RESUMO
BACKGROUND: Health-related quality of life (HRQL) is an important goal for patients with major depressive disorder (MDD), but whether antidepressants improve HRQL in these patients is unclear. Here, we describe the real-world effects of trazodone once-a-day (TzOAD) and selective serotonin reuptake inhibitor (SSRI) treatments on HRQL and functioning in adults with MDD. METHODS: This 8-week prospective, observational, open-label, multicenter study was conducted in adults with moderate or severe MDD for whom TzOAD or SSRI were prescribed as monotherapy. The primary outcome was life enjoyment and satisfaction assessed via the patient-reported Quality-of-Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) from baseline to week 8. Secondary outcomes included change in Q-LES-Q-SF from baseline to weeks 1 and 2; severity of depressive symptoms using the Montgomery Åsberg Depression Rating Scale (MADRS) and sleep disturbance via the PROMIS SF-SD 8b questionnaire at weeks 1, 2, and 8; and overall functioning via the Sheehan Disability Scale (SDS), hedonic capacity using the Snaith-Hamilton Pleasure Scale (SHAPS), and cognitive dysfunction using the Perceived Deficits Questionnaire (PDQ-5) at baseline and week 8. RESULTS: The study included 208 adults with MDD (mean [SD] age = 50.2 [14.3] years; 68.6% female; 98.4% White). Life enjoyment and satisfaction improved from baseline to week 8 for both treatment groups: Q-LES-Q-SF mean (SD) scores were 27.5 (20.4) for the SSRI group and 39.0 (22.1) for the TzOAD group. Depressive symptoms and sleep disturbances also reduced from baseline to week 8: MADRS (SSRI, -15.7 [8.3]; TzOAD, -21.0 [9.8]); PROMIS SF-SD 8b (SSRI, -9.9 [12.6]; TzOAD, -22.0 [12.6]). Mean change scores in Q-LES-Q-SF, MADRS, and PROMIS SF-SD 8b improved as early as week 1 in both groups. Mean scores also improved from baseline to week 8 on SDS (SSRI, -9.2 [7.4]; TzOAD, -14.3 [7.5]), SHAPS (SSRI, -6.6 [4.3]; TzOAD, -8.3 [4.4]), and PDQ-5 (SSRI, -5.8 [4.5]; TzOAD, -7.7 [5.0]). CONCLUSIONS: In adults with MDD who received TzOAD or SSRIs, overall and individual HQRL domains improved rapidly and in parallel with improvements in depressive symptoms, with a slightly greater improvement observed in the TzOAD group.
Assuntos
Transtorno Depressivo Maior , Qualidade de Vida , Inibidores Seletivos de Recaptação de Serotonina , Trazodona , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Feminino , Masculino , Trazodona/farmacologia , Trazodona/administração & dosagem , Adulto , Pessoa de Meia-Idade , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estudos Prospectivos , Recuperação de Função Fisiológica/efeitos dos fármacos , Resultado do Tratamento , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/uso terapêutico , Antidepressivos de Segunda Geração/farmacologiaRESUMO
BACKGROUND: Habenula, a hub brain region controlling monoaminergic brain center, has been implicated in major depressive disorder (MDD) and as a possible target of antidepressant response. Nevertheless, the effect of antidepressant drug treatment on habenular volumes remains unknown. The objective of the present research was to study habenular volume change after antidepressant treatment in patients with MDD, and assess whether it is associated with clinical improvement. METHODS: Fifty patients with a current major depressive episode (MDE) in the context of MDD, and antidepressant-free for at least 1 month, were assessed for habenula volume (3T MRI with manual segmentation) before and after a 3 months sequence of venlafaxine antidepressant treatment. RESULTS: A 2.3% significant increase in total habenular volume (absolute volume: P = 0.0013; relative volume: P = 0.0055) and a 3.3% significant increase in left habenular volume (absolute volume: P = 0.00080; relative volume: P = 0.0028) were observed. A significant greater variation was observed in male patients (4.8%) compared to female patients. No association was observed between habenular volume changes and response and remission. Some habenula volume changes were associated with improvement of olfactory pleasantness. CONCLUSION: Habenular volumes increased after 3 months of venlafaxine treatment in depressed patients. Further studies should assess whether cell proliferation and density or dendritic structure variations are implied in these volume changes.
