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Seo MK, Kim H, Choi AJ, Seog DH, Kho WG, Park SW, Lee JG. Effects of tianeptine on mTORC1-mediated neuronal autophagy in primary rat hippocampal neurons under nutrient deprivation. Sci Rep 2025; 15:14488. [PMID: 40280952 PMCID: PMC12032415 DOI: 10.1038/s41598-025-92988-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Accepted: 03/04/2025] [Indexed: 04/29/2025] Open
Abstract
The aim of this study was to investigate the effects of the antidepressant tianeptine on the mechanistic target of rapamycin complex 1(mTORC1)-mediated autophagy pathway in primary hippocampal neurons exposed to B27-deprived conditions. When primary hippocampal neurons were treated with tianeptine at doses of 1, 10, 50, and 100 µM for 3 days under B27-deprived conditions, we observed that it activated autophagy and increased the formation of autophagosomes through the upregulation of autophagic proteins, including autophagy-activating kinase 1 (ULK1), Beclin 1, LC3B-II/I, and p62. And at a concentration of 100 µM tianeptine, the decrease in mTORC1 phosphorylation induced by B27 deprivation was significantly reversed. Changes in the expression of autophagic proteins induced by B27 deprivation were reversed by tianeptine treatment in a concentration-dependent manner, and tianeptine significantly reduced the increase in LC3B membrane number induced by B27 deprivation, an effect that was blocked by pretreatment with rapamycin. In conclusion, tianeptine attenuated the activity of mTORC1-mediated autophagy in primary rat hippocampal neurons under B27-deprived conditions. These results may suggest a novel mechanism by which tianeptine may affect autophagy in neurons.
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Affiliation(s)
- Mi Kyoung Seo
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea
- Department of Convergence Biomedical Science, College of Medicine, Inje University, Busan, 47392, Republic of Korea
| | - Hyewon Kim
- Department of Psychiatry, College of Medicine, Haeundae Paik Hospital, Inje University, Busan, 48108, Republic of Korea
| | - Ah Jeong Choi
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea
| | - Dae-Hyun Seog
- Department of Convergence Biomedical Science, College of Medicine, Inje University, Busan, 47392, Republic of Korea
- Department of Biochemistry, College of Medicine, Inje University, Busan, 47392, Republic of Korea
- Dementia and Neurodegenerative Disease Research Center, College of Medicine, Inje University, Busan, 47392, Republic of Korea
| | - Weon-Gyu Kho
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea
- Department of Parasitology, College of Medicine, Inje University, Busan, 47392, Republic of Korea
| | - Sung Woo Park
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea.
- Department of Convergence Biomedical Science, College of Medicine, Inje University, Busan, 47392, Republic of Korea.
| | - Jung Goo Lee
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea.
- Department of Psychiatry, College of Medicine, Haeundae Paik Hospital, Inje University, Busan, 48108, Republic of Korea.
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Aslani S, Nafie J, Wahab MF, Armstrong DW. Tianeptine: enantiomeric separations, structural assignment, and biological interactions. Talanta 2025; 294:128197. [PMID: 40339337 DOI: 10.1016/j.talanta.2025.128197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 04/11/2025] [Accepted: 04/20/2025] [Indexed: 05/10/2025]
Abstract
Tianeptine is an atypical tricyclic antidepressant that has gained attention due to its unique mechanism of action, distinguishing it from other such medications. The drug has proliferated in recreational markets as "gas station heroin" since it produces opioid-like effects and euphoric highs as a result of binding to mu opioid receptors. The unrestricted availability of tianeptine has resulted in many irreversible adverse effects and fatal overdoses. Tianeptine is a chiral molecule and has not yet been widely investigated for the therapeutic/toxic effects of its single enantiomers. Such studies require reliable and fast chiral separation methods for separation and quantitation. In this study, the enantioselective HPLC methods in normal phase and polar ionic mode were developed for analytical and preparative separation and purification of tianeptine. Two chiral stationary phases were employed: one based on 1-(3,5-dinitrobenzamido)-1,2,3,4-tetrahydrophenanthrene and another based on a modified macrocyclic glycopeptide, both utilizing 2.7 μm core-shell bonded silica particles. These column chemistries are available under the commercial names of WhelkoShell and NicoShell, respectively. Both columns offer the same elution order, as confirmed by an optical circular dichroism detector. The absolute configurations of the purified single enantiomers were determined using vibrational circular dichroism spectroscopy with a 99 % confidence level. The total tianeptine and its enantiomeric ratio in recreational products were analyzed by HPLC-UV after developing a robust extraction procedure with ethanol for liquid and solid products. The assessment of the enantioselective binding of tianeptine to many essential proteins revealed higher affinity of human serum albumin for the S-tianeptine.
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Affiliation(s)
- Saba Aslani
- Department of Chemistry and Biochemistry, University of Texas at Arlington, 700 Planetarium Place, Arlington, TX, 76019, United States
| | - Jordan Nafie
- BioTools, Inc., Jupiter, FL, 33478, United States
| | - M Farooq Wahab
- Department of Chemistry and Biochemistry, University of Texas at Arlington, 700 Planetarium Place, Arlington, TX, 76019, United States
| | - Daniel W Armstrong
- Department of Chemistry and Biochemistry, University of Texas at Arlington, 700 Planetarium Place, Arlington, TX, 76019, United States.
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Counts CJ, Spadaro AV, Cerbini TA, Krotulski AJ, Walton SE, Greller HA, Nelson LS, Ruck BE, Hung O, Logan B, Calello DP. An Outbreak of Synthetic Cannabinoid-Adulterated Tianeptine Products in New Jersey - Case Series. J Med Toxicol 2025; 21:253-259. [PMID: 40102319 PMCID: PMC11933608 DOI: 10.1007/s13181-025-01068-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 02/26/2025] [Accepted: 02/28/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Tianeptine, an atypical antidepressant not approved in the United States, is readily purchased from unregulated markets such as the internet and gas stations. We became aware of a cluster of 34 patients in New Jersey who became ill following ingestion of the tianeptine containing-product Neptune's Fix, the rate of which (4.6 cases per month) far exceeded the background rate for this substance of 0.5 cases per year. METHODS We retrospectively identified tianeptine exposures reported to the New Jersey Poison Information and Education System (NJPIES) prior to June 2023 to determine the background rate of tianeptine exposure. From June 2023- February 2024 we prospectively surveilled tianeptine exposures reported to NJPIES, recorded demographic and clinical information, and recruited samples for testing. Six samples of the ingested products were obtained and analyzed using gas chromatography mass spectrometry (GC-MS) and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Whole blood samples from two patients were tested for tianeptine and synthetic cannabinoids. RESULTS During the period of interest, NJPIES received 41 exposure calls, with 37 reporting acute toxicity in 34 unique patients, two reporting chronic tianeptine use, and two reporting withdrawal. Among the 37 exposures resulting in acute toxicity, commonly reported effects included altered mental status, tachycardia, hypotension, and seizures. 43% (n = 16) were intubated, and 65% (n = 24) were admitted to the ICU. Analytical testing of six samples identified variable product composition, containing various xenobiotics including tianeptine, kava alkaloids, natural cannabinoids, and the synthetic cannabinoids MDMB-4en-PINACA and ADB-4en-PINACA. MDMB-4en-PINACA was detected in one of the two patient blood specimens. CONCLUSIONS These cases represent a marked increase in tianeptine exposures compared with the poison center's historical average. Analytical testing revealed variable product composition, including the presence of synthetic cannabinoids. Clinicians should be aware that tianeptine containing products are widely available, unregulated, and can be adulterated.
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Affiliation(s)
- Christopher J Counts
- Department of Emergency Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA.
- New Jersey Poison Information and Education System, Newark, NJ, USA.
| | - Anthony V Spadaro
- Department of Emergency Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
- New Jersey Poison Information and Education System, Newark, NJ, USA
| | - Trevor A Cerbini
- Department of Emergency Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
- New Jersey Poison Information and Education System, Newark, NJ, USA
| | - Alex J Krotulski
- Center for Forensic Science Research and Education, Fredric Rieders Family Foundation, Willow Grove, PA, USA
| | - Sara E Walton
- Center for Forensic Science Research and Education, Fredric Rieders Family Foundation, Willow Grove, PA, USA
| | - Howard A Greller
- Department of Emergency Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
- New Jersey Poison Information and Education System, Newark, NJ, USA
| | - Lewis S Nelson
- Department of Emergency Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
- New Jersey Poison Information and Education System, Newark, NJ, USA
| | - Bruce E Ruck
- New Jersey Poison Information and Education System, Newark, NJ, USA
| | - Oliver Hung
- Morristown Medical Center, Morristown, NJ, USA
| | - Barry Logan
- Center for Forensic Science Research and Education, Fredric Rieders Family Foundation, Willow Grove, PA, USA
| | - Diane P Calello
- Department of Emergency Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
- New Jersey Poison Information and Education System, Newark, NJ, USA
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Choquet D, Opazo P, Zhang H. AMPA receptor diffusional trapping machinery as an early therapeutic target in neurodegenerative and neuropsychiatric disorders. Transl Neurodegener 2025; 14:8. [PMID: 39934896 PMCID: PMC11817889 DOI: 10.1186/s40035-025-00470-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Accepted: 01/14/2025] [Indexed: 02/13/2025] Open
Abstract
Over the past two decades, there has been a growing recognition of the physiological importance and pathological implications surrounding the surface diffusion of AMPA receptors (AMPARs) and their diffusional trapping at synapses. AMPAR surface diffusion entails the thermally powered random Brownian lateral movement of these receptors within the plasma membrane, facilitating dynamic exchanges between synaptic and extrasynaptic compartments. This process also enables the activity-dependent diffusional trapping and accumulation of AMPARs at synapses through transient binding to synaptic anchoring slots. Recent research highlights the critical role of synaptic recruitment of AMPARs via diffusional trapping in fundamental neural processes such as the development of the early phases of long-term potentiation (LTP), contextual fear memory, memory consolidation, and sensory input-induced cortical remapping. Furthermore, studies underscore that regulation of AMPAR diffusional trapping is altered across various neurological disease models, including Huntington's disease (HD), Alzheimer's disease (AD), and stress-related disorders like depression. Notably, pharmacological interventions aimed at correcting deficits in AMPAR diffusional trapping have demonstrated efficacy in restoring synapse numbers, LTP, and memory functions in these diverse disease models, despite their distinct pathogenic mechanisms. This review provides current insights into the molecular mechanisms underlying the dysregulation of AMPAR diffusional trapping, emphasizing its role as a converging point for multiple pathological signaling pathways. We propose that targeting AMPAR diffusional trapping represents a promising early therapeutic strategy to mitigate synaptic plasticity and memory deficits in a spectrum of brain disorders, encompassing but not limited to HD, AD, and stress-related conditions. This approach underscores an integrated therapeutic target amidst the complexity of these neurodegenerative and neuropsychiatric diseases.
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Affiliation(s)
- Daniel Choquet
- Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, 33000, Bordeaux, France
- Univ. Bordeaux, CNRS, INSERM, Bordeaux Imaging Center, BIC, UAR 3420, US 4, 33000, Bordeaux, France
| | - Patricio Opazo
- UK Dementia Research Institute, Centre for Discovery Brain Sciences, University of Edinburgh, Chancellor's Building, Edinburgh, EH16 4SB, UK
| | - Hongyu Zhang
- Department of Biomedicine, University of Bergen, 5009, Bergen, Norway.
- Mohn Research Center for the Brain, University of Bergen, 5009, Bergen, Norway.
- Department of Radiology, Haukeland University Hospital, 5021, Bergen, Norway.
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Quadir M, Rine NI, Badeti J, Hays HL, Michaels NL, Yang J, Smith GA. Tianeptine Exposures Reported to United States Poison Centers, 2015-2023. J Med Toxicol 2025; 21:30-41. [PMID: 39724478 PMCID: PMC11706824 DOI: 10.1007/s13181-024-01053-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 12/06/2024] [Accepted: 12/12/2024] [Indexed: 12/28/2024] Open
Abstract
INTRODUCTION Tianeptine is an atypical tricyclic antidepressant not approved for medical use in the US but is found in dietary supplements. This study investigates single-substance tianeptine exposures reported to US poison centers. METHODS We analyzed cases involving tianeptine reported to the National Poison Data System from 2015 to 2023. RESULTS There were 892 single-substance tianeptine exposures reported to US poison centers from 2015 to 2023, and the rate of exposures increased 1,400% from 2015 to 2023, including a 525% increase from 2018 to 2023. Most exposures were associated with moderate (51.5%) or major (12.0%) effects, and 40.1% required medical admission, including 22.9% to a critical care unit. Individuals 50 years and older were more likely to experience major effects (RR: 1.70, 95% CI: 1.13-2.56) or require medical admission (RR: 1.43, 95% CI: 1.20-1.72) than younger individuals. Tianeptine abuse accounted for 40.1% of exposures and was more likely to be associated with moderate or major effects (RR: 1.18, 95% CI: 1.06-1.31) than exposures not attributed to abuse. Withdrawal accounted for 22.5% of tianeptine exposures. Tianeptine exposure rates were highest in the US South. Alabama enacted legislation to regulate tianeptine as a controlled substance in 2021. Alabama's tianeptine exposure rate increased by 1,413.7% from 2018 to 2021, followed by a 74.6% decrease from 2021 to 2023, while the rate in other southern states continued to increase. CONCLUSIONS This study demonstrates the toxicity and rapid increase of tianeptine exposures reported to US poison centers. Uniform regulation of tianeptine across all states may offer an important strategy to help mitigate this public health problem.
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Affiliation(s)
- Mustafa Quadir
- Center for Injury Research and Policy, The Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, USA
- University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Natalie I Rine
- Central Ohio Poison Center, Nationwide Children's Hospital, Columbus, OH, USA
| | - Jaahnavi Badeti
- Center for Injury Research and Policy, The Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, USA
| | - Hannah L Hays
- Center for Injury Research and Policy, The Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, USA
- Central Ohio Poison Center, Nationwide Children's Hospital, Columbus, OH, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Nichole L Michaels
- Center for Injury Research and Policy, The Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Jingzhen Yang
- Center for Injury Research and Policy, The Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Gary A Smith
- Center for Injury Research and Policy, The Abigail Wexner Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, USA.
