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Chen Y, Li J, Liao M, He Y, Dang C, Yu J, Xing S, Zeng J. Efficacy and safety of agomelatine versus SSRIs/SNRIs for post-stroke depression: a systematic review and meta-analysis of randomized controlled trials. Int Clin Psychopharmacol 2024; 39:163-173. [PMID: 37781768 DOI: 10.1097/yic.0000000000000509] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Agomelatine is effective in the treatment of depression, but its effect for post-stroke depression (PSD) remains unclear. This study was conducted to compare the efficacy and safety of agomelatine versus SSRIs/SNRIs in treating PSD. We systematically searched Embase, PubMed, Cochrane Library, WanFang Data, China National Knowledge Infrastructure, and Cqvip databases for double-blind randomized controlled studies comparing the efficacy and safety of agomelatine versus SSRIs/SNRIs for PSD until December 2022. The primary efficacy endpoint was the Hamilton Depression Rating Scale (HAMD) score, and the primary safety endpoint was the incidence of overall adverse reactions. Nine studies comprising 857 patients with PSD were included. After 6-12 weeks of treatment, the HAMD score ( P = 0.16) and the overall response rates ( P = 0.20) in the agomelatine group were comparable to that in the SSRIs/SNRIs group. Participants treated with agomelatine achieved higher Barthel Index scores compared with the SSRIs/SNRIs group ( P = 0.02). There was a significantly lower incidence of overall adverse reactions ( P = 0.008) and neurological adverse reactions ( P < 0.0001) in the agomelatine group. The efficacy of agomelatine for treating PSD is probably comparable to that of SSRIs/SNRIs, and it may improve stroke outcomes with better safety.
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Affiliation(s)
- Yicong Chen
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases; National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China
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Palamarchuk IS, Slavich GM, Vaillancourt T, Rajji TK. Stress-related cellular pathophysiology as a crosstalk risk factor for neurocognitive and psychiatric disorders. BMC Neurosci 2023; 24:65. [PMID: 38087196 PMCID: PMC10714507 DOI: 10.1186/s12868-023-00831-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/24/2023] [Indexed: 12/18/2023] Open
Abstract
In this narrative review, we examine biological processes linking psychological stress and cognition, with a focus on how psychological stress can activate multiple neurobiological mechanisms that drive cognitive decline and behavioral change. First, we describe the general neurobiology of the stress response to define neurocognitive stress reactivity. Second, we review aspects of epigenetic regulation, synaptic transmission, sex hormones, photoperiodic plasticity, and psychoneuroimmunological processes that can contribute to cognitive decline and neuropsychiatric conditions. Third, we explain mechanistic processes linking the stress response and neuropathology. Fourth, we discuss molecular nuances such as an interplay between kinases and proteins, as well as differential role of sex hormones, that can increase vulnerability to cognitive and emotional dysregulation following stress. Finally, we explicate several testable hypotheses for stress, neurocognitive, and neuropsychiatric research. Together, this work highlights how stress processes alter neurophysiology on multiple levels to increase individuals' risk for neurocognitive and psychiatric disorders, and points toward novel therapeutic targets for mitigating these effects. The resulting models can thus advance dementia and mental health research, and translational neuroscience, with an eye toward clinical application in cognitive and behavioral neurology, and psychiatry.
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Affiliation(s)
- Iryna S Palamarchuk
- Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, ON, M6J1H4, Canada.
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Sunnybrook Health Sciences Centre, Division of Neurology, Toronto, ON, Canada.
- Temerty Faculty of Medicine, Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada.
| | - George M Slavich
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA
| | - Tracy Vaillancourt
- Counselling Psychology, Faculty of Education, University of Ottawa, Ottawa, ON, Canada
- School of Psychology, Faculty of Social Sciences, University of Ottawa, Ottawa, ON, Canada
| | - Tarek K Rajji
- Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, ON, M6J1H4, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Temerty Faculty of Medicine, Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada
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Shokrani M, Askari S, Eissazade N, Shariat SV, Shariati B, Yarahmadi M, Shalbafan M. Agomelatine augmentation of sertraline in the treatment of moderate to severe obsessive-compulsive disorder: a randomized double-blinded placebo-controlled clinical trial. BMC Psychiatry 2023; 23:686. [PMID: 37735631 PMCID: PMC10512611 DOI: 10.1186/s12888-023-05189-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 09/12/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND As 40-60% of the patients with obsessive-compulsive disorder (OCD) do not adequately respond to the first-line treatment, finding an effective second-line treatment is required. Our aim was to assess the efficacy and safety of agomelatine (a selective melatonin receptor agonist and a 5-hydroxytryptamine (HT)2 C antagonist) augmentation of sertraline in the treatment of patients with moderate to severe OCD. METHODS In this 12-week randomized, double-blinded, placebo-controlled, parallel-group clinical trial, 65 patients with moderate to severe OCD according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth edition (DSM-5) criteria and a Yale-Brown obsessive compulsive scale (Y-BOCS) score of over 21, were included. They were assigned with sertraline (100 mg/day for the first 4 weeks and 200 mg/day for the next 8 weeks) and either agomelatine (25 mg/day) or placebo. The primary outcome was OCD symptoms measured by the Y-BOCS. RESULTS Fifty patients (24 in agomelatine group and 26 in placebo group) completed the trial. The Y-BOCS scores in total (MD (95% CI) = 12.25 (11.00, 13.49) (P < 0.001) vs. MD (95% CI) = 12.46 (6.65, 15.74) (P < 0.001)), the obsession subscale (MD (95% CI) = 5.04 (4.19, 5.88) (P < 0.001) vs. MD (95% CI) = 5.00 (3.84, 6.16) (P = 0.0001)), and compulsion subscale (MD (95% CI) = 7.21 (6.34, 8.07) (P < 0.001) vs. MD (95% CI) = 7.460 (6.50, 8.42) (P < 0.001)) significantly decreased in both groups. Although, at the end of the trial, no significant difference was observed between the scores of the two groups in total (MD (95% CI) = 0.480 (-1.23, 2.19) (P = 0.78)), the obsession subscale (MD (95% CI) = 1.020 (-0.15, 2.19) (P = 0.38)), and the compulsion subscale (MD (95% CI) = 0.540 (-0.34, 1.42) (P = 0.54)). No major adverse effects were recorded, and the frequency of side effects was not significantly different between the groups. CONCLUSION Agomelatine in augmentation with sertraline is safe and tolerable in patients with moderate to severe OCD. However, our study does not support its efficacy in improving OCD symptoms, compared to placebo. TRIAL REGISTRATION The trial was registered at the Iranian Registry of Clinical Trials on 14/07/2020 ( www.irct.ir ; IRCT ID: IRCT20170123032145N5).
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Affiliation(s)
- Marjan Shokrani
- Mental Health Research Center, Psychosocial Health Research Institute (PHRI), Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sanaz Askari
- Mental Health Research Center, Psychosocial Health Research Institute (PHRI), Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Negin Eissazade
- Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Vahid Shariat
- Mental Health Research Center, Psychosocial Health Research Institute (PHRI), Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Behnam Shariati
- Mental Health Research Center, Psychosocial Health Research Institute (PHRI), Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Masoomeh Yarahmadi
- Mental Health Research Center, Psychosocial Health Research Institute (PHRI), Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Shalbafan
- Mental Health Research Center, Psychosocial Health Research Institute (PHRI), Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Brain and Cognition Clinic, Institute for Cognitive Sciences Studies, Tehran, Iran.
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Sałaciak K, Koszałka A, Lustyk K, Żmudzka E, Jagielska A, Pytka K. Memory impairments in rodent depression models: A link with depression theories. Prog Neuropsychopharmacol Biol Psychiatry 2023; 125:110774. [PMID: 37088171 DOI: 10.1016/j.pnpbp.2023.110774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 04/11/2023] [Accepted: 04/20/2023] [Indexed: 04/25/2023]
Abstract
More than 80% of depressed patients struggle with learning new tasks, remembering positive events, or concentrating on a single topic. These neurocognitive deficits accompanying depression may be linked to functional and structural changes in the prefrontal cortex and hippocampus. However, their mechanisms are not yet completely understood. We conducted a narrative review of articles regarding animal studies to assess the state of knowledge. First, we argue the contribution of changes in neurotransmitters and hormone levels in the pathomechanism of cognitive dysfunction in animal depression models. Then, we used numerous neuroinflammation studies to explore its possible implication in cognitive decline. Encouragingly, we also observed a positive correlation between increased oxidative stress and a depressive-like state with concomitant memory deficits. Finally, we discuss the undeniable role of neurotrophin deficits in developing cognitive decline in animal models of depression. This review reveals the complexity of depression-related memory impairments and highlights the potential clinical importance of gathered findings for developing more reliable animal models and designing novel antidepressants with procognitive properties.
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Affiliation(s)
- Kinga Sałaciak
- Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland
| | - Aleksandra Koszałka
- Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland
| | - Klaudia Lustyk
- Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland
| | - Elżbieta Żmudzka
- Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College Medyczna, 9 Street, Kraków 30-688, Poland
| | - Angelika Jagielska
- Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland
| | - Karolina Pytka
- Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland.
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Qi JS, Su Q, Li T, Liu GW, Zhang YL, Guo JH, Wang ZJ, Wu MN. Agomelatine: a potential novel approach for the treatment of memory disorder in neurodegenerative disease. Neural Regen Res 2023; 18:727-733. [DOI: 10.4103/1673-5374.353479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Sala N, Paoli C, Bonifacino T, Mingardi J, Schiavon E, La Via L, Milanese M, Tornese P, Datusalia AK, Rosa J, Facchinetti R, Frumento G, Carini G, Salerno Scarzella F, Scuderi C, Forti L, Barbon A, Bonanno G, Popoli M, Musazzi L. Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along With Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex. Front Pharmacol 2022; 13:759626. [PMID: 35370690 PMCID: PMC8968915 DOI: 10.3389/fphar.2022.759626] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 01/25/2022] [Indexed: 12/17/2022] Open
Abstract
Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of naïve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites.
