.},
editor = {Ropper, Allan H.},
month = oct,
year = {2019},
pages = {1753--1761},
}
2017 (1)
What Can Different Motor Circuits Tell Us About Psychosis? An RDoC Perspective. Mittal, V. A; Bernard, J. A; and Northoff, G. Schizophrenia Bulletin, 43(5): 949–955. September 2017.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{mittal_what_2017,
title = {What {Can} {Different} {Motor} {Circuits} {Tell} {Us} {About} {Psychosis}? {An} {RDoC} {Perspective}},
volume = {43},
issn = {0586-7614},
shorttitle = {What {Can} {Different} {Motor} {Circuits} {Tell} {Us} {About} {Psychosis}?},
url = {https://doi.org/10.1093/schbul/sbx087},
doi = {10.1093/schbul/sbx087},
abstract = {Signs of motor dysfunction are evidenced across a range of psychiatric disorders including schizophrenia. Historically, these features have been neglected but emerging theoretical and methodological advancements have shed new light on the utility of considering movement abnormalities. Indeed, the National Institute of Mental Health Research Domain Criteria initiative has recently met to develop a Motor Systems Domain. This reflects a growing appreciation for the enhanced reliability and validity that can come along with evaluating disturbances relevant to psychiatric illnesses from multiple levels of analysis, and conceptualizing these domains with respect to the complexity of their role in a broader integrated system (ie, weighing contributions and interactions between the cognitive, affective, and motor domains). This article discusses motor behaviors and seeks to explain how research into basal ganglia, cerebellar, and cortico-motor circuit function/dysfunction, grounded in brain circuit-motor behavior relationships, can elucidate our understanding of pathophysiology, provide vital links to other key systems of interest, significantly improve identification and classification, and drive development of targeted individualized treatments.},
number = {5},
urldate = {2022-07-24},
journal = {Schizophrenia Bulletin},
author = {Mittal, Vijay A and Bernard, Jessica A and Northoff, Georg},
month = sep,
year = {2017},
pages = {949--955},
}
Signs of motor dysfunction are evidenced across a range of psychiatric disorders including schizophrenia. Historically, these features have been neglected but emerging theoretical and methodological advancements have shed new light on the utility of considering movement abnormalities. Indeed, the National Institute of Mental Health Research Domain Criteria initiative has recently met to develop a Motor Systems Domain. This reflects a growing appreciation for the enhanced reliability and validity that can come along with evaluating disturbances relevant to psychiatric illnesses from multiple levels of analysis, and conceptualizing these domains with respect to the complexity of their role in a broader integrated system (ie, weighing contributions and interactions between the cognitive, affective, and motor domains). This article discusses motor behaviors and seeks to explain how research into basal ganglia, cerebellar, and cortico-motor circuit function/dysfunction, grounded in brain circuit-motor behavior relationships, can elucidate our understanding of pathophysiology, provide vital links to other key systems of interest, significantly improve identification and classification, and drive development of targeted individualized treatments.
2016 (2)
BindingDB in 2015: A public database for medicinal chemistry, computational chemistry and systems pharmacology. Gilson, M. K.; Liu, T.; Baitaluk, M.; Nicola, G.; Hwang, L.; and Chong, J. Nucleic Acids Research, 44(D1): D1045–1053. January 2016.