Assuntos
Transtorno Depressivo Maior , Habenula , Imageamento por Ressonância Magnética , Cloridrato de Venlafaxina , Humanos , Cloridrato de Venlafaxina/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/patologia , Feminino , Masculino , Habenula/efeitos dos fármacos , Habenula/diagnóstico por imagem , Habenula/patologia , Adulto , Pessoa de Meia-Idade , Antidepressivos de Segunda Geração/farmacologiaRESUMO
Depression is one of the most common psychiatric disorders. Nanotechnology has emerged to optimize the pharmacological response. Therefore, the aim of this work was to develop and characterize liposomes and nanocapsules containing paroxetine hydrochloride and evaluate their antidepressant-like effect using the open field and tail suspension tests in mice. Liposomes and nanocapsules were prepared using the reverse-phase evaporation and nanoprecipitation methods, respectively. The particle size of the formulation ranged from 121.81 to 310.73 nm, the polydispersity index from 0.096 to 0.303, the zeta potential from -11.94 to -34.50 mV, the pH from 5.31 to 7.38, the drug content from 80.82 to 94.36 %, and the association efficiency was 98 %. Paroxetine hydrochloride showed slower release when associated with liposomes (43.82 %) compared to nanocapsules (95.59 %) after 10 h. In Vero cells, in vitro toxicity showed a concentration-dependent effect for paroxetine hydrochloride nanostructures. Both nanostructures decreased the immobility time in the TST at 2.5 mg/kg without affecting the number of crossings in the open field test, suggesting the antidepressant-like effect of paroxetine. In addition, the nanocapsules decreased the number of groomings, reinforcing the anxiolytic effect of this drug. These results suggest that the nanostructures were effective in preserving the antidepressant-like effect of paroxetine hydrochloride even at low doses.
Assuntos
Lipossomos , Nanocápsulas , Paroxetina , Animais , Paroxetina/administração & dosagem , Paroxetina/farmacologia , Paroxetina/química , Nanocápsulas/química , Camundongos , Chlorocebus aethiops , Masculino , Células Vero , Tamanho da Partícula , Liberação Controlada de Fármacos , Depressão/tratamento farmacológico , Elevação dos Membros Posteriores , Antidepressivos/administração & dosagem , Antidepressivos/química , Antidepressivos/farmacologia , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/química , Antidepressivos de Segunda Geração/farmacologia , Comportamento Animal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacosRESUMO
INTRODUCTION: The impacts of antidepressant pharmacotherapies on cardiovascular risk are unclear. We completed a systematic review with meta-analysis to assess the effect of paroxetine on heart rate variability (HRV) in patients with major depressive disorder (MDD). METHODS: The searches were accomplished via EMBASE, MEDLINE/PubMed (using the National Library of Medicine), Cochrane Library, CINAHL, Scopus, and Web of Science databases. We included non-blind, single, or double-blind randomized control trials in patients older than 18 diagnosed with MDD. Paroxetine needs to be enforced as a chronic therapeutic medication. We included individual studies that investigated resting HRV. RESULTS: We documented 402 studies, only following screening and eligibility phases; only six were included (five studies in the meta-analysis). No significant change was noticed for the SDNN index: subtotal = 8.23 [CI: -2.17, 18.63], p = 0.12, I2 = 54 % (very low quality of evidence). A significant change was distinguished for the LF index: subtotal = 0.74 [CI: 0.33, 1.15], p = 0.0004, I2 = 0 % (low quality of evidence). A significant alteration was perceived for the HF index: subtotal = 0.33 [CI: 0.06, 0.6], p = 0.02, I2 = 0 % (low quality of evidence). CONCLUSION: Meta-analysis demonstrated that paroxetine could advance HRV in MDD patients. Nevertheless, our supposition is founded only on statistical analysis and the very low quality of evidence breakdown reinforces the necessity for further studies to confirm or reject this theory.
