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Kotzalidis GD, Fiaschè F, Alcibiade A, Monti L, Di Segni F, Mazza M, Sani G. New pharmacotherapies to tackle the unmet needs in bipolar disorder: a focus on acute suicidality. Expert Opin Pharmacother 2024; 25:435-446. [PMID: 38517222 DOI: 10.1080/14656566.2024.2334425] [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: 01/26/2024] [Accepted: 03/20/2024] [Indexed: 03/23/2024]
Abstract
INTRODUCTION Suicidal behavior is relatively frequent in patients with bipolar disorder (BD) and constitutes their most frequent cause of death. Suicide rates remain high in patients with BD despite adherence to guidelines recommending lithium as first line, and/or antidepressants, antipsychotics, psychotherapy, psychosocial interventions, and electroconvulsive therapy. Hence the need to identify more effective and rapid anti-suicide interventions. AREAS COVERED To tackle the unmet needs of pharmacotherapy, we investigated the PubMed database on 24-25 January 2024 using strategies like ('acute suicid*'[ti] OR 'suicide crisis syndrome' OR 'acute suicidal affective disturbance') AND (lithium[ti] OR clozapine[ti]), which obtained 3 results, and ('acute suicid*'[ti] OR 'suicide crisis syndrome' OR 'acute suicidal affective disturbance') AND (ketamine[ti] OR esketamine[ti] OR NMDA[ti] OR glutamat*[ti]), which yielded 14 results. We explored glutamatergic abnormalities in BD and suicide and found alterations in both. The noncompetitive NMDS antagonist ketamine and its S-enantiomer esketamine reportedly decrease acute suicidality. EXPERT OPINION Intranasal esketamine or subcutaneous ketamine, single-bolus or intravenous, and possibly other glutamate receptor modulators may improve suicidal behavior in patients with unipolar and bipolar depression. This may be achieved through prompt remodulation of glutamate activity. The correct use of glutamatergic modulators could reduce acute suicidality and mortality in patients with BD.
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Affiliation(s)
- Georgios D Kotzalidis
- Department of Neurosciences, Mental Health, and Sensory Organs (NESMOS), Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Federica Fiaschè
- ASL RM1, Presidio Ospedaliero San Filippo Neri, Servizio Psichiatrico di Diagnosi e Cura, Rome, Italy
| | - Alessandro Alcibiade
- Marina Militare Italiana (Italian Navy), Defense Ministry of Italy, Rome, Italy
- Psychiatry Residency Training Programme, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy
| | - Laura Monti
- UOS Clinical Psychology, Clinical Government, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Federica Di Segni
- Psychiatry Residency Training Programme, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy
| | - Marianna Mazza
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Gabriele Sani
- Department of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Rome, Italy
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Plausible Role of Stem Cell Types for Treating and Understanding the Pathophysiology of Depression. Pharmaceutics 2023; 15:pharmaceutics15030814. [PMID: 36986674 PMCID: PMC10058940 DOI: 10.3390/pharmaceutics15030814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/09/2023] [Accepted: 02/17/2023] [Indexed: 03/06/2023] Open
Abstract
Major Depressive Disorder (MDD), colloquially known as depression, is a debilitating condition affecting an estimated 3.8% of the population globally, of which 5.0% are adults and 5.7% are above the age of 60. MDD is differentiated from common mood changes and short-lived emotional responses due to subtle alterations in gray and white matter, including the frontal lobe, hippocampus, temporal lobe, thalamus, striatum, and amygdala. It can be detrimental to a person’s overall health if it occurs with moderate or severe intensity. It can render a person suffering terribly to perform inadequately in their personal, professional, and social lives. Depression, at its peak, can lead to suicidal thoughts and ideation. Antidepressants manage clinical depression and function by modulating the serotonin, norepinephrine, and dopamine neurotransmitter levels in the brain. Patients with MDD positively respond to antidepressants, but 10–30% do not recuperate or have a partial response accompanied by poor life quality, suicidal ideation, self-injurious behavior, and an increased relapse rate. Recent research shows that mesenchymal stem cells and iPSCs may be responsible for lowering depression by producing more neurons with increased cortical connections. This narrative review discusses the plausible functions of various stem cell types in treating and understanding depression pathophysiology.
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Abstract
Depression is one of the most poorly understood diseases due to its elusive pathogenesis. There is an urgency to identify molecular and biological mechanisms underlying depression and the gut microbiome is a novel area of interest. Here we investigate the relation of fecal microbiome diversity and composition with depressive symptoms in 1,054 participants from the Rotterdam Study cohort and validate these findings in the Amsterdam HELIUS cohort in 1,539 subjects. We identify association of thirteen microbial taxa, including genera Eggerthella, Subdoligranulum, Coprococcus, Sellimonas, Lachnoclostridium, Hungatella, Ruminococcaceae (UCG002, UCG003 and UCG005), LachnospiraceaeUCG001, Eubacterium ventriosum and Ruminococcusgauvreauiigroup, and family Ruminococcaceae with depressive symptoms. These bacteria are known to be involved in the synthesis of glutamate, butyrate, serotonin and gamma amino butyric acid (GABA), which are key neurotransmitters for depression. Our study suggests that the gut microbiome composition may play a key role in depression.
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Sobanski T, Peikert G, Kastner UW, Wagner G. Suicidal behavior-advances in clinical and neurobiological research and improvement of prevention strategies. World J Psychiatry 2022; 12:1115-1126. [PMID: 36186502 PMCID: PMC9521537 DOI: 10.5498/wjp.v12.i9.1115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/26/2022] [Accepted: 08/15/2022] [Indexed: 02/05/2023] Open
Abstract
Suicide is the 14th leading cause of death worldwide. It is responsible for 1%-5% of all mortality. This article highlights the latest developments in universal, selective, and indicated prevention strategies. Concerning universal suicide prevention, current research has shown that strategies such as restricting access to lethal means (e.g., control of analgesics and hot-spots for suicide by jumping) and school-based awareness programs are most efficacious. Regarding selective prevention, substantial progress can be expected in psychological screening methods for suicidal behavior. The measurement of implicit cognition proved to be more valid in predicting future suicide attempts than classic clinical assessment. Latest developments are smartphone-based interventions and real-time monitoring of suicidal behavior. Great effort has been made to establish valid neurobiological screening methods (e.g., genetic and epigenetic risk factors for suicide, hypothalamic-pituitary-adrenal axis) without yielding a major bre-akthrough. Potentially, multiple biomarkers rather than a single one are necessary to identify individuals at risk. With regard to indicated prevention in form of psychopharmacological treatment, recent pharmacoepidemiological studies and meta-analyses have supported a protective role of antidepressants, lithium, and clozapine. However, the data concerning a specific anti-suicidal effect of these drugs are currently not consistent. Promising results exist for ketamine in reducing suicidal ideation, independently of its antidepressant effect. Concerning psychotherapy, recent findings suggest that psychotherapeutic interventions specifically designed to prevent suicide re-attempts are most efficacious. Specifically, cognitive behavioral therapy and psychodynamic therapy approaches proved to decrease the number of suicide re-attempts significantly.
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Affiliation(s)
- Thomas Sobanski
- Department of Psychiatry, Psychotherapy, and Psychosomatic Medicine, THUERINGEN-Kliniken GmbH, Saalfeld 07318, Germany
- Network for Suicide Prevention in Thuringia (NeST), Jena 07743, Germany
| | - Gregor Peikert
- Department of Psychiatry and Psychotherapy, University Hospital Jena, Jena 07743, Germany
| | - Ulrich W Kastner
- Network for Suicide Prevention in Thuringia (NeST), Jena 07743, Germany
- Department of Psychiatry and Psychotherapy, Helios Fachkliniken Hildburghausen, Hildburghausen 98646, Germany
| | - Gerd Wagner
- Network for Suicide Prevention in Thuringia (NeST), Jena 07743, Germany
- Department of Psychiatry and Psychotherapy, University Hospital Jena, Jena 07743, Germany
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Targeting metabotropic glutamate receptors for the treatment of depression and other stress-related disorders. Neuropharmacology 2021; 196:108687. [PMID: 34175327 DOI: 10.1016/j.neuropharm.2021.108687] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 06/11/2021] [Accepted: 06/18/2021] [Indexed: 12/15/2022]
Abstract
The discovery of robust antidepressant effects of ketamine in refractory patients has led to increasing focus on agents targeting glutamatergic signaling as potential novel antidepressant strategy. Among the agents targeting the glutamatergic system, compounds acting at metabotropic glutamate (mGlu) receptors are among the most promising agents under studies for depressive disorders. Further, the receptor diversity, distinct distribution in the CNS, and ability to modulate the glutamatergic neurotransmission in the brain areas implicated in mood disorders make them an exciting target for stress-related disorders. In preclinical models, antidepressant and anxiolytic effects of mGlu5 negative allosteric modulators (NAMs) have been reported. Interestingly, mGlu2/3 receptor antagonists show fast and sustained antidepressant-like effects similar to that of ketamine in rodents. Excitingly, they can also induce antidepressant effects in the animal models of treatment-resistant depression and are devoid of the side-effects associated with ketamine. Unfortunately, clinical trials of both mGlu5 and mGlu2/3 receptor NAMs have been inconclusive, and additional trials using other compounds with suitable preclinical and clinical properties are needed. Although group III mGlu receptors have gained less attention, mGlu7 receptor ligands have been shown to induce antidepressant-like effects in rodents. Collectively, compounds targeting mGlu receptors provide an alternative approach to fill the outstanding clinical need for safer and more efficacious antidepressants. This article is part of the special Issue on "Glutamate Receptors - mGluRs".
