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      Understanding the Complex of Suicide in Depression: from Research to Clinics

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          Abstract

          Objective

          Amongst psychiatric disorders, major depressive disorder (MDD) is the most prevalent, by affecting approximately 15–17% of the population and showing a high suicide risk rate equivalent to around 15%. The present comprehensive overview aims at evaluating main research studies in the field of MDD at suicide risk, by proposing as well as a schematic suicide risk stratification and useful flow-chart for planning suicide preventive and therapeutic interventions for clinicians.

          Methods

          A broad and comprehensive overview has been here conducted by using PubMed/Medline, combining the search strategy of free text terms and exploded MESH headings for the topics of ‘Major Depressive Disorder’ and ‘Suicide’ as following: (( suicide [Title/Abstract]) AND ( major depressive disorder [Title/Abstract])). All articles published in English through May 31, 2019 were summarized in a comprehensive way.

          Results

          Despite possible pathophysiological factors which may explain the complexity of suicide in MDD, scientific evidence supposed the synergic role of genetics, exogenous and endogenous stressors (i.e., interpersonal, professional, financial, as well as psychiatric disorders), epigenetic, the hypothalamic-pituitary-adrenal stress-response system, the involvement of the monoaminergic neurotransmitter systems, particularly the serotonergic ones, the lipid profile, neuro-immunological biomarkers, the Brain-derived neurotrophic factor and other neuromodulators.

          Conclusion

          The present overview reported that suicide is a highly complex and multifaceted phenomenon in which a large plethora of mechanisms could be variable implicated, particularly amongst MDD subjects. Beyond these consideration, modern psychiatry needs a better interpretation of suicide risk with a more careful assessment of suicide risk stratification and planning of clinical and treatment interventions.

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          Most cited references161

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          A neurotrophic model for stress-related mood disorders.

          There is a growing body of evidence demonstrating that stress decreases the expression of brain-derived neurotrophic factor (BDNF) in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neurotrophic factors, could contribute to the atrophy of certain limbic structures, including the hippocampus and prefrontal cortex that has been observed in depressed subjects. Conversely, the neurotrophic actions of antidepressants could reverse neuronal atrophy and cell loss and thereby contribute to the therapeutic actions of these treatments. This review provides a critical examination of the neurotrophic hypothesis of depression that has evolved from this work, including analysis of preclinical cellular (adult neurogenesis) and behavioral models of depression and antidepressant actions, as well as clinical neuroimaging and postmortem studies. Although there are some limitations, the results of these studies are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment.
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            A molecular and cellular theory of depression.

            Recent studies have begun to characterize the actions of stress and antidepressant treatments beyond the neurotransmitter and receptor level. This work has demonstrated that long-term antidepressant treatments result in the sustained activation of the cyclic adenosine 3',5'-monophosphate system in specific brain regions, including the increased function and expression of the transcription factor cyclic adenosine monophosphate response element-binding protein. The activated cyclic adenosine 3',5'-monophosphate system leads to the regulation of specific target genes, including the increased expression of brain-derived neurotrophic factor in certain populations of neurons in the hippocampus and cerebral cortex. The importance of these changes is highlighted by the discovery that stress can decrease the expression of brain-derived neurotrophic factor and lead to atrophy of these same populations of stress-vulnerable hippocampal neurons. The possibility that the decreased size and impaired function of these neurons may be involved in depression is supported by recent clinical imaging studies, which demonstrate a decreased volume of certain brain structures. These findings constitute the framework for an updated molecular and cellular hypothesis of depression, which posits that stress-induced vulnerability and the therapeutic action of antidepressant treatments occur via intracellular mechanisms that decrease or increase, respectively, neurotrophic factors necessary for the survival and function of particular neurons. This hypothesis also explains how stress and other types of neuronal insult can lead to depression in vulnerable individuals and it outlines novel targets for the rational design of fundamentally new therapeutic agents.
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              Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.