Assuntos
Transtorno Depressivo Maior , Frequência Cardíaca , Paroxetina , Paroxetina/uso terapêutico , Paroxetina/farmacologia , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antidepressivos de Segunda Geração/uso terapêutico , Antidepressivos de Segunda Geração/efeitos adversos , Antidepressivos de Segunda Geração/farmacologiaRESUMO
The purpose of this narrative review is to relate current data on the molecular mechanisms of action of trazodone with its clinical effects and applicability in mental disorders caused or triggered by somatic and neurological disease, according to available publications. In the article, the prospects for the use of the multimodal antidepressant trazodone are discussed in accordance with therapeutic targets. The latter are discussed in accordance with the typology of the mentioned above psychosomatic disorders. Trazodone is an antidepressant acting primarily due to the blockade of postsynaptic serotonin 5H2A- and 5H2C-receptors, as well as the blockade of serotonin reuptake, but also has affinity for a number of additional receptors. The drug has a favorable safety profile and a wide range of beneficial effects: antidepressive, somnolent, anxiolytic, anti-dysphoric and somatotropic. This makes it possible to influence a wide range of therapeutic targets in the structure of mental disorders caused or triggered by somatic and neurological diseases, carrying out safe and effective psychopharmacotherapy.
Assuntos
Antidepressivos de Segunda Geração , Transtornos Mentais , Trazodona , Humanos , Trazodona/uso terapêutico , Trazodona/farmacologia , Serotonina , Antidepressivos de Segunda Geração/uso terapêutico , Antidepressivos de Segunda Geração/farmacologia , Antidepressivos/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/etiologiaRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease with a poor prognosis. There is currently no definitive cure for IPF. The present study establishes a platform for the development of a novel therapeutic approach for the treatment of PF using the atypical antidepressant, mirtazapine. In the endotracheal bleomycin rat model, mirtazapine interfered with the activation of NLRP3 inflammasome via downregulating the NLRP3 on the gene and protein expression levels. Accordingly, the downstream mediators IL-1ß and IL-18 were repressed. Such observation is potentially a direct result of the reported improvement in oxidative stress. Additionally, mirtazapine corrected the bleomycin-induced disparities in the levels of the fibrogenic mediators TGF-ß, PDGF-BB, and TIMP-1, in consequence, the lung content of hydroxyproline and the expression of α-SMA were reduced. Besides, mirtazapine curbed the ICAM-1 and the chemotactic cytokines MCP-1 and CXCL4. This protective property of mirtazapine resulted in improving the BALF total and differential cell counts, diminishing LDH activity, and reducing the BALF total protein. Moreover, the inflammation and fibrosis scores were accordingly lower. To conclude, we reveal for the first time the efficacy of mirtazapine as a potential treatment for PF. The combination of social isolation, sleep problems, breathing difficulties, and fear of death can lead to psychological distress and depression in patients with IPF. Hence, mirtazapine is a promising treatment option that may improve the prognosis for IPF patients due to its antifibrotic effects, as well as its ability to alleviate depressive episodes.
Assuntos
Antidepressivos de Segunda Geração , Fibrose Pulmonar Idiopática , Ratos , Animais , Inflamassomos/metabolismo , Mirtazapina/metabolismo , Mirtazapina/farmacologia , Antidepressivos de Segunda Geração/metabolismo , Antidepressivos de Segunda Geração/farmacologia , Bleomicina/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pulmão , Fibrose , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Antidepressivos/farmacologiaRESUMO
We previously identified in laboratory mice an inactive state [being awake with eyes open motionless within the home cage; inactive but awake, 'IBA'] sharing etiological factors and symptoms with human clinical depression. We further test the hypothesis that greater time spent displaying IBA indicates a depression-like state in mice by investigating whether the antidepressant Venlafaxine, environmental enrichment, and their combination, alleviate IBA. Seventy-two C57BL/6J and 72 DBA/2J female mice were pseudo-randomly housed post-weaning in mixed strain-pairs in non-enriched (NE; 48 pairs) or in environmentally enriched (EE; 24 pairs) cages. After 34 days, half of the mice housed in NE cages were either relocated to EE cages or left in NE cages. For each of these conditions, half of the mice drank either a placebo or the antidepressant Venlafaxine (10 mg/kg). The 48 mice housed in EE cages were all relocated to NE cages and allocated to either the placebo (n = 24) or Venlafaxine (n = 24). IBA data were collected prior to and after environmental adjustment by trained observers blind to the pharmacological and environmental adjustment treatments. Data were analyzed using GLM models. NE cages triggered more IBA than EE cages (Likelihood-Ratio-Test Chi23 = 53.501, p < 0.0001). Venlafaxine and environmental enrichment appeared equally effective at reducing IBA (LRT Chi23 = 18.262, p < 0.001), and combining these approaches did not magnify their effects. Enrichment removal triggered IBA increase (LRT Chi21 = 23.050, p < 0.001), but Venlafaxine did not overcome the increase in IBA resulting from enrichment loss (LTR Chi21 = 0.081, p = 0.775). Theoretical implications for putative depression-like states in mice, and further research directions, are discussed.
