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1.
Med Hypotheses ; 146: 110468, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33385878

RESUMO

Currently, no single medication has been approved for the management of coronavirus disease-2019 (COVID-19) caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, drug repositioningby investigating the use of existing drugs for management of COVID-19 patients is considered a desperate need. Tramadol is a commonly prescribed analgesic drug for treatment of moderate to severe pain with less potential for dependence and respiratory depression. Multiple evidence support that tramadol is a promising drug for treatment of COVID-19 patients. Herein, we discuss the possible beneficial effects of using tramadol against SARS-CoV-2 infection and their underlying mechanism of action. The anti-inflammatory effect of tramadol may help to suppress the COVID-19 related cytokine storm through decreasing interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Besides, tramadol activates natural killer (NK) and T-cells and enhances IL-2 secretion, which produce immune-enhancing effect against SARS-CoV-2. Recent studies confirmed that COVID-19 patients with acute respiratory failure showed increased fibrin formation and polymerization that may lead to thrombosis. Tramadol owing to its hypocoagulable effect may protect against venous thromboembolism in these patients. Moreover, tramadol can exert a cardioprotective effect via decreasing lactate dehydrogenase (LDH) level which is elevated in most of patients with COVID-19. Furthermore, the severity and mortality of COVID-19 have been correlated with old age patients, which may be due to the lack of antioxidant mechanisms and increased oxidative damage. Tramadol could protect COVID-19 patient from disease complications by increases the antioxidant enzymes superoxide dismutase and glutathione peroxidase while diminished malondialdehyde. More interestingly, tramadol as an effective analgesic and antitussive may have a beneficial effect on COVID-19 patients suffering from cough, headache, ache, and pain. The tramadol anti-psychotic effect may also protect against psychiatric disorders associated with SARS-CoV-2 infection. Moreover, tramadol has bactericidal activity against a wide range of pathogens including Pseudomonas aeruginosa which is common in severe COVID-19 patients leading to pneumonia with worse clinical outcomes. Therefore, we hypothesize that tramadol might be a promising adjuvant therapeutic option against SARS-CoV-2 infection. Based on that, tramadol should be considered as adjuvant therapy for COVID-19 clinical trials.


Assuntos
/tratamento farmacológico , Tramadol/farmacologia , Analgésicos Opioides/farmacologia , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Antidepressivos/farmacologia , Antioxidantes/farmacologia , /fisiopatologia , Reposicionamento de Medicamentos , Humanos , Fatores Imunológicos/farmacologia , Modelos Biológicos , Pandemias
2.
Phytomedicine ; 81: 153436, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33360346

RESUMO

BACKGROUND: Depression is a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history, although its efficacy and potential mechanism are still uncertain. PURPOSE: The present study aimed to investigate anti-depression effect and potential mechanism of U. rhynchophylla extract (URE). STUDY DESIGN AND METHODS: A mouse depression model was established using unpredictable chronic mild stress (UCMS). Effects of URE on depression-like behaviours, neurotransmitters, and neuroendocrine hormones were investigated in UCMS-induced mice. The potential target of URE was analyzed by transcriptomics and bioinformatics methods and validated by RT-PCR and Western blot. The agonistic effect on 5-HT1A receptor was assayed by dual-luciferase reporter system. RESULTS: URE ameliorated depression-like behaviours, and modulated levels of neurotransmitters and neuroendocrine hormones, including 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH), in UCMS-induced mice. Transcriptomics and bioinformatics results indicated that URE could regulate glutamatergic, cholinergic, serotonergic, and GABAergic systems, especially neuroactive ligand-receptor and cAMP signaling pathways, revealing that Htr1a encoding 5-HT1A receptor was a potential target of URE. The expression levels of downstream proteins of 5-HT1A signaling pathway 5-HT1A, CREB, BDNF, and PKA were increased in UCMS-induced mice after URE administration, and URE also displayed an agonistic effect against 5-HT1A receptor with an EC50 value of 17.42 µg/ml. CONCLUSION: U. rhynchophylla ameliorated depression-like behaviours in UCMS-induced mice through activating 5-HT1A receptor.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Uncaria/química , Hormônio Adrenocorticotrópico/sangue , Animais , Antidepressivos/química , Biologia Computacional , Corticosterona/sangue , Hormônio Liberador da Corticotropina/sangue , Depressão/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Extratos Vegetais/farmacologia , Receptor 5-HT1A de Serotonina , Serotonina/metabolismo , Estresse Psicológico
3.
J Ethnopharmacol ; 266: 113283, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32827659