              The cAMP signaling pathway, and its downstream neurotrophic factor BDNF, are major targets of antidepressant medications. Abnormalities in this pathway have previously been reported in postmortem brain of subjects with mood disorders. This study was designed to test whether the diagnosis of a mood disorder, or treatment with an antidepressant or mood stabilizer was associated with changes in hippocampal BDNF in postmortem brain. Frozen postmortem anterior hippocampus sections were obtained from the Stanley Foundation Neuropathology Consortium. Tissue from subjects with major depression, bipolar disorder, schizophrenia and nonpsychiatric control subjects were stained for BDNF using immunohistochemistry. Increased BDNF expression was found in dentate gyrus, hilus and supragranular regions in subjects treated with antidepressant medications at the time of death, compared with antidepressant-untreated subjects. Furthermore, there was a trend toward increased BDNF expression in hilar and supragranular regions in depressed subjects treated with antidepressants, compared with the subjects not on these medications at the time of death. These findings are consistent with recent studies measuring CREB levels in this same subject sample, and support current animal and cellular models of antidepressant function.
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                Author and article information

                Journal
                Psychiatry Investig
                Psychiatry Investig
                PI
                Psychiatry Investigation
                Korean Neuropsychiatric Association
                1738-3684
                1976-3026
                March 2020
                23 March 2020
                : 17
                : 3
                : 207-221
                Affiliations
                [1 ]Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK
                [2 ]Neomesia Mental Health, Villa Jolanda Hospital, Jesi, Italy
                [3 ]Polyedra, Teramo, Italy
                [4 ]Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, S. Andrea Hospital, Sapienza University, Rome, Italy
                [5 ]Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Psychiatry, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
                [6 ]Department of Clinical Neurosciences/DIMSC, School of Medicine, Section of Psychiatry, Polytechnic University of Marche, Ancona, Italy
                [7 ]Department of Neuroscience, Imaging and Clinical Science, Chair of Psychiatry, University of “G. D’Annunzio”, Chieti, Italy
                [8 ]Department of Psychiatry, Federico II University, Naples, Italy
                [9 ]Villa S. Giuseppe Hospital, Hermanas Hospitalarias, Ascoli Piceno, Italy
                [10 ]Department of Mental Health, National Health Service, Psychiatric Service of Diagnosis and Treatment, Hospital “SS. Annunziata” ASL 4, Giulianova, Italy
                [11 ]Department of Mental Health, National Health Service, Azienda Sanitaria Locale, Pescara, Italy
                [12 ]Department of Mental Health, National Health Service, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”, ASL 4, Teramo, Italy
                Author notes
                Correspondence: Domenico De Berardis, MD, PhD Department of Mental Health, National Health Service, Psychiatric Service of Diagnosis and Treatment, “G. Mazzini” Hospital, p.zza Italia 1, 64100 Teramo, Italy Tel: +39-0861429708, Fax: +39-0861429709, E-mail: domenico.deberardis@ 123456aslteramo.it
                Author information
                http://orcid.org/0000-0002-6882-3770
                http://orcid.org/0000-0003-1886-4977
                http://orcid.org/0000-0002-6631-856X
                http://orcid.org/0000-0001-9166-7609
                http://orcid.org/0000-0002-4844-5688
                http://orcid.org/0000-0002-9647-0853
                http://orcid.org/0000-0002-3130-6569
                http://orcid.org/0000-0002-7292-2341
                http://orcid.org/0000-0001-9681-8058
                http://orcid.org/0000-0003-4415-5058
                Article
                pi-2019-0171
                10.30773/pi.2019.0171
                7113180
                32209966
                c4674efa-81fc-45d6-b04c-cb3b11d194a4
                Copyright © 2020 Korean Neuropsychiatric Association

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 October 2019
                : 23 February 2020
                : 27 February 2020
                Categories
                Review Article

                Clinical Psychology & Psychiatry
                major depressive disorder,suicide,depression,suicidal risk
                Clinical Psychology & Psychiatry
                major depressive disorder, suicide, depression, suicidal risk

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