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Underwood MD, Bakalian MJ, Johnson VL, Kassir SA, Ellis SP, Mann JJ, Arango V. Less NMDA Receptor Binding in Dorsolateral Prefrontal Cortex and Anterior Cingulate Cortex Associated With Reported Early-Life Adversity but Not Suicide. Int J Neuropsychopharmacol 2020; 23:311-318. [PMID: 32060512 PMCID: PMC7251634 DOI: 10.1093/ijnp/pyaa009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 01/13/2020] [Accepted: 02/06/2020] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Glutamate is an excitatory neurotransmitter binding to 3 classes of receptors, including the N-methyl, D-aspartate (NMDA) receptor. NMDA receptor binding is lower in major depression disorder and suicide. NMDA receptor blocking with ketamine can have antidepressant and anti-suicide effects. Early-life adversity (ELA) may cause glutamate-mediated excitotoxicity and is more common with major depression disorder and in suicide decedents. We sought to determine whether NMDA-receptor binding is altered with suicide and ELA. METHODS A total 52 postmortem cases were organized as 13 quadruplets of suicide and non-suicide decedents matched for age, sex, and postmortem interval, with or without reported ELA (≤16 years). Tissue blocks containing dorsal prefrontal (BA8), dorsolateral prefrontal (BA9), or anterior cingulate (BA24) cortex were collected at autopsy. Psychiatrically healthy controls and suicide decedents underwent psychological autopsy to determine psychiatric diagnoses and details of childhood adversity. NMDA receptor binding was determined by quantitative autoradiography of [3H]MK-801 binding (displaced by unlabeled MK-801) in 20-µm-thick sections. RESULTS [3H]MK-801 binding was not associated with suicide in BA8, BA9, or BA24. However, [3H]MK-801 binding with ELA was less in BA8, BA9, and BA24 independent of suicide (P < .05). [3H]MK-801 binding was not associated with age or postmortem interval in any brain region or group. CONCLUSIONS Less NMDA receptor binding with ELA is consistent with the hypothesis that stress can cause excitotoxicity via excessive glutamate, causing either NMDA receptor downregulation or less receptor binding due to neuron loss consequent to the excitotoxicity.
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Affiliation(s)
- Mark D Underwood
- Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY,Department of Psychiatry, Columbia College of Physicians and Surgeons, New York, NY,Correspondence: Mark D. Underwood, PhD, Division of Molecular Imaging and Neuropathology/New York State Psychiatric Institute, Department of Psychiatry/Columbia Psychiatry, 1051 Riverside Drive, Box 42, New York, NY 10032 ()
| | - Mihran J Bakalian
- Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY
| | - Virginia L Johnson
- Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY
| | - Suham A Kassir
- Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY
| | - Steven P Ellis
- Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY
| | - J John Mann
- Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY,Department of Psychiatry, Columbia College of Physicians and Surgeons, New York, NY
| | - Victoria Arango
- Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY,Department of Psychiatry, Columbia College of Physicians and Surgeons, New York, NY
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Jimenez-Trevino L, Gonzalez-Blanco L, Alvarez-Vazquez C, Rodriguez-Revuelta J, Saiz Martinez PA. Glutamine and New Pharmacological Targets to Treat Suicidal Ideation. Curr Top Behav Neurosci 2020; 46:179-196. [PMID: 32926351 DOI: 10.1007/7854_2020_168] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Glutamate is the major excitatory neurotransmitter in the central nervous system, and it is linked with the amino acid glutamine through a metabolic relationship of enzymatic compound interconversion and transportation, also known as the glutamate-glutamine cycle.A growing body of evidence suggests involvement of the glutamatergic neurotransmitter system in suicidal behaviours. The initial evidence comes from the pathophysiology of neuropsychiatric disorders, as disruptions in glutamate neurotransmission have been found underlying pathology in multiple suicide-related psychiatric conditions such as major depressive disorder, schizophrenia, post-traumatic stress disorder, and bipolar disorder.Existing data from experimental animal models and human in vivo studies also demonstrate that glutamate plays a key role in suicide-related personality traits including aggression and impulsive aggression.Further studies on glutamate system dysfunction underlying suicidal behaviours have focused on the different steps of the glutamate-glutamine cycle: an inflammation-mediated reduction of glutamine synthetase activity has been found in depressed suicide attempters, phosphate-activated glutaminase genes are reduced in suicide completers, and gene expression abnormalities in NMDA receptors have also been discovered in suicide victims.Evidence of a role of the glutamate-glutamine cycle in suicidal behaviours unveils new targets for anti-suicide interventions. Lithium's mechanism to reduce the risk of suicide in people with mood disorders may be related to its ability to increase glutamine synthetase, whereas novel NMDA antagonists such as ketamine [or its S(+) enantiomer esketamine] have already demonstrated positive results in reducing suicidal ideation.
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Affiliation(s)
- Luis Jimenez-Trevino
- Department of Psychiatry, University of Oviedo, Oviedo, Spain
- Biomedical Research Networking Centre in Mental Health (CIBERSAM), Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Mental Health Services of Principado de Asturias (SESPA), Oviedo, Spain
| | - Leticia Gonzalez-Blanco
- Department of Psychiatry, University of Oviedo, Oviedo, Spain
- Biomedical Research Networking Centre in Mental Health (CIBERSAM), Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Mental Health Services of Principado de Asturias (SESPA), Oviedo, Spain
| | | | - Julia Rodriguez-Revuelta
- Department of Psychiatry, University of Oviedo, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Mental Health Services of Principado de Asturias (SESPA), Oviedo, Spain
| | - Pilar A Saiz Martinez
- Department of Psychiatry, University of Oviedo, Oviedo, Spain.
- Biomedical Research Networking Centre in Mental Health (CIBERSAM), Oviedo, Spain.
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
- Mental Health Services of Principado de Asturias (SESPA), Oviedo, Spain.
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Shwartz A, Betzer O, Kronfeld N, Kazimirsky G, Cazacu S, Finniss S, Lee HK, Motiei M, Dagan SY, Popovtzer R, Brodie C, Yadid G. Therapeutic Effect of Astroglia-like Mesenchymal Stem Cells Expressing Glutamate Transporter in a Genetic Rat Model of Depression. Theranostics 2017; 7:2690-2703. [PMID: 28819456 PMCID: PMC5558562 DOI: 10.7150/thno.18914] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 02/15/2017] [Indexed: 12/12/2022] Open
Abstract
Recent studies have proposed that abnormal glutamatergic neurotransmission and glial pathology play an important role in the etiology and manifestation of depression. It was postulated that restoration of normal glutamatergic transmission, by enhancing glutamate uptake, may have a beneficial effect on depression. We examined this hypothesis using unique human glial-like mesenchymal stem cells (MSCs), which in addition to inherent properties of migration to regions of injury and secretion of neurotrophic factors, were differentiated to express high levels of functional glutamate transporters (excitatory amino acid transporters; EAAT). Additionally, gold nanoparticles (GNPs), which serve as contrast agents for CT imaging, were loaded into the cells for non-invasive, real-time imaging and tracking of MSC migration and final location within the brain. MSC-EAAT (2×105; 10 μl) were administered (i.c.v.) to Flinder Sensitive Line rats (FSLs), a genetic model for depression, and longitudinal behavioral and molecular changes were monitored. FSL rats treated with MSC-EAAT showed attenuated depressive-like behaviors (measured by the forced swim test, novelty exploration test and sucrose self-administration paradigm), as compared to controls. CT imaging, Flame Atomic Absorption Spectroscopy analysis and immunohistochemistry showed that the majority of MSCs homed specifically to the dentate gyrus of the hippocampus, a region showing structural brain changes in depression, including loss of glial cells. mRNA and protein levels of EAAT1 and BDNF were significantly elevated in the hippocampus of MSC-EAAT-treated FSLs. Our findings indicate that MSC-EAATs effectively improve depressive-like manifestations, possibly in part by increasing both glutamate uptake and neurotropic factor secretion in the hippocampus.