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Zhi-zi-chi decoction (ZZCD) is used for treating depression as an effectively traditional Chinese medicine. Until now, studies on pharmacological research of ZZCD have mostly been centered in pharmacokinetic level. Little was known about its pharmacological mechanism of relieving depression. AIM OF THE STUDY: This study was to evaluate the effect of ZZCD on relieving depression via behavioral tests, serum metabolomics and signaling target expression analysis on chronic unpredictable mild stress (CUMS) model mice. MATERIALS AND METHODS: The CUMS exposure lasted 7 consecutive weeks. The mice were administrated with ZZCD for the last 3 weeks. Behavioral tests were applied and a serum metabolomics method based on UFLC/Q-TOF-MS with multivariate statistical and global metabolic network analysis was performed to identify relevant metabolites and pathways. Finally, the protein expressions in mouse hippocampi were determined by western blot to verify the metabolomics deduction. RESULTS: Behavioral parameters were visibly changed after modeling, while high and medium dosage groups showed status improvement compared to the model group. Seventy six metabolites were identified as potential biomarkers from the metabolomics profiles in C18 and HILIC systems. In addition, 9 significant pathways related to changed biomarkers were conducted. The pathways were closely connected by some key targets, which were significantly reduced in the model group compared with those in control group, while ZZCD treated groups showed corrections after 3-week administration. The results revealed that the anti-depression efficacy of ZZCD might be associated with PKA-CREB-BDNF-TrkB-PSD-95 pathway influenced by metabolic changes, verifying the pathway annotation speculation. CONCLUSION: This study demonstrated that ZZCD had a positive treatment effect on CUMS depression model mice. Metabolomics results revealed the holistic and interconnected metabolic changes of ZZCD in CUMS mice. The metabolic pathway annotation suggested that the anti-depression mechanism of ZZCD might be related to signaling pathway in brain. PKA-CREB-BDNF-TrkB-PSD-95 signaling expression was a verification and complement to the metabolomics results.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Estresse Psicológico/tratamento farmacológico , Animais , Antidepressivos/isolamento & purificação , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Masculino , Medicina Tradicional Chinesa , Metabolômica , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos
4.
J Ethnopharmacol ; 265: 113317, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32861821

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Polygalae (RP) has been traditionally used for the treatment of various psychiatric disorders in East Asia. AIM OF THE STUDY: Depression is a severe mental disease with high prevalence in people, and neurobiology changes of depression are not fully clarified yet. The present study aimed to investigate the antidepressant effect and underlying mechanism of RP in behavioral despair mice and chronic restraint stress (CRS)-induced rats. MATERIALS AND METHODS: ICR mice were treated with various doses of RP (0.13-1.0 g/kg) for 14 days and then subjected to forced swimming test (FST). Wistar rats were exposed to 6-hour restraint stress daily for 28 days, and RP (0.5 and 1 g/kg) was administered by gavage 1 h prior to CRS procedure. Subsequently, behavioral tests were performed and brains were collected for biochemical analysis. RESULTS: RP reduced immobility time of mice in FST and reversed abnormal behaviors of rats induced by CRS in sucrose preference test, novelty-suppressed feeding test, open field test and FST. Moreover, RP could enhance the expression of LC3-II and beclin1 and decrease the level of p62 both in cortex of mice and prefrontal cortex (PFC) of rats, and regulate the dysfunction of AMPK-mTOR pathway in PFC of CRS rats. Activated microglia, impaired astrocyte, elevated protein expression of NLRP3, ASC and caspase-1, and increased mRNA levels of proinflammatory cytokines were observed in PFC of CRS rats, all of which were corrected by RP treatment. CONCLUSION: RP exerted remarkable antidepressant activity in behavioral despair mice and CRS-induced rats, probably by promoting autophagy and inhibiting neuroinflammation.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Estresse Psicológico/tratamento farmacológico , Animais , Antidepressivos/administração & dosagem , Autofagia/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ratos , Ratos Wistar , Restrição Física , Natação
5.
J Ethnopharmacol ; 265: 113316, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32866569