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
- Child Injury Prevention Alliance, Columbus, OH, USA.
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6
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Breivik TJ, Gjermo P, Gundersen Y, Opstad PK, Murison R, Hugoson A, von Hörsten S, Fristad I. Microbiota-immune-brain interactions: A new vision in the understanding of periodontal health and disease. Periodontol 2000 2024; 96:20-41. [PMID: 39233381 PMCID: PMC11579829 DOI: 10.1111/prd.12610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 08/01/2024] [Accepted: 08/19/2024] [Indexed: 09/06/2024]
Abstract
This review highlights the significance of interactions between the microbiota, immune system, nervous and hormonal systems, and the brain on periodontal health and disease. Microorganisms in the microbiota, immune cells, and neurons communicate via homeostatic nervous and hormonal systems, regulating vital body functions. By modulating pro-inflammatory and anti-inflammatory adaptive immune responses, these systems control the composition and number of microorganisms in the microbiota. The strength of these brain-controlled responses is genetically determined but is sensitive to early childhood stressors, which can permanently alter their responsiveness via epigenetic mechanisms, and to adult stressors, causing temporary changes. Clinical evidence and research with humans and animal models indicate that factors linked to severe periodontitis enhance the responsiveness of these homeostatic systems, leading to persistent hyperactivation. This weakens the immune defense against invasive symbiotic microorganisms (pathobionts) while strengthening the defense against non-invasive symbionts at the gingival margin. The result is an increased gingival tissue load of pathobionts, including Gram-negative bacteria, followed by an excessive innate immune response, which prevents infection but simultaneously destroys gingival and periodontal tissues. Thus, the balance between pro-inflammatory and anti-inflammatory adaptive immunity is crucial in controlling the microbiota, and the responsiveness of brain-controlled homeostatic systems determines periodontal health.
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Affiliation(s)
- Torbjørn Jarle Breivik
- Department of Periodontology, Faculty of Dentistry, Institute of Clinical OdontologyUniversity of OsloOsloNorway
- Division for ProtectionNorwegian Defence Research EstablishmentKjellerNorway
| | - Per Gjermo
- Department of Periodontology, Faculty of Dentistry, Institute of Clinical OdontologyUniversity of OsloOsloNorway
| | - Yngvar Gundersen
- Division for ProtectionNorwegian Defence Research EstablishmentKjellerNorway
| | - Per Kristian Opstad
- Division for ProtectionNorwegian Defence Research EstablishmentKjellerNorway
| | - Robert Murison
- Department of Biological and Medical Psychology, Faculty of PsychologyUniversity of BergenBergenNorway
| | - Anders Hugoson
- Department of Periodontology, Institute of OdontologyThe Sahlgrenska Academy at University of Gothenburg and School of Health and WelfareGothenburgSweden
| | - Stephan von Hörsten
- Department for Experimental Therapy, University Hospital Erlangen, Preclinical Experimental CenterFriedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU)ErlangenGermany
| | - Inge Fristad
- Department of Clinical Dentistry, Faculty of MedicineUniversity of BergenBergenNorway
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Ersoy B, Herzog ML, Pan W, Schilling S, Endres M, Göttert R, Kronenberg GD, Gertz K. The atypical antidepressant tianeptine confers neuroprotection against oxygen-glucose deprivation. Eur Arch Psychiatry Clin Neurosci 2024; 274:777-791. [PMID: 37653354 PMCID: PMC11127858 DOI: 10.1007/s00406-023-01685-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 08/14/2023] [Indexed: 09/02/2023]
Abstract
Proregenerative and neuroprotective effects of antidepressants are an important topic of inquiry in neuropsychiatric research. Oxygen-glucose deprivation (OGD) mimics key aspects of ischemic injury in vitro. Here, we studied the effects of 24-h pretreatment with serotonin (5-HT), citalopram (CIT), fluoxetine (FLU), and tianeptine (TIA) on primary mouse cortical neurons subjected to transient OGD. 5-HT (50 μM) significantly enhanced neuron viability as measured by MTT assay and reduced cell death and LDH release. CIT (10 μM) and FLU (1 μM) did not increase the effects of 5-HT and neither antidepressant conferred neuroprotection in the absence of supplemental 5-HT in serum-free cell culture medium. By contrast, pre-treatment with TIA (10 μM) resulted in robust neuroprotection, even in the absence of 5-HT. Furthermore, TIA inhibited mRNA transcription of candidate genes related to cell death and hypoxia and attenuated lipid peroxidation, a hallmark of neuronal injury. Finally, deep RNA sequencing of primary neurons subjected to OGD demonstrated that OGD induces many pathways relating to cell survival, the inflammation-immune response, synaptic dysregulation and apoptosis, and that TIA pretreatment counteracted these effects of OGD. In conclusion, this study highlights the comparative strength of the 5-HT independent neuroprotective effects of TIA and identifies the molecular pathways involved.
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Affiliation(s)
- Burcu Ersoy
- Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Center for Stroke Research Berlin, Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin-Brandenburg School for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Marie-Louise Herzog
- Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Center for Stroke Research Berlin, Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Center for Cardiovascular Research), Partner site, Berlin, Germany
| | - Wen Pan
- Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Center for Stroke Research Berlin, Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Center for Cardiovascular Research), Partner site, Berlin, Germany
| | - Simone Schilling
- Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Center for Stroke Research Berlin, Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Center for Cardiovascular Research), Partner site, Berlin, Germany
- Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany
| | - Matthias Endres
- Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Center for Stroke Research Berlin, Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Center for Cardiovascular Research), Partner site, Berlin, Germany
- Einstein Center for Neurosciences, Charité-Universitätsmedizin Berlin, Berlin, Germany
- DZNE (German Center for Neurodegenerative Diseases), Partner site, Berlin, Germany
- DZPG (German Center for Mental Health), Partner site, Berlin, Germany
| | - Ria Göttert
- Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Center for Stroke Research Berlin, Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Center for Cardiovascular Research), Partner site, Berlin, Germany
| | - Golo D Kronenberg
- Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Psychiatry Zürich, Lenggstrasse 31, P.O. Box 363, 8032, Zurich, Switzerland
| | - Karen Gertz
- Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
- Center for Stroke Research Berlin, Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
- DZHK (German Center for Cardiovascular Research), Partner site, Berlin, Germany.
- Einstein Center for Neurosciences, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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8
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Galust H, Seltzer JA, Hardin JR, Friedman NA, Minns A. "Tianeptine abuse via novel, extended-release, star-shaped, drug delivery device". Toxicol Rep 2023; 11:162-164. [PMID: 37559671 PMCID: PMC10407812 DOI: 10.1016/j.toxrep.2023.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/19/2023] [Accepted: 07/27/2023] [Indexed: 08/11/2023] Open
Abstract
We report a rare domestic case of exposure to tianeptine and use of a novel, extended-release, six-armed, star-shaped, drug delivery capsule. A 40-year-old male with a history of depression, anxiety, ethanol, opioid, cannabis, and tobacco use disorders presented to the emergency department (ED) from a substance abuse residential recovery treatment program after developing hypertension, tachycardia, and tremor for two day. He used an extended-release, six-armed, star-shaped, drug delivery device he purchased online, filling each arm with 15 mg of tianeptine (90 mg total). His intention was to mitigate the symptoms of kratom/opioid withdrawal through this extended-release method while simultaneously undergoing formal treatment for ethanol withdrawal. Tianeptine is an atypical tricyclic antidepressant that exerts complex mechanisms of action including serotonin (5-HT) neuromodulation as well as full μ-opioid and ∂-opioid receptor agonism. The capsule itself is made of caprolactone, which is a bioabsorbable material similar to absorbable sutures, initially developed as a long-term enteral antimalarial delivery method and is not FDA approved for human use. Over the course of the patients two day hospitalization course he developed symptoms consistent with uncomplicated ethanol withdrawal, which were treated with as-needed phenobarbital. No clinical manifestations of opioid or serotonin toxicity developed. Serial EKGs and telemetry monitoring remained unchanged. The patient was then medically cleared and discharged back to the residential recovery treatment program.
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Affiliation(s)
- Henrik Galust
- UCSD Fellowship in Medical Toxicology, Department of Emergency Medicine, UCSD Medical Center, 200W. Arbor Dr. #8676, San Diego, CA 92103, USA
| | - Justin A. Seltzer
- UCSD Fellowship in Medical Toxicology, Department of Emergency Medicine, UCSD Medical Center, 200W. Arbor Dr. #8676, San Diego, CA 92103, USA
| | - Jeremy R. Hardin
- UCSD Fellowship in Medical Toxicology, Department of Emergency Medicine, UCSD Medical Center, 200W. Arbor Dr. #8676, San Diego, CA 92103, USA
| | - Nathan A. Friedman
- UCSD Fellowship in Medical Toxicology, Department of Emergency Medicine, UCSD Medical Center, 200W. Arbor Dr. #8676, San Diego, CA 92103, USA
| | - Alicia Minns
- UCSD Fellowship in Medical Toxicology, Department of Emergency Medicine, UCSD Medical Center, 200W. Arbor Dr. #8676, San Diego, CA 92103, USA
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9
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Serafini RA, Estill M, Pekarskaya EA, Sakloth F, Shen L, Javitch JA, Zachariou V. Tianeptine promotes lasting antiallodynic effects in a mouse model of neuropathic pain. Neuropsychopharmacology 2023; 48:1680-1689. [PMID: 37474762 PMCID: PMC10517169 DOI: 10.1038/s41386-023-01645-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 05/31/2023] [Accepted: 06/27/2023] [Indexed: 07/22/2023]
Abstract
Tricyclic antidepressants (TCAs), such as desipramine (DMI), are effective at managing neuropathic pain symptoms but often take several weeks to become effective and also lead to considerable side effects. Tianeptine (TIAN) is an atypical antidepressant that activates the mu-opioid receptor but does not produce analgesic tolerance or withdrawal in mice, nor euphoria in humans, at clinically-relevant doses. Here, we evaluate the efficacy of TIAN at persistently alleviating mechanical allodynia in the spared nerve injury (SNI) model of neuropathic pain, even well after drug clearance. After finding an accelerated onset of antiallodynic action compared to DMI, we used genetically modified mice to gain insight into RGS protein-associated pathways that modulate the efficacy of TIAN relative to DMI in models of neuropathic pain. Because we observed similar behavioral responses to both TIAN and DMI treatment in RGS4, RGSz1, and RGS9 knockout mice, we performed RNA sequencing on the NAc of TIAN- and DMI-treated mice after prolonged SNI to further clarify potential mechanisms underlying TIANs faster therapeutic actions. Our bioinformatic analysis revealed distinct transcriptomic signatures between the two drugs, with TIAN more directly reversing SNI-induced differentially expressed genes, and further predicted several upstream regulators that may be implicated in onset of action. This new understanding of the molecular pathways underlying TIAN action may enable the development of novel and more efficacious pharmacological approaches for the management of neuropathic pain.
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Affiliation(s)
- Randal A Serafini
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pharmacology, Physiology and Biophysics, Chobanian & Avedisian School of Medicine at Boston University, Boston, MA, USA
| | - Molly Estill
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Elizabeth A Pekarskaya
- Department of Neuroscience, Columbia University, New York, NY, USA
- Department of Psychiatry, Columbia University, New York, NY, USA
- Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
| | - Farhana Sakloth
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Li Shen
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jonathan A Javitch
- Department of Psychiatry, Columbia University, New York, NY, USA
- Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, USA
| | - Venetia Zachariou
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Pharmacology, Physiology and Biophysics, Chobanian & Avedisian School of Medicine at Boston University, Boston, MA, USA.
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10
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Jung K, Kwon JT. Tianeptine Affects the Improvement of Behavioral Defects, such as Schizophrenia, Caused by Maternal Immune Activation in the Mice Offspring. Cent Nerv Syst Agents Med Chem 2023; 23:CNSAMC-EPUB-134286. [PMID: 37670703 PMCID: PMC10680080 DOI: 10.2174/1871524923666230905142700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 07/10/2023] [Accepted: 07/19/2023] [Indexed: 09/07/2023]
Abstract
BACKGROUND Simultaneously with studies on animal models of fetal-induced maternal immune activation, related studies documented behavior, neurophysiological, and/or neurochemical disorders observed in some neuropsychiatric disorders, including autism and schizophrenia. OBJECTIVE To investigate whether treatment tianeptine might ameliorate maternal immune activation (MIA)-induced behavioral deficits in the offspring. MATERIALS AND METHODS The pregnant mice were injected through tail vein injection at a concentration of 5 mg/kg of polyriboinosinic-polyribocytidilic acid (polyI:C) and/or used saline as a vehicle. The injection was performed on the 9th day of pregnancy. Each group of MIA offspring was subjected to vehicle, clozapine, or tianeptine treatment. RESULTS In prepulse inhibition (PPI) test, oral treatment with tianeptine ameliorated MIA-induced sensorimotor gating deficit. Most behavioral parameters of social interaction test (SIT), forced swimming test (FST), and open field test (OFT) were significantly changed in the MIA offspring. Tianeptine treatment significantly recovered behavioral changes observed in the SIT, OFT, and FST. In order to confirm expression level of neurodevelopmental proteins, immunohistochemical image analysis and Western blot were performed, and the medial prefrontal cortex (mPFC) was targeted. As a result, it was confirmed that the neurodevelopmental proteins were decreased, which was recovered after administration of tianeptine to MIA offspring. CONCLUSION Tianeptine might be useful for treating psychiatric disorders with neurodevelopmental issues.