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Affiliation(s)
- Nathalie Sala
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Milano, Italy
| | - Caterina Paoli
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Milano, Italy.,School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Tiziana Bonifacino
- Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, Genoa, Italy
| | - Jessica Mingardi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Emanuele Schiavon
- Department of Biotechnology and Life Sciences, University of Insubria, Busto Arsizio, Italy
| | - Luca La Via
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Marco Milanese
- Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, Genoa, Italy
| | - Paolo Tornese
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Milano, Italy
| | - Ashok K Datusalia
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Milano, Italy.,Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, India
| | - Jessica Rosa
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Milano, Italy.,Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirao Preto, Brazil
| | - Roberta Facchinetti
- Department of Physiology and Pharmacology "Vittorio Erspamer", SAPIENZA University of Rome, Rome, Italy
| | - Giulia Frumento
- Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, Genoa, Italy
| | - Giulia Carini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | | | - Caterina Scuderi
- Department of Physiology and Pharmacology "Vittorio Erspamer", SAPIENZA University of Rome, Rome, Italy
| | - Lia Forti
- Department of Biotechnology and Life Sciences, University of Insubria, Busto Arsizio, Italy
| | - Alessandro Barbon
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Giambattista Bonanno
- Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, Genoa, Italy.,IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Maurizio Popoli
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Milano, Italy
| | - Laura Musazzi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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Millan MJ. Agomelatine for the treatment of generalized anxiety disorder: focus on its distinctive mechanism of action. Ther Adv Psychopharmacol 2022; 12:20451253221105128. [PMID: 35795687 PMCID: PMC9251978 DOI: 10.1177/20451253221105128] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/04/2022] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED Generalized anxiety disorder (GAD), the most frequently diagnosed form of anxiety, is usually treated by cognitive-behavioural approaches or medication; in particular, benzodiazepines (acutely) and serotonin or serotonin/noradrenaline reuptake inhibitors (long term). Efficacy, compliance, and acceptability are, however, far from ideal, reinforcing interest in alternative options. Agomelatine, clinically employed in the treatment of major depression, expresses anxiolytic properties in rodents and was effective in the treatment of GAD (including severely ill patients) in several double-blind, short-term (12 weeks) and relapse-prevention (6 months) studies. At active doses, the incidence of adverse effects was no higher than for placebo. Agomelatine possesses a unique binding profile, behaving as a melatonin (MT1/MT2) receptor agonist and 5-HT2C receptor antagonist, yet recognizing neither monoamine transporters nor GABAA receptors. Extensive evidence supports a role for 5-HT2C receptors in the induction of anxious states, and their blockade likely plays a primary role in mediating the anxiolytic actions of agomelatine, including populations in the amygdala and bed nucleus of stria terminalis, as well as the hippocampus. Recruitment of MT receptors in the suprachiasmatic nucleus, thalamic reticular nucleus, and hippocampus appears to fulfil a complimentary role. Downstream of 5-HT2C and MT receptors, modulation of stress-sensitive glutamatergic circuits and altered release of the anxiogenic neuropeptides, corticotrophin-releasing factor, and vasopressin, may be implicated in the actions of agomelatine. To summarize, agomelatine exerts its anxiolytic actions by mechanisms clearly distinct from those of other agents currently employed for the management of GAD. PLAIN LANGUAGE SUMMARY How agomelatine helps in the treatment of anxiety disorders. INTRODUCTION • Anxiety disorders have a significant negative impact on quality of life.• The most common type of anxiety disorder, called generalized anxiety disorder (GAD), is associated with nervousness and excessive worry.• These symptoms can lead to additional symptoms like tiredness, sleeplessness, irritability, and poor attention.• GAD is generally treated through either cognitive-behavioural therapy or medication. However, widely used drugs like benzodiazepines and serotonin reuptake inhibitors have adverse effects.• Agomelatine, a well-established antidepressant drug, has shown anxiety-lowering ('anxiolytic') properties in rats and has been shown to effectively treat GAD with minimal side effects.• However, exactly how it acts on the brain to manage GAD is not yet clear.• Thus, this review aims to shed light on agomelatine's mechanism of action in treating GAD. METHODS • The authors reviewed studies on how agomelatine treats anxiety in animals.• They also looked at clinical studies on the effects of agomelatine in people with GAD. RESULTS • The study showed that agomelatine 'blocks' a receptor in nerve cells, which plays a role in causing anxiety, called the 5-HT2C receptor.• Blocking this receptor, especially in specific brain regions such as nerve cells of the amygdala, bed nucleus of stria terminalis, and hippocampus, produced the anxiety reduction seen during agomelatine treatment.• Agomelatine also activates the melatonin (MT) receptor, which is known to keep anxiety in check, promote sleep, and maintain the sleep cycle.• Agomelatine should thus tackle sleep disturbances commonly seen in patients with GAD.• Beyond 5-HT2C and MT receptors, signalling molecules in nerve cells that are known to be involved in anxiety disorders (called 'neurotransmitters' and 'neuropeptides') are also affected by agomelatine. CONCLUSION • Agomelatine's anxiolytic effects are caused by mechanisms that are distinct from those of other medications currently used to treat GAD.• This explains its therapeutic success and minimal adverse side effects.
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Affiliation(s)
- Mark J Millan
- Institute of Neuroscience and Psychology, College of Medicine, Vet and Life Sciences, Glasgow University, 28 Hillhead Street, Glasgow G12 8QB, UK
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Haduch A, Bromek E, Rysz M, Pukło R, Papp M, Gruca P, Łasoń M, Niemczyk M, Daniel WA. The effects of agomelatine and imipramine on liver cytochrome P450 during chronic mild stress (CMS) in the rat. Pharmacol Rep 2020; 72:1271-1287. [PMID: 32748256 PMCID: PMC7550324 DOI: 10.1007/s43440-020-00151-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 07/10/2020] [Accepted: 07/27/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND The aim of our research was to determine the effects of chronic treatment with the atypical antidepressant agomelatine on the expression and activity of liver cytochrome P450 (CYP) in the chronic mild stress (CMS) model of depression, and to compare the results with those obtained for the first-generation antidepressant imipramine. METHODS Male Wistar rats were subjected to CMS for 7 weeks. Imipramine (10 mg/kg ip/day) or agomelatine (40 mg/kg ip/day) was administered to nonstressed or stressed animals for 5 weeks (weeks 3-7 of CMS). The levels of cytochrome P450 mRNA, protein and activity were measured in the liver. RESULTS Agomelatine and imipramine produced different broad-spectrum effects on cytochrome P450. Like imipramine, agomelatine increased the expression/activity of CYP2B and CYP2C6, and decreased the CYP2D activity. Unlike imipramine, agomelatine raised the expression/activity of CYP1A, CYP2A and reduced that of CYP2C11 and CYP3A. CMS modified the effects of antidepressants at transcriptional/posttranscriptional level; however, the enzyme activity in stressed rats remained similar to that in nonstressed animals. CMS alone decreased the CYP2B1 mRNA level and increased that of CYP2C11. CONCLUSION We conclude the following: (1) the effects of agomelatine and imipramine on cytochrome P450 are different and involve both central and peripheral regulatory mechanisms, which implicates the possibility of drug-drug interactions; (2) CMS influences the effects of antidepressants on cytochrome P450 expression, but does not change appreciably their effects on the enzyme activity. This suggests that the rate of antidepressant drug metabolism under CMS is similar to that under normal conditions.
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Affiliation(s)
- Anna Haduch
- Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
| | - Ewa Bromek
- Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
| | - Marta Rysz
- Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
| | - Renata Pukło
- Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
| | - Mariusz Papp
- Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
| | - Piotr Gruca
- Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
| | - Magdalena Łasoń
- Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
| | - Monika Niemczyk
- Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
| | - Władysława A Daniel
- Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland.
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Kirlioglu SS, Balcioglu YH. Chronobiology Revisited in Psychiatric Disorders: From a Translational Perspective. Psychiatry Investig 2020; 17:725-743. [PMID: 32750762 PMCID: PMC7449842 DOI: 10.30773/pi.2020.0129] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 05/15/2020] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE Several lines of evidence support a relationship between circadian rhythms disruption in the onset, course, and maintenance of mental disorders. Despite the study of circadian phenotypes promising a decent understanding of the pathophysiologic or etiologic mechanisms of psychiatric entities, several questions still need to be addressed. In this review, we aimed to synthesize the literature investigating chronobiologic theories and their associations with psychiatric entities. METHODS The Medline, Embase, PsycInfo, and Scopus databases were comprehensively and systematically searched and articles published between January 1990 and October 2019 were reviewed. Different combinations of the relevant keywords were polled. We first introduced molecular elements and mechanisms of the circadian system to promote a better understanding of the chronobiologic implications of mental disorders. Then, we comprehensively and systematically reviewed circadian system studies in mood disorders, schizophrenia, and anxiety disorders. RESULTS Although subject characteristics and study designs vary across studies, current research has demonstrated that circadian pathologies, including genetic and neurohumoral alterations, represent the neural substrates of the pathophysiology of many psychiatric disorders. Impaired HPA-axis function-related glucocorticoid rhythm and disrupted melatonin homeostasis have been prominently demonstrated in schizophrenia and other psychotic disorders, while alterations of molecular expressions of circadian rhythm genes including CLOCK, PER, and CRY have been reported to be involved in the pathogenesis of mood disorders. CONCLUSION Further translational work is needed to identify the causal relationship between circadian physiology abnormalities and mental disorders and related psychopathology, and to develop sound pharmacologic interventions.