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Calea zacatechichi is a plant with an extensive popular and ritual use in Mexico. In healthy volunteers, it induces well-being and tranquility senses, and facilitates superficial stages of sleep. However, anxiolytic, and antidepressant-like effects and changes on the sleep-waking stages have not been explored. AIM: To determine anxiolytic and antidepressant-like effects of an aqueous extract of C. zacatechichi (CZ) in rodents and to analyze their effects on hippocampal activity in the rat sleep-waking cycle. MATERIAL AND METHODS: CZ anxiolytic- and antidepressant-like effects were evaluated in several mice and rat behavioral paradigms. CZ effects on temporal distribution of sleep were described, and hippocampus EEG frequency patterns were analyzed during the sleep-waking cycle; absolute and relative powers were analyzed during Rapid Eye Movements (REM) and non-REM sleep stages. CZ chemical analysis was performed by UPLC-ESI-MS. RESULTS: CZ produced specific and robust anxiolytic- and antidepressant-like effects in mice and rats, similar to those of prototypical drugs, at doses ranging from 0.5 to 50 mg/kg. CZ at 100 mg/kg produced visible mild sedative effects in rats, associated with a significant increase in Slow Wave Sleep episodes during a 6 h recording, and enhanced fast frequencies of hippocampus (gamma-band:31-50 Hz) during REM sleep. CONCLUSION: Results could support the well-being and tranquility senses reported by healthy consumers, and to explain the oneiric content during dreams and some improvements in cognitive processes described by consumers. Anxiolytic- and antidepressant-like effects of this species, reported for first time in this study could improve some aspects of mental health.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Asteraceae/química , Extratos Vegetais/farmacologia , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/isolamento & purificação , Antidepressivos/administração & dosagem , Antidepressivos/isolamento & purificação , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , México , Camundongos , Extratos Vegetais/administração & dosagem , Ratos , Ratos Wistar , Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacos
6.
Psychiatr Danub ; 32(3-4): 325-333, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33370729

RESUMO

Major depressive disorder is the greatest burden of developed countries in the context of morbidity caused by mental disorders. Until recent, ketamine has been mostly used for anesthesia, analgesia, sedation and treatment of chronic pain syndromes. However, unique pharmacodynamic properties of ketamine have increased interests in it's use for treatment of depression. It is assumed that ketamine reverses synaptic chronic stress pathology within one day of administration by postsynaptic glutamate activation, providing synaptic connectivity restoration that last for days or weeks. Potential glutamatergic agents, in context of treatment of major depressive disorder are not entirely novel phenomenon. Considering the aforementioned, current neurobiological view of depression as a solely monoaminergic phenomenon should be reassessed in order to prompt discovery of putative antidepressant drugs of novel generation. Acute side effects, such as increased salivation, increase in heart rate, systemic arterial pressure and intracranial pressure necessitate careful monitoring during intravenous administration of ketamine, even in subanesthetic doses. However, major burden of ketamine administration lies in it's ability to produce psychotomimetic side effects and emergence delirium. Esketamine nasal spray has now been widely approved and is considered safe in terms of acute side effects, tolerability and consistent therapeutic benefit.


Assuntos
Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Ketamina/farmacologia , Ketamina/uso terapêutico , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Interações Medicamentosas , Epigênese Genética/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Humanos , Ketamina/efeitos adversos , Ketamina/química
7.
Braz J Med Biol Res ; 54(2): e10107, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33331415

RESUMO

Ketamine (KET) is an N-methyl-D-aspartate (NMDA) antagonist with rapid and long-lasting antidepressant effects, but how the drug shows its sustained effects is still a matter of controversy. The objectives were to evaluate the mechanisms for KET rapid (30 min) and long-lasting (15 and 30 days after) antidepressant effects in mice. A single dose of KET (2, 5, or 10 mg/kg, po) was administered to male Swiss mice and the forced swim test (FST) was performed 30 min, 15, or 30 days later. Imipramine (IMI, 30 mg/kg, ip), a tricyclic antidepressant drug, was used as reference. The mice were euthanized, separated into two time-point groups (D1, first day after KET injection; D30, 30 days later), and brain sections were processed for glycogen synthase kinase-3 (GSK-3), histone deacetylase (HDAC), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) immunohistochemical assays. KET (5 and 10 mg/kg) presented rapid and long-lasting antidepressant-like effects. As expected, the immunoreactivities for brain GSK-3 and HDAC decreased compared to control groups in all areas (striatum, DG, CA1, CA3, and mainly pre-frontal cortex, PFC) after KET injection. Increases in BDNF immunostaining were demonstrated in the PFC, DG, CA1, and CA3 areas at D1 and D30 time-points. GFAP immunoreactivity was also increased in the PFC and striatum at both time-points. In conclusion, KET changed brain BDNF and GFAP expressions 30 days after a single administration. Although neuroplasticity could be involved in the observed effects of KET, more studies are needed to explain the mechanisms for the drug's sustained antidepressant-like effects.