doi link bibtex abstract
doi link bibtex abstract
@article{gilson_bindingdb_2016,
title = {{BindingDB} in 2015: {A} public database for medicinal chemistry, computational chemistry and systems pharmacology},
volume = {44},
issn = {1362-4962},
shorttitle = {{BindingDB} in 2015},
doi = {10.1093/nar/gkv1072},
abstract = {BindingDB, www.bindingdb.org, is a publicly accessible database of experimental protein-small molecule interaction data. Its collection of over a million data entries derives primarily from scientific articles and, increasingly, US patents. BindingDB provides many ways to browse and search for data of interest, including an advanced search tool, which can cross searches of multiple query types, including text, chemical structure, protein sequence and numerical affinities. The PDB and PubMed provide links to data in BindingDB, and vice versa; and BindingDB provides links to pathway information, the ZINC catalog of available compounds, and other resources. The BindingDB website offers specialized tools that take advantage of its large data collection, including ones to generate hypotheses for the protein targets bound by a bioactive compound, and for the compounds bound by a new protein of known sequence; and virtual compound screening by maximal chemical similarity, binary kernel discrimination, and support vector machine methods. Specialized data sets are also available, such as binding data for hundreds of congeneric series of ligands, drawn from BindingDB and organized for use in validating drug design methods. BindingDB offers several forms of programmatic access, and comes with extensive background material and documentation. Here, we provide the first update of BindingDB since 2007, focusing on new and unique features and highlighting directions of importance to the field as a whole.},
language = {eng},
number = {D1},
journal = {Nucleic Acids Research},
author = {Gilson, Michael K. and Liu, Tiqing and Baitaluk, Michael and Nicola, George and Hwang, Linda and Chong, Jenny},
month = jan,
year = {2016},
pmid = {26481362},
pmcid = {PMC4702793},
keywords = {Databases, Pharmaceutical, Drug Design, Internet, Ligands, Patents as Topic, Pharmaceutical Preparations, Protein Binding, Protein Folding, Proteins, Software, Systems Biology},
pages = {D1045--1053},
}
BindingDB, www.bindingdb.org, is a publicly accessible database of experimental protein-small molecule interaction data. Its collection of over a million data entries derives primarily from scientific articles and, increasingly, US patents. BindingDB provides many ways to browse and search for data of interest, including an advanced search tool, which can cross searches of multiple query types, including text, chemical structure, protein sequence and numerical affinities. The PDB and PubMed provide links to data in BindingDB, and vice versa; and BindingDB provides links to pathway information, the ZINC catalog of available compounds, and other resources. The BindingDB website offers specialized tools that take advantage of its large data collection, including ones to generate hypotheses for the protein targets bound by a bioactive compound, and for the compounds bound by a new protein of known sequence; and virtual compound screening by maximal chemical similarity, binary kernel discrimination, and support vector machine methods. Specialized data sets are also available, such as binding data for hundreds of congeneric series of ligands, drawn from BindingDB and organized for use in validating drug design methods. BindingDB offers several forms of programmatic access, and comes with extensive background material and documentation. Here, we provide the first update of BindingDB since 2007, focusing on new and unique features and highlighting directions of importance to the field as a whole.
Maternal immune activation: Implications for neuropsychiatric disorders. Estes, M. L.; and McAllister, A. K. Science, 353(6301): 772–777. August 2016.
Paper doi link bibtex abstract
Paper doi link bibtex abstract
@article{estes_maternal_2016,
title = {Maternal immune activation: {Implications} for neuropsychiatric disorders},
volume = {353},
issn = {0036-8075, 1095-9203},
shorttitle = {Maternal immune activation},
url = {https://www.science.org/doi/10.1126/science.aag3194},
doi = {10.1126/science.aag3194},
abstract = {Epidemiological evidence implicates maternal infection as a risk factor for autism spectrum disorder and schizophrenia. Animal models corroborate this link and demonstrate that maternal immune activation (MIA) alone is sufficient to impart lifelong neuropathology and altered behaviors in offspring. This Review describes common principles revealed by these models, highlighting recent findings that strengthen their relevance for schizophrenia and autism and are starting to reveal the molecular mechanisms underlying the effects of MIA on offspring. The role of MIA as a primer for a much wider range of psychiatric and neurologic disorders is also discussed. Finally, the need for more research in this nascent field and the implications for identifying and developing new treatments for individuals at heightened risk for neuroimmune disorders are considered.},
language = {en},
number = {6301},
urldate = {2022-05-29},
journal = {Science},
author = {Estes, Myka L. and McAllister, A. Kimberley},
month = aug,
year = {2016},
pages = {772--777},
}
Epidemiological evidence implicates maternal infection as a risk factor for autism spectrum disorder and schizophrenia. Animal models corroborate this link and demonstrate that maternal immune activation (MIA) alone is sufficient to impart lifelong neuropathology and altered behaviors in offspring. This Review describes common principles revealed by these models, highlighting recent findings that strengthen their relevance for schizophrenia and autism and are starting to reveal the molecular mechanisms underlying the effects of MIA on offspring. The role of MIA as a primer for a much wider range of psychiatric and neurologic disorders is also discussed. Finally, the need for more research in this nascent field and the implications for identifying and developing new treatments for individuals at heightened risk for neuroimmune disorders are considered.