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Affiliation(s)
- Amit Shwartz
- The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel
| | - Oshra Betzer
- Faculty of Engineering and the Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 5290002, Israel
- Leslie Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan 52900, Israel
| | - Noam Kronfeld
- The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel
| | - Gila Kazimirsky
- The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel
| | - Simona Cazacu
- Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA 48202
| | - Susan Finniss
- Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA 48202
| | - Hae Kyung Lee
- Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA 48202
| | - Menachem Motiei
- Faculty of Engineering and the Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 5290002, Israel
| | - Shani Yael Dagan
- The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel
| | - Rachela Popovtzer
- Faculty of Engineering and the Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 5290002, Israel
| | - Chaya Brodie
- The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel
- Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA 48202
| | - Gal Yadid
- The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel
- Leslie Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan 52900, Israel
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Dean B, Gibbons AS, Boer S, Uezato A, Meador-Woodruff J, Scarr E, McCullumsmith RE. Changes in cortical N-methyl- d-aspartate receptors and post-synaptic density protein 95 in schizophrenia, mood disorders and suicide. Aust N Z J Psychiatry 2016; 50:275-83. [PMID: 26013316 PMCID: PMC7683009 DOI: 10.1177/0004867415586601] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVES In humans, depending on dose, blocking the N-methyl-D-aspartate receptor (NMDAR) with ketamine can cause psychomimetic or antidepressant effects. The overall outcome for drugs such as ketamine depends on dose and the number of its available binding sites in the central nervous system, and to understand something of the latter variable we measure NMDAR in the frontal pole, dorsolateral prefrontal, anterior cingulate and parietal cortices from people with schizophrenia, bipolar disorder, major depressive disorders and age/sex matched controls. METHOD We measured levels of NMDARs (using [(3)H]MK-801 binding) and NMDAR sub-unit mRNAs (GRINs: using in situ hybridisation) as well as post-synaptic density protein 95 (anterior cingulate cortex only; not major depressive disorders: an NMDAR post-synaptic associated protein) in bipolar disorder, schizophrenia and controls. RESULTS Compared to controls, levels of NMDAR were lower in the outer laminae of the dorsolateral prefrontal cortex (-17%, p = 0.01) in people with schizophrenia. In bipolar disorder, levels of NMDAR binding (laminae IV-VI; -19%, p < 0.01) and GRIN2C mRNA (laminae I-VI; -27%, p < 0.05) were lower in the anterior cingulate cortex and NMDAR binding was lower in the outer lamina IV of the dorsolateral prefrontal cortex (-19%, p < 0.01). In major depressive disorders, levels of GRIN2D mRNA were higher in frontal pole (+22%, p < 0.05). In suicide completers, levels of GRIN2B mRNA were higher in parietal cortex (+20%, p < 0.01) but lower (-35%, p = 0.02) in dorsolateral prefrontal cortex while post-synaptic density protein 95 was higher (+26%, p < 0.05) in anterior cingulate cortex. CONCLUSION These data suggest that differences in cortical NMDAR expression and post-synaptic density protein 95 are present in psychiatric disorders and suicide completion and may contribute to different responses to ketamine.
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Affiliation(s)
- Brian Dean
- Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, VIC, Australia,Psychiatric Neuropathology Laboratory, Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia
| | - Andrew S Gibbons
- Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, VIC, Australia,Psychiatric Neuropathology Laboratory, Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia
| | - Simone Boer
- Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, VIC, Australia
| | - Akihito Uezato
- Department of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | | | - Elizabeth Scarr
- Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, VIC, Australia,Psychiatric Neuropathology Laboratory, Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia
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McOmish CE, Pavey G, Gibbons A, Hopper S, Udawela M, Scarr E, Dean B. Lower [3H]LY341495 binding to mGlu2/3 receptors in the anterior cingulate of subjects with major depressive disorder but not bipolar disorder or schizophrenia. J Affect Disord 2016; 190:241-248. [PMID: 26521087 DOI: 10.1016/j.jad.2015.10.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 09/10/2015] [Accepted: 10/02/2015] [Indexed: 01/20/2023]
Abstract
INTRODUCTION The glutamatergic system has recently been implicated in the pathogenesis and treatment of major depressive disorders(MDD) and mGlu2/3 receptors play an important role in regulating glutamatergic tone. We therefore measured cortical levels of mGlu2/3 to determine if they were changed in MDD. METHODS Binding parameters for [(3)H]LY341495 (mGlu2/3 antagonist) were determined to allow optimized in situ binding with autoradiography to be completed using a number of CNS regions. Subsequently, density of [(3)H]LY341495 binding was measured in BA24(anterior cingulate cortex), BA17(visual cortex) and BA46(dorsolateral prefrontal cortex) from subjects with MDD, Bipolar Disorder(BPD), Schizophrenia(SCZ), and controls, as well as rats treated with imipramine (20mg/kg), fluoxetine (10mg/kg), or vehicle. RESULTS mGlu2/3 are widely expressed throughout the brain with high levels observed in cortex. [(3)H]LY341495 binding was significantly lower in BA24 from subjects with MDD (mean ± SEM=141.3 ± 14.65 fmol/ETE) relative to controls (184.9 ± 7.76 fmol/ETE; Cohen's d=1.005, p<0.05). There were no other differences with diagnoses, and chronic antidepressant treatment in rats had minimal effect on binding. LIMITATIONS Using this approach we are unable to determine whether the change represents fluctuations in mGlu2, mGlu3, or both. Moreover, using postmortem tissue we are unable to dissociate the irrevocable confound of suicidality upon binding levels. CONCLUSION We have demonstrated lower [(3)H]LY341495 binding levels in MDD in BA24-a brain region implicated in depression. Moreover we show that the lower levels are unlikely to be the result of antidepressant treatment. These data suggest that levels of either mGlu2 and/or mGlu3 are affected in the aetiology of MDD.
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Affiliation(s)
- Caitlin E McOmish
- The Florey Institute for Neuroscience and Mental Health and the University of Melbourne, Victoria, Australia; Department of Psychiatry, Columbia University, New York, NY, USA.
| | - Geoff Pavey
- The Florey Institute for Neuroscience and Mental Health and the University of Melbourne, Victoria, Australia
| | - Andrew Gibbons
- The Florey Institute for Neuroscience and Mental Health and the University of Melbourne, Victoria, Australia
| | - Shaun Hopper
- The Florey Institute for Neuroscience and Mental Health and the University of Melbourne, Victoria, Australia
| | - Madhara Udawela
- The Florey Institute for Neuroscience and Mental Health and the University of Melbourne, Victoria, Australia
| | - Elizabeth Scarr
- Department of Psychiatry, University of Melbourne, Victoria, Australia
| | - Brian Dean
- The Florey Institute for Neuroscience and Mental Health and the University of Melbourne, Victoria, Australia; Department of Psychiatry, University of Melbourne, Victoria, Australia
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Sex differences in glutamate receptor gene expression in major depression and suicide. Mol Psychiatry 2015; 20:1057-68. [PMID: 26169973 DOI: 10.1038/mp.2015.91] [Citation(s) in RCA: 156] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 05/27/2015] [Accepted: 06/01/2015] [Indexed: 02/06/2023]
Abstract
Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59=2.32, P=0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups. These data reveal further evidence that, in addition to the NMDA receptor, the AMPA, kainate and the metabotropic GluRs may be targets for the development of rapidly acting antidepressant drugs.
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Lee EE, Della Selva MP, Liu A, Himelhoch S. Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative meta-analysis. Gen Hosp Psychiatry 2015; 37:178-84. [PMID: 25698228 DOI: 10.1016/j.genhosppsych.2015.01.003] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 12/29/2014] [Accepted: 01/08/2015] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Given the significant disability, morbidity and mortality associated with depression, the promising recent trials of ketamine highlight a novel intervention. A meta-analysis was conducted to assess the efficacy of ketamine in comparison with placebo for the reduction of depressive symptoms in patients who meet criteria for a major depressive episode. METHOD Two electronic databases were searched in September 2013 for English-language studies that were randomized placebo-controlled trials of ketamine treatment for patients with major depressive disorder or bipolar depression and utilized a standardized rating scale. Studies including participants receiving electroconvulsive therapy and adolescent/child participants were excluded. Five studies were included in the quantitative meta-analysis. RESULTS The quantitative meta-analysis showed that ketamine significantly reduced depressive symptoms. The overall effect size at day 1 was large and statistically significant with an overall standardized mean difference of 1.01 (95% confidence interval 0.69-1.34) (P<.001), with the effects sustained at 7 days postinfusion. The heterogeneity of the studies was low and not statistically significant, and the funnel plot showed no publication bias. CONCLUSIONS The large and statistically significant effect of ketamine on depressive symptoms supports a promising, new and effective pharmacotherapy with rapid onset, high efficacy and good tolerability.