Assuntos
Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Ketamina , Animais , Astrócitos , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida , Quinase 3 da Glicogênio Sintase , Histona Desacetilases , Ketamina/farmacologia , Masculino , Camundongos
8.
Nihon Yakurigaku Zasshi ; 155(6): 381-385, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132254

RESUMO

Conventional monoaminergic antidepressants have significant limitations, including delayed onset of therapeutic response and relatively low efficacy. Recent studies reveal that the NMDA receptor antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant depressed patients. Despite the unique antidepressant efficacy, clinical use of ketamine as an antidepressant is limited due to its serious drawbacks, such as abuse potential and psychotomimetic/dissociative effects. The molecular and neuronal mechanisms underlying the antidepressant actions of ketamine have been intensively studied to pave the way for the development of novel, rapid and more efficacious antidepressants with fewer side effects than ketamine. Preclinical studies demonstrate that ketamine produces antidepressant effects through rapid release and/or expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and stimulation of mechanistic target of rapamycin complex 1 (mTORC1) signaling in the medial prefrontal cortex and hippocampus. We have recently found that resolvins (RvD1, RvD2, RvE1, RvE2 and RvE3), bioactive metabolites derived from docosahexaenoic acid and eicosapentaenoic acid, produce antidepressant effects, and that the antidepressant effects of RvD1, RvD2 and RvE1 require mTORC1 activation. These findings suggest that resolvins could be promising targets for the development of novel rapid antidepressants with fewer side effects than ketamine because they are endogenous lipid mediators that play an important role in homeostasis.


Assuntos
Ketamina , Fator A de Crescimento do Endotélio Vascular , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Ketamina/farmacologia , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato
10.
Emerg Microbes Infect ; 9(1): 2245-2255, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32975484

RESUMO

The Coronavirus Disease 2019 (COVID-19) pandemic caused by the Severe Acute Respiratory Syndrome Related Coronavirus 2 (SARS-CoV-2) is a global health emergency. As only very limited therapeutic options are clinically available, there is an urgent need for the rapid development of safe, effective, and globally available pharmaceuticals that inhibit SARS-CoV-2 entry and ameliorate COVID-19 severity. In this study, we explored the use of small compounds acting on the homeostasis of the endolysosomal host-pathogen interface, to fight SARS-CoV-2 infection. We find that fluoxetine, a widely used antidepressant and a functional inhibitor of acid sphingomyelinase (FIASMA), efficiently inhibited the entry and propagation of SARS-CoV-2 in the cell culture model without cytotoxic effects and also exerted potent antiviral activity against two currently circulating influenza A virus subtypes, an effect which was also observed upon treatment with the FIASMAs amiodarone and imipramine. Mechanistically, fluoxetine induced both impaired endolysosomal acidification and the accumulation of cholesterol within the endosomes. As the FIASMA group consists of a large number of small compounds that are well-tolerated and widely used for a broad range of clinical applications, exploring these licensed pharmaceuticals may offer a variety of promising antivirals for host-directed therapy to counteract enveloped viruses, including SARS-CoV-2.


Assuntos
Antidepressivos/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/virologia , Inibidores Enzimáticos/farmacologia , Fluoxetina/farmacologia , Pneumonia Viral/virologia , Betacoronavirus/fisiologia , Linhagem Celular , Endossomos/virologia , Humanos , Pandemias , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos
11.
PLoS One ; 15(8): e0237950, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853222

RESUMO

BACKGROUND: The observation that some patients appear to respond better to antidepressants for depression than others encourages the assumption that the effect of antidepressants differs between individuals and that treatment can be personalized. OBJECTIVE: To compare the outcome variance in patients receiving antidepressants with the outcome variance in patients receiving placebo in randomized controlled trials (RCTs) of adults with major depressive disorder (MDD) and to illustrate, using simulated data, components of variation of RCTs. METHODS: From a dataset comprising 522 RCTs of antidepressants for adult MDD, we selected the placebo-controlled RCTs reporting outcomes on the 17 or 21 item Hamilton Depression Rating Scale or the Montgomery-Asberg Depression Rating Scale and extracted the means and SDs of raw endpoint scores or baseline to endpoint changes scores on eligible depression symptom rating scales. We conducted inverse variance random-effects meta-analysis with the variability ratio (VR), the ratio between the outcome variance in the group of patients receiving antidepressants and the outcome variance in the group receiving placebo, as the primary outcome. An increased variance in the antidepressant group would indicate individual differences in response to antidepressants. RESULTS: We analysed 222 RCTs that investigated 19 different antidepressants compared with placebo in 345 comparisons, comprising a total of 61144 adults with an MDD diagnosis. Across all comparisons, the VR for raw endpoint scores was 0.98 (95% CI 0.96 to 1.00, I2 = 0%) and 1.00 (95% CI 0.99 to 1.02, I2 = 0%) for baseline-to-endpoint change scores. CONCLUSION: Based on these data, we cannot reject the null hypothesis of equal variances in the antidepressant group and the placebo group. Given that RCTs cannot provide direct evidence for individual treatment effects, it may be most reasonable to assume that the average effect of antidepressants applies also to the individual patient.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Antidepressivos/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
12.
PLoS One ; 15(8): e0237196, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764777