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Affiliation(s)
- Simge Seren Kirlioglu
- Department of Psychiatry, Bakirkoy Prof Mazhar Osman Training and Research Hospital for Psychiatry, Neurology and Neurosurgery, Istanbul, Turkey
| | - Yasin Hasan Balcioglu
- Department of Psychiatry, Bakirkoy Prof Mazhar Osman Training and Research Hospital for Psychiatry, Neurology and Neurosurgery, Istanbul, Turkey
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Villas Boas GR, Boerngen de Lacerda R, Paes MM, Gubert P, Almeida WLDC, Rescia VC, de Carvalho PMG, de Carvalho AAV, Oesterreich SA. Molecular aspects of depression: A review from neurobiology to treatment. Eur J Pharmacol 2019; 851:99-121. [PMID: 30776369 DOI: 10.1016/j.ejphar.2019.02.024] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 02/14/2019] [Accepted: 02/14/2019] [Indexed: 12/14/2022]
Abstract
Major depressive disorder (MDD), also known as unipolar depression, is one of the leading causes of disability and disease worldwide. The signs and symptoms are low self‑esteem, anhedonia, feeling of worthlessness, sense of rejection and guilt, suicidal thoughts, among others. This review focuses on studies with molecular-based approaches involving MDD to obtain an integrated, more detailed and comprehensive view of the brain changes produced by this disorder and its treatment and how the Central Nervous System (CNS) produces neuroplasticity to orchestrate adaptive defensive behaviors. This article integrates affective neuroscience, psychopharmacology, neuroanatomy and molecular biology data. In addition, there are two problems with current MDD treatments, namely: 1) Low rates of responsiveness to antidepressants and too slow onset of therapeutic effect; 2) Increased stress vulnerability and autonomy, which reduces the responses of currently available treatments. In the present review, we encourage the prospection of new bioactive agents for the development of treatments with post-transduction mechanisms, neurogenesis and pharmacogenetics inducers that bring greater benefits, with reduced risks and maximized access to patients, stimulating the field of research on mood disorders in order to use the potential of preclinical studies. For this purpose, improved animal models that incorporate the molecular and anatomical tools currently available can be applied. Besides, we encourage the study of drugs that do not present "classical application" as antidepressants, (e.g., the dissociative anesthetic ketamine and dextromethorphan) and drugs that have dual action mechanisms since they represent potential targets for novel drug development more useful for the treatment of MDD.
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Affiliation(s)
- Gustavo Roberto Villas Boas
- Research Group on Development of Pharmaceutical Products (P&DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil; Faculty of Health Sciences, Federal University of Grande Dourados, Dourados Rodovia Dourados, Itahum Km 12, Cidade Universitaria, Caixa. postal 364, CEP 79804-970, Dourados, Mato Grosso do Sul, Brazil.
| | - Roseli Boerngen de Lacerda
- Department of Pharmacology of the Biological Sciences Center, Federal University of Paraná, Jardim das Américas, Caixa. postal 19031, CEP 81531-990, Curitiba, Paraná, Brazil.
| | - Marina Meirelles Paes
- Research Group on Development of Pharmaceutical Products (P&DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil.
| | - Priscila Gubert
- Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil.
| | - Wagner Luis da Cruz Almeida
- Research Group on Development of Pharmaceutical Products (P&DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil.
| | - Vanessa Cristina Rescia
- Research Group on Development of Pharmaceutical Products (P&DProFar), Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil.
| | - Pablinny Moreira Galdino de Carvalho
- Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil.
| | - Adryano Augustto Valladao de Carvalho
- Center for Biological and Health Sciences, Federal University of Western Bahia, Rua Bertioga, 892, Morada Nobre II, CEP 47810-059, Barreiras, Bahia, Brazil.
| | - Silvia Aparecida Oesterreich
- Faculty of Health Sciences, Federal University of Grande Dourados, Dourados Rodovia Dourados, Itahum Km 12, Cidade Universitaria, Caixa. postal 364, CEP 79804-970, Dourados, Mato Grosso do Sul, Brazil.
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11
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Santos P, Herrmann AP, Elisabetsky E, Piato A. Anxiolytic properties of compounds that counteract oxidative stress, neuroinflammation, and glutamatergic dysfunction: a review. ACTA ACUST UNITED AC 2018; 41:168-178. [PMID: 30328963 PMCID: PMC6781690 DOI: 10.1590/1516-4446-2018-0005] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 01/31/2018] [Indexed: 01/27/2023]
Abstract
Objective: Anxiety disorders are highly prevalent and the efficacy of the available anxiolytic drugs is less than desired. Adverse effects also compromise patient quality of life and adherence to treatment. Accumulating evidence shows that the pathophysiology of anxiety and related disorders is multifactorial, involving oxidative stress, neuroinflammation, and glutamatergic dysfunction. The aim of this review was to evaluate data from animal studies and clinical trials showing the anxiolytic effects of agents whose mechanisms of action target these multiple domains. Methods: The PubMed database was searched for multitarget agents that had been evaluated in animal models of anxiety, as well as randomized double-blind placebo-controlled clinical trials of anxiety and/or anxiety related disorders. Results: The main multitarget agents that have shown consistent anxiolytic effects in various animal models of anxiety, as well in clinical trials, are agomelatine, N-acetylcysteine (NAC), and omega-3 fatty acids. Data from clinical trials are preliminary at best, but reveal good safety profiles and tolerance to adverse effects. Conclusion: Agomelatine, NAC and omega-3 fatty acids show beneficial effects in clinical conditions where mainstream treatments are ineffective. These three multitarget agents are considered promising candidates for innovative, effective, and better-tolerated anxiolytics.
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Affiliation(s)
- Patrícia Santos
- Programa de Pós-Graduação em Farmacologia e Terapêutica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Ana P Herrmann
- Programa de Pós-Graduação em Farmacologia e Terapêutica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Elaine Elisabetsky
- Programa de Pós-Graduação em Farmacologia e Terapêutica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Angelo Piato
- Programa de Pós-Graduação em Farmacologia e Terapêutica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
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12
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Lu Y, Ho CS, McIntyre RS, Wang W, Ho RC. Agomelatine-induced modulation of brain-derived neurotrophic factor (BDNF) in the rat hippocampus. Life Sci 2018; 210:177-184. [PMID: 30193943 DOI: 10.1016/j.lfs.2018.09.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/14/2018] [Accepted: 09/01/2018] [Indexed: 01/10/2023]
Abstract
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that serves as a survival factor for neurons. Agomelatine is a novel antidepressant as well as a potent agonist of melatonin (MT), MT1 and MT2 receptor types and an antagonist of the serotonin (5HT), 5-HT2C receptor. The study herein established whether treatment with agomelatine alters hippocampal BDNF protein expression under chronic unpredictable mild stress (CUMS) condition. Twenty-one day treatment with agomelatine, fluoxetine or vehicle was assessed in 52 Sprague-Dawley rats undergoing CUMS. Ten naïve control rats were also evaluated after 21 days. The behavioral effects of treatments were studied using the open field test (OFT) on day 0, 7 and 21 and sucrose preference test on day 21. Hippocampal BDNF protein expression was measured using immunohistochemistry. The effect of the interventions on hippocampal neurons was histologically examined after H&E staining. Agomelatine mitigated the reduction in rearing behavior by CUMS in the OFT on day 7 as well as sucrose preference on day 21. The mean optical density value of BDNF was significantly higher in the CUMS + agomelatine group than the CUMS and CUMS + fluoxetine groups. The CUMS + agomelatine group had a significantly higher number of BDNF positive cells compared to naïve controls and CUMS group. Histology showed that hippocampal neurons in the CUMS + agomelatine and CUMS + fluoxetine groups were intact and few of them demonstrated karyopyknosis. Agomelatine-a novel antidepressant, but not fluoxetine, increased hippocampal BDNF level and of BDNF positive neurons in rats subject to CUMS.
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Affiliation(s)
- Yanxia Lu
- Department of Clinical Psychology and Psychiatry/School of Public Health, Zhejiang University College of Medicine, Hangzhou, China.
| | - Cyrus S Ho
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Psychological Medicine, National University Health System, Singapore
| | - Roger S McIntyre
- Brain and Cognition Discovery Foundation (BCDF) Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Toxicology and Pharmacology, University of Toronto, Toronto, ON, Canada
| | - Wei Wang
- Department of Clinical Psychology and Psychiatry/School of Public Health, Zhejiang University College of Medicine, Hangzhou, China.
| | - Roger C Ho
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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13
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Ethemoglu MS, Kutlu S, Seker FB, Erdogan CS, Bingol CA, Yilmaz B. Effects of agomelatine on electrocorticogram activity on penicillin-induced seizure model of rats. Neurosci Lett 2018; 690:120-125. [PMID: 30213622 DOI: 10.1016/j.neulet.2018.09.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 09/05/2018] [Accepted: 09/08/2018] [Indexed: 10/28/2022]
Abstract
Agomelatine is a new antidepressant drug acting as an antagonist of 5-hydroxytryptamine receptor 2C (5-HTR2C) and agonist of melatonergic receptors 1 and 2 (MT1 and MT2). Because of this dual action, it is an atypical antidepressant. The aim of this study was to investigate chronic anticonvulsant effects of agomelatine on penicillin-induced epilepsy model. Adult male Sprague-Dawley rats divided into four groups and were administered with tap water (vehicle), and agomelatine doses of 10 mg/kg, 50 mg/kg and 100 mg/kg for 14 days via oral gavage. After the last doses were given, epileptic seizures were induced by intracortical penicillin (500 IU/2.5 μl) application in rats under urethane (1.25 g/kg intraperitoneal) anesthesia. Electrocorticogram (ECoG) recordings were obtained from the somatomotor cortex through 90 min, and spike frequencies and amplitudes were analyzed. The spike frequency analyses revealed that only 50 mg/kg agomelatine administration decreased the spike frequencies of hypersynchronous discharge of neurons caused by penicillin (p < 0.05). No significant differences in amplitudes between experimental groups were observed. In addition, mRNA expressions of vesicular glutamate transporter 1 (VGLUT1) and vesicular gamma-aminobutyric acid transporter (VGAT) in response to the agomelatine active dose, 50 mg/kg, showed no significant effect of agomelatine on the mRNA expression. Our results indicate that chronic treatment with agomelatine may have potential anticonvulsant effects. Agomelatine may be a promising drug for epilepsy patients having depression due to its antiepileptic and antidepressant effects.
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Affiliation(s)
- M S Ethemoglu
- Yeditepe University, Medical School, Department of Physiology, Ataşehir, İstanbul, Turkey
| | - S Kutlu
- Necmettin Erbakan University, Meram Faculty of Medicine, Department of Physiology, Meram, Konya, Turkey
| | - F B Seker
- Yeditepe University, Medical School, Department of Physiology, Ataşehir, İstanbul, Turkey
| | - C S Erdogan
- Yeditepe University, Medical School, Department of Physiology, Ataşehir, İstanbul, Turkey
| | - C A Bingol
- Yeditepe University, Medical School, Department of Neurology, Ataşehir, İstanbul, Turkey
| | - B Yilmaz
- Yeditepe University, Medical School, Department of Physiology, Ataşehir, İstanbul, Turkey.