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Affiliation(s)
- Kooseung Jung
- Department of Clinical Pharmacology, College of Medicine, Soon Chun Hyang University, Cheonan, Republic of Korea
| | - Jun-Tack Kwon
- Department of Clinical Pharmacology, College of Medicine, Soon Chun Hyang University, Cheonan, Republic of Korea
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11
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Cutler AJ, Mattingly GW, Maletic V. Understanding the mechanism of action and clinical effects of neuroactive steroids and GABAergic compounds in major depressive disorder. Transl Psychiatry 2023; 13:228. [PMID: 37365161 PMCID: PMC10293235 DOI: 10.1038/s41398-023-02514-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 05/12/2023] [Accepted: 06/12/2023] [Indexed: 06/28/2023] Open
Abstract
The pathophysiology of major depressive disorder (MDD) is thought to result from impaired connectivity between key brain networks. Gamma-aminobutyric acid (GABA) is the key inhibitory neurotransmitter in the brain, working primarily via GABAA receptors, with an important role in virtually all physiologic functions in the brain. Some neuroactive steroids (NASs) are positive allosteric modulators (PAMs) of GABAA receptors and potentiate phasic and tonic inhibitory responses via activation of synaptic and extrasynaptic GABAA receptors, respectively. This review first discusses preclinical and clinical data that support the association of depression with diverse defects in the GABAergic system of neurotransmission. Decreased levels of GABA and NASs have been observed in adults with depression compared with healthy controls, while treatment with antidepressants normalized the altered levels of GABA and NASs. Second, as there has been intense interest in treatment approaches for depression that target dysregulated GABAergic neurotransmission, we discuss NASs approved or currently in clinical development for the treatment of depression. Brexanolone, an intravenous NAS and a GABAA receptor PAM, is approved by the U.S. Food and Drug Administration for the treatment of postpartum depression (PPD) in patients 15 years and older. Other NASs include zuranolone, an investigational oral GABAA receptor PAM, and PH10, which acts on nasal chemosensory receptors; clinical data to date have shown improvement in depressive symptoms with these investigational NASs in adults with MDD or PPD. Finally, the review discusses how NAS GABAA receptor PAMs may potentially address the unmet need for novel and effective treatments with rapid and sustained antidepressant effects in patients with MDD.
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12
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Wagner ML, Pergolizzi J, LeQuang JAK, Breve F, Varrassi G. From Antidepressant Tianeptine to Street Drug ZaZa: A Narrative Review. Cureus 2023; 15:e40688. [PMID: 37485121 PMCID: PMC10359047 DOI: 10.7759/cureus.40688] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 06/19/2023] [Indexed: 07/25/2023] Open
Abstract
Tianeptine is often incorrectly described as a selective serotonin reuptake inhibitor, but it actually is a µ-opioid receptor agonist with anxiolytic effects. It has been approved since the last 1980s in about 24 countries as a treatment for depression, but it was never cleared to market in the United States for this purpose. Nevertheless, tianeptine joined the billion-dollar US market of nootropics as ZaZa or Tianna Red and is widely available online and in small shops without a prescription, to the point that it has been nicknamed "gas station heroin." While the therapeutic dose range is about 25 to 50 mg/day, tianeptine abusers may take 100 times that amount. Tolerance occurs rapidly and users who seek to recapture the short-lived euphoric effects of the drug have to take more and more. Social media has peer-support sites for those trying to discontinue tianeptine. Tianeptine is associated with multiple side effects at high doses along with dependence, withdrawal symptoms, toxicity, respiratory depression, and even mortality. Agitation is more often a presenting symptom of withdrawal than toxicity. Tianeptine is often used by polysubstance drug abusers who may be unaware of the drug's dangers. Few clinicians are aware of tianeptine and most urine assays do not screen for it. Greater awareness is needed for this drug and steps must be taken as tianeptine or "gas station heroin" is emerging as a new public health threat.
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Affiliation(s)
| | | | | | - Frank Breve
- Pharmacy, Temple University, Philadelphia, USA
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13
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Allain F, Ehrlich AT, McNicholas M, Gross F, Ma W, Kieffer BL, Darcq E. Chronic tianeptine induces tolerance in analgesia and hyperlocomotion via mu-opioid receptor activation in mice. Front Psychiatry 2023; 14:1186397. [PMID: 37287667 PMCID: PMC10242025 DOI: 10.3389/fpsyt.2023.1186397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/24/2023] [Indexed: 06/09/2023] Open
Abstract
Introduction Tianeptine is approved in some countries to treat depression and anxiety. In addition to its activity on serotonin and glutamate neurotransmission, tianeptine has been proven to be a mu-opioid receptor (MOR) agonist, but only a few preclinical studies have characterized the opioid-like behavioral effects of tianeptine. Methods In this study, we tested tianeptine activity on G protein activation using the [S35] GTPγS binding assay in brain tissue from MOR+/+ and MOR-/- mice. Then, to determine whether tianeptine behavioral responses are MOR-dependent, we characterized the analgesic, locomotor, and rewarding responses of tianeptine in MOR+/+ and MOR-/- mice using tail immersion, hot plate, locomotor, and conditioned place preference tests. Results Using the [S35] GTPγS binding assay, we found that tianeptine signaling is mediated by MOR in the brain with properties similar to those of DAMGO (a classic MOR agonist). Furthermore, we found that the MOR is necessary for tianeptine's analgesic (tail immersion and hot plate), locomotor, and rewarding (conditioned place preference) effects. Indeed, these behavioral effects could only be measured in MOR+/+ mice but not in MOR-/- mice. Additionally, chronic administration of tianeptine induced tolerance to its analgesic and hyperlocomotor effects. Discussion These findings suggest that tianeptine's opioid-like effects require MOR and that chronic use could lead to tolerance.
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Affiliation(s)
- Florence Allain
- Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, QC, Canada
- Centre de Recherche en Biomédecine de Strasbourg, INSERM, Université de Strasbourg, Strasbourg, France
| | - Aliza T. Ehrlich
- Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Michael McNicholas
- Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Florence Gross
- Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Weiya Ma
- Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Brigitte L. Kieffer
- Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, QC, Canada
- Centre de Recherche en Biomédecine de Strasbourg, INSERM, Université de Strasbourg, Strasbourg, France
| | - Emmanuel Darcq
- Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, QC, Canada
- Centre de Recherche en Biomédecine de Strasbourg, INSERM, Université de Strasbourg, Strasbourg, France
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14
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Inhibition of Microglial GSK3β Activity Is Common to Different Kinds of Antidepressants: A Proposal for an In Vitro Screen to Detect Novel Antidepressant Principles. Biomedicines 2023; 11:biomedicines11030806. [PMID: 36979785 PMCID: PMC10045655 DOI: 10.3390/biomedicines11030806] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 02/17/2023] [Accepted: 03/04/2023] [Indexed: 03/09/2023] Open
Abstract
Depression is a major public health concern. Unfortunately, the present antidepressants often are insufficiently effective, whilst the discovery of more effective antidepressants has been extremely sluggish. The objective of this review was to combine the literature on depression with the pharmacology of antidepressant compounds, in order to formulate a conceivable pathophysiological process, allowing proposals how to accelerate the discovery process. Risk factors for depression initiate an infection-like inflammation in the brain that involves activation microglial Toll-like receptors and glycogen synthase kinase-3β (GSK3β). GSK3β activity alters the balance between two competing transcription factors, the pro-inflammatory/pro-oxidative transcription factor NFκB and the neuroprotective, anti-inflammatory and anti-oxidative transcription factor NRF2. The antidepressant activity of tricyclic antidepressants is assumed to involve activation of GS-coupled microglial receptors, raising intracellular cAMP levels and activation of protein kinase A (PKA). PKA and similar kinases inhibit the enzyme activity of GSK3β. Experimental antidepressant principles, including cannabinoid receptor-2 activation, opioid μ receptor agonists, 5HT2 agonists, valproate, ketamine and electrical stimulation of the Vagus nerve, all activate microglial pathways that result in GSK3β-inhibition. An in vitro screen for NRF2-activation in microglial cells with TLR-activated GSK3β activity, might therefore lead to the detection of totally novel antidepressant principles with, hopefully, an improved therapeutic efficacy.
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15
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Perić I, Lješević M, Beškoski V, Nikolić M, Filipović D. Metabolomic profiling relates tianeptine effectiveness with hippocampal GABA, myo-inositol, cholesterol, and fatty acid metabolism restoration in socially isolated rats. Psychopharmacology (Berl) 2022; 239:2955-2974. [PMID: 35776189 DOI: 10.1007/s00213-022-06180-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 06/16/2022] [Indexed: 12/28/2022]
Abstract
RATIONALE Discovering biomarkers of major depressive disorder (MDD) can give a deeper understanding of this mood disorder and improve the ability to screen for, diagnose, and treat MDD. OBJECTIVES In this study, metabolomics was used in unraveling metabolite fluctuations of MDD and drug outcome by creating specific metabolomic fingerprints. We report metabolomic patterns of change of the hippocampus of adult male Wistar rats following chronic social isolation (CSIS) (6 weeks), an animal model of depression, and/or chronic tianeptine (Tian) treatment (10 mg kg-1 per day) (lasting 3 weeks of 6-week CSIS), monitored by using comprehensive GC × GC-MS. RESULTS The comparative metabolomic analysis highlighted the role of gamma aminobutyric acid (GABA), iso-allocholate, and unsaturated fatty acid metabolism alterations following the CSIS, which was corroborated with moderate to strong negative Pearson's correlation of GABA, docosahexaenoic, 9-hexadecenoic acid, 5,8,11,14-eicosatetraynoic, and arachidonic acids with immobility behavior in the forced swim test. The antidepressant effect of Tian restored GABA levels, which was absent in Tian resilient rats. Tian decreased myo-inositol and increased TCA cycle intermediates, amino acids, and cholesterol and its metabolite. As key molecules of divergence between Tian effectiveness and resilience, metabolomics revealed myo-inositol, GABA, cholesterol, and its metabolite. A significant moderate positive correlation between myo-inositol and immobility was revealed. Tian probably acted by upregulating NMDAR's and α2 adrenergic receptors (AR) or norepinephrine transporter in both control and stressed animals. CONCLUSION Metabolomics revealed several dysregulations underlying CSIS-induced depressive-like behavior and responsiveness to Tian, predominantly converging into NMDAR-mediated glutamate and myo-inositol signalization and GABA inhibitory pathways.
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Affiliation(s)
- Ivana Perić
- Department of Molecular Biology and Endocrinology, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovića Alasa 12-14, 11351, Vinča, Belgrade, Serbia
| | - Marija Lješević
- Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Njegoševa 12, 11000, Belgrade, Serbia
| | - Vladimir Beškoski
- Department of Biochemistry, University of Belgrade - Faculty of Chemistry, Studentski trg 12-16, 11000, Belgrade, Serbia
| | - Milan Nikolić
- Department of Biochemistry, University of Belgrade - Faculty of Chemistry, Studentski trg 12-16, 11000, Belgrade, Serbia
| | - Dragana Filipović
- Department of Molecular Biology and Endocrinology, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovića Alasa 12-14, 11351, Vinča, Belgrade, Serbia.
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16
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The Opioid System in Depression. Neurosci Biobehav Rev 2022; 140:104800. [PMID: 35914624 PMCID: PMC10166717 DOI: 10.1016/j.neubiorev.2022.104800] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 06/20/2022] [Accepted: 07/25/2022] [Indexed: 12/16/2022]
Abstract
Opioid receptors are widely distributed throughout the brain and play an essential role in modulating aspects of human mood, reward, and well-being. Accumulating evidence indicates the endogenous opioid system is dysregulated in depression and that pharmacological modulators of mu, delta, and kappa opioid receptors hold potential for the treatment of depression. Here we review animal and clinical data, highlighting evidence to support: dysregulation of the opioid system in depression, evidence for opioidergic modulation of behavioural processes and brain regions associated with depression, and evidence for opioidergic modulation in antidepressant responses. We evaluate clinical trials that have examined the safety and efficacy of opioidergic agents in depression and consider how the opioid system may be involved in the effects of other treatments, including ketamine, that are currently understood to exert antidepressant effects through non-opioidergic actions. Finally, we explore key neurochemical and molecular mechanisms underlying the potential therapeutic effects of opioid system engagement, that together provides a rationale for further investigation into this relevant target in the treatment of depression.
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17
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García-Alberca JM, Gris E, de la Guía P, Mendoza S. Effects of Tianeptine Treatment on Depression and Cognitive Function in Patients with Alzheimer’s Disease: A 12-Month Retrospective Observational Study. J Alzheimers Dis 2022; 88:707-720. [PMID: 35694919 PMCID: PMC9398087 DOI: 10.3233/jad-215630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Background: Depression is a common manifestation in Alzheimer’s disease (AD). In clinical practice, antidepressant medication is often used for depression in AD. Objective: We explore the effectiveness of the atypical antidepressant tianeptine compared with other conventional antidepressants in AD patients with depression in a real-life setting. Methods: We retrospectively identified 126 AD patients who had received antidepressant treatment for 12 months with tianeptine or other antidepressants. Subjects were divided into two groups according to the treatment they had received: tianeptine group (n = 38) or other antidepressant group (n = 88). Drug effects on depression, cognition, behavior, and functional performance were evaluated at baseline, 6, and 12 months. A Mixed Effects Model Analysis was carried out to evaluate changes in performance scores. Results: Both tianeptine and other antidepressants showed an antidepressant effect after 12 months with significant improvement on the Cornell Scale for Depression in Dementia, the Hamilton Depression Rating Scale, and the Neuropsychiatric Inventory-Depression subscale. A statistically significant improvement at 12 months was shown in the tianeptine group versus the other antidepressants group on most of the cognitive measures such as the Mini-Mental State Examination, the Letter and Category Fluency Test, the Rey Auditory Verbal Learning Test, and the Boston Naming Test. Conclusion: Our results suggest that tianeptine reduces depressive symptoms and improves cognition in AD patients. This could be considered clinically relevant and should inspire the design of future long-term randomized controlled trials that contribute to supporting the use of tianeptine for improving cognitive function in AD patients.