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Affiliation(s)
- Ellen E Lee
- Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD
| | - Megan P Della Selva
- Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD
| | - Anson Liu
- Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD
| | - Seth Himelhoch
- Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD
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Oquendo MA, Sullivan GM, Sudol K, Baca-Garcia E, Stanley BH, Sublette ME, Mann JJ. Toward a biosignature for suicide. Am J Psychiatry 2014; 171:1259-77. [PMID: 25263730 PMCID: PMC4356635 DOI: 10.1176/appi.ajp.2014.14020194] [Citation(s) in RCA: 185] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Suicide, a major cause of death worldwide, has distinct biological underpinnings. The authors review and synthesize the research literature on biomarkers of suicide, with the aim of using the findings of these studies to develop a coherent model for the biological diathesis for suicide. METHOD The authors examined studies covering a large range of neurobiological systems implicated in suicide. They provide succinct descriptions of each system to provide a context for interpreting the meaning of findings in suicide. RESULTS Several lines of evidence implicate dysregulation in stress response systems, especially the hypothalamic-pituitary-adrenal axis, as a diathesis for suicide. Additional findings related to neuroinflammatory indices, glutamatergic function, and neuronal plasticity at the cellular and circuitry level may reflect downstream effects of such dysregulation. Whether serotonergic abnormalities observed in individuals who have died by suicide are independent of stress response abnormalities is an unresolved question. CONCLUSIONS The most compelling biomarkers for suicide are linked to altered stress responses and their downstream effects, and to abnormalities in the serotonergic system. Studying these systems in parallel and in the same populations may elucidate the role of each and their interplay, possibly leading to identification of new treatment targets and biological predictors.
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Sowa-Kućma M, Szewczyk B, Sadlik K, Piekoszewski W, Trela F, Opoka W, Poleszak E, Pilc A, Nowak G. Zinc, magnesium and NMDA receptor alterations in the hippocampus of suicide victims. J Affect Disord 2013; 151:924-31. [PMID: 24055117 DOI: 10.1016/j.jad.2013.08.009] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 08/09/2013] [Accepted: 08/09/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND There is evidence for an association between suicidal behavior and depression. Accumulating data suggests that depression is related to a dysfunction of the brain's glutamatergic system, and that the N-methyl-d-aspartate (NMDA) receptor plays an important role in antidepressant activity. Zinc and magnesium, the potent antagonists of the NMDA receptor complex, are involved in the pathophysiology of depression and exhibit antidepressant activity. METHODS The present study investigated the potency of Zn(2+) and Mg(2+) to [(3)H] MK-801, which binds to the NMDA receptor channel in the hippocampus of suicide victims (n=17) and sudden death controls (n=6). Moreover, the concentrations of zinc and magnesium (by flame atomic absorption spectrometry) and levels of NMDA subunits (NR2A and NR2B) and PSD-95 protein (by Western blotting) were determined. RESULTS Our results revealed that there was a statistically significant decrease (by 29% and 40%) in the potency of zinc and magnesium (respectively) to inhibit [(3)H] MK-801 binding to NMDA receptors in the hippocampus in suicide tissue relative to the controls. These alterations were associated with increased NR2A (+68%) and decreases in both the NR2B (-46%) and PSD-95 (-35%) levels. Furthermore, lower concentrations (-9%) of magnesium (although not of zinc) were demonstrated in suicide tissue. CONCLUSIONS Our findings indicate that alterations in the zinc, magnesium and NMDA receptor complex in the hippocampus are potentially involved in the pathophysiology of suicide-related disorders (depression), which may lead to functional NMDA receptor hyperactivity.
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Furczyk K, Schutová B, Michel TM, Thome J, Büttner A. The neurobiology of suicide - A Review of post-mortem studies. J Mol Psychiatry 2013; 1:2. [PMID: 25408895 PMCID: PMC4223890 DOI: 10.1186/2049-9256-1-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Accepted: 02/15/2013] [Indexed: 01/15/2023] Open
Abstract
The neurobiology of suicidal behaviour, which constitutes one of the most serious problems both in psychiatry and general medical practice, still remains to a large degree unclear. As a result, scientists constantly look for new opportunities of explaining the causes underlying suicidality. In order to elucidate the biological changes occurring in the brains of the suicide victims, studies based on post-mortem brain tissue samples are increasingly being used. These studies employ different research methods to provide an insight into abnormalities in brain functioning on various levels, including gene and protein expression, neuroplasticity and neurotransmission, as well as many other areas. The aim of this paper to summarize the available data on the post-mortem studies, to provide an overview of main research directions and the most up-to-date findings, and to indicate the possibilities of further research in this field.
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Affiliation(s)
- Karolina Furczyk
- Department of Psychiatry, University of Rostock, Gehlsheimerstrasse 20, 18147 Rostock, Germany
| | - Barbora Schutová
- Department of Psychiatry, University of Rostock, Gehlsheimerstrasse 20, 18147 Rostock, Germany
| | - Tanja M Michel
- Department of Psychiatry, University of Rostock, Gehlsheimerstrasse 20, 18147 Rostock, Germany
| | - Johannes Thome
- Department of Psychiatry, University of Rostock, Gehlsheimerstrasse 20, 18147 Rostock, Germany ; College of Medicine, Swansea University, Singleton Park, Swansea, SA2 PP UK
| | - Andreas Büttner
- Institute of Forensic Medicine, University of Rostock, St.-Georg-Strasse 108, 18055 Rostock, Germany
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Mathews DC, Henter ID, Zarate CA. Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs 2012; 72:1313-33. [PMID: 22731961 DOI: 10.2165/11633130-000000000-00000] [Citation(s) in RCA: 158] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Major depressive disorder (MDD) is a severe, debilitating medical illness that affects millions of individuals worldwide. The young age of onset and chronicity of the disorder has a significant impact on the long-term disability that affected individuals face. Most existing treatments have focused on the 'monoamine hypothesis' for rational design of compounds. However, patients continue to experience low remission rates, residual subsyndromal symptoms, relapses and overall functional impairment. In this context, growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of MDD. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of MDD, and discuss the efficacy of glutamatergic agents as novel therapeutics. Preliminary clinical evidence has been promising, particularly with regard to the N-methyl-D-aspartate (NMDA) antagonist ketamine as a 'proof-of-concept' agent. The review also highlights potential molecular and inflammatory mechanisms that may contribute to the rapid antidepressant response seen with ketamine. Because existing pharmacological treatments for MDD are often insufficient for many patients, the next generation of treatments needs to be more effective, rapid acting and better tolerated than currently available medications. There is extant evidence that the glutamatergic system holds considerable promise for developing the next generation of novel and mechanistically distinct agents for the treatment of MDD.
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Affiliation(s)
- Daniel C Mathews
- Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA
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Quiroz JA, Manji HK. Enhancing synaptic plasticity and cellular resilience to develop novel, improved treatments for mood disorders. DIALOGUES IN CLINICAL NEUROSCIENCE 2012. [PMID: 22034240 PMCID: PMC3181673 DOI: 10.31887/dcns.2002.4.1/jquiroz] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
There is mounting evidence that recurrent mood disorders - once considered “good prognosis diseases”- are, in fact, often very severe and life-threatening illnesses. Furthermore, although mood disorders have traditionally been conceptualized as neurochemical disorders, there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes ofglia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggest that mood disorders are associated with impairments of synaptic plasticity and cellular resilience. In this context, it is noteworthy that there is increasing preclinical evidence that antidepressants regulate the function of the glutamatergic system. Moreover, although clearly preliminary, the available clinical data suggest that attenuation of N-methyl-D-aspartate (NMDA) function has antidepressant effects. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell survival and cell death are long-term targets for the actions of antidepressant agents. Antidepressants and mood stabilizers indirectly regulate a number of factors involved in cell survival pathways, including cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), the antiapoptotic protein bcl-2, and mitogen-activated protein (MAP) kinases, and may thus bring about some of their delayed long-term beneficial effects via underappreciated neurotrophic effects. There is much promise for the future development of treatments that more directly target molecules in critical CNS signaling pathways regulating synaptic plasticity and cellular resilience. These will represent improved long-term treatments for mood disorders.
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Affiliation(s)
- Jorge A Quiroz
- Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Bethesda, Md, USA
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18
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Mathews DC, Henter ID, Zarate CA. Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs 2012. [PMID: 22731961 DOI: 10.2165/11633130‐000000000‐00000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Major depressive disorder (MDD) is a severe, debilitating medical illness that affects millions of individuals worldwide. The young age of onset and chronicity of the disorder has a significant impact on the long-term disability that affected individuals face. Most existing treatments have focused on the 'monoamine hypothesis' for rational design of compounds. However, patients continue to experience low remission rates, residual subsyndromal symptoms, relapses and overall functional impairment. In this context, growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of MDD. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of MDD, and discuss the efficacy of glutamatergic agents as novel therapeutics. Preliminary clinical evidence has been promising, particularly with regard to the N-methyl-D-aspartate (NMDA) antagonist ketamine as a 'proof-of-concept' agent. The review also highlights potential molecular and inflammatory mechanisms that may contribute to the rapid antidepressant response seen with ketamine. Because existing pharmacological treatments for MDD are often insufficient for many patients, the next generation of treatments needs to be more effective, rapid acting and better tolerated than currently available medications. There is extant evidence that the glutamatergic system holds considerable promise for developing the next generation of novel and mechanistically distinct agents for the treatment of MDD.