Assuntos
Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Cloridrato de Venlafaxina/farmacologia , Animais , Antidepressivos de Segunda Geração/farmacologia , Depressão/metabolismo , Meio Ambiente , Feminino , Abrigo para Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBARESUMO
BACKGROUND: Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT). METHODS: This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine. RESULTS: All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout. CONCLUSION: These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.
Assuntos
Antidepressivos de Segunda Geração , Transtorno Depressivo Maior , Antidepressivos de Segunda Geração/farmacologia , Antidepressivos de Segunda Geração/uso terapêutico , Cloridrato de Atomoxetina/farmacologia , Cicloexanóis/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Norepinefrina , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Paroxetina/farmacologia , Paroxetina/uso terapêutico , Serotonina , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Tiramina/farmacologia , Cloridrato de Venlafaxina/farmacologia , Cloridrato de Venlafaxina/uso terapêuticoRESUMO
OBJECTIVES: The objective of this study was to develop a method for the preparation and characterization of paroxetine (PRX) tablets, obtained by coupling hot-melt extrusion and fused deposition modelling (FDM)-based three-dimensional printing (3DP) technology. The impact of the printing process parameters on the drug stability and on the tablets performance was assessed. METHODS: Tablets were obtained by FDM of hot-melt extruded PRX-loaded filaments. Physicochemical, thermal, spectroscopic, diffractometric analysis and in-vitro dissolution tests of the intermediate products and the finished dosage forms were performed. KEY FINDINGS: The characterization of printed tablets evidenced mass and dimensions uniformity, and consistency of drug content and dissolution profile. The formation of amorphous solid dispersions and interaction of formulation components throughout the manufacturing process were demonstrated. Layer thickness, printing temperature, printing and travelling speeds, and infill were the most impacting process parameters on both the physicochemical properties and the in-vitro performance of the 3D-printed tablets. CONCLUSIONS: PRX tablets, meeting compendial limits, were manufactured by 3DP, envisaging their clinical use as individually designed dosage forms. The assessment of the impact of processing parameters on the printed tablets provided insights, which will ultimately allow streamlining of the 3D process set-up for quicker and easier production of patient-centric medicines.