RESUMO

Current antidepressant therapy has several disadvantages related to the properties of antidepressants. Considering their unfavourable features, the process of searching for new antidepressant drugs with better safety and tolerability requires consistent efforts and many complementary studies. Serotonin 5-HT1A receptor is considered as an interesting target of antidepressant therapy. In the present study, the intrinsic activity at different signaling pathways coupled to serotonin 5-HT1A receptor, antidepressant-like and pharmacokinetic properties, and the safety profile of two novel imidazopurine-2,4-dione derivatives, namely compounds AZ-853 (8-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-1,3-dimethyl-1H- imidazo[2,1-f]purine-2,4(3H,8H)-dione) and AZ-861 (1,3-dimethyl-8-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), were studied in animal models through in vitro and in vivo experiments. We demonstrated that AZ-853 and AZ-861, which structurally differ by one substituent and its placement in the phenyl ring, showed varied functional, pharmacological, and pharmacokinetic properties as well as side effect profiles. AZ-861 exhibited stronger agonistic action in all functional assays. After acute and repeated administration in mice, both compounds showed antidepressant-like activity in the forced swim test, which was partially mediated by 5-HT1A receptor activation. AZ-853 showed a more potent antidepressant-like effect, presumably due to its better penetration into brain structures. Both compounds did not show anticholinergic properties, but after repeated administration, they induced weak sedation and lipid metabolism disturbances without affecting serum glucose level. The stronger α1-adrenolytic effect of AZ-853 is responsible for decreased systolic blood pressure, and in contrast to AZ-861, AZ-853 induced weight gain in mice. The interesting comparative pharmacological profiles of AZ-853 and AZ-861 encourage to conduct further experiments to fully understand their mechanisms and differences in action.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Animais , Antidepressivos/química , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Depressão/diagnóstico , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Piperazinas/química , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Agonistas do Receptor 5-HT1 de Serotonina/química , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Relação Estrutura-Atividade , Ganho de Peso/efeitos dos fármacos
13.
Artigo em Russo | MEDLINE | ID: mdl-32790975

RESUMO

OBJECTIVE: To study the use of combination therapy for post-stroke depression using antidepressants and antioxidants. MATERIAL AND METHODS: The dynamics of the clinical status of post-stroke depression and parameters of oxidative stress were evaluated in 60 patients with post-stroke depression before and after a 3-month treatment with fluvoxamine in a daily dose of 100 mg per day and cytoflavin in a dose of 10 ml/day (200 ml of 5% glucose solution or physiological saline in patients with diabetes mellitus) intravenously in the morning for 10 days followed by transfer to tablet form (2 tabs in the morning and 2 tabs in the evening for 90 days). RESULTS AND CONCLUSION: The results on the comparative effectiveness of the treatment of post-stroke depression with fluvoxamine monotherapy and the combination of fluvoxamine and cytoflavin confirmed the great effectiveness of the combination therapy, which should be taken into account when developing new treatment regimens for post-stroke depression, and the need for prescribing antidepressants and antioxidant drugs should be determined based on an individual assessment of the severity of depressive disorder and parameters of oxidative stress: endogenous antioxidant activities in each individual patient with ischemic stroke.


Assuntos
Depressão , Acidente Vascular Cerebral , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Humanos , Estresse Oxidativo/efeitos dos fármacos
14.
Mol Pharmacol ; 98(3): 203-210, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32606205