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Affiliation(s)
- Daniel C Mathews
- Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA
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Zarate CA, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA, Liberty V, Luckenbaugh DA. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry 2012; 71:939-46. [PMID: 22297150 PMCID: PMC3343177 DOI: 10.1016/j.biopsych.2011.12.010] [Citation(s) in RCA: 580] [Impact Index Per Article: 44.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2011] [Revised: 12/01/2011] [Accepted: 12/05/2011] [Indexed: 11/29/2022]
Abstract
BACKGROUND Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample. METHODS In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion. RESULTS Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo (d = .89, 95% confidence interval = .61-1.16, and .98, 95% confidence interval = .64-1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point. CONCLUSIONS This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.
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Affiliation(s)
- Carlos A Zarate
- Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland, USA.
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Bao AM, Ruhé HG, Gao SF, Swaab DF. Neurotransmitters and neuropeptides in depression. HANDBOOK OF CLINICAL NEUROLOGY 2012; 106:107-36. [PMID: 22608619 DOI: 10.1016/b978-0-444-52002-9.00008-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- A-M Bao
- Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
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21
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Prins J, Olivier B, Korte SM. Triple reuptake inhibitors for treating subtypes of major depressive disorder: the monoamine hypothesis revisited. Expert Opin Investig Drugs 2011; 20:1107-30. [DOI: 10.1517/13543784.2011.594039] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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DiazGranados N, Ibrahim L, Brutsche N, Ameli R, Henter ID, Luckenbaugh DA, Machado-Vieira R, Zarate CA. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry 2010; 71:1605-11. [PMID: 20673547 PMCID: PMC3012738 DOI: 10.4088/jcp.09m05327blu] [Citation(s) in RCA: 438] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Accepted: 07/14/2009] [Indexed: 10/19/2022]
Abstract
OBJECTIVE Suicidal ideation is a medical emergency, especially when severe. Little research has been done on pharmacologic interventions that could address this problem. Ketamine, an N-methyl-D-asparate antagonist, has been reported to have antidepressant effects within hours. We examined the effects of a single dose of ketamine on suicidal ideation in subjects with treatment-resistant major depressive disorder (MDD). METHOD Thirty-three subjects with DSM-IV-diagnosed MDD received a single open-label infusion of ketamine (0.5 mg/kg) and were rated at baseline and at 40, 80, 120, and 230 minutes postinfusion with the Scale for Suicide Ideation (SSI), the Montgomery-Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. The study was conducted between October 2006 and January 2009. RESULTS Suicidal ideation scores decreased significantly on the SSI as well as on the suicide subscales of other rating instruments within 40 minutes; these decreases remained significant through the first 4 hours postinfusion (P < .001). Ten subjects (30%) had an SSI score ≥ 4 at baseline; all these scores dropped below 4 (9 dropped by 40 minutes and 1 by 80 minutes). For those patients with a starting score below 4 on the SSI, only 1 reached a score of 4. Depression, anxiety, and hopelessness were significantly improved at all time points (P < .001). CONCLUSIONS Suicidal ideation in the context of MDD improved within 40 minutes of a ketamine infusion and remained improved for up to 4 hours postinfusion. Future studies with ketamine in suicidal ideation are warranted due to the potential impact on public health. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00088699.
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Abstract
OBJECTIVE To review the literature on the involvement of glutamate (Glu), including its interactions with other neurochemical systems, in the pathophysiology of depression. METHOD A MEDLINE search using the terms glutamate, depression and major depressive disorder, was performed. RESULTS Alterations in proteins involved in glutamatergic signalling are implicated in variations in behaviour in animal models of depression. Drugs acting at Glu receptors appear to have antidepressant-like effects in these models, and traditional antidepressant pharmacotherapies act on the glutamatergic system. Recent evidence from genetic studies and in vivo spectroscopy also correlate glutamatergic dysfunction with depression. Trials of N-methyl-d-aspartate receptor antagonists in humans have provided mixed results. CONCLUSION A growing body of evidence indicates that the glutamatergic system is involved in the pathophysiology of depression, and may represent a target for intervention.
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Affiliation(s)
- Nicholas D Mitchell
- Department of Psychiatry, University of Alberta Hospital, Edmonton, AB, Canada.
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24
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Gao SF, Bao AM. Corticotropin-Releasing Hormone, Glutamate, and γ-Aminobutyric Acid in Depression. Neuroscientist 2010; 17:124-44. [DOI: 10.1177/1073858410361780] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Stress response and depression have a significant impact on modern society. Although the symptoms are well characterized, the molecular mechanisms underlying depression are largely unknown. The monoamine hypothesis, which postulates dysfunctional noradrenergic and serotonergic systems as the underlying primary cause of depression, has been valuable for the development of conventional antidepressants, which can reverse these dysfunctional states to some degree. However, recent data from various neuroscience disciplines have questioned the major role of amines in the pathogenesis of depression. A considerable amount of evidence has accumulated that suggests that normalization of the hypothalamo—pituitary—adrenal (HPA) system might be the final step necessary for a remission of depression. In addition, an increasing body of clinical and postmortem evidence is pointing to a role played by γ-aminobutyric acid (GABA) and glutamate in the etiology of depression. This review examines the evidence, mainly obtained from clinical studies or from postmortem brain material, for a major role of the HPA axis, glutamatergic, and GABAergic systems in the pathogenesis of major and bipolar depression. The authors hope that these insights will stimulate further studies with the final aim of developing new types of antidepressants that combine increased efficacy with a shorter delay of the onset of action and reduced side-effect profiles.
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Affiliation(s)
- Shang-Feng Gao
- Department of Neurobiology, Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China
| | - Ai-Min Bao
- Department of Neurobiology, Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China,
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25
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Baca-Garcia E, Vaquero-Lorenzo C, Perez-Rodriguez MM, Gratacòs M, Bayés M, Santiago-Mozos R, Leiva-Murillo JM, de Prado-Cumplido M, Artes-Rodriguez A, Ceverino A, Diaz-Sastre C, Fernandez-Navarro P, Costas J, Fernandez-Piqueras J, Diaz-Hernandez M, de Leon J, Baca-Baldomero E, Saiz-Ruiz J, Mann JJ, Parsey RV, Carracedo A, Estivill X, Oquendo MA. Nucleotide variation in central nervous system genes among male suicide attempters. Am J Med Genet B Neuropsychiatr Genet 2010; 153B:208-13. [PMID: 19455598 DOI: 10.1002/ajmg.b.30975] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Despite marked morbidity and mortality associated with suicidal behavior, accurate identification of individuals at risk remains elusive. The goal of this study is to identify a model based on single nucleotide polymorphisms (SNPs) that discriminates between suicide attempters and non-attempters using data mining strategies. We examined functional SNPs (n = 840) of 312 brain function and development genes using data mining techniques. Two hundred seventy-seven male psychiatric patients aged 18 years or older were recruited at a University hospital psychiatric emergency room or psychiatric short stay unit. The main outcome measure was history of suicide attempts. Three SNPs of three genes (rs10944288, HTR1E; hCV8953491, GABRP; and rs707216, ACTN2) correctly classified 67% of male suicide attempters and non-attempters (0.50 sensitivity, 0.82 specificity, positive likelihood ratio = 2.80, negative likelihood ratio = 1.64). The OR for the combined three SNPs was 4.60 (95% CI: 1.31-16.10). The model's accuracy suggests that in the future similar methodologies may generate simple genetic tests with diagnostic utility in identification of suicide attempters. This strategy may uncover new pathophysiological pathways regarding the neurobiology of suicidal acts.
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Affiliation(s)
- Enrique Baca-Garcia
- Department of Psychiatry at Fundacion Jimenez Diaz Hospital, Autonoma University, Madrid, Spain.
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Abstract
In this review, we examine the history of the neurobiology of suicide, as well as the genetics, molecular and neurochemical findings in suicide research. Our analysis begins with a summary of family, twin, and adoption studies, which provide support for the investigation of genetic variation in suicide risk. This leads to an overview of neurochemical findings restricted to neurotransmitters and their receptors, including recent findings in whole genome gene expression studies. Next, we look at recent studies investigating lipid metabolism, cell signalling with a particular emphasis on growth factors, stress systems with a focus on the role of polyamines, and finally, glial cell pathology in suicide. We conclude with a description of new ideas to study the neurobiology of suicide, including subject-specific analysis, protein modification assessment, neuroarchitecture studies, and study design strategies to investigate the complex suicide phenotype.