Assuntos
Composição de Medicamentos/métodos , Desenho de Fármacos/métodos , Paroxetina/farmacologia , Impressão Tridimensional , Antidepressivos de Segunda Geração/farmacologia , Formas de Dosagem , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Solubilidade , Comprimidos , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/tendênciasRESUMO
The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces Alu RNA-induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Reposicionamento de Medicamentos/métodos , Fluoxetina/farmacologia , Degeneração Macular/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Epitélio Pigmentado da Retina/efeitos dos fármacos , Elementos Alu/genética , Animais , Cegueira/patologia , Cegueira/prevenção & controle , Linhagem Celular , Citocinas/metabolismo , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Inflamassomos/metabolismo , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , RNA/genética , Retina/patologia , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/patologiaRESUMO
Selective 5-HT reuptake inhibitor antidepressants (SSRIs) are the first choice in major depressive disorder (MDD), but 50% of affected patients do not show improvement. Galanin(1-15) [GAL(1-15)] enhanced Fluoxetine antidepressant-like effects in an animal model of depression, the olfactory bulbectomy (OBX); however, further detailed analysis of GAL(1-15) effects as augmentation treatment in OBX rats are needed. In OBX rats, we analysed the effect of GAL(1-15) on Escitalopram (ESC)-mediated responses in behavioural tests related to despair. We studied whether GAL(1-15) effects involved 5-HT1AR using an in vivo model siRNA 5-HT1A knockdown rats. Moreover, we analysed by immunohistochemistry the expression of the immediate-early gene c-Fos (c-Fos IR) after the administration of GAL(1-15)+ESC in OBX rats in several nuclei involved in MDD. GAL(1-15) enhances the antidepressant-like effects of ESC, and the GALR2 antagonist M871 blocked GAL(1-15) mediated actions. The downregulation of 5-HT1AR by siRNA was sufficient to block GAL(1-15) effects. Our immunohistochemistry and principal component analysis (PCA) analysis suggest that two functional networks are involved in these effects; one includes the lateral (LHb) and medial (mHb) habenula, dorsal raphe (DR) and ventral tegmental area (VTA), and the other consists of the dentate gyrus (DG), and prefrontal cortex (PFC). The results open up the possibility of using GAL(1-15) in combination with SSRIs as a novel strategy for treating MDD.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Comportamento Animal/efeitos dos fármacos , Citalopram/farmacologia , Depressão/tratamento farmacológico , Galanina/farmacologia , Animais , Depressão/metabolismo , Depressão/patologia , Quimioterapia Combinada , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Fluoxetine (FLX) represents the antidepressant of choice for the management of pediatric mood-related illnesses. Accumulating preclinical evidence suggests that ontogenic FLX exposure leads to deregulated affect-related phenotypes in adulthood. Mood-related symptomatology constitutes a risk-factor for various neurological disorders, including Alzheimer's disease (AD), making it possible for juvenile FLX history to exacerbate the development of neurodegenerative diseases. OBJECTIVE: Because AD is characterized by the pathological accumulation of hyperphosphorylated tau, which can result from impaired function of protein degradation pathways, such as autophagy and the ubiquitin-proteasome system (UPS), we evaluated the long-term effects of adolescent FLX exposure on these pathways, using mice as a model system. METHODS: We subjected C57BL/6 adolescent male mice to FLX (20âmg/kg/day) from postnatal day (PD) 35 to PD49. Twenty-one days after the last FLX injection (i.e., adulthood; PD70), mice were euthanized and, using immunoblotting analysis, we evaluated protein markers of autophagy (Beclin-1, LC3-II, p62) and the UPS (K48-pUb), as well as AD-associated forms of phosphorylated tau, within the hippocampus and prefrontal cortex. RESULTS: Juvenile FLX pre-exposure mediated long-term changes in the expression of protein markers (increased LC3-II and decreased p62) that is consistent with autophagy activation, particularly in the prefrontal cortex. Furthermore, FLX history induced persistent accumulation of AD-associated variants of tau in both the hippocampus and prefrontal cortexConclusion: Adolescent FLX treatment may have enduring effects in the neuronal protein degradation machinery, which could adversely influence clearance of abnormal proteins, potentially predisposing individuals to developing AD in later life.