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Affiliation(s)
- José María García-Alberca
- Alzheimer Research Center and Memory Clinic, Instituto Andaluz de Neurociencia (IANEC), Málaga, Spain
| | - Esther Gris
- Alzheimer Research Center and Memory Clinic, Instituto Andaluz de Neurociencia (IANEC), Málaga, Spain
| | - Paz de la Guía
- Alzheimer Research Center and Memory Clinic, Instituto Andaluz de Neurociencia (IANEC), Málaga, Spain
| | - Silvia Mendoza
- Alzheimer Research Center and Memory Clinic, Instituto Andaluz de Neurociencia (IANEC), Málaga, Spain
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18
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Han J, Andreu V, Langreck C, Pekarskaya EA, Grinnell SG, Allain F, Magalong V, Pintar J, Kieffer BL, Harris AZ, Javitch JA, Hen R, Nautiyal KM. Mu opioid receptors on hippocampal GABAergic interneurons are critical for the antidepressant effects of tianeptine. Neuropsychopharmacology 2022; 47:1387-1397. [PMID: 34593976 PMCID: PMC9117297 DOI: 10.1038/s41386-021-01192-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 08/28/2021] [Accepted: 09/15/2021] [Indexed: 11/09/2022]
Abstract
Tianeptine is an atypical antidepressant used in Europe to treat patients who respond poorly to selective serotonin reuptake inhibitors (SSRIs). The recent discovery that tianeptine is a mu opioid receptor (MOR) agonist has provided a potential avenue for expanding our understanding of antidepressant treatment beyond the monoamine hypothesis. Thus, our studies aim to understand the neural circuits underlying tianeptine's antidepressant effects. We show that tianeptine induces rapid antidepressant-like effects in mice after as little as one week of treatment. Critically, we also demonstrate that tianeptine's mechanism of action is distinct from fluoxetine in two important aspects: (1) tianeptine requires MORs for its chronic antidepressant-like effect, while fluoxetine does not, and (2) unlike fluoxetine, tianeptine does not promote hippocampal neurogenesis. Using cell-type specific MOR knockouts we further show that MOR expression on GABAergic cells-specifically somatostatin-positive neurons-is necessary for the acute and chronic antidepressant-like responses to tianeptine. Using central infusion of tianeptine, we also implicate the ventral hippocampus as a potential site of antidepressant action. Moreover, we show a dissociation between the antidepressant-like phenotype and other opioid-like phenotypes resulting from acute tianeptine administration such as analgesia, conditioned place preference, and hyperlocomotion. Taken together, these results suggest a novel entry point for understanding what circuit dysregulations may occur in depression, as well as possible targets for the development of new classes of antidepressant drugs.
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Affiliation(s)
- Jaena Han
- Department of Biology, Columbia University, New York, NY, 10027, USA
| | - Valentine Andreu
- Department of Neuroscience, New York State Psychiatric Institute, Columbia University, New York, NY, 10032, USA
| | - Cory Langreck
- Department of Pharmacology, Columbia University, New York, NY, 10027, USA
| | - Elizabeth A Pekarskaya
- Department of Neuroscience, New York State Psychiatric Institute, Columbia University, New York, NY, 10032, USA
| | - Steven G Grinnell
- Department of Psychiatry, Columbia University, and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY, 10032, USA
| | - Florence Allain
- Department of Psychiatry, Douglas Mental Health Institute, McGill University, Montreal, QC, Canada
| | - Valerie Magalong
- Department of Neuroscience, New York State Psychiatric Institute, Columbia University, New York, NY, 10032, USA
| | - John Pintar
- Department of Neuroscience & Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA
| | - Brigitte L Kieffer
- Department of Psychiatry, Douglas Mental Health Institute, McGill University, Montreal, QC, Canada
| | - Alexander Z Harris
- Department of Psychiatry, Columbia University, and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY, 10032, USA
| | - Jonathan A Javitch
- Department of Pharmacology, Columbia University, New York, NY, 10027, USA
- Department of Psychiatry, Columbia University, and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY, 10032, USA
| | - René Hen
- Department of Neuroscience, New York State Psychiatric Institute, Columbia University, New York, NY, 10032, USA.
- Department of Psychiatry, Columbia University, and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY, 10032, USA.
| | - Katherine M Nautiyal
- Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH, 03755, USA.
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Morais FA, Lemos IS, Matiola RT, Freitas MLS, Alano CG, Cabral J, Wessler LB, Generoso JS, Scaini G, Réus GZ, Streck EL. Coadministration of tianeptine alters behavioral parameters and levels of neurotrophins in a chronic model of Maple Syrup Urine disease. Metab Brain Dis 2022; 37:1585-1596. [PMID: 35394251 DOI: 10.1007/s11011-022-00969-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 03/21/2022] [Indexed: 10/18/2022]
Abstract
Maple Syrup Urine Disease (MSUD) is caused by the deficiency in the activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), resulting in the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, and their respective branched-chain α-keto acids. Patients with MSUD are at high risk of developing chronic neuropsychiatric disorders; however, the pathophysiology of brain damage in these patients remains unclear. We hypothesize that MSUD can cause depressive symptoms in patients. To test our hypothesis, Wistar rats were submitted to the BCAA and tianeptine (antidepressant) administration for 21 days, starting seven days postnatal. Depression-like symptoms were assessed by testing for anhedonia and forced swimming after treatments. After the last test, the brain structures were dissected for the evaluation of neutrophins. We demonstrate that chronic BCAA administration induced depressive-like behavior, increased BDNF levels, and decreased NGF levels, suggesting a relationship between BCAA toxicity and brain damage, as observed in patients with MSUD. However, the administration of tianeptine was effective in preventing behavioral changes and restoring neurotrophins levels.
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Affiliation(s)
- Fábio A Morais
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Isabela S Lemos
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Rafaela T Matiola
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Maria Luísa S Freitas
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Carolina G Alano
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Julia Cabral
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Leticia B Wessler
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Jaqueline S Generoso
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Giselli Scaini
- Laboratório de Fisiopatologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Gislaine Z Réus
- Laboratório de Psiquiatria Translacional, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Emilio L Streck
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil.
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Tyler RE, Bluitt MN, Engers JL, Lindsley CW, Besheer J. The effects of predator odor (TMT) exposure and mGlu 3 NAM pretreatment on behavioral and NMDA receptor adaptations in the brain. Neuropharmacology 2022; 207:108943. [PMID: 35007623 PMCID: PMC8844221 DOI: 10.1016/j.neuropharm.2022.108943] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 12/09/2021] [Accepted: 01/04/2022] [Indexed: 12/13/2022]
Abstract
A stressor can trigger lasting adaptations that contribute to neuropsychiatric disorders. Predator odor (TMT) exposure is an innate stressor that may activate the metabotropic glutamate receptor 3 (mGlu3) to produce stress adaptations. To evaluate functional involvement, the mGlu3 negative allosteric modulator (NAM, VU6010572; 3 mg/kg, i.p.) was administered before TMT exposure in male, Long Evans rats. Two weeks after, rats underwent context re-exposure, elevated zero maze (ZM), and acoustic startle (ASR) behavioral tests, followed by RT-PCR gene expression in the insular cortex and bed nucleus of the stria terminalis (BNST) to evaluate lasting behavioral and molecular adaptations from the stressor. Rats displayed stress-reactive behaviors in response to TMT exposure that were not affected by VU6010572. Freezing and hyperactivity were observed during the context re-exposure, and mGlu3-NAM pretreatment during stressor prevented the context freezing response. TMT exposure did not affect ZM or ASR measures, but VU6010572 increased time spent in the open arms of the ZM and ASR habituation regardless of stressor treatment. In the insular cortex, TMT exposure increased expression of mGlu (Grm3, Grm5) and NMDA (GriN2A, GriN2B, GriN2C, GriN3A, GriN3B) receptor transcripts, and mGlu3-NAM pretreatment blocked GriN3B upregulation. In the BNST, TMT exposure increased expression of GriN2B and GriN3B in vehicle-treated rats, but decreased expression in the mGlu3-NAM group. Similar to the insular cortex, mGlu3-NAM reversed the stressor-induced upregulation of GriN3B in the BNST. mGlu3-NAM also upregulated GriN2A, GriN2B, GriN3B and Grm2 in the control group, but not the TMT group. Together, these data implicate mGlu3 receptor signaling in some lasting adaptations of predator odor stressor and anxiolytic-like effects.
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Affiliation(s)
- Ryan E Tyler
- Neuroscience Curriculum, School of Medicine, University of North Carolina - Chapel Hill, Chapel Hill, NC, USA; Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Maya N Bluitt
- Neuroscience Curriculum, School of Medicine, University of North Carolina - Chapel Hill, Chapel Hill, NC, USA; Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Julie L Engers
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA
| | - Craig W Lindsley
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA
| | - Joyce Besheer
- Neuroscience Curriculum, School of Medicine, University of North Carolina - Chapel Hill, Chapel Hill, NC, USA; Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina, Chapel Hill, NC, USA; Department of Psychiatry, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
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21
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Development of Dibenzothiazepine Derivatives as Multifunctional Compounds for Neuropathic Pain. Pharmaceuticals (Basel) 2022; 15:ph15040407. [PMID: 35455404 PMCID: PMC9030932 DOI: 10.3390/ph15040407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/18/2022] [Accepted: 03/23/2022] [Indexed: 11/16/2022] Open
Abstract
Neuropathic pain is a chronic and sometimes intractable condition caused by lesions or diseases of the somatosensory nervous system. Many drugs are available but unfortunately do not provide satisfactory effects in patients, producing limited analgesia and undesirable side effects. Thus, there is an urgent need to develop new pharmaceutical agents to treat neuropathic pain. To date, highly specific agents that modulate a single target, such as receptors or ion channels, never progress to the clinic, which may reflect the diverse etiologies of neuropathic pain seen in the human patient population. Therefore, the development of multifunctional compounds exhibiting two or more pharmacological activities is an attractive strategy for addressing unmet medical needs for the treatment of neuropathic pain. To develop novel multifunctional compounds, key pharmacophores of currently used clinical pain drugs, including pregabalin, fluoxetine and serotonin analogs, were hybridized to the side chain of tianeptine, which has been used as an antidepressant. The biological activities of the hybrid analogs were evaluated at the human transporters of neurotransmitters, including serotonin (hSERT), norepinephrine (hNET) and dopamine (hDAT), as well as mu (μ) and kappa (κ) opioid receptors. The most advanced hybrid of these multifunctional compounds, 17, exhibited multiple transporter inhibitory activities for the uptake of neurotransmitters with IC50 values of 70 nM, 154 nM and 2.01 μM at hSERT, hNET and hDAT, respectively. Additionally, compound 17 showed partial agonism (EC50 = 384 nM) at the μ-opioid receptor with no influence at the κ-opioid receptor. In in vivo pain animal experiments, the multifunctional compound 17 showed significantly reduced allodynia in a spinal nerve ligation (SNL) model by intrathecal administration, indicating that multitargeted strategies in single therapy could considerably benefit patients with multifactorial diseases, such as pain.
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22
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Pan X, Chen K, Han S, Luo X, Zhang D, Zhang H, Zhang L, Zhou X, Li J, Fang J, Wang S, Ye X. Total Triterpenes of Wolfiporia cocos (Schwein.) Ryvarden & Gilb Exerts Antidepressant-Like Effects in a Chronic Unpredictable Mild Stress Rat Model and Regulates the Levels of Neurotransmitters, HPA Axis and NLRP3 Pathway. Front Pharmacol 2022; 13:793525. [PMID: 35237160 PMCID: PMC8883346 DOI: 10.3389/fphar.2022.793525] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 01/17/2022] [Indexed: 12/29/2022] Open
Abstract
Purpose:Wolfiporia cocos is frequently used in traditional Chinese medicine to treat depression. However, antidepressant-like effects of the main active ingredients of Wolfiporia cocos, total triterpenes of Wolfiporia cocos (TTWC), are not well studied. This study aimed to investigate those effects and explore their specific mechanisms of action in depth. Methods: Chemical components of TTWC were analyzed using LC-MS. Depression-like behavior in rats were induced by chronic unpredictable mild stress (CUMS). The suppressive effects of TTWC (60, 120, 240 mg/kg) against CUMS-induced depression-like behavior were evaluated using the forced swimming test (FST), open field test (OFT) and sucrose preference test (SPT). Levels of 5-hydroxytryptamine (5-HT), glutamate (GLU), corticotropin-releasing hormone (CRH), interleukin-1 beta (IL-1beta), interleukin-18 (IL-18), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in different groups were determined by ELISA. Western blotting (WB) was used to detect the expression of NLRP3, ASC, pro-caspase-1, caspase-1, pro-IL-1beta, IL-1beta, pro-IL-18, and IL-18 in the prefrontal cortex. Additionally, the mRNA levels of NLRP3, ASC, caspase-1, IL-1beta and IL-18 were detected by RT-PCR. Results: A total of 69 lanostane-type triterpene acids of TTWC were identified. The results showed that TTWC exhibited an antidepressant-like effect in CUMS rats, reversed the decreased sugar preference in the SPT, reduction of immobility time in the FST, reduced the rest time, increased the total moving distance in the OFT. TTWC increased 5-HT levels and decreased GLU levels in the hippocampus. Moreover, TTWC decreased CRH levels in serum, indicating the regulation of over-activation of the hypothalamic-pituitary-adrenal (HPA) axis. In addition, reduced serum levels of IL-1beta, IL-18, IL-6, and TNF-alpha. The WB results implied that TTWC inhibited the expression of NLRP3, ASC, caspase-1, IL-1beta, and IL-18 in the prefrontal cortex and enhanced the expression of pro-caspase-1, pro-IL-1beta, and pro-IL-18. Although most of the results were not significant, PCR results showed that TTWC inhibited the expression of NLRP3, ASC, caspase-1, IL-1beta, and IL-18 in the prefrontal cortex. Conclusion: TTWC treatment exerted an antidepressant-like effect and regulates neurotransmitters, HPA axis and NLRP3 signaling pathway. These results indicated the potential of TTWC in preventing the development of depression.