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Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V, Rehal S, Klempan T, Gratton A, Benkelfat C, Rouleau GA, Mechawar N, Turecki G. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS One 2009; 4:e6585. [PMID: 19668376 PMCID: PMC2719799 DOI: 10.1371/journal.pone.0006585] [Citation(s) in RCA: 283] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2008] [Accepted: 05/04/2009] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Most studies investigating the neurobiology of depression and suicide have focused on the serotonergic system. While it seems clear that serotonergic alterations play a role in the pathogenesis of these major public health problems, dysfunction in additional neurotransmitter systems and other molecular alterations may also be implicated. Microarray expression studies are excellent screening tools to generate hypotheses about additional molecular processes that may be at play. In this study we investigated brain regions that are known to be implicated in the neurobiology of suicide and major depression are likely to represent valid global molecular alterations. METHODOLOGY/PRINCIPAL FINDINGS We performed gene expression analysis using the HG-U133AB chipset in 17 cortical and subcortical brain regions from suicides with and without major depression and controls. Total mRNA for microarray analysis was obtained from 663 brain samples isolated from 39 male subjects, including 26 suicide cases and 13 controls diagnosed by means of psychological autopsies. Independent brain samples from 34 subjects and animal studies were used to control for the potential confounding effects of comorbidity with alcohol. Using a Gene Ontology analysis as our starting point, we identified molecular pathways that may be involved in depression and suicide, and performed follow-up analyses on these possible targets. Methodology included gene expression measures from microarrays, Gene Score Resampling for global ontological profiling, and semi-quantitative RT-PCR. We observed the highest number of suicide specific alterations in prefrontal cortical areas and hippocampus. Our results revealed alterations of synaptic neurotransmission and intracellular signaling. Among these, Glutamatergic (GLU) and GABAergic related genes were globally altered. Semi-quantitative RT-PCR results investigating expression of GLU and GABA receptor subunit genes were consistent with microarray data. CONCLUSIONS/SIGNIFICANCE The observed results represent the first overview of global expression changes in brains of suicide victims with and without major depression and suggest a global brain alteration of GLU and GABA receptor subunit genes in these conditions.
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Affiliation(s)
- Adolfo Sequeira
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
| | - Firoza Mamdani
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
| | - Carl Ernst
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
| | - Marquis P. Vawter
- Department of Psychiatry and Human Behavior, School of Medicine, University of California Irvine, Irvine, California, United States of America
| | - William E. Bunney
- Department of Psychiatry and Human Behavior, School of Medicine, University of California Irvine, Irvine, California, United States of America
| | - Veronique Lebel
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
| | - Sonia Rehal
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
| | - Tim Klempan
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
| | - Alain Gratton
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
| | - Chawki Benkelfat
- Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada
| | - Guy A. Rouleau
- Ste Justine Hospital, Université de Montréal, Montreal, Quebec, Canada
| | - Naguib Mechawar
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
| | - Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
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Boyce-Rustay JM, Holmes A. Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic- and antidepressant-like effects in mice. Neuropsychopharmacology 2006; 31:2405-14. [PMID: 16482087 DOI: 10.1038/sj.npp.1301039] [Citation(s) in RCA: 171] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
There is growing evidence implicating the glutamate system in the pathophysiology and treatment of mood and anxiety disorders. Glutamatergic neurotransmission is mediated by several receptor subfamilies including multiple NMDA receptor subunits (NR2A-D). However, little is currently understood about the specific roles of NMDA subunits in the mediation of emotional behavior due to a lack of subunit-specific ligands. In the present study, we employed a mouse gene-targeting approach to examine the role of the NR2A subunit in the mediation of anxiety- and depressive-related behaviors. Results showed that NR2A knockout (KO) mice exhibit decreased anxiety-like behavior relative to wild-type littermates (WT) across multiple tests (elevated plus maze, light-dark exploration test, novel open field). NR2A KO mice showed antidepressant-like profiles in the forced swim test and tail suspension test, as compared to WT controls. Locomotor activity in the nonaversive environments of the home cage or a familiar open field were normal in the NR2A KO mice, as were gross neurological and sensory functions, including prepulse inhibition of startle. Taken together, these data demonstrate a selective and robust reduction in anxiety- and depression-related behavior in NMDA receptor NR2A subunit KO mice. Present results support a role for the NR2A subunit in the modulation of emotional behaviors in rodents and provide insight into the role of glutamate in the pathophysiology and treatment of mood and anxiety disorders.
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Affiliation(s)
- Janel M Boyce-Rustay
- Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20892, USA.
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29
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Kendell SF, Krystal JH, Sanacora G. GABA and glutamate systems as therapeutic targets in depression and mood disorders. Expert Opin Ther Targets 2005; 9:153-68. [PMID: 15757488 DOI: 10.1517/14728222.9.1.153] [Citation(s) in RCA: 116] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Advances made in diverse areas of neuroscience suggest that neurotransmitter systems, additional to the monoaminergic, contribute to the pathophysiology of mood disorders. This ever accruing body of preclinical and clinical research is providing increased recognition of the contribution made by amino acid neurotransmitters to the neurobiology of mood disorders. This review examines evidence supporting the role of GABA and glutamate in these processes and explores the potential to target these systems in the development of novel compounds; the viability of these agents for treatment-related co-morbidities will also be considered.
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Affiliation(s)
- Steven F Kendell
- Yale University School of Medicine, Department of Psychiatry, 333 Cedar Street, New Haven, CT 06510, USA
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30
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Sanacora G, Rothman DL, Mason G, Krystal JH. Clinical studies implementing glutamate neurotransmission in mood disorders. Ann N Y Acad Sci 2004; 1003:292-308. [PMID: 14684453 DOI: 10.1196/annals.1300.018] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Emerging evidence suggests that the amino acid neurotransmitter systems are associated with the pathophysiology and treatment of mood disorders. Recent advances in the areas of molecular neurobiology, pharmacology, and magnetic resonance spectroscopy (MRS) now provide better tools to probe the function of the amino acid neurotransmitter systems and are affording us the opportunity to better investigate the relationship of these systems to mood disorders. Here we review the available literature in the field and suggest a possible pathophysiological model that may account for the many of the findings.
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Affiliation(s)
- Gerard Sanacora
- Department of Psychiatry, Yale University, School of Medicine, New Haven, Connecticut 06519, USA.
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31
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Zarate CA, Du J, Quiroz J, Gray NA, Denicoff KD, Singh J, Charney DS, Manji HK. Regulation of cellular plasticity cascades in the pathophysiology and treatment of mood disorders: role of the glutamatergic system. Ann N Y Acad Sci 2004; 1003:273-91. [PMID: 14684452 DOI: 10.1196/annals.1300.017] [Citation(s) in RCA: 139] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
There is increasing evidence from a variety of sources that mood disorders are associated with regional reductions in brain volume, as well as reductions in the number, size, and density of glia and neurons in discrete brain areas. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. In this context, it is noteworthy that a growing body of data suggests that the glutamatergic system--which is known to play a major role in neuronal plasticity and cellular resilience--may be involved in the pathophysiology and treatment of mood disorders. Preclinical studies have shown that the glutamatergic system represents targets (often indirect) for the actions of antidepressants and mood stabilizers. There are a number of glutamatergic "plasticity enhancing" strategies that may be of considerable utility in the treatment of mood disorders. Among the most immediate ones are NMDA antagonists, inhibitors of glutamate-release agents, and AMPA potentiators; this research progress holds much promise for the development of novel therapeutics for the treatment of severe, refractory mood disorders.
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Affiliation(s)
- Carlos A Zarate
- Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
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32
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Manji HK, Quiroz JA, Sporn J, Payne JL, Denicoff K, A Gray N, Zarate CA, Charney DS. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry 2003; 53:707-42. [PMID: 12706957 DOI: 10.1016/s0006-3223(03)00117-3] [Citation(s) in RCA: 346] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
There is growing evidence from neuroimaging and ostmortem studies that severe mood disorders, which have traditionally been conceptualized as neurochemical disorders, are associated with impairments of structural plasticity and cellular resilience. It is thus noteworthy that recent preclinical studies have shown that critical molecules in neurotrophic signaling cascades (most notably cyclic adenosine monophosphate [cAMP] response element binding protein, brain-derived neurotrophic factor, bcl-2, and mitogen activated protein [MAP] kinases) are long-term targets for antidepressant agents and antidepressant potentiating modalities. This suggests that effective treatments provide both trophic and neurochemical support, which serves to enhance and maintainnormal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. For many refractory patients, drugs mimicking "traditional" strategies, which directly or indirectly alter monoaminergic levels, may be of limited benefit. Newer "plasticity enhancing" strategies that may have utility in the treatment of refractory depression include N-methyl-D-aspartate antagonists, alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA) potentiators, cAMP phosphodiesterase inhibitors, and glucocorticoid receptor antagonists. Small-molecule agents that regulate the activity f growth factors, MAP kinases cascades, and the bcl-2 family of proteins are also promising future avenues. The development of novel, nonaminergic-based therapeutics holds much promise for improved treatment of severe, refractory mood disorders.