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14
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Yuen EY, Wei J, Yan Z. Molecular and Epigenetic Mechanisms for the Complex Effects of Stress on Synaptic Physiology and Cognitive Functions. Int J Neuropsychopharmacol 2017; 20:948-955. [PMID: 29016816 PMCID: PMC5737802 DOI: 10.1093/ijnp/pyx052] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 06/13/2017] [Accepted: 07/08/2017] [Indexed: 12/16/2022] Open
Abstract
Evidence over the past decades has found that stress, particularly through the corticosterone stress hormones, produces complex changes in glutamatergic signaling in prefrontal cortex, which leads to the alteration of cognitive processes medicated by this brain region. Interestingly, the effects of stress on glutamatergic transmission appear to be "U-shaped," depending upon the duration and severity of the stressor. These biphasic effects of acute vs chronic stress represent the adaptive vs maladaptive responses to stressful stimuli. Animal studies suggest that the stress-induced modulation of excitatory synaptic transmission involves changes in presynaptic glutamate release, postsynaptic glutamate receptor membrane trafficking and degradation, spine structure and cytoskeleton network, and epigenetic control of gene expression. This review will discuss current findings on the key molecules involved in the stress-induced regulation of prefrontal cortex synaptic physiology and prefrontal cortex-mediated functions. Understanding the molecular and epigenetic mechanisms that underlie the complex effects of stress will help to develop novel strategies to cope with stress-related mental disorders.
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Affiliation(s)
- Eunice Y. Yuen
- Yale Child Study Center, Yale University School of Medicine, New Haven, Connecticut (Dr Yuen); Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York (Drs Wei and Yan)
| | - Jing Wei
- Yale Child Study Center, Yale University School of Medicine, New Haven, Connecticut (Dr Yuen); Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York (Drs Wei and Yan)
| | - Zhen Yan
- Yale Child Study Center, Yale University School of Medicine, New Haven, Connecticut (Dr Yuen); Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York (Drs Wei and Yan)
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15
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Pesarico AP, Rosa SG, Stangherlin EC, Mantovani AC, Zeni G, Nogueira CW. 7-Fluoro-1,3-diphenylisoquinoline-1-amine reverses the reduction in self-care behavior induced by maternal separation stress in rats by modulating glutamatergic/GABAergic systems. J Psychiatr Res 2017; 89:28-37. [PMID: 28153643 DOI: 10.1016/j.jpsychires.2017.01.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 01/12/2017] [Accepted: 01/19/2017] [Indexed: 12/18/2022]
Abstract
7-Fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) is a promising isoquinoline that elicits an antidepressant-like action in rodents. In this study, an animal model of stress induced by maternal separation was used to investigate the effects of FDPI in Wistar rats of 30 and 90 days of age. It was investigated the effects of maternal separation in the self-care behavior and the contribution of glutamatergic and gamma-aminobutyric acid (GABA)ergic systems in the FDPI action. Male Wistar rats were separated from their mothers for 3 h/day from postnatal day (PND) 1-10. The rats were treated at different ages (PND-30 and PND-90) with FDPI (5 mg/kg, intragastrically/7 days) and performed the splash test. Maternal separation reduced total grooming time in the splash test, an index of motivational and self-care behavior, and FDPI treatment was effective in reversing this behavior in rats at both ages. The neurochemical parameters were differently affected, dependent on the age of rats, by maternal separation and FDPI. Maternal separation increased the GABA uptake and the excitatory amino acid transporter 1 levels in the prefrontal cortices of rats at PND-30 and FDPI was effective against these alterations. At PND-90, maternal separation decreased the glutamate uptake and increased the GABA uptake and the N-methyl-D-aspartate (NMDA) receptor 2B levels in the prefrontal cortices of rats. FDPI reversed the neurochemical alterations caused by maternal separation in the prefrontal cortices of rats at PND-90. The results of this study demonstrated that FDPI reversed the reduction in self-care behavior induced by maternal separation stress in rats by modulating the glutamatergic/GABAergic systems in rats.
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Affiliation(s)
- Ana Paula Pesarico
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil
| | - Suzan G Rosa
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil
| | - Eluza C Stangherlin
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil
| | - Anderson C Mantovani
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil
| | - Gilson Zeni
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil
| | - Cristina Wayne Nogueira
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil.
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16
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Medvedev VE, Retiunsky KY, Ovchinnikov AA, Barylnik YB, Shmilovich AA, Antokhin EY, Usov GM, Cheremin RA, Poletsky VM, Onegin AV, Kireeva IP, Frolova VI, Filippova NV, Antonova AA, Deeva MA, Onegina DA. [The differences in the estimation of depression severity by psychiatrists and patients during the combined treatment with agomelatine (a multicenter study "EMOTSIA")]. Zh Nevrol Psikhiatr Im S S Korsakova 2017; 116:26-34. [PMID: 28091498 DOI: 10.17116/jnevro201611611126-34] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
AIM To compare the prognosis of depression severity estimated by the physician and by the patient based on the treatment outcome. MATERIAL AND METHODS One hundred and seven patients with depression were examined. Mental status was assessed with HАМ-D, SHAPS, CGI-S, CGI-I, PGI-S, PGI-I and VAS. A data analysis was performed. RESULTS There were differences in the estimation of depression severity by psychiatrists and patients. Moreover, the scores on HАМ-D and CGI-S were not consistent when assessed by psychiatrists. As the severity of depression decreased and patient's state improved during the treatment with agomelatine (valdoxan), the assessments of the changes by the psychiatrist and the patient became similar. CONCLUSION Agomelatine (valdoxan) is effective and tolerable in the treatment of depression of any severity. The differences between the psychiatrist's and patient's estimation of the depression severity at baseline using different psychometric scales can level the prognostic value of treatment outcome.
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Affiliation(s)
- V E Medvedev
- Russian University of People's Friendship Moscow, Russia
| | | | | | - Yu B Barylnik
- Razumovsky Saratov State Medical University, Saratov, Russia
| | - A A Shmilovich
- Pirogov National Research Medical University, Moscow, Russia
| | | | - G M Usov
- Omsk State Medical Academy, Omsk, Russia
| | - R A Cheremin
- Organizatsion, Methodical and Consultation Unit for and Psychiatry And Suicidology Public Health Department, Moscow, Russia
| | - V M Poletsky
- South Ural State Medical University, Chelyabinsk, Russia
| | - A V Onegin
- Murmansk Regional Psychoneurological Dispensary, Murmansk, Russia
| | - I P Kireeva
- Pirogov National Research Medical University, Moscow, Russia
| | - V I Frolova
- Russian University of People's Friendship Moscow, Russia
| | - N V Filippova
- Razumovsky Saratov State Medical University, Saratov, Russia
| | - A A Antonova
- Razumovsky Saratov State Medical University, Saratov, Russia
| | - M A Deeva
- Razumovsky Saratov State Medical University, Saratov, Russia
| | - D A Onegina
- Murmansk Regional Psychoneurological Dispensary, Murmansk, Russia
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17
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Gahr M. Agomelatine in the treatment of major depressive disorder: an assessment of benefits and risks. Curr Neuropharmacol 2014; 12:287-398. [PMID: 25426008 PMCID: PMC4243030 DOI: 10.2174/1570159x12999140619122914] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 05/29/2014] [Accepted: 06/01/2014] [Indexed: 12/13/2022] Open
Abstract
Agomelatine (AGM) was approved for the treatment of major depressive disorder (MDD) in adults by the European Medicines Agency (EMA) in February 2009. It is an analogue of melatonin and features a unique pharmacodynamic profile with agonism on both types of melatonergic receptors (MT1/MT2) and antagonism at serotonergic 5-HT2C receptors. There is, however, an ongoing debate regarding the efficacy and safety of this novel antidepressant agent, originally evoked by claims of a significant publication bias underlying the assessment of AGM being an effective antidepressant. Indeed, two recent comprehensive metaanalyses of published and unpublished clinical trials found evidence for a relevant publication bias. However, due to its statistically significant advantage over placebo based on the results of these metaanalyses AGM must be referred to as an effective antidepressant agent in the acute phase of MDD. However, the effect sizes of AGM in the treatment of MDD were evaluated as being small in comparison to other antidepressant agents. In addition, there is insufficient evidence for the efficacy of AGM in relapse prevention of MDD. Apart from efficacy issues, AGM appears to have the potential to exhibit severe hepatotoxicity (the EMA has identified AGM-associated “hepatotoxic reactions” as a new safety concern in September 2013) that is currently poorly understood. Considering these aspects, it seems inappropriate to evaluate AGM as an antidepressant agent of first choice. Nevertheless, its unique mechanism of action with particular sleep modulating effects may represent a specific treatment strategy for patients with particular characteristics; further studies with thorough characterization of patients are needed to test this hypothesis.
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Affiliation(s)
- Maximilian Gahr
- University of Ulm, Department of Psychiatry and Psychotherapy III. Leimgrubenweg 12-14, 89075 Ulm, Ulm, Germany
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18
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Harvey BH, Slabbert FN. New insights on the antidepressant discontinuation syndrome. Hum Psychopharmacol 2014; 29:503-16. [PMID: 25111000 DOI: 10.1002/hup.2429] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 06/13/2014] [Accepted: 06/23/2014] [Indexed: 01/04/2023]
Abstract
OBJECTIVE Antidepressants are at best 50–55% effective. Non-compliance and the antidepressant discontinuation syndrome (ADS) are causally related yet poorly appreciated. While ADS is associated with most antidepressants, agomelatine seems to be devoid of such risk. We review the neurobiology and clinical consequences of antidepressant non-compliance and the ADS. Agomelatine is presented as a counterpoint to learn more on how ADS risk is determined by pharmacokinetics and pharmacology. DESIGN The relevant literature is reviewed through a MEDLINE search via PubMed, focusing on agomelatine and clinical and preclinical research on ADS. RESULTS Altered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems. CONCLUSIONS This review raises awareness of the long-term negative aspects of non-compliance and inappropriate antidepressant discontinuation, and suggests possible approaches to “design-out” a risk for ADS. It reveals intuitive and rational ideas for antidepressant drug design, and provides new thoughts on antidepressant pharmacology, ADS risk and how these affect long-term outcome.