2001 (1)
Trace amines: Identification of a family of mammalian G protein-coupled receptors. Borowsky, B.; Adham, N.; Jones, K. A.; Raddatz, R.; Artymyshyn, R.; Ogozalek, K. L.; Durkin, M. M.; Lakhlani, P. P.; Bonini, J. A.; Pathirana, S.; Boyle, N.; Pu, X.; Kouranova, E.; Lichtblau, H.; Ochoa, F. Y.; Branchek, T. A.; and Gerald, C. Proceedings of the National Academy of Sciences, 98(16): 8966–8971. July 2001. Publisher: Proceedings of the National Academy of Sciences
Paper doi link bibtex
Paper doi link bibtex
@article{borowsky_trace_2001,
title = {Trace amines: {Identification} of a family of mammalian {G} protein-coupled receptors},
volume = {98},
shorttitle = {Trace amines},
url = {https://www.pnas.org/doi/full/10.1073/pnas.151105198},
doi = {10.1073/pnas.151105198},
number = {16},
urldate = {2022-07-21},
journal = {Proceedings of the National Academy of Sciences},
author = {Borowsky, Beth and Adham, Nika and Jones, Kenneth A. and Raddatz, Rita and Artymyshyn, Roman and Ogozalek, Kristine L. and Durkin, Margaret M. and Lakhlani, Parul P. and Bonini, James A. and Pathirana, Sudam and Boyle, Noel and Pu, Xiaosui and Kouranova, Evguenia and Lichtblau, Harvey and Ochoa, F. Yulina and Branchek, Theresa A. and Gerald, Christophe},
month = jul,
year = {2001},
note = {Publisher: Proceedings of the National Academy of Sciences},
pages = {8966--8971},
}
undefined (8)
Manual \textbar ApiNATOMY Lyph Viewer.
Paper link bibtex
Paper link bibtex
@misc{noauthor_manual_nodate,
title = {Manual {\textbar} {ApiNATOMY} {Lyph} {Viewer}},
url = {http://open-physiology-viewer-docs.surge.sh/},
urldate = {2022-09-12},
}
Inflammatory bowel disease-associated gene set projecte \textbar Open-i.
Paper link bibtex
Paper link bibtex
@misc{noauthor_inflammatory_nodate,
title = {Inflammatory bowel disease-associated gene set projecte {\textbar} {Open}-i},
url = {https://openi.nlm.nih.gov/detailedresult?img=PMC4251289_fphar-05-00252-g003&query=multiscale%20neuron&it=xg&req=4&npos=52},
urldate = {2022-08-16},
}
Impact of GPCR Structures on Drug Discovery - ScienceDirect.
Paper link bibtex
Paper link bibtex
@misc{noauthor_impact_nodate,
title = {Impact of {GPCR} {Structures} on {Drug} {Discovery} - {ScienceDirect}},
url = {https://www.sciencedirect.com/science/article/pii/S0092867420302658#mmc4},
urldate = {2022-07-25},
}
Actions of Trace Amines in the Brain-Gut-Microbiome Axis via Trace Amine-Associated Receptor-1 (TAAR1). Bugda Gwilt, K.; González, D. P.; Olliffe, N.; Oller, H.; Hoffing, R.; Puzan, M.; El Aidy, S.; and Miller, G. M. Cellular and Molecular Neurobiology, 40(2): 191–201. .