Assuntos
Doença de Alzheimer/patologia , Autofagia/efeitos dos fármacos , Fluoxetina , Hipocampo/patologia , Córtex Pré-Frontal/patologia , Proteínas tau , Adolescente , Animais , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Fluoxetina/administração & dosagem , Fluoxetina/farmacologia , Humanos , Immunoblotting , Masculino , Camundongos , Camundongos Endogâmicos C57BL , FosforilaçãoRESUMO
In recent years, escitalopram (ESC) has been suggested to have different mechanisms of action beyond its well known selective serotonin reuptake inhibition. The aim of this study is to investigate the effects of escitalopram on oxidative stress, apoptosis, brain-derived neurotrophic factor (BDNF), Methyl-CpG-binding protein 2 (MeCP2), and oligodendrocytes number in the brain of chronic unpredictable mild stress-induced depressed rats. The animals were randomised in four groups (8 in each group): control, stress, stress + ESC 5 and stress + ESC 5/10. ESC was administered for 42 days in a fixed dose (5 mg/kg b.w.) or in an up-titration regimen (21 days ESC 5 mg/kg b.w. then 21 days ESC 10 mg/kg b.w.). Sucrose preference test (SPT) and elevated plus maze (EPM) were also performed. ESC improved the percentage of sucrose preference, locomotion and anxiety. ESC5/10 reduced the oxidative damage in the hippocampus and improved the antioxidant defence in the hippocampus and frontal lobe. ESC5/10 lowered caspase 3 activity in the hippocampus. Escitalopram had a modulatory effect on BDNF and the number of oligodendrocytes in the hippocampus and frontal lobe and also improved the MeCP2 expressions. The results confirm the multiple pathways implicated in the pathogenesis of depression and suggest that escitalopram exerts an antidepressant effect via different intricate mechanisms.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Citalopram/farmacologia , Depressão/tratamento farmacológico , Proteína 2 de Ligação a Metil-CpG/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Psicológico/complicações , Animais , Antidepressivos de Segunda Geração/farmacologia , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Caspase 3/genética , Depressão/etiologia , Depressão/patologia , Modelos Animais de Doenças , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Ratos , Ratos WistarRESUMO
Despite the existing therapies and lack of receptors such as HER-2, estrogen receptor and progesterone receptor, triple-negative breast cancer is one of the most aggressive subtypes of breast cancer. TNBCs are known for their highly aggressive metastatic behavior and typically migrate to brain and bone for secondary site propagation. Many diseases share similar molecular pathology exposing new avenues in molecular signaling for engendering innovative therapies. Generation of newer therapies and novel drugs are time consuming associated with very high resources. In order to provide personalized or precision medicine, drug repositioning will contribute in a cost-effective manner. In our study, we have repurposed and used a neoteric combination of two drug molecules namely, fluvoxamine and tivozanib, to target triple-negative breast cancer growth and progression. Our combination regime significantly targets two diverse but significant pathways in TNBCs. Subsequent analysis on migratory, invasive, and angiogenic properties showed the significance of our repurposed drug combination. Molecular array data resulted in identifying the specific and key players participating in cancer progression when the drug combination was used. The innovative combination of fluvoxamine and tivozanib reiterates the use of drug repositioning for precision medicine and subsequent companion diagnostic development.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Reposicionamento de Medicamentos/métodos , Fluvoxamina/farmacologia , Compostos de Fenilureia/farmacologia , Medicina de Precisão/métodos , Quinolinas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antidepressivos de Segunda Geração/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Fluvoxamina/administração & dosagem , Humanos , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Trazodone is a widely used antidepressant that is also useful in the control of agitation and insomnia in Alzheimer's disease. This drug is now recognized as having a new mechanism of action, an effect on the unfolded protein response (UPR) pathway, restoring protein translation and slowing neurodegenerative progression in mice. This mechanism may have a role in dementia-modifying treatment. To explore the effects of trazodone on human cognition and to search for clinical evidence of its putative benefits in human neurodegenerative diseases, a systematic review was conducted for studies that evaluated the effect of a minimum dose of 25 mg of trazodone daily, for at least 1 week, on cognition in adult humans. The search was run in MEDLINE, Web of Science, and