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Affiliation(s)
- Husseini K Manji
- Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Bethesda, Maryland 20892-4405, USA
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33
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Abstract
Our current knowledge about the neurobiology of suicide is still limited. Technical limitations and the complexity of the CNS are major obstacles. However, there is evidence for a hereditary disposition to suicide, which appears to be independent of diagnosis. Clinical, postmortem, genetic, and animal studies suggest that serotonin has a central role. The main regions of interest in the CNS have been the dorsal and median raphe nuclei in the midbrain that host the main serotonergic cell bodies and the prefrontal cortex, particularly the ventral PFC, innervated by the serotonergic system. In vivo and postmortem studies indicate serotonergic hypofunction in suicide and serious suicide attempts. This deficiency in turn can lead to a predisposition to impulsive and aggressive behavior, probably due to a breakdown in the inhibitory function of the ventral prefrontal cortex as a result of less serotonin input. In the context of this predisposition and the development of mental illness or other life stressors, the individual is at risk of acting on suicidal thoughts. Such deficient serotonin input into the PFC may arise as a result of genetic, parenting, head injury, and other effects. Identifying psychiatric, social, and environmental predictors of suicide are studied to improve prediction and prevention of suicide. A better understanding of the neurobiology of suicide can help detect at risk populations and help develop better treatment interventions.
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Affiliation(s)
- M Kamali
- Department of Neuroscience, Columbia University, College of Physicians and Surgeons and New York State Psychiatric Institute, New York, New York 10032, USA
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34
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Harro J, Oreland L. Depression as a spreading adjustment disorder of monoaminergic neurons: a case for primary implication of the locus coeruleus. BRAIN RESEARCH. BRAIN RESEARCH REVIEWS 2001; 38:79-128. [PMID: 11750928 DOI: 10.1016/s0165-0173(01)00082-0] [Citation(s) in RCA: 114] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
A model for the pathophysiology of depression is discussed in the context of other existing theories. The classic monoamine theory of depression suggests that a deficit in monoamine neurotransmitters in the synaptic cleft is the primary cause of depression. More recent elaborations of the classic theory also implicitly include this postulate, other theories of depression frequently prefer to depart from the monoamine-based model altogether. We suggest that the primary defect emerges in the regulation of firing rates in brainstem monoaminergic neurons, which brings about a decrease in the tonic release of neurotransmitters in their projection areas, an increase in postsynaptic sensitivity, and concomitantly, exaggerated responses to acute increases in the presynaptic firing rate and transmitter release. It is proposed that the initial defect involves, in particular, the noradrenergic innervation from the locus coeruleus (LC). Dysregulation of the LC projection activities may lead in turn to dysregulation of serotonergic and dopaminergic neurotransmission. Failure of the LC function could explain the basic impairments in the processing of novel information, intensive processing of irrational beliefs, and anxiety. Concomitant impairments in the serotonergic neurotransmission may contribute to the mood changes and reduction in the mesotelencephalic dopaminergic activity to loss of motivation, and anhedonia. Dysregulation of CRF and other neuropeptides such as neuropeptide Y, galanin and substance P may reinforce the LC dysfunction and thus further weaken the adaptivity to stressful stimuli.
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Affiliation(s)
- J Harro
- Department of Psychology, University of Tartu, Tiigi 78, EE-50410 Tartu, Estonia.
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35
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Robichaud M, Beauchemin V, Lavoie N, Dennis T, Debonnel G. Effects of bilateral olfactory bulbectomy on N-methyl-D-aspartate receptor function: autoradiographic and behavioral studies in the rat. Synapse 2001; 42:95-103. [PMID: 11574946 DOI: 10.1002/syn.1105] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Rat bilateral olfactory bulbectomy (OBX) serves as a useful model in the study of depression and the mechanisms of action of antidepressant treatments. Considering the evidence of NMDA receptors involvement in depression, the present study was undertaken in order to investigate the time-course effects of OBX on the NMDA receptor function. Following bilateral olfactory bulbectomy, rats display an increase in locomotor activity and changes in other types of behavior in a novel environment. Autoradiographic experiments using the noncompetitive NMDA antagonist [(125)I]-iodo-MK-801 as the labeling agent showed that this increase in behavioral activities corresponds to a decrease in [(125)I]-iodo-MK-801 binding in a number of brain regions. In most regions, this reduction reached significance by the third week following OBX. However, in some cortical areas-a nucleus of the thalamus (AV) and one of the amygdala (LA)-this reduction was already significant in the first or second week following OBX and lasted throughout the 4 weeks of the study. We also compared the behavioral modifications induced by a challenge injection of MK-801 (0.2 mg/kg i.p.) in OBX and sham-operated rats. This challenge is known to induce hyperlocomotion and a number of stereotypies in naive rats. These effects were drastically reduced in OBX as compared to sham-operated rats. These data are consistent with the above-mentioned decrease in cerebral binding of MK-801 to NMDA receptors.
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Affiliation(s)
- M Robichaud
- McGill University, Department of Psychiatry, 1033 Pine Avenue West, Montréal, Québec, Canada H3A 1A1
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36
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Berk M, Plein H, Ferreira D. Platelet glutamate receptor supersensitivity in major depressive disorder. Clin Neuropharmacol 2001; 24:129-32. [PMID: 11391122 DOI: 10.1097/00002826-200105000-00002] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Dysregulation of glutamate has been described in depression, and supersensitivity of platelet glutamate receptors has been found in both psychotic major depression and schizophrenia. The aim of this study was to examine the platelet glutamate receptor sensitivity in patients with nonpsychotic, unipolar major depression to assess whether this is a marker of depression or of psychosis. Glutamate receptor sensitivity was assessed using the platelet intracellular calcium response to glutamate (0-100 micromol) measured by spectrofluorometry. The depression group showed a significantly greater platelet intracellular calcium response to glutamate stimulation than the control group, both in terms of absolute values (p = 0.007) and percentage of response from baseline (p = 0.030). These data suggest that platelet glutamate receptors may be supersensitive in depression and that the platelet may be a possible peripheral marker of glutamate function in depression.
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Affiliation(s)
- M Berk
- Department of Psychiatry, University of the Witwatersrand, Johannesburg, South Africa
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37
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Abstract
Glutamate, a dicarboxylic amino acid, is the most abundantly active neurotransmitter in the mammalian brain; it is also the principal excitatory neurotransmitter in the cerebral cortex. As our knowledge of this neurotransmitter deepens, it is increasingly being implicated in the pathophysiology of mental illness. This review begins by examining the physiology of glutamate and its receptors. Its role in memory, movement, perception and neuronal development is discussed. The development of the glutamate hypothesis of schizophrenia is traced, and the emerging lines of evidence for attenuated function of the N-methyl-D-aspartate receptor in schizophrenia are examined. For ease of discussion, these are divided into pharmacological, post-mortem, imaging, platelet and genetic studies. Interactions between glutamate and other neurotransmitters are discussed, as are possible mechanisms by which such altered receptor activity might result in the clinical expression of schizophrenia. The possible role of glutamate in major depression and bipolar disorder is explored. The review concludes by highlighting the importance of avoiding a reductionist approach to the pathophysiology of any mental illness. Copyright 2001 John Wiley & Sons, Ltd.
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Affiliation(s)
- Brendan Belsham
- Department of Psychiatry, University of the Witwatersrand, Johannesburg, South Africa
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38
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Nathan PJ. Hypericum perforatum (St John's Wort): a non-selective reuptake inhibitor? A review of the recent advances in its pharmacology. J Psychopharmacol 2001; 15:47-54. [PMID: 11277608 DOI: 10.1177/026988110101500109] [Citation(s) in RCA: 87] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Hypericum possesses a unique pharmacology in that it displays the pharmacology of many classes of antidepressants and new mechanisms not typical of standard antidepressants. The most potent of all its action is the moderate to high potency for inhibition of the reuptake of monoamines, serotonin, dopamine and noradrenaline and the amino-acid neurotransmitters GABA and glutamate. Unlike standard reuptake inhibitors, hypericum exerts this reuptake inhibition non-competitively by enhancing intracellular Na+ ion concentrations. At a receptor level, chronic treatment with hypericum downregulates beta1-adrenoceptor, upregulates post-synaptic 5-HT1A receptors and 5-HT2 receptors. Although the major constituent responsible for the antidepressant effect is thought to be hyperforin, other constituents such as hypericin, pseudohypericin, flavonoids and oligomeric procyanidines may also play a direct or indirect role. While reuptake inhibition may more than likely be responsible for most of the antidepressant effect, other mechanisms may also contribute alone or in combination to exert the overall antidepressant action.
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Affiliation(s)
- P J Nathan
- Brain Sciences Institute, Swinburne University of Technology, Hawthorn Victoria, Australia.
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39
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Berk M, Plein H, Belsham B. The specificity of platelet glutamate receptor supersensitivity in psychotic disorders. Life Sci 2000; 66:2427-32. [PMID: 10894085 DOI: 10.1016/s0024-3205(00)80002-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Hypoglutamatergic function is implicated in the pathogenesis of schizophrenia, and supersensitivity of platelet NMDA receptors has been reported in schizophrenia. The aim of this study was to examine the platelet glutamate receptor sensitivity in patients with schizophrenia (n=12), mania with psychotic features (n=10) and depression with psychotic features (n=10) and matched controls (n=12) in order to assess if this is a marker of schizophrenia or occurs in other psychotic conditions. Glutamate receptor sensitivity was assessed using the intracellular calcium response to glutamate measured with spectrofluorometry. The percentage response of the schizophrenic and depressed psychotic subjects to glutamate stimulation was significantly greater than control subjects (p<0.005). The mania with psychotic features group was not significantly different to controls. This data suggests that platelet glutamate receptors may be supersensitive in schizophrenia and depression with psychotic features. Furthermore, the platelet may be a possible peripheral marker of glutamate function in schizophrenia and depression with psychotic features.