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Affiliation(s)
- Brian H. Harvey
- Centre of Excellence for Pharmaceutical Sciences; School of Pharmacy, North-West University; Potchefstroom South Africa
| | - Francois N. Slabbert
- Medicines Usage Group (MUSA), School of Pharmacy; North-West University; Potchefstroom South Africa
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19
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Guardiola-Lemaitre B, De Bodinat C, Delagrange P, Millan MJ, Munoz C, Mocaër E. Agomelatine: mechanism of action and pharmacological profile in relation to antidepressant properties. Br J Pharmacol 2014; 171:3604-19. [PMID: 24724693 PMCID: PMC4128060 DOI: 10.1111/bph.12720] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Revised: 03/26/2014] [Accepted: 04/03/2014] [Indexed: 12/12/2022] Open
Abstract
Agomelatine behaves both as a potent agonist at melatonin MT1 and MT2 receptors and as a neutral antagonist at 5-HT2C receptors. Accumulating evidence in a broad range of experimental procedures supports the notion that the psychotropic effects of agomelatine are due to the synergy between its melatonergic and 5-hydroxytryptaminergic effects. The recent demonstration of the existence of heteromeric complexes of MT1 and MT2 with 5-HT2C receptors at the cellular level may explain how these two properties of agomelatine translate into a synergistic action that, for example, leads to increases in hippocampal proliferation, maturation and survival through modulation of multiple cellular pathways (increase in trophic factors, synaptic remodelling, glutamate signalling) and key targets (early genes, kinases). The present review focuses on the pharmacological properties of this novel antidepressant. Its mechanism of action, strikingly different from that of conventional classes of antidepressants, opens perspectives towards a better understanding of the physiopathological bases underlying depression.
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20
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Mechanism of action of agomelatine: a novel antidepressant exploiting synergy between monoaminergic and melatonergic properties. CNS Spectr 2014; 19:207-12. [PMID: 24901504 DOI: 10.1017/s1092852914000248] [Citation(s) in RCA: 182] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
A striking and unexpected pharmacologic synergy has been shown between antagonist actions at serotonergic 5HT2C receptors, and agonist actions at melatonergic receptors by agomelatine, a drug that has both of these properties.
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21
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An organoselenium compound improves behavioral, endocrinal and neurochemical changes induced by corticosterone in mice. Psychopharmacology (Berl) 2014; 231:2119-30. [PMID: 24306280 DOI: 10.1007/s00213-013-3361-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 11/14/2013] [Indexed: 12/14/2022]
Abstract
RATIONALE 3-(4-Fluorophenylselenyl)-2,5-diphenylselenophene (F-DPS) is a promising organoselenium compound that shows antidepressant-like properties related to interaction with the serotonergic system. OBJECTIVES In this study, a mouse model of anxiety/depressant-like behavior induced by long-term corticosterone treatment was used to evaluate behavioral, endocrinal, and neurochemical changes in mice and their possible modulation of F-DPS treatment. METHODS Swiss mice were subjected to 4 weeks of corticosterone administration (20 μg/ml in drinking water) and a new therapeutic approach with F-DPS (0.1 mg/kg/day, intragastric route, during 1 week) was employed to modulate changes induced by corticosterone exposure. RESULTS Treatment with corticosterone caused a significant depressant-like behavior in the forced swimming test and tail suspension test, which was accompanied by anxiety-like condition in the light-dark test and novelty suppressed-feeding; similarly to the classical antidepressant drug paroxetine, F-DPS treatment was effective in reversing these behavioral changes. Further, F-DPS normalized serum levels of corticosterone and adrenocorticotropic hormone, which were increased after corticosterone exposure. Corticosterone also significantly inhibited glutamate uptake in the prefrontal cortex of mice, whereas glutamate release was not modified. Besides normalizing glutamate uptake in the corticosterone-exposed mice, F-DPS promoted an inhibition of 5-HT uptake in the prefrontal cortex and hippocampus. In addition, hippocampal monoamine oxidase-A activity was also inhibited by F-DPS treatment. CONCLUSIONS These findings suggest a modulation of both serotonergic and glutamatergic systems by F-DPS after a long-term corticosterone exposure in mice, which may be involved in the antidepressant- and anxiolytic-like actions of this organoselenium compound.
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Treccani G, Musazzi L, Perego C, Milanese M, Nava N, Bonifacino T, Lamanna J, Malgaroli A, Drago F, Racagni G, Nyengaard JR, Wegener G, Bonanno G, Popoli M. Stress and corticosterone increase the readily releasable pool of glutamate vesicles in synaptic terminals of prefrontal and frontal cortex. Mol Psychiatry 2014; 19:433-43. [PMID: 24535456 DOI: 10.1038/mp.2014.5] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 12/18/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023]
Abstract
Stress and glucocorticoids alter glutamatergic transmission, and the outcome of stress may range from plasticity enhancing effects to noxious, maladaptive changes. We have previously demonstrated that acute stress rapidly increases glutamate release in prefrontal and frontal cortex via glucocorticoid receptor and accumulation of presynaptic SNARE complex. Here we compared the ex vivo effects of acute stress on glutamate release with those of in vitro application of corticosterone, to analyze whether acute effect of stress on glutamatergic transmission is mediated by local synaptic action of corticosterone. We found that acute stress increases both the readily releasable pool (RRP) of vesicles and depolarization-evoked glutamate release, while application in vitro of corticosterone rapidly increases the RRP, an effect dependent on synaptic receptors for the hormone, but does not induce glutamate release for up to 20 min. These findings indicate that corticosterone mediates the enhancement of glutamate release induced by acute stress, and the rapid non-genomic action of the hormone is necessary but not sufficient for this effect.
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Affiliation(s)
- G Treccani
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics-Dipartimento di Scienze Farmacologiche e Biomolecolari and CEND, Università di Milano, Milano, Italy
| | - L Musazzi
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics-Dipartimento di Scienze Farmacologiche e Biomolecolari and CEND, Università di Milano, Milano, Italy
| | - C Perego
- Laboratory of Cell Physiology-Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milano, Italy
| | - M Milanese
- Department of Pharmacy-Unit of Pharmacology and Toxicology, Center of Excellence for Biomedical Research, Università di Genova, Genova, Italy
| | - N Nava
- 1] Stereology and Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus, Denmark [2] Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - T Bonifacino
- Department of Pharmacy-Unit of Pharmacology and Toxicology, Center of Excellence for Biomedical Research, Università di Genova, Genova, Italy
| | - J Lamanna
- Neurobiology of Learning Unit, Scientific Institute San Raffaele and Università Vita e Salute San Raffaele, Milano, Italy
| | - A Malgaroli
- Neurobiology of Learning Unit, Scientific Institute San Raffaele and Università Vita e Salute San Raffaele, Milano, Italy
| | - F Drago
- Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Università di Catania, Catania, Italy
| | - G Racagni
- 1] Laboratory of Neuropsychopharmacology and Functional Neurogenomics-Dipartimento di Scienze Farmacologiche e Biomolecolari and CEND, Università di Milano, Milano, Italy [2] IRCCS San Giovanni di Dio-Fatebenefratelli, Brescia, Italy
| | - J R Nyengaard
- Stereology and Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus, Denmark
| | - G Wegener
- 1] Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark [2] Centre of Excellence for Pharmaceutical Sciences, North West University, Potchefstroom, South Africa
| | - G Bonanno
- Department of Pharmacy-Unit of Pharmacology and Toxicology, Center of Excellence for Biomedical Research, Università di Genova, Genova, Italy
| | - M Popoli
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics-Dipartimento di Scienze Farmacologiche e Biomolecolari and CEND, Università di Milano, Milano, Italy
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The effects of antidepressant treatment in prenatally stressed rats support the glutamatergic hypothesis of stress-related disorders. J Neurosci 2014; 34:2015-24. [PMID: 24501344 DOI: 10.1523/jneurosci.4131-13.2014] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Abnormalities of synaptic transmission in the hippocampus represent an integral part of the altered programming triggered by early life stress, which enhances the vulnerability to stress-related disorders in the adult life. Rats exposed to prenatal restraint stress (PRS) develop enduring biochemical and behavioral changes characteristic of an anxious/depressive-like phenotype. Most neurochemical abnormalities in PRS rats are found in the ventral hippocampus, a region that encodes memories related to stress and emotions. We have recently demonstrated a causal link between the reduction of glutamate release in the ventral hippocampus and anxiety-like behavior in PRS rats. To confer pharmacological validity to the glutamatergic hypothesis of stress-related disorders, we examined whether chronic treatment with two antidepressants with different mechanisms of action could correct the defect in glutamate release and associated behavioral abnormalities in PRS rats. Adult unstressed or PRS rats were treated daily with either agomelatine (40 mg/kg, i.p.) or fluoxetine (5 mg/kg, i.p.) for 21 d. Both treatments reversed the reduction in depolarization-evoked glutamate release and in the expression of synaptic vesicle-associated proteins in the ventral hippocampus of PRS rats. Antidepressant treatment also corrected abnormalities in anxiety-/depression-like behavior and social memory performance in PRS rats. The effect on glutamate release was strongly correlated with the improvement of anxiety-like behavior and social memory. These data offer the pharmacological demonstration that glutamatergic hypofunction in the ventral hippocampus lies at the core of the pathological phenotype caused by early life stress and represents an attractive pharmacological target for novel therapeutic strategies.