CENTRAL from the Cochrane databases, yielding a total of 16 studies after selection. Overall, seven studies showed no effect of trazodone on cognition, five showed a beneficial effect by improving or reducing cognitive decline, and four evidenced impaired cognitive function. Our analysis highlights the possibility of a dose-independent dual effect of trazodone on human cognition, with acute utilization associated with impaired cognitive function and long-term use with preventing cognitive deterioration. There was no clinical evidence that trazodone could be used as a specific treatment of neurodegenerative diseases. Future studies should explore the role of trazodone in the UPR pathway and the implications in neurodegenerative diseases in humans.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/prevenção & controle , Trazodona/uso terapêutico , Antidepressivos de Segunda Geração/efeitos adversos , Antidepressivos de Segunda Geração/farmacologia , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/prevenção & controle , Estudos Cross-Over , Relação Dose-Resposta a Droga , Doenças Neurodegenerativas/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Trazodona/efeitos adversos , Trazodona/farmacologiaRESUMO
BACKGROUND Acupuncture, which has many good effects and few adverse effects, is widely recognized as an alternative therapy for depression in clinical practice. This study aimed to explore the mechanism of acupuncture in antidepressant treatment. MATERIAL AND METHODS In this experiment, Sprague-Dawley rats were randomly divided into 4 groups: control, chronic unpredictable mild stress (CUMS), acupuncture, and fluoxetine groups. The CUMS, acupuncture, and fluoxetine groups were orphaned and subjected to chronic unpredictable stress for 6 weeks, and the acupuncture and fluoxetine groups were treated with their respective intervention in weeks 4-6. The body weight of rats was monitored weekly. After behavioral tests were completed, serum, feces, and hippocampal tissue of rats were collected. RESULTS The results showed that the acupuncture and fluoxetine treatments could alleviate the behavioral changes caused by CUMS. The treatments increased the total distance of rat crossing in the open-field test, prolonged the activity time of the open cross maze in the open arm, and improved the rate of sucrose consumption in the sucrose preference test. In addition, both the decreased level of dopamine (DA) and 5-hydroxytryptamine (5-HT) in serum and hippocampus caused by CUMS were improved after the treatments with acupuncture and fluoxetine, and the decreased expression of brain-derived neurotrophic factor signaling and the astrocytes in the hippocampus caused by CUMS were increased after the treatments with acupuncture and fluoxetine. Acupuncture and fluoxetine also decreased the ß isoform of calmodulin-dependent protein kinase II in the hippocampus, which was increased by CUMS. Furthermore, acupuncture regulated intestinal microbial disorders caused by CUMS, which reduced the relative abundance ratio of Bacteroidetes/Firmicutes in rats. CONCLUSIONS Our experimental results indicate that acupuncture can alleviate depression-like performance in CUMS rats by regulating intestinal microbes and neurotransmitters.
Assuntos
Terapia por Acupuntura/métodos , Antidepressivos de Segunda Geração , Comportamento Animal/efeitos dos fármacos , Depressão/terapia , Fluoxetina , Hipocampo/efeitos dos fármacos , Animais , Antidepressivos de Segunda Geração/farmacologia , Antidepressivos de Segunda Geração/uso terapêutico , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
One-week treatment with escitalopram decreases amygdala responses to fearful facial expressions in depressed patients, but it remains unknown whether it also modulates processing of complex and freely processed emotional stimuli resembling daily life emotional situations. Inter-subject correlation (ISC) offers a means to track brain activity during complex, dynamic stimuli in a model-free manner. Twenty-nine treatment-seeking patients with major depressive disorder were randomized in a double-blind study design to receive either escitalopram or placebo for one week, after which functional magnetic resonance imaging (fMRI) was performed. During fMRI the participants listened to spoken emotional narratives. Level of ISC between the escitalopram and the placebo group was compared across all the narratives and separately for the episodes with positive and negative valence. Across all the narratives, the escitalopram group had higher ISC in the default mode network of the brain as well as in the fronto-temporal narrative processing regions, whereas lower ISC was seen in the middle temporal cortex, hippocampus and occipital cortex. Escitalopram increased ISC during positive parts of the narratives in the precuneus, medial prefrontal cortex, anterior cingulate and fronto-insular cortex, whereas there was no significant synchronization in brain responses to positive vs negative events in the placebo group. Increased ISC may imply improved emotional synchronization with others, particularly during observation of positive events. Further studies are needed to test whether this contributes to the later therapeutic effect of escitalopram.