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Affiliation(s)
- Xiang Pan
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Kezhuo Chen
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Sijie Han
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Xinyao Luo
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Dandan Zhang
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Hanrui Zhang
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Lian Zhang
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Xuxiang Zhou
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Jing Li
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Jingxian Fang
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Shiqin Wang
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Xiaochuan Ye
- Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
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Singh K, Bhatia R, Kumar B, Singh G, Monga V. Design Strategies, Chemistry and Therapeutic Insights of Multi-target Directed Ligands as Antidepressant Agents. Curr Neuropharmacol 2022; 20:1329-1358. [PMID: 34727859 PMCID: PMC9881079 DOI: 10.2174/1570159x19666211102154311] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/21/2021] [Accepted: 10/19/2021] [Indexed: 11/22/2022] Open
Abstract
Depression is one of the major disorders of the central nervous system worldwide and causes disability and functional impairment. According to the World Health Organization, around 265 million people worldwide are affected by depression. Currently marketed antidepressant drugs take weeks or even months to show anticipated clinical efficacy but remain ineffective in treating suicidal thoughts and cognitive impairment. Due to the multifactorial complexity of the disease, single-target drugs do not always produce satisfactory results and lack the desired level of therapeutic efficacy. Recent literature reports have revealed improved therapeutic potential of multi-target directed ligands due to their synergistic potency and better safety. Medicinal chemists have gone to great extents to design multitarget ligands by generating structural hybrids of different key pharmacophores with improved binding affinities and potency towards different receptors or enzymes. This article has compiled the design strategies of recently published multi-target directed ligands as antidepressant agents. Their biological evaluation, structural-activity relationships, mechanistic and in silico studies have also been described. This article will prove to be highly useful for the researchers to design and develop multi-target ligands as antidepressants with high potency and therapeutic efficacy.
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Affiliation(s)
- Karanvir Singh
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga-142001, Punjab, India
| | - Rohit Bhatia
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga-142001, Punjab, India
| | - Bhupinder Kumar
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga-142001, Punjab, India
| | - Gurpreet Singh
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga-142001, Punjab, India
| | - Vikramdeep Monga
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga-142001, Punjab, India
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, VPO-Ghudda, Bathinda-151401, Punjab, India
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Pekarskaya EA, Holt ES, Gingrich JA, Ansorge MS, Javitch JA, Canetta SE. Tianeptine, but not fluoxetine, decreases avoidant behavior in a mouse model of early developmental exposure to fluoxetine. Sci Rep 2021; 11:22852. [PMID: 34819526 PMCID: PMC8613176 DOI: 10.1038/s41598-021-02074-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 10/14/2021] [Indexed: 01/12/2023] Open
Abstract
Depression and anxiety, two of the most common mental health disorders, share common symptoms and treatments. Most pharmacological agents available to treat these disorders target monoamine systems. Currently, finding the most effective treatment for an individual is a process of trial and error. To better understand how disease etiology may predict treatment response, we studied mice exposed developmentally to the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX). These mice show the murine equivalent of anxiety- and depression-like symptoms in adulthood and here we report that these mice are also behaviorally resistant to the antidepressant-like effects of adult SSRI administration. We investigated whether tianeptine (TIA), which exerts its therapeutic effects through agonism of the mu-opioid receptor instead of targeting monoaminergic systems, would be more effective in this model. We found that C57BL/6J pups exposed to FLX from postnatal day 2 to 11 (PNFLX, the mouse equivalent in terms of brain development to the human third trimester) showed increased avoidant behaviors as adults that failed to improve, or were even exacerbated, by chronic SSRI treatment. By contrast, avoidant behaviors in these same mice were drastically improved following chronic treatment with TIA. Overall, this demonstrates that TIA may be a promising alternative treatment for patients that fail to respond to typical antidepressants, especially in patients whose serotonergic system has been altered by in utero exposure to SSRIs.
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Affiliation(s)
- Elizabeth A Pekarskaya
- Department of Neuroscience, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
- Division of Molecular Therapeutics, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, USA
| | - Emma S Holt
- Division of Molecular Therapeutics, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, USA
- Division of Developmental Neuroscience, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, USA
| | - Jay A Gingrich
- Division of Developmental Neuroscience, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, USA
- Sackler Institute for Developmental Psychobiology, Columbia University Vagelos College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, USA
| | - Mark S Ansorge
- Division of Developmental Neuroscience, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, USA
- Sackler Institute for Developmental Psychobiology, Columbia University Vagelos College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, USA
| | - Jonathan A Javitch
- Division of Molecular Therapeutics, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, USA.
- Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
| | - Sarah E Canetta
- Division of Molecular Therapeutics, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, USA.
- Division of Developmental Neuroscience, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, USA.
- Sackler Institute for Developmental Psychobiology, Columbia University Vagelos College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, USA.
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Tianeptine induces expression of dual specificity phosphatases and evokes rebound emergence of cortical slow wave electrophysiological activity. Neurosci Lett 2021; 764:136200. [PMID: 34464676 DOI: 10.1016/j.neulet.2021.136200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/24/2021] [Accepted: 08/26/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The precise mechanism governing the antidepressant effects of tianeptine is unknown. Modulation of brain glutamatergic neurotransmission has been however implicated, suggesting potential shared features with rapid-acting antidepressants targeting N-methyl-D-aspartate receptors (NMDAR). Our recent studies suggest that a single subanesthetic dose of NMDAR antagonists ketamine or nitrous oxide (N2O) gradually evoke 1-4 Hz electrophysiological activity (delta-rhythm) of cerebral cortex that is accompanied by molecular signaling associated with synaptic plasticity (e.g. activation of tropomyosin receptor kinase B (TrkB) and inhibition of glycogen synthase kinase 3β (GSK3β)). METHODS We have here investigated the time-dependent effects of tianeptine (30 mg/kg, i.p.) on electrocorticogram, focusing on potential biphasic regulation of the delta-rhythm. Selected molecular markers associated with ketamine's antidepressant effects were analyzed in the medial prefrontal cortex after the treatment using quantitative polymerase chain reaction and western blotting. RESULTS An acute tianeptine treatment induced changes of electrocorticogram typical for active wakefulness that lasted for 2-2.5 h, which was followed by high amplitude delta-activity rebound. The levels of Arc and Homer1a, but not c-Fos, BdnfIV and Zif268, were increased by tianeptine. Phosphorylation of mitogen-activated protein kinase (MAPK), TrkB and GSK3β remained unaltered at 2-hours and at 3-hours post-treatment. Notably, tianeptine also increased the level of mRNA of several dual specificity phosphatases (Duspss) - negative regulators of MAPK. CONCLUSION Tianeptine produces acute changes of electrocorticogram resembling rapid-acting antidepressants ketamine and N2O. Concomitant regulation of Dusps may hamper the effects of tianeptine on MAPK pathway and influence the magnitude of homeostatic emergence of delta-activity and TrkB-GSK3β signaling.
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Perić I, Costina V, Djordjević S, Gass P, Findeisen P, Inta D, Borgwardt S, Filipović D. Tianeptine modulates synaptic vesicle dynamics and favors synaptic mitochondria processes in socially isolated rats. Sci Rep 2021; 11:17747. [PMID: 34493757 PMCID: PMC8423821 DOI: 10.1038/s41598-021-97186-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 08/09/2021] [Indexed: 11/09/2022] Open
Abstract
Deregulation of synaptic function and neurotransmission has been linked with the development of major depression disorder (MDD). Tianeptine (Tian) has been used as antidepressant with anxiolytic properties and recently as a nootropic to improve cognitive performance, but its mechanism of action is unknown. We conducted a proteomic study on the hippocampal synaptosomal fractions of adult male Wistar rats exposed to chronic social isolation (CSIS, 6 weeks), an animal model of depression and after chronic Tian treatment in controls (nootropic effect) and CSIS-exposed rats (lasting 3 weeks of 6-week CSIS) (therapeutic effect). Increased expression of Syn1 and Camk2-related neurotransmission, vesicle transport and energy processes in Tian-treated controls were found. CSIS led to upregulation of proteins associated with actin cytoskeleton, signaling transduction and glucose metabolism. In CSIS rats, Tian up-regulated proteins involved in mitochondrial energy production, mitochondrial transport and dynamics, antioxidative defense and glutamate clearance, while attenuating the CSIS-increased glycolytic pathway and cytoskeleton organization proteins expression and decreased the expression of proteins involved in V-ATPase and vesicle endocytosis. Our overall findings revealed that synaptic vesicle dynamics, specifically exocytosis, and mitochondria-related energy processes might be key biological pathways modulated by the effective nootropic and antidepressant treatment with Tian and be a potential target for therapeutic efficacy of the stress-related mood disorders.
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Affiliation(s)
- Ivana Perić
- Department of Molecular Biology and Endocrinology, "VINČA", Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Victor Costina
- Institute for Clinical Chemistry, Medical Faculty Mannheim of the University of Heidelberg, University Hospital Mannheim, 68159, Mannheim, Germany
| | | | - Peter Gass
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159, Mannheim, Germany
| | - Peter Findeisen
- Institute for Clinical Chemistry, Medical Faculty Mannheim of the University of Heidelberg, University Hospital Mannheim, 68159, Mannheim, Germany
| | - Dragoš Inta
- Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
| | - Stefan Borgwardt
- Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany
| | - Dragana Filipović
- Department of Molecular Biology and Endocrinology, "VINČA", Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.
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Persico AM, Ricciardello A, Lamberti M, Turriziani L, Cucinotta F, Brogna C, Vitiello B, Arango C. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110326. [PMID: 33857522 DOI: 10.1016/j.pnpbp.2021.110326] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 03/17/2021] [Accepted: 04/09/2021] [Indexed: 12/28/2022]
Abstract
Autism Spectrum Disorder (ASD) is a severe and lifelong neurodevelopmental disorder, with high social costs and a dramatic burden on the quality of life of patients and family members. Despite its high prevalence, reaching 1/54 children and 1/45 adults in the United States, no pharmacological treatment is still directed to core symptoms of ASD, encompassing social and communication deficits, repetitive behaviors, restricted interests, and abnormal sensory processing. The purpose of this review is to provide an overview of the state-of-the-art of psychopharmacological therapy available today for ASD in children and adolescents, in order to foster best practices and to organize new strategies for future research. To date, atypical antipsychotics such as risperidone and aripiprazole represent the first line of intervention for hyperactivity, impulsivity, agitation, temper outbursts or aggression towards self or others. Tricyclic antidepressants are less prescribed because of uncertain efficacy and important side effects. SSRIs, especially fluoxetine and sertraline, may be effective in treating repetitive behaviors (anxiety and obsessive-compulsive symptoms) and irritability/agitation, while mirtazapine is more helpful with sleep problems. Low doses of buspirone have shown some efficacy on restrictive and repetitive behaviors in combination with behavioral interventions. Stimulants, and to a lesser extent atomoxetine, are effective in reducing hyperactivity, inattention and impulsivity also in comorbid ASD-ADHD, although with somewhat lower efficacy and greater incidence of side effects compared to idiopathic ADHD. Clonidine and guanfacine display some efficacy on hyperactivity and stereotypic behaviors. For several other drugs, case reports and open-label studies suggest possible efficacy, but no randomized controlled trial has yet been performed. Research in the pediatric psychopharmacology of ASD is still faced with at least two major hurdles: (a) Great interindividual variability in clinical response and side effect sensitivity is observed in the ASD population. This low level of predictability would benefit from symptom-specific treatment algorithms and from biomarkers to support drug choice; (b) To this date, no psychoactive drug appears to directly ameliorate core autism symptoms, although some indirect improvement has been reported with several drugs, once the comorbid target symptom is abated.
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Affiliation(s)
- Antonio M Persico
- Interdepartmental Program "Autism 0-90", "G. Martino" University Hospital, University of Messina, Italy.
| | - Arianna Ricciardello
- Interdepartmental Program "Autism 0-90", "G. Martino" University Hospital, University of Messina, Italy
| | - Marco Lamberti
- Child & Adolescent Psychiatry Unit, "Franz Tappeiner" Hospital, Merano (BZ), Italy
| | - Laura Turriziani
- Interdepartmental Program "Autism 0-90", "G. Martino" University Hospital, University of Messina, Italy
| | - Francesca Cucinotta
- Interdepartmental Program "Autism 0-90", "G. Martino" University Hospital, University of Messina, Italy
| | - Claudia Brogna
- Pediatric Neurology, Catholic University of the Sacred Heart, Rome, Italy; Neuropsychiatric Unit -ASL Avellino, Avellino (AV), Italy
| | - Benedetto Vitiello
- Department of Public Health and Pediatric Sciences, Section of Child and Adolescent Neuropsychiatry, University of Turin, Turin, Italy
| | - Celso Arango
- Child and Adolescent Psychiatry Department, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, School of Medicine Universidad Complutense, IiSGM, CIBERSAM, Madrid, Spain
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Challa AP, Zaleski NM, Jerome RN, Lavieri RR, Shirey-Rice JK, Barnado A, Lindsell CJ, Aronoff DM, Crofford LJ, Harris RC, Alp Ikizler T, Mayer IA, Holroyd KJ, Pulley JM. Human and Machine Intelligence Together Drive Drug Repurposing in Rare Diseases. Front Genet 2021; 12:707836. [PMID: 34394194 PMCID: PMC8355705 DOI: 10.3389/fgene.2021.707836] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 07/06/2021] [Indexed: 01/31/2023] Open
Abstract
Repurposing is an increasingly attractive method within the field of drug development for its efficiency at identifying new therapeutic opportunities among approved drugs at greatly reduced cost and time of more traditional methods. Repurposing has generated significant interest in the realm of rare disease treatment as an innovative strategy for finding ways to manage these complex conditions. The selection of which agents should be tested in which conditions is currently informed by both human and machine discovery, yet the appropriate balance between these approaches, including the role of artificial intelligence (AI), remains a significant topic of discussion in drug discovery for rare diseases and other conditions. Our drug repurposing team at Vanderbilt University Medical Center synergizes machine learning techniques like phenome-wide association study-a powerful regression method for generating hypotheses about new indications for an approved drug-with the knowledge and creativity of scientific, legal, and clinical domain experts. While our computational approaches generate drug repurposing hits with a high probability of success in a clinical trial, human knowledge remains essential for the hypothesis creation, interpretation, "go-no go" decisions with which machines continue to struggle. Here, we reflect on our experience synergizing AI and human knowledge toward realizable patient outcomes, providing case studies from our portfolio that inform how we balance human knowledge and machine intelligence for drug repurposing in rare disease.