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Schmelting B, Corbach-Söhle S, Kohlhause S, Schlumbohm C, Flügge G, Fuchs E. Agomelatine in the tree shrew model of depression: effects on stress-induced nocturnal hyperthermia and hormonal status. Eur Neuropsychopharmacol 2014; 24:437-47. [PMID: 23978391 DOI: 10.1016/j.euroneuro.2013.07.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 07/08/2013] [Accepted: 07/26/2013] [Indexed: 12/14/2022]
Abstract
The antidepressive drug agomelatine combines the properties of an agonist of melatonergic receptors 1 and 2 with an antagonist of the 5-HT2C receptor. We analyzed the effects of agomelatine in psychosocially stressed male tree shrews, an established preclinical model of depression. Tree shrews experienced daily social stress for a period of 5 weeks and were concomitantly treated with different drugs daily for 4 weeks. The effects of agomelatine (40 mg/kg/day) were compared with those of the agonist melatonin (40 mg/kg/day), the inverse 5-HT2C antagonist S32006 (10mg/kg/day), and the SSRI fluoxetine (15 mg/kg/day). Nocturnal core body temperature (CBT) was recorded by telemetry, and urinary norepinephrine and cortisol concentrations were measured. Chronic social stress induced nocturnal hyperthermia. Agomelatine normalized the CBT in the fourth week of the treatment (T4), whereas the other drugs did not significantly counteract the stress-induced hyperthermia. Agomelatine also reversed the stress-induced reduction in locomotor activity. Norepinephrine concentration was elevated by the stress indicating sympathetic hyperactivity, and was normalized in the stressed animals treated with agomelatine or fluoxetine but not in those treated with melatonin or S32006. Cortisol concentration was elevated by stress but returned to basal levels by T4 in all animals, irrespective of the treatment. These observations show that agomelatine has positive effects to counteract stress-induced physiological processes and to restore the normal rhythm of nocturnal CBT. The data underpin the antidepressant properties of agomelatine and are consistent with a distinctive profile compared to its constituent pharmacological components and other conventional agents.
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Affiliation(s)
- Barthel Schmelting
- Clinical Neurobiology Laboratory, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany
| | - Silke Corbach-Söhle
- Clinical Neurobiology Laboratory, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany
| | - Susan Kohlhause
- Clinical Neurobiology Laboratory, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany
| | - Christina Schlumbohm
- Clinical Neurobiology Laboratory, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany
| | - Gabriele Flügge
- Clinical Neurobiology Laboratory, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany; DFG Research Center Molecular Physiology of the Brain (CMPB), University of Göttingen, Göttingen, Germany
| | - Eberhard Fuchs
- Clinical Neurobiology Laboratory, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany; DFG Research Center Molecular Physiology of the Brain (CMPB), University of Göttingen, Göttingen, Germany; Department of Neurology, Medical School, University of Göttingen, Göttingen, Germany.
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Fornaro M, Bandini F, Cestari L, Cordano C, Ogliastro C, Albano C, De Berardis D, Martino M, Escelsior A, Rocchi G, Fornaro P, De Pasquale C. Electroretinographic modifications induced by agomelatine: a novel avenue to the understanding of the claimed antidepressant effect of the drug? Neuropsychiatr Dis Treat 2014; 10:907-14. [PMID: 24899809 PMCID: PMC4038423 DOI: 10.2147/ndt.s63459] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Agomelatine, the first melatonergic antidepressant, has been postulated to enhance the dopaminergic activity at the central nervous system by 5-hydroxytryptamine receptor type 2C (5-HT2C) antagonism, yet the impact of melatonergic agonism on this pathway is unclear. Previous studies employing simplified, yet reliable, proxy (retinal) measures of the central nervous system dopaminergic activity, namely the standard electroretinogram (ERG) technique, suggested a reduction of the dopaminergic activity of the main ERG parameter, the b-wave, by pure melatonin, notably a hormone devoid of any antidepressant activity. Therefore, the antidepressant effects of the melatonergic antidepressant drug agomelatine should be reflected by a differential b-wave trend at ERG versus the effect exerted by pure melatonin, which was eventually found to be due to a contrasting effect on central dopaminergic transmission between the two drugs. OBJECTIVE AND METHODS The aim of the present preliminary ERG study carried out on healthy volunteers (n=23) receiving agomelatine was to explore the impact of this antidepressant drug on b-wave amplitude and latency of cones in daylight conditions using standard ERG. RESULTS As postulated, agomelatine induced an enhancement of retinal dopaminergic activity, in contrast to what has been previously documented for melatonin. CONCLUSION Given the limits of this explorative study, especially the lack of a control group and that of a luminance response function to measure retinal sensitivity, further studies in clinical samples are recommended to allow more tenable conclusions about the potential role of ERG in discriminating between 5-HT antagonism and melatonergic (MT) agonism in relationship to the claimed antidepressant effect of agomelatine.
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Affiliation(s)
- Michele Fornaro
- Department of Educative Science, University of Catania, Catania, Italy
| | - Fabio Bandini
- Department of Neurology, San Paolo Hospital, Savona, Italy
| | - Luca Cestari
- Department of Ophthalmology, University of Pisa, Pisa, Italy
| | - Christian Cordano
- Department of Neurosciences, Ophthalmology and Genetics - Section of Neurology, University of Genoa, Genoa, Italy
| | - Carla Ogliastro
- Department of Neurosciences, Ophthalmology and Genetics - Section of Neurology, University of Genoa, Genoa, Italy
| | - Claudio Albano
- Department of Neurosciences, Ophthalmology and Genetics - Section of Neurology, University of Genoa, Genoa, Italy
| | - Domenico De Berardis
- National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital G. Mazzini, ASL 4, Teramo, Italy
| | - Matteo Martino
- Department of Neurosciences, Ophthalmology and Genetics - Section of Psychiatry, University of Genoa, Genoa, Italy
| | - Andrea Escelsior
- Department of Neurosciences, Ophthalmology and Genetics - Section of Psychiatry, University of Genoa, Genoa, Italy
| | - Giulio Rocchi
- Department of Neurosciences, Ophthalmology and Genetics - Section of Psychiatry, University of Genoa, Genoa, Italy
| | - Pantaleo Fornaro
- Department of Neurosciences, Ophthalmology and Genetics - Section of Psychiatry, University of Genoa, Genoa, Italy
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MacIsaac SE, Carvalho AF, Cha DS, Mansur RB, McIntyre RS. The mechanism, efficacy, and tolerability profile of agomelatine. Expert Opin Pharmacother 2013; 15:259-74. [DOI: 10.1517/14656566.2014.862233] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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De Berardis D, Conti CM, Marini S, Ferri F, Iasevoli F, Valchera A, Fornaro M, Cavuto M, Srinivasan V, Perna G, Carano A, Piersanti M, Martinotti G, Di Giannantonio M. Is there a role for agomelatine in the treatment of anxiety disorders?A review of published data. Int J Immunopathol Pharmacol 2013; 26:299-304. [PMID: 23755745 DOI: 10.1177/039463201302600203] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Anxiety disorders (Ads) are the most common type of psychiatric disorders, Pharmacologic options studied for treating ADs may include benzodiazepines, tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRIs), noradrenergic and specific serotonergic antidepressants (NaSSA) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Agomelatine, a new melatonergic antidepressant, has been shown effective in various types of mood disorders. Moreover, some evidence points towards a possible efficacy of such a drug in the treatment of ADs. Therefore, the aim of this review was to elucidate current (facts and views) data on the role of agomelatine in the treatment of ADs. The trials evaluating agomelatine in the treatment of generalized anxiety disorder are few but, overall, encouraging in regards to its efficacy. However, further randomized, placebo-controlled studies on larger samples use are needed. Apart from some interesting case reports, no large studies are, to date, present in literature regarding agomelatine in the treatment of other ADs, such as panic disorder, social anxiety disorder, obsessive-compulsive disorder and post-traumatic stress disorder. Therefore, the clinical efficacy and the relative good tolerability of agomelatine in generalized anxiety (GAD) warrants further investigation in ADs.
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Affiliation(s)
- D De Berardis
- Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital G. Mazzini, ASL 4 Teramo, Italy
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Leading compounds for the validation of animal models of psychopathology. Cell Tissue Res 2013; 354:309-30. [DOI: 10.1007/s00441-013-1692-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 07/01/2013] [Indexed: 12/18/2022]
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Grégoire S, Neugebauer V. 5-HT2CR blockade in the amygdala conveys analgesic efficacy to SSRIs in a rat model of arthritis pain. Mol Pain 2013; 9:41. [PMID: 23937887 PMCID: PMC3751088 DOI: 10.1186/1744-8069-9-41] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 08/09/2013] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pain, including arthritic pain, has a negative affective component and is often associated with anxiety and depression. However, selective serotonin reuptake inhibitor antidepressants (SSRIs) show limited effectiveness in pain. The amygdala plays a key role in the emotional-affective component of pain, pain modulation and affective disorders. Neuroplasticity in the basolateral and central amygdala (BLA and CeA, respectively) correlate positively with pain behaviors. Evidence suggests that serotonin receptor subtype 5-HT2CR in the amygdala contributes critically to anxiogenic behavior and anxiety disorders. In this study, we tested the hypothesis that 5-HT2CR in the amygdala accounts for the limited effectiveness of SSRIs in reducing pain behaviors and that 5-HT2CR blockade in the amygdala renders SSRIs effective. RESULTS Nocifensive reflexes, vocalizations and anxiety-like behavior were measured in adult male Sprague-Dawley rats. Behavioral experiments were done in sham controls and in rats with arthritis induced by kaolin/carrageenan injections into one knee joint. Rats received a systemic (i.p.) administration of an SSRI (fluvoxamine, 30 mg/kg) or vehicle (sterile saline) and stereotaxic application of a selective 5-HT2CR antagonist (SB242084, 10 μM) or vehicle (ACSF) into BLA or CeA by microdialysis. Compared to shams, arthritic rats showed decreased hindlimb withdrawal thresholds (increased reflexes), increased duration of audible and ultrasonic vocalizations, and decreased open-arm choices in the elevated plus maze test suggesting anxiety-like behavior. Fluvoxamine (i.p.) or SB242084 (intra-BLA) alone had no significant effect, but their combination inhibited the pain-related increase of vocalizations and anxiety-like behavior without affecting spinal reflexes. SB242084 applied into the CeA in combination with systemic fluvoxamine had no effect on vocalizations and spinal reflexes. CONCLUSIONS The data suggest that 5-HT2CR in the amygdala, especially in the BLA, limits the effectiveness of SSRIs to inhibit pain-related emotional-affective behaviors.