RESUMO

Ketamine, a dissociative anesthetic, is experiencing a clinical resurgence as a fast-acting antidepressant. In the central nervous system, ketamine acts primarily by blocking NMDA receptor currents. Although it is generally safe in a clinical setting, it can be addictive, and several of its derivatives are being investigated as preferable alternatives. 2R,6R-Hydroxynorketamine (HNK), a ketamine metabolite, reproduces some of the therapeutic effects of ketamine and appears to lack abuse liability. Here, we report a systematic investigation of the effects of HNK on macroscopic responses elicited from recombinant NMDA receptors expressed in human embryonic kidney 293 cells. We found that, like ketamine, HNK reduced NMDA receptor currents in a dose-, pH-, and voltage-dependent manner. Relative to ketamine, it had 100-fold-lower potency (46 µM at pH 7.2), 10-fold-slower inhibition onset, slower apparent dissociation rate, weaker voltage dependence, and complete competition by magnesium. Notably, HNK inhibition was fully effective when applied to resting receptors. These results revealed unexpected properties of hydroxynorketamine that warrant its further investigation as a possible therapeutic in pathologies associated with NMDA receptor dysfunction. SIGNIFICANCE STATEMENT: NMDA receptors are excitatory ion channels with fundamental roles in synaptic transmission and plasticity, and their dysfunction associates with severe neuropsychiatric disorders. 2R,6R-Hydroxynorketamine, a metabolite of ketamine, mimics some of the neuroactive properties of ketamine and may lack its abuse liability. Results show that 2R,6R-hydroxynorketamine blocks NMDA receptor currents with low affinity and weak voltage dependence and is effective when applied to resting receptors. These properties highlight its effectiveness to a subset of NMDA receptor responses and recommend it for further investigation.


Assuntos
Antidepressivos/farmacologia , Cicloexanos/farmacologia , Ketamina/análogos & derivados , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Antidepressivos/química , Cicloexanos/química , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Ratos , Proteínas Recombinantes/metabolismo , Transmissão Sináptica/efeitos dos fármacos
15.
PLoS Med ; 17(7): e1003215, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32697803

RESUMO

BACKGROUND: The use of antidepressants in children and adolescents remains controversial. We examined trends over time and variation in antidepressant prescribing in children and young people in England and whether the drugs prescribed reflected UK licensing and guidelines. METHODS AND FINDINGS: QResearch is a primary care database containing anonymised healthcare records of over 32 million patients from more than 1,500 general practices across the UK. All eligible children and young people aged 5-17 years in 1998-2017 from QResearch were included. Incidence and prevalence rates of antidepressant prescriptions in each year were calculated overall, for 4 antidepressant classes (selective serotonin reuptake inhibitors [SSRIs], tricyclic and related antidepressants [TCAs], serotonin and norepinephrine reuptake inhibitors [SNRIs], and other antidepressants), and for individual drugs. Adjusted trends over time and differences by social deprivation, region, and ethnicity were examined using Poisson regression, taking clustering within general practitioner (GP) practices into account using multilevel modelling. Of the 4.3 million children and young people in the cohort, 49,434 (1.1%) were prescribed antidepressants for the first time during 20 million years of follow-up. Males made up 52.0% of the cohorts, but only 34.1% of those who were first prescribed an antidepressant in the study period. The largest proportion of the cohort was from London (24.4%), and whilst ethnicity information was missing for 39.5% of the cohort, of those with known ethnicity, 75.3% were White. Overall, SSRIs (62.6%) were the most commonly prescribed first antidepressant, followed by TCAs (35.7%). Incident antidepressant prescribing decreased in 5- to 11-year-olds from a peak of 0.9 in females and 1.6 in males in 1999 to less than 0.2 per 1,000 for both sexes in 2017, but incidence rates more than doubled in 12- to 17-year-olds between 2005 and 2017 to 9.7 (females) and 4.2 (males) per 1,000 person-years. The lowest prescription incidence rates were in London, and the highest were in the South East of England (excluding London) for all sex and age groups. Those living in more deprived areas were more likely to be prescribed antidepressants after adjusting for region. The strongest trend was seen in 12- to 17-year-old females (adjusted incidence rate ratio [aIRR] 1.12, 95% confidence interval [95% CI] 1.11-1.13, p < 0.001, per deprivation quintile increase). Prescribing rates were highest in White and lowest in Black adolescents (aIRR 0.32, 95% CI 0.29-0.36, p < 0.001 [females]; aIRR 0.32, 95% CI 0.27-0.38, p < 0.001 [males]). The 5 most commonly prescribed antidepressants were either licensed in the UK for use in children and young people (CYP) or included in national guidelines. Limitations of the study are that, because we did not have access to secondary care prescribing information, we may be underestimating the prevalence and misidentifying the first antidepressant prescription. We could not assess whether antidepressants were dispensed or taken. CONCLUSIONS: Our analysis provides evidence of a continuing rise of antidepressant prescribing in adolescents aged 12-17 years since 2005, driven by SSRI prescriptions, but a decrease in children aged 5-11 years. The variation in prescribing by deprivation, region, and ethnicity could represent inequities. Future research should examine whether prescribing trends and variation are due to true differences in need and risk factors, access to diagnosis or treatment, prescribing behaviour, or young people's help-seeking behaviour.