doi link bibtex abstract
doi link bibtex abstract
@article{bugda_gwilt_actions_nodate,
title = {Actions of {Trace} {Amines} in the {Brain}-{Gut}-{Microbiome} {Axis} via {Trace} {Amine}-{Associated} {Receptor}-1 ({TAAR1})},
volume = {40},
doi = {10.1007/s10571-019-00772-7},
abstract = {Trace amines and their primary receptor, Trace Amine-Associated Receptor-1 (TAAR1) are widely studied for their involvement in the pathogenesis of neuropsychiatric disorders despite being found in the gastrointestinal tract at physiological levels. With the emergence of the “brain-gut-microbiome axis,” we take the opportunity to review what is known about trace amines in the brain, the defined sources of trace amines in the gut, and emerging understandings on the levels of trace amines in various gastrointestinal disorders. Similarly, we discuss localization of TAAR1 expression in the gut, novel findings that TAAR1 may be implicated in inflammatory bowel diseases, and the reported comorbidities of neuropsychiatric disorders and gastrointestinal disorders. With the emergence of TAAR1 specific compounds as next-generation therapeutics for schizophrenia (Roche) and Parkinson’s related psychoses (Sunovion), we hypothesize a therapeutic benefit of these compounds in clinical trials in the brain-gut-microbiome axis, as well as a potential for thoughtful manipulation of the brain-gut-microbiome axis to modulate symptoms of neuropsychiatric disease.},
number = {2},
journal = {Cellular and Molecular Neurobiology},
author = {Bugda Gwilt, Katlynn and González, Dulce Pamela and Olliffe, Neva and Oller, Haley and Hoffing, Rachel and Puzan, Marissa and El Aidy, Sahar and Miller, Gregory M.},
pages = {191--201},
}
Trace amines and their primary receptor, Trace Amine-Associated Receptor-1 (TAAR1) are widely studied for their involvement in the pathogenesis of neuropsychiatric disorders despite being found in the gastrointestinal tract at physiological levels. With the emergence of the “brain-gut-microbiome axis,” we take the opportunity to review what is known about trace amines in the brain, the defined sources of trace amines in the gut, and emerging understandings on the levels of trace amines in various gastrointestinal disorders. Similarly, we discuss localization of TAAR1 expression in the gut, novel findings that TAAR1 may be implicated in inflammatory bowel diseases, and the reported comorbidities of neuropsychiatric disorders and gastrointestinal disorders. With the emergence of TAAR1 specific compounds as next-generation therapeutics for schizophrenia (Roche) and Parkinson’s related psychoses (Sunovion), we hypothesize a therapeutic benefit of these compounds in clinical trials in the brain-gut-microbiome axis, as well as a potential for thoughtful manipulation of the brain-gut-microbiome axis to modulate symptoms of neuropsychiatric disease.
Redefining the standard of care for brain disorders \textbar MapLight Therapeutics.
Paper link bibtex abstract
Paper link bibtex abstract
@misc{noauthor_redefining_nodate,
title = {Redefining the standard of care for brain disorders {\textbar} {MapLight} {Therapeutics}},
url = {https://maplightrx.com/},
abstract = {Targeted treatment for Autism Spectrum Disorder, Parkinson’s Disease and Schizophrenia.},
language = {en-US},
urldate = {2022-07-11},
journal = {MapLight},
}
Targeted treatment for Autism Spectrum Disorder, Parkinson’s Disease and Schizophrenia.
Candidates for Drug Repurposing to Address the Cognitive Symptoms in Schizophrenia \textbar bioRxiv.
Paper link bibtex
Paper link bibtex
@misc{noauthor_candidates_nodate,
title = {Candidates for {Drug} {Repurposing} to {Address} the {Cognitive} {Symptoms} in {Schizophrenia} {\textbar} {bioRxiv}},
url = {https://www.biorxiv.org/content/10.1101/2022.03.07.483231v1},
urldate = {2022-05-29},
}
Results \textbar SCHEMA browser.
Paper link bibtex
Paper link bibtex
@misc{noauthor_results_nodate,
title = {Results {\textbar} {SCHEMA} browser},
url = {https://schema.broadinstitute.org/results},
urldate = {2022-05-05},
}
Experimental schizophrenia drug could reduce long-neglected symptoms.
Paper link bibtex abstract
Paper link bibtex abstract
@misc{noauthor_experimental_nodate,
title = {Experimental schizophrenia drug could reduce long-neglected symptoms},
url = {https://www.science.org/content/article/experimental-schizophrenia-drug-could-reduce-long-neglected-symptoms},
abstract = {New compound targets different neural receptors than existing antipsychotic drugs do},
language = {en},
urldate = {2021-12-27},
}
New compound targets different neural receptors than existing antipsychotic drugs do