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Affiliation(s)
- Stéphanie Grégoire
- Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston Texas 77555-1069, USA
| | - Volker Neugebauer
- Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston Texas 77555-1069, USA
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Pompili M, Serafini G, Innamorati M, Venturini P, Fusar-Poli P, Sher L, Amore M, Girardi P. Agomelatine, a novel intriguing antidepressant option enhancing neuroplasticity: a critical review. World J Biol Psychiatry 2013; 14:412-431. [PMID: 23530731 DOI: 10.3109/15622975.2013.765593] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVES The treatment of major affective disorders, commonly associated with high disability and elevated social costs may be still considered unsatisfactory. Among all antidepressant drugs, predominantly acting through monoaminergic mechanisms, agomelatine is of particular interest due to another alternative mechanism of action. Targeting melatonergic receptors, agomelatine play a crucial role in synchronizing circadian rhythms, known to be altered in depressed subjects. METHODS A critical review of the literature focusing on efficacy, safety and tolerability of agomelatine in major affective disorders was performed. Additionally, we focused on the potential of agomelatine in enhancing neuroplasticity mechanisms and promote neurogenesis. A total of 136 articles from peer-reviewed journals were identified, of which 50 were assessed for eligibility and 21 were included. RESULTS Agomelatine, a melatonergic analogue drug acting as MT1/MT2 agonist and 5-HT2C antagonist, has been reported to be effective as antidepressant drug. Studies confirmed not only clinical efficacy but also safety and tolerability of agomelatine. Also, it enhances neuroplasticity mechanisms and adult neurogenesis in brain areas such as hippocampus and prefrontal cortex. CONCLUSIONS Agomelatine actually represents an intriguing option in the treatment of affective disorders.
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Affiliation(s)
- Maurizio Pompili
- Department of Neurosciences, Mental Health and Sensory Organs, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.
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Milanese M, Tardito D, Musazzi L, Treccani G, Mallei A, Bonifacino T, Gabriel C, Mocaer E, Racagni G, Popoli M, Bonanno G. Chronic treatment with agomelatine or venlafaxine reduces depolarization-evoked glutamate release from hippocampal synaptosomes. BMC Neurosci 2013; 14:75. [PMID: 23895555 PMCID: PMC3734058 DOI: 10.1186/1471-2202-14-75] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Accepted: 07/26/2013] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Growing compelling evidence from clinical and preclinical studies has demonstrated the primary role of alterations of glutamatergic transmission in cortical and limbic areas in the pathophysiology of mood disorders. Chronic antidepressants have been shown to dampen endogenous glutamate release from rat hippocampal synaptic terminals and to prevent the marked increase of glutamate overflow induced by acute behavioral stress in frontal/prefrontal cortex. Agomelatine, a new antidepressant endowed with MT1/MT2 agonist and 5-HT2C serotonergic antagonist properties, has shown efficacy at both preclinical and clinical levels. RESULTS Chronic treatment with agomelatine, or with the reference drug venlafaxine, induced a marked decrease of depolarization-evoked endogenous glutamate release from purified hippocampal synaptic terminals in superfusion. No changes were observed in GABA release. This effect was accompanied by reduced accumulation of SNARE protein complexes, the key molecular effector of vesicle docking, priming and fusion at presynaptic membranes. CONCLUSIONS Our data suggest that the novel antidepressant agomelatine share with other classes of antidepressants the ability to modulate glutamatergic transmission in hippocampus. Its action seems to be mediated by molecular mechanisms located on the presynaptic membrane and related with the size of the vesicle pool ready for release.
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Affiliation(s)
- Marco Milanese
- Department of Pharmacy, Unit of Pharmacology and Toxicology and Center of Excellence for Biomedical Research, Università degli Studi di Genova, Genova, Italy
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Mutlu O, Gumuslu E, Ulak G, Celikyurt IK, Akar F, Bektas E, Demirtas T, Kır HM, Musul MM, Erden F. Antidepressant-Like Activity of Agomelatine in the Mouse Unpredictable Chronic Mild Stress Model. Drug Dev Res 2013. [DOI: 10.1002/ddr.21064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Oguz Mutlu
- Department of Pharmacology; Kocaeli University Medical Faculty; 41380; Kocaeli; Turkey
| | - Esen Gumuslu
- Department of Medical Genetics; Kocaeli University Medical Faculty; 41380; Kocaeli; Turkey
| | - Guner Ulak
- Department of Pharmacology; Kocaeli University Medical Faculty; 41380; Kocaeli; Turkey
| | | | - Furuzan Akar
- Department of Pharmacology; Kocaeli University Medical Faculty; 41380; Kocaeli; Turkey
| | - Emine Bektas
- Department of Pharmacology; Kocaeli University Medical Faculty; 41380; Kocaeli; Turkey
| | - Tugce Demirtas
- Department of Pharmacology; Kocaeli University Medical Faculty; 41380; Kocaeli; Turkey
| | - Hale Maral Kır
- Department of Biochemistry; Kocaeli University Medical Faculty; 41380; Kocaeli; Turkey
| | - Mahmut Mert Musul
- Department of Biochemistry; Kocaeli University Medical Faculty; 41380; Kocaeli; Turkey
| | - Faruk Erden
- Department of Pharmacology; Kocaeli University Medical Faculty; 41380; Kocaeli; Turkey
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Molinaro P, Cantile M, Cuomo O, Secondo A, Pannaccione A, Ambrosino P, Pignataro G, Fiorino F, Severino B, Gatta E, Sisalli MJ, Milanese M, Scorziello A, Bonanno G, Robello M, Santagada V, Caliendo G, Di Renzo G, Annunziato L. Neurounina-1, a novel compound that increases Na+/Ca2+ exchanger activity, effectively protects against stroke damage. Mol Pharmacol 2013; 83:142-56. [PMID: 23066092 DOI: 10.1124/mol.112.080986] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Previous studies have demonstrated that the knockdown or knockout of the three Na(+)/Ca(2+) exchanger (NCX) isoforms, NCX1, NCX2, and NCX3, worsens ischemic brain damage. This suggests that the activation of these antiporters exerts a neuroprotective action against stroke damage. However, drugs able to increase the activity of NCXs are not yet available. We have here succeeded in synthesizing a new compound, named neurounina-1 (7-nitro-5-phenyl-1-(pyrrolidin-1-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one), provided with an high lipophilicity index and able to increase NCX activity. Ca(2+) radiotracer, Fura-2 microfluorimetry, and patch-clamp techniques revealed that neurounina-1 stimulated NCX1 and NCX2 activities with an EC(50) in the picomolar to low nanomolar range, whereas it did not affect NCX3 activity. Furthermore, by using chimera strategy and site-directed mutagenesis, three specific molecular determinants of NCX1 responsible for neurounina-1 activity were identified in the α-repeats. Interestingly, NCX3 became responsive to neurounina-1 when both α-repeats were replaced with the corresponding regions of NCX1. In vitro studies showed that 10 nM neurounina-1 reduced cell death of primary cortical neurons exposed to oxygen-glucose deprivation followed by reoxygenation. Moreover, in vitro, neurounina-1 also reduced γ-aminobutyric acid (GABA) release, enhanced GABA(A) currents, and inhibited both glutamate release and N-methyl-d-aspartate receptors. More important, neurounina-1 proved to have a wide therapeutic window in vivo. Indeed, when administered at doses of 0.003 to 30 μg/kg i.p., it was able to reduce the infarct volume of mice subjected to transient middle cerebral artery occlusion even up to 3 to 5 hours after stroke onset. Collectively, the present study shows that neurounina-1 exerts a remarkable neuroprotective effect during stroke and increases NCX1 and NCX2 activities.
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Affiliation(s)
- Pasquale Molinaro
- Division of Pharmacology, Department of Neuroscience, School of Medicine, "Federico II" University of Naples, Via Pansini 5, 80131 Naples, Italy
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Cardinali DP, Vidal MF, Vigo DE. Agomelatine: Its Role in the Management of Major Depressive Disorder. ACTA ACUST UNITED AC 2012. [DOI: 10.4137/cmpsy.s7989] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Circadian rhythm abnormalities, as shown by sleep/wake cycle disturbances, constitute one the most prevalent signs of depressive illness; advances or delays in the circadian phase are documented in patients with major depressive disorder (MDD), bipolar disorder, and seasonal affective disorder (SAD). The disturbances in the amplitude and phase of rhythm in melatonin secretion that occur in patients with depression resemble those seen in chronobiological disorders, thus suggesting a link between disturbed melatonin secretion and depressed mood. Based on this, agomelatine, the first MT1/MT2 melatonergic agonist displaying also 5-HT2C serotonergic antagonism, has been introduced as an antidepressant. Agomelatine has been shown to be effective in several animal models of depression and anxiety and it has beneficial effects in patients with MDD, bipolar disorder, or SAD. Among agomelatine's characteristics are a rapid onset of action and a pronounced effectiveness for correcting circadian rhythm abnormalities and improving the sleep/wake cycle. Agomelatine also improves the 3 functional dimensions of depression—emotional, cognitive, and social—thus aiding in the full recovery of patients to a normal life.
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Affiliation(s)
- Daniel P. Cardinali
- Department of Teaching and Research, Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina
| | - María F. Vidal
- Department of Teaching and Research, Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina
| | - Daniel E. Vigo
- Department of Teaching and Research, Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina
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Bali A, Singh N, Jaggi AS. Investigations into mild electric foot shock stress-induced cognitive enhancement: possible role of angiotensin neuropeptides. J Renin Angiotensin Aldosterone Syst 2012; 14:197-203. [DOI: 10.1177/1470320312456579] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Affiliation(s)
- Anjana Bali
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala, India
| | - Nirmal Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala, India
| | - Amteshwar Singh Jaggi
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala, India
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The antidepressant agomelatine inhibits stress-mediated changes in amino acid efflux in the rat hippocampus and amygdala. Brain Res 2012; 1466:91-8. [DOI: 10.1016/j.brainres.2012.05.039] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Revised: 03/28/2012] [Accepted: 05/21/2012] [Indexed: 12/14/2022]
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Serafini G. Neuroplasticity and major depression, the role of modern antidepressant drugs. World J Psychiatry 2012; 2:49-57. [PMID: 24175168 PMCID: PMC3782176 DOI: 10.5498/wjp.v2.i3.49] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Revised: 06/19/2012] [Accepted: 06/20/2012] [Indexed: 02/05/2023] Open
Abstract
The pathophysiology of depression has been traditionally attributed to a chemical imbalance and critical interactions between genetic and environmental risk factors, and antidepressant drugs suggested to act predominantly amplifying monoaminergic neurotransmission. This conceptualization may be currently considered reductive. The current literature about the pathophysiological mechanisms underlying depression, stress-related disorders and antidepressant treatment was examined. In order to provide a critical overview about neuroplasticity, depression and antidepressant drugs, a detailed Pubmed/Medline, Scopus, PsycLit, and PsycInfo search to identify all papers and book chapters during the period between 1980 and 2011 was performed. Pathological stress and depression determine relevant brain changes such as loss of dendritic spines and synapses, dendritic atrophy as well as reduction of glial cells (both in number and size) in specific areas such as the hippocampus and prefrontal cortex. An increased dendritic arborisation and synaptogenesis may instead be observed in the amygdala as a consequence of depression and stress-related disorders. While hippocampal and prefrontal functioning was impaired, amygdala functioning was abnormally amplified. Most of molecular abnormalities and biological changes of aberrant neuroplasticity may be explained by the action of glutamate. Antidepressant treatment is associated with neurogenesis, gliogenesis, dendritic arborisation, new synapse formation and cell survival both in the hippocampus and prefrontal cortex. Antidepressants (ADs) induce neuroplasticity mechanisms reversing the pathological effects of depression and stress-related disorders. The neuroplasticity hypothesis may explain the therapeutic and prophylactic action of ADs representing a new innovative approach to the pathophysiology of depression and stress-related disorders.