Assuntos
Antidepressivos/uso terapêutico , Prescrições de Medicamentos/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Adolescente , Antidepressivos/farmacologia , Criança , Pré-Escolar , Estudos de Coortes , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/epidemiologia , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Masculino , Prevalência , Inibidores de Captação de Serotonina/uso terapêutico
16.
Adv Pharmacol ; 89: 103-129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616204

RESUMO

Depression represents one of the most common and debilitating mental illnesses in the world today. Despite this pressing issue, the majority treatments for depression give patients therapeutic response only approximately half of the time, with many not responding at all. In part, this stagnation has been due to the dominance of the monoamine hypothesis that guides the current approach to understanding and treating depression. While therapies that increase levels of monoamines have been useful, clearly a more complete understanding of the neural circuits and treatments is needed to better help patients. Recent work that exploits the glutamatergic system within the brain has demonstrated a functional role for glutamate in combatting depression. While more research is required to understand the specific glutamatergic pathophysiological mechanisms within depression, emerging clinical work has already demonstrated promising results. Current treatments that target the glutamatergic system, especially NMDA receptor antagonists have already shown efficacy in several clinical trials. In this chapter we briefly introduce a mechanistic basis for a role of glutamate in the pathophysiology of depression. We further review basic and translational studies that describes potential mechanisms and roles for glutamate. A discussion of the first promising NMDA receptor antagonist for depression, ketamine, follows afterward. The development of NMDA receptor antagonists for treatment of depression is chronicled, from initial studies up through the recent FDA approval of intranasal esketamine as well as other newer compounds that have shown recent promise in clinical trials.


Assuntos
Padrões de Prática Médica , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Ácido Glutâmico/uso terapêutico , Humanos , Ketamina/uso terapêutico , Receptores de N-Metil-D-Aspartato/metabolismo
17.
Adv Pharmacol ; 89: 163-194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616206

RESUMO

A paradigm shift in the conceptualization of the neurobiology of depression and the serendipitous discovery of ketamine's rapid-acting antidepressant (RAAD) effects has ushered in a new era of innovative research and novel drug development. Since the initial discovery of ketamine's RAAD effects, multiple studies have supported its short-term efficacy for fast-tracked improvements in treatment-resistant depression. Evidence from MRI studies have repeatedly demonstrated functional connectivity alterations in stress- and trauma-related disorders suggesting this may be a viable biomarker of chronic stress pathology (CSP). Human mechanistic studies further support this by coupling functional connectivity to ketamine's RAAD effects including connectivity to glutamate neurotransmission, ketamine to normalized connectivity, and these advantageous normalizations to symptom improvement/ketamine response. This review provides an abridged discussion of the suspected neurobiological underpinnings of ketamine's RAAD effects, highlighting ketamine-induced alterations in prefrontal, striatal, and anterior cingulate cortex functional connectivity in major depressive disorder. We present a model of CSP underscoring the role of synaptic loss and dysconnectivity and discuss how ketamine may be used both as (1) a treatment to restore and normalize these stress-induced neural alterations and (2) a tool to study potential biomarkers of CSP and treatment response. We conclude by noting challenges and future directions including heterogeneity, sex differences, the role of early life stress, and the need for proliferation of new methods, paradigms, and tools that will optimize signal and allow analyses at different levels of complexity, according to the needs of the question at hand, perhaps by thinking hierarchically about both clinical and biological phenotypes.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Ketamina/uso terapêutico , Rede Nervosa/fisiopatologia , Estresse Psicológico/fisiopatologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Doença Crônica , Humanos , Ketamina/farmacologia
18.
Adv Pharmacol ; 89: 237-259, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616208