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Affiliation(s)
- M Berk
- Department of Psychiatry, University of the Witwatersrand, Johannesburg, South Africa.
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40
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Petrie RX, Reid IC, Stewart CA. The N-methyl-D-aspartate receptor, synaptic plasticity, and depressive disorder. A critical review. Pharmacol Ther 2000; 87:11-25. [PMID: 10924739 DOI: 10.1016/s0163-7258(00)00063-2] [Citation(s) in RCA: 98] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The roles of the N-methyl-D-aspartate (NMDA) receptor and NMDA receptor-mediated synaptic plasticity are reviewed in the context of depressive disorder and its treatment. The mode of action of antidepressant treatment is poorly understood. Animal studies have suggested that many antidepressant drugs show activity at the NMDA receptor and that NMDA antagonists have antidepressant profiles in preclinical models of depression. A post-mortem study in humans has suggested that certain binding characteristics of the NMDA receptor may be down-regulated in the brains of suicide victims. "Depressogenic" stressors in animals and chronic administration of antidepressant agents perturb NMDA-dependent synaptic plasticity in the hippocampus.
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Affiliation(s)
- R X Petrie
- Department of Psychiatry, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK
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41
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Auer DP, Pütz B, Kraft E, Lipinski B, Schill J, Holsboer F. Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry 2000; 47:305-13. [PMID: 10686265 DOI: 10.1016/s0006-3223(99)00159-6] [Citation(s) in RCA: 411] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Functional imaging studies suggest a specific role of the anterior brain regions in the pathogenesis of major depression. The aim of this study was to evaluate possible neurochemical alterations in the frontomesial cortex in patients with major depressive episode using in vivo proton magnetic resonance spectroscopy ((1)H-MRS). METHODS Single voxel (1)H-MRS was performed in 19 patients with major depressive episodes and 18 age-matched healthy controls within the anterior cingulate cortex and the parietal white matter. Absolute concentrations were estimated for N-acetyl-aspartate, choline-containing compounds, total creatine, myo-inositol, unresolved glutamate and glutamine (Glx) and glutamate alone (Glu). Voxel composition was analyzed by image segmentation into cerebrospinal fluid (CSF), grey and white matter. RESULTS MANOVA test for Glx and Glu using age, percent CSF and percent grey matter contribution as covariates yielded a significant group effect within the anterior cingulate due to decrease of Glx in patients (-10.4%, p =.013). Considering only severely depressed patients, both Glx and Glu (-14.3%, p =.03) showed a significant decrease. There was no significant group effect for the neuronal marker NAA, creatine, choline or myo-inositol in either localization. CONCLUSIONS This study suggests a possible role of altered glutamatergic neurotransmission within the anterior cingulate in the pathogenesis of mood disorders. The otherwise unremarkable findings of major brain metabolites confirms lack of neurodegenerative or membrane metabolic changes in major depression.
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Affiliation(s)
- D P Auer
- Max Planck Institute of Psychiatry, Munich, Germany
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42
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Banay-Schwartz M, DeGuzman T, Faludi G, Lajtha A, Palkovits M. Alteration of protease levels in different brain areas of suicide victims. Neurochem Res 1998; 23:953-9. [PMID: 9690737 DOI: 10.1023/a:1021028304481] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Numerous recent studies found that proteases play a major role in brain function. In addition to their role in protein turnover, they have modulatory functions and an important role in apoptosis, pathological changes, and other mechanisms. To explore possible differences in brain protein metabolism of suicide victims, we examined the activity of two proteases, cathepsin D and calpain (I and II combined), in eleven discrete areas of postmortem brain tissue of 21 victims of suicide and of 31 age- and sex-matched control subjects without a history of psychiatric or neurological disease. The levels of functionally important amino acids in five of these areas were also measured. Cathepsin D activity was found to be lower in two of eleven regions of brains of suicide victims, the parahippocampal cortex and the medial hypothalamus, by 26% and 27%, respectively. Calpain activity was lower in two different areas tested, 29% in the medulla oblongata and 26% in the lateral prefrontal cortex, and was 18% higher in the midbrain. There were no significant differences in the other areas (globus pallidus, hippocampus, amygdala, caudate nucleus, ventral tegmental area, and nucleus accumbens). Protease distribution was regionally heterogeneous--the levels in the globus pallidus were low, and in the hippocampus high, with about a two-fold difference. The length of the postmortem period for obtaining tissue, the storage time of the frozen tissue, and the age of the subject had no apparent influence on the results obtained. Although there was a tendency toward higher levels of aspartate and glycine in brain areas from suicide victims, the difference was not significant. The variations among individual brains were greater in amino acid levels than in protease levels. The findings indicate the possible role of protein metabolism in depressive or suicidal behavior.
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Affiliation(s)
- M Banay-Schwartz
- The Nathan S. Kline Inst. for Psychiatric Research, Orangeburg, NY 10962, USA.
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43
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Abstract
The outlines of a theory of the pathophysiology of depression are presented. The classic monoamine theory of depression as well as its more recent elaborations suggests that a deficit in monoamine neurotransmitters in the synaptic cleft is the primary cause of depression. We suggest that the primary defect emerges in the regulation of firing rates in brainstem monoaminergic neurons, which brings about a decrease in the tonic release of neurotransmitters in their projection areas, an increase in postsynaptic sensitivity and, concomitantly, exaggerated responses to acute increases in presynaptic firing rate and transmitter release. We propose that the initial defect involves, in particular, the noradrenergic innervation from the locus coeruleus, which in turn leads to dysregulation of 5-HT-ergic and dopaminergic neurotransmission.
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Affiliation(s)
- J Harro
- Department of Medical Pharmacology, University of Uppsala, Sweden
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44
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Nowak G, Ordway GA, Paul IA. Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims. Brain Res 1995; 675:157-64. [PMID: 7796124 DOI: 10.1016/0006-8993(95)00057-w] [Citation(s) in RCA: 184] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Chronic antidepressant treatment results in adaptation of the NMDA receptor complex in the rodent cortex. This adaptation consists of a reduction in the potency of glycine to displace [3H]5,7-dichlorokynurenic acid from strychnine-insensitive glycine receptors and a reduction in high affinity, glycine-displaceable [3H]CGP-39653 binding to glutamate receptors. We hypothesized that dysfunction of NMDA receptors might occur in frontal cortices from human suicide victims. We now report that the proportion of high affinity, glycine displaceable [3H]CGP-39653 binding to glutamate receptors is reduced from 45 +/- 5% in controls to 27 +/- 6% in age- and post-mortem interval-matched suicide victims. In contrast, neither the potency nor the maximum efficacy of glycine to inhibit [3H]CGP-39653 binding is altered in the frontal cortex of suicide victims compared to controls. Moreover, neither the potency of glycine to inhibit [3H]5,7-dichlorokynurenic acid binding to the strychnine-insensitive glycine receptor nor the specific binding of [3H]5,7-dichlorokynurenic acid binding differed in suicide victims compared to controls. Likewise, neither basal nor glycine- or glutamate enhanced non-equilibrium binding of [3H]dizocilpine was altered in the frontal cortex of suicide victims compared to controls. These data represent the first demonstration supporting the hypothesis that glutamatergic dysfunction is involved in psychopathology underlying suicide and, potentially in human major depression.
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Affiliation(s)
- G Nowak
- Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson 39216-4505, USA
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45
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Toru M, Kurumaji A, Ishimaru M. Excitatory amino acids: implications for psychiatric disorders research. Life Sci 1994; 55:1683-99. [PMID: 7968248 DOI: 10.1016/0024-3205(94)00337-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The hyperdopaminergic theory of schizophrenia may account for some types of schizophrenia, but schizophrenia with negative symptoms or resulting in a chronic state of deterioration after repeated relapses cannot be explained by this theory. This minireview first discusses the interactions between dopamine and excitatory amino acid (EAA) neurons to produce abnormal behavior. Secondly, it deals with the influence of the psychotropic drugs on EAA, such as the relationship between phencyclidine and the hypoglutamate theory, the involvement of EAA in behavioral sensitization induced by amphetamines, the interactions between antipsychotic, antidepressant and antianxiety drugs and EAA, considering the possibility of developing newer psychotropic drugs related with EAA. Finally, glutamate receptors measured in postmortem schizophrenic brains are tabulated and the bases of the hypoglutamate hypothesis are discussed.
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Affiliation(s)
- M Toru
- Department of Neuropsychiatry, Tokyo Medical and Dental University School of Medicine, Japan
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