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Affiliation(s)
- Gianluca Serafini
- Gianluca Serafini, Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, Sant'Andrea Hospital, Sapienza University of Rome, Rome 00189, Italy
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Synergistic mechanisms involved in the antidepressant effects of agomelatine. Eur Neuropsychopharmacol 2012; 22 Suppl 3:S482-6. [PMID: 22867907 DOI: 10.1016/j.euroneuro.2012.06.016] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Accepted: 06/18/2012] [Indexed: 11/21/2022]
Abstract
Agomelatine is a novel and clinically effective antidepressant drug with melatonergic (MT1/MT2) agonist and 5-HT(2C) receptor antagonist properties. Both receptorial components are widely expressed in the central nervous system and it seems that this compound could act synergistically on both the melatonergic and the 5-HT(2C) receptors. In this review we will briefly summarize the preclinical evidence suggesting that the molecular-cellular effects of agomelatine and in turn its antidepressant activity are the result of a synergistic action between its agonism at MT1/MT2 and antagonism at 5-HT(2C) receptors. The antidepressant properties of agomelatine related to its effect on neurogenesis, cell survival, brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeleton associated protein (Arc) and stress-induced glutamate release, appear to be due to this synergistic action. Compared with traditional antidepressants which also affect these parameters, agomelatine is the only one able to resynchronize these effectors at distinct levels, circuital and intracellular. This suggests that agomelatine effects in restoring circadian rhythms and relieving depressive symptoms result from a synergistic interaction between melatonergic and serotonergic receptors.
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Racagni G, Riva MA, Molteni R, Musazzi L, Calabrese F, Popoli M, Tardito D. Mode of action of agomelatine: synergy between melatonergic and 5-HT2C receptors. World J Biol Psychiatry 2011; 12:574-87. [PMID: 21999473 DOI: 10.3109/15622975.2011.595823] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVES The association between depression and circadian rhythm disturbances is well established and successful treatment of depressed patients is accompanied by restoration of circadian rhythms. The new antidepressant agomelatine is an agonist of melatonergic MT₁/MT₂ receptors as well as an antagonist of serotonergic 5-HT2C receptors. Animal studies showed that agomelatine resynchronizes disturbed circadian rhythms and reduces depression-like behaviour. METHODS This review analyzes results from different experimental studies. RESULTS Recent data on the effects of agomelatine on cellular processes involved in antidepressant mechanisms have shown that the drug is able to increase the expression of brain-derived neurotrophic factor in prefrontal cortex and hippocampus, as well as the expression of activity-regulated cytoskeleton associated protein (Arc) in the prefrontal cortex. In line with this, prolonged treatment with agomelatine increases neurogenesis within the hippocampus, particularly via enhancement of neuronal cell survival. Agomelatine attenuates stress-induced glutamate release in the prefrontal/frontal cortex. Treatment with 5-HT2C antagonists or melatonin alone failed to reproduce these effects. CONCLUSIONS The unique mode of action of agomelatine may improve the management of major depression by counteracting the pathogenesis of depression at cellular level, thereby relieving the symptoms of depression. These effects are suggested to be due to a synergistic action on MT₁/MT₂ and 5-HT2C receptors.
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Affiliation(s)
- Giorgio Racagni
- Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Milan, Italy.
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Fineberg NA, Chamberlain SR, Hollander E, Boulougouris V, Robbins TW. Translational approaches to obsessive-compulsive disorder: from animal models to clinical treatment. Br J Pharmacol 2011; 164:1044-61. [PMID: 21486280 PMCID: PMC3229751 DOI: 10.1111/j.1476-5381.2011.01422.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2010] [Revised: 02/20/2011] [Accepted: 03/28/2011] [Indexed: 01/04/2023] Open
Abstract
Obsessive-compulsive disorder (OCD) is characterized by obsessions (intrusive thoughts) and compulsions (repetitive ritualistic behaviours) leading to functional impairment. Accumulating evidence links these conditions with underlying dysregulation of fronto-striatal circuitry and monoamine systems. These abnormalities represent key targets for existing and novel treatment interventions. However, the brain bases of these conditions and treatment mechanisms are still not fully elucidated. Animal models simulating the behavioural and clinical manifestations of the disorder show great potential for augmenting our understanding of the pathophysiology and treatment of OCD. This paper provides an overview of what is known about OCD from several perspectives. We begin by describing the clinical features of OCD and the criteria used to assess the validity of animal models of symptomatology; namely, face validity (phenomenological similarity between inducing conditions and specific symptoms of the human phenomenon), predictive validity (similarity in response to treatment) and construct validity (similarity in underlying physiological or psychological mechanisms). We then survey animal models of OC spectrum conditions within this framework, focusing on (i) ethological models; (ii) genetic and pharmacological models; and (iii) neurobehavioural models. We also discuss their advantages and shortcomings in relation to their capacity to identify potentially efficacious new compounds. It is of interest that there has been rather little evidence of 'false alarms' for therapeutic drug effects in OCD models which actually fail in the clinic. While it is more difficult to model obsessive cognition than compulsive behaviour in experimental animals, it is feasible to infer cognitive inflexibility in certain animal paradigms. Finally, key future neurobiological and treatment research areas are highlighted.
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Affiliation(s)
- N A Fineberg
- National OCDs Treatment Service, Hertfordshire Partnership NHS Foundation Trust, Welwyn Garden City, UK.
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Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats. Psychopharmacology (Berl) 2011; 217:301-13. [PMID: 21503609 DOI: 10.1007/s00213-011-2280-x] [Citation(s) in RCA: 123] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Accepted: 03/23/2011] [Indexed: 12/16/2022]
Abstract
RATIONALE AND OBJECTIVES The rat model of prenatal restraint stress (PRS) replicates factors that are implicated in the etiology of anxious/depressive disorders. We used this model to test the therapeutic efficacy of agomelatine, a novel antidepressant that behaves as a mixed MT1/MT2 melatonin receptor agonist/5-HT(2c) serotonin receptor antagonist. RESULTS Adult PRS rats showed behavioral, cellular, and biochemical abnormalities that were consistent with an anxious/depressive phenotype. These included an increased immobility in the forced swim test, an anxiety-like behavior in the elevated plus maze, reduced hippocampal levels of phosphorylated cAMP-responsive element binding protein (p-CREB), reduced hippocampal levels of mGlu2/3 and mGlu5 metabotropic glutamate receptors, and reduced neurogenesis in the ventral hippocampus, the specific portion of the hippocampus that encodes memories related to stress and emotions. All of these changes were reversed by a 3- or 6-week treatment with agomelatine (40-50 mg/kg, i.p., once a day). Remarkably, agomelatine had no effect in age-matched control rats, thereby behaving as a "disease-dependent" drug. CONCLUSIONS These data indicate that agomelatine did not act on individual symptoms but corrected all aspects of the pathological epigenetic programming triggered by PRS. Our findings strongly support the antidepressant activity of agomelatine and suggest that the drug impacts mechanisms that lie at the core of anxious/depressive disorders.
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Fornaro M. Switching from serotonin reuptake inhibitors to agomelatine in patients with refractory obsessive-compulsive disorder: a 3 month follow-up case series. Ann Gen Psychiatry 2011; 10:5. [PMID: 21356085 PMCID: PMC3058071 DOI: 10.1186/1744-859x-10-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Accepted: 02/28/2011] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Serotonin reuptake inhibitors (SRIs) currently represent the cornerstone of obsessive-compulsive disorder (OCD) pharmacotherapy. However, OCD is characterized by high rates of partial and/or absent response to standard, recommended treatments, often prompting pharmacological and non-pharmacological augmentation or switching of strategies. Agomelatine, a novel melatonin agonist and selective serotonin antagonist (MASSA) antidepressant approved for major depressive disorder (MDD) has recently been additionally proposed as a treatment for anxiety disorders such as social anxiety disorder (SAD) and panic disorder (PD), but not yet OCD. Nonetheless, agomelatine may have a role in the management of OCD, essentially due to its anxiolytic 5-hydroxytryptamine (HT)2C blockade action, while melatonin (MT)1 and MT2 modulation might contribute to circadian rhythm restoration if impaired. METHODS This case series reports the outcome of six patients with or without comorbid mood and/or other anxiety disorders who were treated with SRIs at adequate doses for at least 8 weeks, showing partial or no response. Patients were then switched to agomelatine 50 mg/day, and followed up for 12 weeks. RESULTS Three out of six patients, in particular those with relevant circadian rhythm subjective impairment, showed a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score reduction of ≥35%. No relevant side effects were observed, but initial, transient, self-remitting dizziness in one patient and weight gain in another were seen. CONCLUSIONS Although clinical confounding factors (subthreshold bipolarity and eventually the presence of impaired circadian rhythms) and methodological boundaries (lack of control and neurophysiological recording, tiny sample size and short follow-up) limit the validity of this preliminary observation, it does indicate agomelatine may have a role in some SRI-refractory OCD cases, thus prompting the validity of investigation by further controlled studies, even for drug-naïve OCD patients.
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Affiliation(s)
- Michele Fornaro
- University of Genova, Department of Psychiatry, Genoa, Italy.
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