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Affiliation(s)
- Anup P. Challa
- Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, United States
- Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, United States
| | - Nicole M. Zaleski
- Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Rebecca N. Jerome
- Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Robert R. Lavieri
- Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jana K. Shirey-Rice
- Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, United States
| | - April Barnado
- Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt Medical Center, Nashville, TN, United States
| | - Christopher J. Lindsell
- Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - David M. Aronoff
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
- Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, United States
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Leslie J. Crofford
- Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt Medical Center, Nashville, TN, United States
| | - Raymond C. Harris
- Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - T. Alp Ikizler
- Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Ingrid A. Mayer
- Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Kenneth J. Holroyd
- Center for Technology Transfer and Commercialization, Vanderbilt University, Nashville, TN, United States
| | - Jill M. Pulley
- Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, United States
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Onaolapo AY, Onaolapo OJ. Glutamate and depression: Reflecting a deepening knowledge of the gut and brain effects of a ubiquitous molecule. World J Psychiatry 2021; 11:297-315. [PMID: 34327123 PMCID: PMC8311508 DOI: 10.5498/wjp.v11.i7.297] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/13/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
The versatility of glutamate as the brain’s foremost excitatory neurotransmitter and modulator of neurotransmission and function is considered common knowledge. Years of research have continued to uncover glutamate’s effects and roles in several neurological and neuropsychiatric disorders, including depression. It had been considered that a deeper understanding of the roles of glutamate in depression might open a new door to understanding the pathological basis of the disorder, improve the approach to patient management, and lead to the development of newer drugs that may benefit more patients. This review examines our current understanding of the roles of endogenous and exogenous sources of glutamate and the glutamatergic system in the aetiology, progression and management of depression. It also examines the relationships that link the gut-brain axis, glutamate and depression; as it emphasizes how the gut-brain axis could impact depression pathogenesis and management via changes in glutamate homeostasis. Finally, we consider what the likely future of glutamate-based therapies and glutamate-based therapeutic manipulations in depression are, and if with them, we are now on the final chapter of understanding the neurochemical milieu of depressive disorders.
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Affiliation(s)
- Adejoke Yetunde Onaolapo
- Behavioural Neuroscience Unit, Neurobiology Subdivision, Department of Anatomy, Ladoke Akintola University of Technology, Oyo State 234, Nigeria
| | - Olakunle James Onaolapo
- Behavioural Neuroscience Unit, Neuropharmacology Subdivision, Department of Pharmacology, Ladoke Akintola University of Technology, Oyo State 234, Nigeria
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A white paper on a neurodevelopmental framework for drug discovery in autism and other neurodevelopmental disorders. Eur Neuropsychopharmacol 2021; 48:49-88. [PMID: 33781629 DOI: 10.1016/j.euroneuro.2021.02.020] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/08/2021] [Accepted: 02/15/2021] [Indexed: 12/20/2022]
Abstract
In the last decade there has been a revolution in terms of genetic findings in neurodevelopmental disorders (NDDs), with many discoveries critical for understanding their aetiology and pathophysiology. Clinical trials in single-gene disorders such as fragile X syndrome highlight the challenges of investigating new drug targets in NDDs. Incorporating a developmental perspective into the process of drug development for NDDs could help to overcome some of the current difficulties in identifying and testing new treatments. This paper provides a summary of the proceedings of the 'New Frontiers Meeting' on neurodevelopmental disorders organised by the European College of Neuropsychopharmacology in conjunction with the Innovative Medicines Initiative-sponsored AIMS-2-TRIALS consortium. It brought together experts in developmental genetics, autism, NDDs, and clinical trials from academia and industry, regulators, patient and family associations, and other stakeholders. The meeting sought to provide a platform for focused communication on scientific insights, challenges, and methodologies that might be applicable to the development of CNS treatments from a neurodevelopmental perspective. Multidisciplinary translational consortia to develop basic and clinical research in parallel could be pivotal to advance knowledge in the field. Although implementation of clinical trials for NDDs in paediatric populations is widely acknowledged as essential, safety concerns should guide each aspect of their design. Industry and academia should join forces to improve knowledge of the biology of brain development, identify the optimal timing of interventions, and translate these findings into new drugs, allowing for the needs of users and families, with support from regulatory agencies.
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Abstract
After participating in this activity, learners should be better able to:• Identify the effects of dysregulated opioid signalling in depression• Evaluate the use of opioid compounds and ketamine in patients with depression ABSTRACT: Major depressive disorder (MDD) remains one of the leading causes of disability and functional impairment worldwide. Current antidepressant therapeutics require weeks to months of treatment prior to the onset of clinical efficacy on depressed mood but remain ineffective in treating suicidal ideation and cognitive impairment. Moreover, 30%-40% of individuals fail to respond to currently available antidepressant medications. MDD is a heterogeneous disorder with an unknown etiology; novel strategies must be developed to treat MDD more effectively. Emerging evidence suggests that targeting one or more of the four opioid receptors-mu (MOR), kappa (KOR), delta (DOR), and the nociceptin/orphanin FQ receptor (NOP)-may yield effective therapeutics for stress-related psychiatric disorders. Furthermore, the effects of the rapidly acting antidepressant ketamine may involve opioid receptors. This review highlights dysregulated opioid signaling in depression, evaluates clinical trials with opioid compounds, and considers the role of opioid mechanisms in rapidly acting antidepressants.
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Smith KE, Rogers JM, Strickland JC, Epstein DH. When an obscurity becomes trend: social-media descriptions of tianeptine use and associated atypical drug use. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2021; 47:455-466. [PMID: 33909525 DOI: 10.1080/00952990.2021.1904408] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Background: Originally believed to be an atypical antidepressant acting at serotonin transporters, tianeptine is now known to also be an atypical agonist at mu-opioid receptors. Its nonmedical use may be increasing amidst the broader context of novel drug and supplement use.Objectives: To analyze social-media text from current, former, and prospective tianeptine users for better understanding of their conceptualizations of tianeptine, motives for and patterns of use, and reported benefits and harms.Methods: Reddit posts were obtained and thematically coded; additional quantitative analyses were conducted.Results: A total of 210 posts mentioning tianeptine were made between 2012 and 2020. Eighteen thematic categories were identified, 10 of which were consistent with expected themes. Two independent raters coded all text, generating 1,382 unique codes, of which 1,090 were concordant (78.9% interrater agreement). Tianeptine use was frequently associated with use of other drugs, particularly kratom, phenibut, and racetams. People conceptualized and variously used tianeptine as an opioid, antidepressant, and "nootropic" (cognitive enhancer). Between 2014 and 2020, mentions of positive effects decreased, while mentions of adverse effects and withdrawal increased. Motivations for use included substitution or withdrawal mitigation for other drugs (especially opioids) and for kratom itself; self-treatment for psychiatric symptoms; and improvement of quality of life, mood, or performance. Descriptions of tolerance, withdrawal, and addiction were evident. Intravenous use was rare and strongly discouraged, with detrimental effects described.Conclusion: Tianeptine is recognized as an opioid (though not only an opioid) in online communities. Posts describe benefits, acute risks, and patterns of co-use that warrant greater clinical attention.
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Affiliation(s)
- Kirsten E Smith
- National Institute on Drug Abuse Intramural Research Program, Translational Addiction Medicine Branch, Baltimore, MD, USA
| | - Jeffery M Rogers
- National Institute on Drug Abuse Intramural Research Program, Translational Addiction Medicine Branch, Baltimore, MD, USA
| | - Justin C Strickland
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - David H Epstein
- National Institute on Drug Abuse Intramural Research Program, Translational Addiction Medicine Branch, Baltimore, MD, USA
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Duval F, Mokrani MC, Erb A, Gonzalez Lopera F, Danila V, Tomsa M. Neuroendocrine Assessment of Dopaminergic Function during Antidepressant Treatment in Major Depressed Patients. Brain Sci 2021; 11:425. [PMID: 33810562 PMCID: PMC8065982 DOI: 10.3390/brainsci11040425] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/09/2021] [Accepted: 03/23/2021] [Indexed: 11/20/2022] Open
Abstract
The effects of antidepressants on dopamine (DA) receptor sensitivity in the mesolimbic-hypothalamic system have yielded contradictory results. The postsynaptic DA receptor function was evaluated by the cortisol response to apomorphine (APO; 0.75 mg SC) in 16 drug-free DSM-5 major depressed inpatients and 18 healthy hospitalized control (HC) subjects. Cortisol response to the dexamethasone suppression test (DST) was also measured. After two and four weeks of antidepressant treatment (ADT), the DST and APO test were repeated in all patients. Cortisol response to APO (∆COR) was not influenced by the hypothalamic-pituitary-adrenal (HPA) axis activity, as assessed by the DST. Pre-treatment ∆COR values did not differ significantly between patients and HCs. During ADT, ∆COR values were lower than in HCs at week 2 and 4. After four weeks of treatment, among the eight patients who had blunted ∆COR values, seven were subsequent remitters, while among the eight patients who had normal ∆COR values, seven were non-remitters. Considering the limitations of our study, the results suggest that following chronic ADT, the desensitization of postsynaptic DA receptors connected with the regulation of the HPA axis at the hypothalamic level is associated with clinical remission. These results could reflect increased DA levels in the mesolimbic pathway.
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Affiliation(s)
- Fabrice Duval
- Pôle 8/9-APF2R, Centre Hospitalier, 68250 Rouffach, France; (M.-C.M.); (A.E.); (F.G.L.); (V.D.); (M.T.)
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Wichers RH, Findon JL, Jelsma A, Giampietro V, Stoencheva V, Robertson DM, Murphy CM, Blainey S, McAlonan G, Ecker C, Rubia K, Murphy DGM, Daly EM. Modulation of atypical brain activation during executive functioning in autism: a pharmacological MRI study of tianeptine. Mol Autism 2021; 12:14. [PMID: 33608048 PMCID: PMC7893772 DOI: 10.1186/s13229-021-00422-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 02/08/2021] [Indexed: 02/07/2023] Open
Abstract
Background Autism spectrum disorder (ASD) is associated with deficits in executive functioning (EF), and these have been suggested to contribute to core as well as co-occurring psychiatric symptoms. The biological basis of these deficits is unknown but may include the serotonergic system, which is involved both in regulating EF in neurotypical populations and in the pathophysiology of ASD. We previously demonstrated that reducing serotonin by acute tryptophan depletion (ATD) shifts differences in brain function during performance of EF tasks towards control levels. However, ATD cannot be easily used in the clinic, and we therefore need to adopt alternative approaches to challenge the serotonin system. Hence, we investigated the role of the serotonergic modulator tianeptine on EF networks in ASD. Method We conducted a pharmacological magnetic resonance imaging study, using a randomized double-blind crossover design, to compare the effect of an acute dosage of 12.5 mg tianeptine and placebo on brain activation during two EF tasks (of response inhibition and sustained attention) in 38 adult males: 19 with ASD and 19 matched controls. Results Under placebo, compared to controls, individuals with ASD had atypical brain activation in response inhibition regions including the inferior frontal cortex, premotor regions and cerebellum. During sustained attention, individuals with ASD had decreased brain activation in the right middle temporal cortex, right cuneus and left precuneus. Most of the case–control differences in brain function observed under placebo conditions were abolished by tianeptine administration. Also, within ASD individuals, brain functional differences were shifted significantly towards control levels during response inhibition in the inferior frontal and premotor cortices. Limitations We conducted a pilot study using a single dose of tianeptine, and therefore, we cannot comment on long-term outcome. Conclusions Our findings provide the first evidence that tianeptine can shift atypical brain activation during EF in adults with ASD towards control levels. Future studies should investigate whether this shift in the biology of ASD is maintained after prolonged treatment with tianeptine and whether it improves clinical symptoms.
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Affiliation(s)
- Robert H Wichers
- Department of Forensic and Neurodevelopmental Sciences, The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO50 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK. .,Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley NHS Trust, London, UK.
| | - James L Findon
- Department of Forensic and Neurodevelopmental Sciences, The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO50 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK
| | - Auke Jelsma
- Department of Forensic and Neurodevelopmental Sciences, The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO50 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.,VU University Medical Center, Amsterdam, The Netherlands
| | - Vincent Giampietro
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Vladimira Stoencheva
- Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley NHS Trust, London, UK
| | - Dene M Robertson
- Department of Forensic and Neurodevelopmental Sciences, The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO50 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.,Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley NHS Trust, London, UK
| | - Clodagh M Murphy
- Department of Forensic and Neurodevelopmental Sciences, The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO50 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.,Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley NHS Trust, London, UK
| | - Sarah Blainey
- Department of Forensic and Neurodevelopmental Sciences, The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO50 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK
| | - Grainne McAlonan
- Department of Forensic and Neurodevelopmental Sciences, The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO50 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.,Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley NHS Trust, London, UK
| | - Christine Ecker
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe-University, Frankfurt am Main, Germany
| | - Katya Rubia
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Declan G M Murphy
- Department of Forensic and Neurodevelopmental Sciences, The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO50 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.,Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley NHS Trust, London, UK
| | - Eileen M Daly
- Department of Forensic and Neurodevelopmental Sciences, The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO50 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK
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Different molecular targets, one purpose – treatment of depression. CURRENT ISSUES IN PHARMACY AND MEDICAL SCIENCES 2021. [DOI: 10.2478/cipms-2020-0036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract
Although vast scientific progress has been made, the current pharmacotherapy of depression is still not fully effective. In adults, depressive disorders are among the most common diseases in industrialized countries, impact upon all aspects of family and working life and significantly disturb social functioning. Moreover, increasingly, they affect children and teenagers.
Depressive disorders have a complex etiology. This includes a number of mechanisms that are not yet fully understood. Therefore, the current review concentrates on bringing to the foreground the many molecular areas involved in occurrence of this disease. The work highlights the notion that depression has a complex pharmacology and inevitably requires the adoption of individual pharmacotherapy. This manuscript concentrates on currently used drugs drawn from diverse therapeutic groups and presents new promising targets for the treatment of depression. This is a particularly important issue due to the continuous lack of effective therapy and the constant search for new drugs and molecular targets for its treatment.