RESUMO

Major depressive disorder (MDD) is the leading cause of disability worldwide and reduces life expectancy. Achieving and sustaining remission from depression is challenging after initial improvement of an acute episode with an antidepressant, especially for patients whose depressive episodes have proven treatment-resistant in response to conventional antidepressant pharmacotherapy. While standard antidepressants are at least partly effective for the short-term treatment of acute depressive episodes of MDD, many patients relapse within 6 months of apparent clinical remission, with faster and higher rates observed in those with treatment-resistant depression (TRD). Efficacy of IV ketamine, a rapid-acting N-methyl d-aspartate (NMDA) receptor antagonist, in maintaining antidepressant effect was suggested in a few small, single center, open-label studies and case series. More recently, maintenance of antidepressant effects beyond the initial acute (induction) treatment period has been shown with esketamine nasal spray, an enantiomer of ketamine, in conjunction with an oral antidepressant in three phase 2/3 registration studies (SYNAPSE, SUSTAIN-1, SUSTAIN-2) of adult patients with TRD. In these studies the maintenance of efficacy of an intermittently-dosed esketamine treatment regimen was established in which twice-weekly dose administration during a 4-week induction period was followed initially by weekly administration and later by either weekly or every-other-week administration. During long-term maintenance therapy the antidepressant effect persisted in most patients with this regimen, despite their history of being resistant to conventional antidepressants prior to entering esketamine studies. These data suggest that the neurobiological changes induced by initial esketamine treatment, which putatively underlie its antidepressant effect, can be maintained using repeated administration.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Prevenção Secundária , Antidepressivos/farmacologia , Ensaios Clínicos como Assunto , Humanos , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Ketamina/uso terapêutico
19.
Adv Pharmacol ; 89: 261-286, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616209

RESUMO

A serious lack of effective pharmacotherapeutic interventions for posttraumatic stress disorder (PTSD) raises the urgent need for the development of novel treatments. Ketamine-a noncompetitive glutamate N-methyl-d-aspartate (NMDA) receptor antagonist in use for decades as an anesthetic and analgesic agent-has more recently been demonstrated to have rapid-onset antidepressant effects in patients with treatment-resistant depression (TRD). In the present review of ketamine as an emerging novel pharmacotherapeutic intervention for chronic PTSD, we discuss findings from the first proof-of-concept, randomized clinical trial (RCT) of single-dose intravenous ketamine in patients with chronic PTSD, as well as open-label studies and current practice. We introduce ongoing RCTs investigating the efficacy of repeated ketamine infusions in rapidly reducing symptoms and maintaining improvement in samples of individuals with PTSD stemming from civilian and military traumas. Additionally, we discuss mixed findings from published reports on ketamine administration in the acute aftermath of trauma. Studies in animal models of chronic stress have investigated molecular mechanisms underlying ketamine's effects, generating a shift in the conceptualization of PTSD as a disorder of impaired neural connectivity. We review animal studies examining the potential of ketamine to modify the expression of fear by altering memory reconsolidation or enhancing fear extinction, as well as others investigating ketamine administration prophylactically prior to stress exposure. We introduce the need for additional study in humans to evaluate whether ketamine might enhance the efficacy of psychotherapeutic interventions in individuals with chronic PTSD, harnessing a window of ketamine-induced neuroplasticity. While research on ketamine for PTSD is still in its early stages, it brings about the promise of novel and more effective treatments for this disabling condition.


Assuntos
Ketamina/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Modelos Animais de Doenças , Humanos , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Ketamina/farmacologia , Padrões de Prática Médica , Ensaios Clínicos Controlados Aleatórios como Assunto , Transtornos de Estresse Pós-Traumáticos/terapia
20.
Adv Pharmacol ; 89: 289-309, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616210

RESUMO

Given that ketamine, a noncompetitive N-methyl-d-aspartate receptor antagonist that exerts rapid antidepressant effects in patients with treatment-resistant depression, also has undesirable adverse effects, agents that can be used as alternatives to ketamine have been actively pursued. Group II metabotropic glutamate (mGlu) receptors, consisting of mGlu2 and mGlu3 receptors, have emerged as one of the most promising targets in the development of ketamine-like antidepressants. Indeed, mGlu2/3 receptor antagonists have been demonstrated to exert rapid antidepressant effects in animal models and to be efficacious in animal models refractory to conventional antidepressants. Moreover, there are striking similarities between mGlu2/3 receptor antagonists and ketamine in terms of not only their antidepressant profiles, but also the underlying mechanisms of their antidepressant effects. Nonetheless, studies in rodents have shown that mGlu2/3 receptor antagonists do not cause ketamine-like adverse events, such as psychotomimetic-like behavior, abuse potential or neurotoxicity, supporting the usefulness of mGlu2/3 receptor antagonists as alternatives to ketamine. In this chapter, the past and recent research on the antidepressant effects of mGlu2/3 receptor antagonists will be reviewed. In particular, the potential of mGlu2/3 receptor antagonists as novel ketamine-like antidepressants will be emphasized.


Assuntos
Antidepressivos/farmacologia , Terapia de Alvo Molecular , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Receptores de Glutamato Metabotrópico/antagonistas & inibidores
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