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Brain circuits at risk in psychiatric diseases and pharmacological pathways. Therapie 2020; 76:75-86. [PMID: 33358639 DOI: 10.1016/j.therap.2020.12.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/24/2020] [Indexed: 12/23/2022]
Abstract
The multiple brain circuits involved in psychiatric diseases may appear daunting, but we prefer to concentrate on a select few, with a particular sensitivity to stress and neurodevelopmental issues, with a clear pharmacotherapy. This review is structured around 1. the key circuits, their role in health and disease, and the neurotransmitters maintaining them, 2. The influence of upbringing, stress, chronobiology, inflammation and infection, 3. The genetic and epigenetic influence on these circuits, particularly regarding copy number variants and neuronal plasticity, 4. The use and abuse of pharmacological agents with the particular risks of stress and chronobiology at critical periods. A major emphasis is placed on the links between hippocampus, prefrontal cortex and amygdala/periaqueductal grey which control specific aspects of cognition, mood, pain and even violence. Some of the research findings were from the innovative medicine initiative (IMI) NEWMEDS, a 22M€ academic/industrial consortium on the brain circuits critical for psychiatric disease.
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Petermann M, Kronenberg G, Mosienko V, Bader M, Alenina N, Hellweg R, Klempin F. Alterations in BDNF Protein Concentrations in the Hippocampus do not Explain the Pro-Neurogenic Effect of Citalopram on Adult Neurogenesis. PHARMACOPSYCHIATRY 2020; 54:101-105. [PMID: 33197939 DOI: 10.1055/a-1291-8079] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Brain-derived neurotrophic factor (BDNF) has been implicated in the pro-neurogenic effect of selective serotonin reuptake inhibitors. In this study, we used Tph2 -/- mice lacking brain serotonin to dissect the interplay between BDNF and the serotonin system in mediating the effects of antidepressant pharmacotherapy on adult neurogenesis in the hippocampus. METHODS Besides citalopram (CIT), we tested tianeptine (TIA), an antidepressant whose mechanism of action is not well understood. Specifically, we examined cell survival and endogenous concentrations of BDNF following daily injection of the drugs. RESULTS Twenty-one days of CIT, but not of TIA, led to a significant increase in the survival of newly generated cells in the dentate gyrus of wild-type mice, without a significant effect on BDNF protein levels by either treatment. In Tph2 -/- mice, adult neurogenesis was consistently increased. Furthermore, Tph2 -/- mice showed increased BDNF protein levels, which were not affected by TIA but were significantly reduced by CIT. DISCUSSION We conclude that the effects of CIT on adult neurogenesis are not explained by changes in BDNF protein concentrations in the hippocampus.
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Affiliation(s)
- Markus Petermann
- Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,Berlin Institute of Health, Berlin, Germany
| | - Golo Kronenberg
- University of Leicester and Leicestershire Partnership NHS Trust, Leicester, UK.,Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany
| | - Valentina Mosienko
- Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,current address: University of Exeter, College of Medicine and Health, EX4 4PS, Exeter, UK
| | - Michael Bader
- Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,Berlin Institute of Health, Berlin, Germany.,Charité-University Medicine Berlin, Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.,University of Lübeck, Lübeck, Germany
| | - Natalia Alenina
- Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.,Institute of Cytology, Russian Academy of Science, St. Petersburg, Russia
| | - Rainer Hellweg
- Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany
| | - Friederike Klempin
- Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,Berlin Institute of Health, Berlin, Germany.,Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany
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Ramoz N, Hoertel N, Nobile B, Voegeli G, Nasr A, Le Strat Y, Courtet P, Gorwood P. Corticotropin releasing hormone receptor CRHR1 gene is associated with tianeptine antidepressant response in a large sample of outpatients from real-life settings. Transl Psychiatry 2020; 10:378. [PMID: 33154348 PMCID: PMC7644692 DOI: 10.1038/s41398-020-01067-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 09/29/2020] [Accepted: 10/19/2020] [Indexed: 11/19/2022] Open
Abstract
Polymorphisms of genes involved in the hypothalamic-pituitary-adrenocortical (HPA) axis have been associated with response to several antidepressant treatments in patients suffering of depression. These pharmacogenetics findings have been reported from independent cohorts of patients mostly treated with selective serotonin reuptake inhibitors, tricyclic antidepressant, and mirtazapine. Tianeptine, an atypical antidepressant, recently identified as a mu opioid receptor agonist, which prevents and reverses the stress induced by glucocorticoids, has been investigated in this present pharmacogenetics study. More than 3200 Caucasian outpatients with a major depressive episode (MDE) from real-life settings were herein analyzed for clinical response to tianeptine, a treatment initiated from 79.5% of the subjects, during 6-8 weeks follow-up, assessing polymorphisms targeting four genes involved in the HPA axis (NR3C1, FKPB5, CRHR1, and AVPR1B). We found a significant association (p < 0.001) between CRHR1 gene variants rs878886 and rs16940665, or haplotype rs878886*C-rs16940665*T, and tianeptine antidepressant response and remission according to the hospital anxiety and depression scale. Analyses, including a structural equation model with simple mediation, suggest a moderate effect of sociodemographic characteristics and depressive disorder features on treatment response in individuals carrying the antidepressant responder allele rs8788861 (allele C). These findings suggest direct pharmacological consequences of CRHR1 polymorphisms in the antidepressant tianeptine response and remission, in MDE patients. This study replicates the association of the CRHR1 gene, involved in the HPA axis, with (1) a specificity attributed to treatment response, (2) a lower risk of chance finding, and in (3) an ecological situation.
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Affiliation(s)
- Nicolas Ramoz
- Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Team Vulnerability of Psychiatric and Addictive Disorders, 75014, Paris, France.
| | - Nicolas Hoertel
- Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Team Vulnerability of Psychiatric and Addictive Disorders, 75014 Paris, France ,grid.50550.350000 0001 2175 4109Assistance Publique-Hôpitaux de Paris (APHP), Corentin Celton Hospital, Department of Psychiatry, 92130 Issy-les-Moulineaux, France ,grid.10988.380000 0001 2173 743XUniversity of Paris, Paris, France
| | - Bénédicte Nobile
- grid.121334.60000 0001 2097 0141Department of Emergency Psychiatry and Acute Care, CHU Montpellier, INSERM U1061, Montpellier University, Montpellier, France
| | - Géraldine Voegeli
- Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Team Vulnerability of Psychiatric and Addictive Disorders, 75014 Paris, France ,grid.414435.30000 0001 2200 9055GHU Paris Psychiatrie et Neurosciences, Clinique des Maladies Mentales et de l’Encéphale (CMME), Centre Hospitalier Sainte-Anne, Paris, France
| | - Ariane Nasr
- Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Team Vulnerability of Psychiatric and Addictive Disorders, 75014 Paris, France
| | - Yann Le Strat
- Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Team Vulnerability of Psychiatric and Addictive Disorders, 75014 Paris, France ,grid.50550.350000 0001 2175 4109Service de Psychiatrie, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, France
| | - Philippe Courtet
- grid.121334.60000 0001 2097 0141Department of Emergency Psychiatry and Acute Care, CHU Montpellier, INSERM U1061, Montpellier University, Montpellier, France
| | - Philip Gorwood
- Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Team Vulnerability of Psychiatric and Addictive Disorders, 75014 Paris, France ,grid.414435.30000 0001 2200 9055GHU Paris Psychiatrie et Neurosciences, Clinique des Maladies Mentales et de l’Encéphale (CMME), Centre Hospitalier Sainte-Anne, Paris, France
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Nicolas A, Ruby PM. Dreams, Sleep, and Psychotropic Drugs. Front Neurol 2020; 11:507495. [PMID: 33224081 PMCID: PMC7674595 DOI: 10.3389/fneur.2020.507495] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 09/28/2020] [Indexed: 02/04/2023] Open
Abstract
Over the past 60 years, the impact of psychotropic drugs on dream recall and content has been scarcely explored. A review of the few existing experimental results on the topic leads us to the following conclusions. For antidepressant drugs, in the great majority, they reduce dream recall frequency (DRF), and the improvement of depressive symptoms is associated with an increase of positive emotion in dream content. For sedative psychotropic drugs, their improvement of sleep quality is associated with a reduction of DRF, but the effect on dream content is less clear. Few occurrences of nightmare frequency increase have been reported, with intake of molecules disturbing sleep or with the withdrawal of some psychotropic drugs. Importantly, the impact of psychotropic drugs on rapid eye movement (REM) sleep does not explain DRF modulations. The reduction of intra-sleep awakenings seems to be the parameter explaining best the modulation of DRF by psychotropic drugs. Indeed, molecules that improve sleep continuity by reducing intra-sleep awakenings also reduce the frequency of dream recall, which is coherent with the “arousal-retrieval model” stating that nighttime awakenings enable dreams to be encoded into long-term memory and therefore facilitate dream recall. DRF is nonetheless influenced by several other factors (e.g., interest in dreams, the method of awakening, and personality traits), which may explain a large part of the variability of results observed and cited in this article.
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Affiliation(s)
- Alain Nicolas
- Lyon Neuroscience Research Center, CNRS UMR 5292 - INSERM U1028 - Lyon 1 University, Lyon, France
| | - Perrine M Ruby
- Lyon Neuroscience Research Center, CNRS UMR 5292 - INSERM U1028 - Lyon 1 University, Lyon, France
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40
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Filipović D, Perić I, Costina V, Stanisavljević A, Gass P, Findeisen P. Social isolation stress-resilient rats reveal energy shift from glycolysis to oxidative phosphorylation in hippocampal nonsynaptic mitochondria. Life Sci 2020; 254:117790. [DOI: 10.1016/j.lfs.2020.117790] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 05/04/2020] [Accepted: 05/12/2020] [Indexed: 11/28/2022]
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Lumangtad LA, Bell TW. The signal peptide as a new target for drug design. Bioorg Med Chem Lett 2020; 30:127115. [PMID: 32209293 PMCID: PMC7138182 DOI: 10.1016/j.bmcl.2020.127115] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 03/06/2020] [Accepted: 03/15/2020] [Indexed: 01/16/2023]
Abstract
Many current and potential drug targets are membrane-bound or secreted proteins that are expressed and transported via the Sec61 secretory pathway. They are targeted to translocon channels across the membrane of the endoplasmic reticulum (ER) by signal peptides (SPs), which are temporary structures on the N-termini of their nascent chains. During translation, such proteins enter the lumen and membrane of the ER by a process known as co-translational translocation. Small molecules have been found that interfere with this process, decreasing protein expression by recognizing the unique structures of the SPs of particular proteins. The SP may thus become a validated target for designing drugs for numerous disorders, including certain hereditary diseases.
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Affiliation(s)
| | - Thomas W Bell
- Department of Chemistry, University of Nevada, Reno, NV 89557-0216, USA.
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Naguy A, Ali M, Elsori DH, Alamiri B. A Case of Prepubertal Low-Functioning Autism With Behavioral Decompensation Favorably Responding to Tianeptine. J Clin Psychopharmacol 2020; 39:524-525. [PMID: 31425465 DOI: 10.1097/jcp.0000000000001103] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- Ahmed Naguy
- Child/Adolescent Psychiatry Al-Manara CAP Centre Kuwait Centre for Mental Health Shuwaikh, Kuwait General Adult Psychiatry Kuwait Centre for Mental Health Shuwaikh, Kuwait Department of Pediatrics Cleveland Clinic Children's Cleveland, OH Child/Adolescent Psychiatry Al-Manara CAP Centre Kuwait Centre for Mental Health Shuwaikh, Kuwait and Tufts University Medford, MA
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Tran L, Sharrad K, Kopsaftis Z, Stallman HM, Tai A, Spurrier N, Esterman A, Carson-Chahhoud K. Pharmacological interventions for the treatment of psychological distress in patients with asthma: a systematic review and meta-analysis. J Asthma 2020; 58:759-769. [PMID: 32065543 DOI: 10.1080/02770903.2020.1731826] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Objective: To evaluate the effectiveness and safety of pharmacological interventions for the treatment of psychological distress in people with asthma.Data sources: Electronic searches were performed in Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, PubMed/Medline, Embase, PsycInfo, Health Technology Assessment Database and Web of Science (inception to April 2019).Study selections: Included studies were randomized controlled trials (RCT) or controlled clinical trials investigating the effect of pharmacological interventions for psychological distress in people with asthma. Records were screened and data extracted by two independent authors into standardized pilot-tested extraction templates. Data was analyzed according to standard Cochrane methodology and entered into Review Manager Software version 5.3.Results: From 5,689 studies, six RCTs (n = 215) met inclusion criteria and were included in the systematic review, of which four studies were included in the meta-analysis. A meta-analysis of four studies (n = 158) indicated no evidence of an effect for selective serotonin reuptake inhibitors (Citalopram or Escitalopram) on reduction of psychological distress in adult patients with asthma. Similarly, antiepileptic medication (Levetiracetam) was no better than placebo in the treatment of psychological distress in people with asthma. Adverse events were poorly reported across all studies but were slightly increased among intervention participants compared to control participants.Conclusions: There was great heterogeneity between studies and overall poor methodological quality providing insufficient evidence to make recommendations for or against the use of pharmacotherapy in asthma patients with psychological distress. Further confirmatory trials are warranted to make recommendations for clinical practice.
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Affiliation(s)
- Liem Tran
- School of Medicine, Deakin University, Geelong, Australia.,Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, Australia.,School of Health Sciences, University of South Australia, Adelaide, Australia.,School of Medicine, University of Adelaide, Adelaide, Australia
| | - Kelsey Sharrad
- Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, Australia.,School of Health Sciences, University of South Australia, Adelaide, Australia.,School of Medicine, University of Adelaide, Adelaide, Australia
| | - Zoe Kopsaftis
- Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, Australia.,School of Health Sciences, University of South Australia, Adelaide, Australia.,School of Medicine, University of Adelaide, Adelaide, Australia.,Respiratory Medicine Unit, The Queen Elizabeth Hospital, Adelaide, Australia
| | - Helen M Stallman
- School of Social Sciences, University of the Sunshine Coast, Queensland, Australia.,Sunshine Coast Mind and Neuroscience - Thompson Institute, Queensland, Australia
| | - Andrew Tai
- Respiratory and Sleep Medicine, Women's & Children's Hospital, Adelaide, Australia.,Robinson Research Institute, University of Adelaide, Adelaide, Australia
| | - Nicola Spurrier
- SA Health, Department for Health and Ageing, Adelaide, South Australia, Australia.,Department of Paediatrics and Child Health, Flinders University, Bedford Park, South Australia, Australia.,School of Public Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Adrian Esterman
- School of Nursing and Midwifery, University of South Australia, Adelaide, Australia.,UniSA Cancer Research Institute, University of South Australia, Adelaide, Australia
| | - Kristin Carson-Chahhoud
- Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, Australia.,School of Health Sciences, University of South Australia, Adelaide, Australia.,School of Medicine, University of Adelaide, Adelaide, Australia
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Influence of the CB1 and CB2 cannabinoid receptor ligands on the activity of atypical antidepressant drugs in the behavioural tests in mice. Pharmacol Biochem Behav 2020; 188:172833. [DOI: 10.1016/j.pbb.2019.172833] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 01/19/2023]
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Syme KL, Hagen EH. Mental health is biological health: Why tackling "diseases of the mind" is an imperative for biological anthropology in the 21st century. AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY 2019; 171 Suppl 70:87-117. [PMID: 31762015 DOI: 10.1002/ajpa.23965] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 10/23/2019] [Accepted: 10/24/2019] [Indexed: 12/23/2022]
Abstract
The germ theory of disease and the attendant public health initiatives, including sanitation, vaccination, and antibiotic treatment, led to dramatic increases in global life expectancy. As the prevalence of infectious disease declines, mental disorders are emerging as major contributors to the global burden of disease. Scientists understand little about the etiology of mental disorders, however, and many of the most popular psychopharmacological treatments, such as antidepressants and antipsychotics, have only moderate-to-weak efficacy in treating symptoms and fail to target biological systems that correspond to discrete psychiatric syndromes. Consequently, despite dramatic increases in the treatment of some mental disorders, there has been no decrease in the prevalence of most mental disorders since accurate record keeping began. Many researchers and theorists are therefore endeavoring to rethink psychiatry from the ground-up. Anthropology, especially biological anthropology, can offer critical theoretical and empirical insights to combat mental illness globally. Biological anthropologists are unique in that we take a panhuman approach to human health and behavior and are trained to address each of Tinbergen's four levels of analysis as well as culture. The field is thus exceptionally well-situated to help resolve the mysteries of mental illness by integrating biological, evolutionary, and sociocultural perspectives.
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Affiliation(s)
- Kristen L Syme
- Department of Anthropology, Washington State University, Vancouver, Washington
| | - Edward H Hagen
- Department of Anthropology, Washington State University, Vancouver, Washington
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Fitzgerald PJ, Watson BO. In vivo electrophysiological recordings of the effects of antidepressant drugs. Exp Brain Res 2019; 237:1593-1614. [PMID: 31079238 PMCID: PMC6584243 DOI: 10.1007/s00221-019-05556-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 05/06/2019] [Indexed: 12/11/2022]
Abstract
Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic effects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local field potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic effects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants. The existing studies on neuromodulator-based drugs have focused on recording in the brainstem nuclei, with much less known about their effects on prefrontal or sensory cortex. Studies on neuromodulatory drugs have moreover focused on single unit firing patterns with less emphasis on LFPs, whereas the rapidly acting antidepressant literature shows the opposite trend. In a synthesis of this information, we hypothesize that all classes of antidepressants could have common final effects on limbic circuitry. Whereas NMDA receptor blockade may induce a high powered gamma oscillatory state via direct and fast alteration of glutamatergic systems in mood-related circuits, neuromodulatory antidepressants may induce similar effects over slower timescales, corresponding with the timecourse of response in patients, while resetting synaptic excitatory versus inhibitory signaling to a normal level. Thus, gamma signaling may provide a biomarker (or “neural readout”) of the therapeutic effects of all classes of antidepressants.
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Affiliation(s)
- Paul J Fitzgerald
- Department of Psychiatry, University of Michigan, Ann Arbor, MI, 48109-5720, USA.
| | - Brendon O Watson
- Department of Psychiatry, University of Michigan, Ann Arbor, MI, 48109-5720, USA.
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Kauer-Sant'Anna M, Frey BN, Fijtman A, Loredo-Souza AC, Dargél AA, Pfaffenseller B, Wollenhaupt-Aguiar B, Gazalle FK, Colpo GD, Passos IC, Bücker J, Walz JC, Jansen K, Ceresér M, Bürke Bridi KP, Dos Santos Sória L, Kunz M, Pinho M, Kapczinski NS, Goi PD, Magalhães PV, Reckziegel R, Burque RK, de Azevedo Cardoso T, Kapczinski F. Adjunctive tianeptine treatment for bipolar disorder: A 24-week randomized, placebo-controlled, maintenance trial. J Psychopharmacol 2019; 33:502-510. [PMID: 30835152 DOI: 10.1177/0269881119826602] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE The purpose of this study was to assess the efficacy and tolerability of tianeptine as an adjunctive maintenance treatment for bipolar depression. METHODS This is a multicenter double-blind randomized placebo-controlled maintenance trial of adjunctive tianeptine 37.5 mg/day. Participants ( n=161) had a Montgomery-Asberg Depression Rating Scale ⩾12 at entry. After eight weeks of open-label tianeptine treatment, those who responded to tianeptine ( n=69) were randomized to adjunctive tianeptine ( n=36) or placebo ( n=33) in addition to usual treatment. Kaplan-Meier estimates and the Mantel-Cox log-rank test were used to evaluate differences in time to intervention for a mood episode between the tianeptine and placebo groups. We also assessed overall functioning, biological rhythms, quality of life, rates of manic switch and serum brain-derived neurotrophic factor levels. RESULTS There were no differences between adjunctive tianeptine or placebo regarding time to intervention or depression scores in the 24-week double-blind controlled phase. Patients in the tianeptine group showed better performance in the letter-number sequencing subtest from the Wechsler Adult Intelligence Scale at the endpoint ( p=0.014). Tianeptine was well tolerated and not associated with higher risk for manic switch compared to placebo. CONCLUSION Tianeptine was not more effective than placebo in the maintenance treatment of bipolar depression. There is preliminary evidence suggesting a pro-cognitive effect of tianeptine in working memory compared to placebo.
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Affiliation(s)
- Márcia Kauer-Sant'Anna
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,2 Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Benicio N Frey
- 3 Women's Health Concerns Clinic, St Joseph's Healthcare, Hamilton, ON, Canada.,4 Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
| | - Adam Fijtman
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,2 Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Ana C Loredo-Souza
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Aroldo A Dargél
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Bianca Pfaffenseller
- 4 Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
| | - Bianca Wollenhaupt-Aguiar
- 4 Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
| | - Fernando K Gazalle
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Gabriela D Colpo
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Ives C Passos
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,2 Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Joana Bücker
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Júlio C Walz
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Karen Jansen
- 6 Department of Health and Behavior, Catholic University of Pelotas, Pelotas, Brazil
| | - Mendes Ceresér
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,2 Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Kelen P Bürke Bridi
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Lisiane Dos Santos Sória
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Maurício Kunz
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,2 Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Michele Pinho
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Natália S Kapczinski
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,2 Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Pedro D Goi
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,5 Department of Internal Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Brazil
| | - Pedro Vs Magalhães
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,2 Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Ramiro Reckziegel
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Renan K Burque
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Taiane de Azevedo Cardoso
- 4 Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
| | - Flávio Kapczinski
- 1 Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,2 Department of Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,4 Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
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Agomelatine and tianeptine antidepressant activity in mice behavioral despair tests is enhanced by DMPX, a selective adenosine A 2A receptor antagonist, but not DPCPX, a selective adenosine A 1 receptor antagonist. Pharmacol Rep 2019; 71:676-681. [PMID: 31200233 DOI: 10.1016/j.pharep.2019.03.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 02/12/2019] [Accepted: 03/11/2019] [Indexed: 01/13/2023]
Abstract
BACKGROUND Adenosine, an endogenous nucleoside, modulates the release of monoamines, e.g., noradrenaline, serotonin, and dopamine in the brain. Both nonselective and selective stimulation of adenosine receptors produce symptoms of depression in some animal models. Therefore, the main objective of our study was to assess the influence of a selective adenosine A1 receptor antagonist (DPCPX) and a selective adenosine A2A receptor antagonist (DMPX) on the activity of agomelatine and tianeptine. METHODS The forced swim test (FST) and tail suspension test (TST) were performed to assess the effects of DPCPX and DMPX on the antidepressant-like activity of agomelatine and tianeptine. Drug serum and brain levels were analyzed using HPLC. RESULTS Co-administration of agomelatine (20 mg/kg) or tianeptine (15 mg/kg) with DMPX (3 mg/kg), but not with DPCPX (1 mg/kg), significantly reduced the immobility time both in the FST and TST in mice. These effects were not associated with an enhancement in animals' spontaneous locomotor activity. The observed changes in the mouse behavior after concomitant injection of DMPX and the tested antidepressant agents were associated with elevated brain concentration of agomelatine and tianeptine. CONCLUSION Our study shows a synergistic action of the selective A2A receptor antagonist and the studied antidepressant drugs, and a lack of such interaction in the case of the selective A1 receptor antagonist. The interaction between DMPX and agomelatine/tianeptine at least partly occurs in the pharmacokinetic phase. A combination of a selective A2A receptor antagonist and an antidepressant may be a new strategy for treating depression.
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Perić I, Stanisavljević A, Inta D, Gass P, Lang UE, Borgwardt S, Filipović D. Tianeptine antagonizes the reduction of PV+ and GAD67 cells number in dorsal hippocampus of socially isolated rats. Prog Neuropsychopharmacol Biol Psychiatry 2019; 89:386-399. [PMID: 30367961 DOI: 10.1016/j.pnpbp.2018.10.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 10/08/2018] [Accepted: 10/23/2018] [Indexed: 12/21/2022]
Abstract
Adult male rats exposed to chronic social isolation (CSIS) show depressive- and anxiety-like behaviors and reduce the numbers of parvalbumin-positive (PV+) interneurons in the dorsal hippocampus. We aimed to determine whether tianeptine (Tian), administered during the last three weeks of a six-week-social isolation (10 mg/kg/day), may reverse CSIS-induced behavioral changes and antagonize the CSIS-induced reduction in the number of PV+ interneurons. We also studied whether Tian affects the GABA-producing enzyme GAD67+ cells, in Stratum Oriens (SO), Stratum Pyramidale (SP), Stratum Radiatum (SR) and Stratum Lacunosum Moleculare (LM) of CA1-3, as well as in molecular layer-granule cell layer (ML-GCL) and Hilus (H) of the dentate gyrus (DG). CSIS-induced reduction in the number of PV+ cells was layer/subregion-specific with the greatest decrease in SO of CA2. Reduction in the number of PV+ cells was significantly higher than GAD67+ cells, indicating that PV+ cells are the main target following CSIS. Tian reversed CSIS-induced behavior phenotype and antagonized the reduction in the number of PV+ and GAD67+ cells in all subregions. In controls, Tian led to an increase in the number of PV+ and GAD67+ cells in SP of all subregions and PV+ interneurons in ML-GCL of DG, while treatment during CSIS, compared to CSIS alone, resulted with an increase of PV+ interneurons in SO and SP CA1, SP CA2/CA3 and ML-GCL DG with simultaneous increase in GAD67+ cells in all CA1, LM CA2, SO/SR/LM CA3. Data show that Tian offers protection from CSIS via modulation of the dorsal hippocampal GABAergic system.
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Affiliation(s)
- Ivana Perić
- Vinča Institute of Nuclear Sciences, Laboratory for molecular biology and endocrinology, University of Belgrade, Serbia
| | - Andrijana Stanisavljević
- Vinča Institute of Nuclear Sciences, Laboratory for molecular biology and endocrinology, University of Belgrade, Serbia
| | - Dragos Inta
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Psychiatry (UPK), University of Basel, Switzerland
| | - Peter Gass
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Undine E Lang
- Department of Psychiatry (UPK), University of Basel, Switzerland
| | - Stefan Borgwardt
- Department of Psychiatry (UPK), University of Basel, Switzerland
| | - Dragana Filipović
- Vinča Institute of Nuclear Sciences, Laboratory for molecular biology and endocrinology, University of Belgrade, Serbia.
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Koek RJ, Luong TN. Theranostic pharmacology in PTSD: Neurobiology and timing. Prog Neuropsychopharmacol Biol Psychiatry 2019; 90:245-263. [PMID: 30529001 DOI: 10.1016/j.pnpbp.2018.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/17/2018] [Accepted: 12/05/2018] [Indexed: 02/06/2023]
Abstract
Recent reviews and treatment guidelines regard trauma-focused cognitive-behavior therapies as the treatments of choice for chronic post-traumatic stress disorder (PTSD). However, many patients do not engage in this treatment when it is available, drop out before completion, or do not respond. Medications remain widely used, alone and in conjunction with psychotherapy, although the limitations of traditional monoamine-based pharmacotherapy are increasingly recognized. This article will review recent developments in psychopharmacology for PTSD, with a focus on current clinical data that apply putative neurobiologic mechanisms to medication use-i.e., a theranostic approach. A theranostic approach however, also requires consideration of timing, pre, peri or post trauma in conjunction with underlying dynamic processes affecting synaptic plasticity, the HPA axis, hippocampal activation, PFC-amygdala circuitry and fear memory.
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Affiliation(s)
- Ralph J Koek
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Sepulveda Ambulatory Care Center, VA Greater Los Angeles Healthcare System, North Hills, CA, USA.
| | - Tinh N Luong
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Olive View Medical Center, Sylmar, CA, USA
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