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Córtex Cerebral , Citalopram/farmacologia , Rede de Modo Padrão , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Emoções , Percepção Social , Percepção da Fala , Adulto , Antidepressivos de Segunda Geração/administração & dosagem , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiopatologia , Citalopram/administração & dosagem , Rede de Modo Padrão/diagnóstico por imagem , Rede de Modo Padrão/fisiopatologia , Transtorno Depressivo Maior/diagnóstico por imagem , Método Duplo-Cego , Emoções/efeitos dos fármacos , Emoções/fisiologia , Feminino , Neuroimagem Funcional , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Personalidade/fisiologia , Percepção da Fala/efeitos dos fármacos , Percepção da Fala/fisiologia , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: The aim of this study was to investigate the potential dose-dependent CYP2D6 inhibition by bupropion (BUP) in patients with depression. METHODS: Patients combining BUP with venlafaxine were included from a therapeutic drug monitoring (TDM) database at the Diakonhjemmet Hospital (Oslo, Norway). The O/N-desmethylvenlafaxine metabolic ratio measured in TDM samples was used as a biomarker for CYP2D6 phenotype and was compared between patients treated with BUP 150 mg/d and 300 mg/d or greater. In addition, reference groups of venlafaxine-treated patients genotyped as CYP2D6 poor metabolizers (PMs, no CYP2D6 activity) and normal metabolizers (NMs, fully functional CYP2D6 activity) were included. FINDINGS: A total of 221 patients were included in the study. The median O/N-desmethylvenlafaxine metabolic ratio was significantly higher in patients treated with BUP 150 mg/d (n = 59) versus 300 mg/d or greater (n = 34, 1.77 vs 0.96, P < 0.001). In CYP2D6 NMs (n = 62) and PMs (n = 66), the median metabolic ratios were 40.55 and 0.48, respectively. For patients treated with BUP 150 mg/d, 11 (19%) of the 59 patients were phenoconverted to PMs, whereas this was the case for 17 (50%) of the 34 patients treated with BUP 300 mg/d or greater. CONCLUSIONS: Bupropion exhibits a clear dose-dependent CYP2D6 inhibitory effect during treatment of patients with depression. This finding is of clinical relevance when adjusting dosing of CYP2D6 substrates during comedication with BUP. Half of the patients treated with high-dose BUP are converted to CYP2D6 PM phenotype. Because of the variability in CYP2D6 inhibition, TDM of CYP2D6 substrates should be considered to provide individualized dose adjustments during comedication with BUP.
Assuntos
Antidepressivos de Segunda Geração/administração & dosagem , Bupropiona/administração & dosagem , Inibidores do Citocromo P-450 CYP2D6/administração & dosagem , Depressão/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antidepressivos de Segunda Geração/farmacologia , Bupropiona/farmacologia , Citocromo P-450 CYP2D6/efeitos dos fármacos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Succinato de Desvenlafaxina/farmacocinética , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Cloridrato de Venlafaxina/administração & dosagem , Adulto JovemRESUMO
Selective serotonin reuptake inhibitors (SSRIs) are designed to improve mood by raising extracellular serotonin levels through the blockade of the serotonin transporter. However, they exhibit a slow onset of action, suggesting the involvement of adaptive regulatory mechanisms. We hypothesized that the microRNA-34 family facilitates the therapeutic activity of SSRIs. We show that genetic deletion of these microRNAs in mice impairs the response to chronic, but not acute, fluoxetine treatment, with a specific effect on behavioral constructs that are related to depression, rather than anxiety. Moreover, using a pharmacological strategy, we found that an increased expression of the serotonin 2C (5-HT2C) receptor in the dorsal raphe region of the brain contributes to this phenotype. The onset of the therapeutic efficacy of SSRIs is paralleled by the desensitization of the 5-HT2C receptor in the dorsal raphe, and 5-HT2C is a putative target of microRNA-34. In this study, acute and chronic fluoxetine treatment differentially alters the expression of 5-HT2C and microRNA-34a in the dorsal raphe. Moreover, by in vitro luciferase assay, we demonstrated the repressive regulatory activity of microRNA-34a against 5-HT2C mRNA. Specific blockade of this interaction through local infusion of a target site blocker was sufficient to prevent the behavioral effects of chronic fluoxetine. Our results demonstrate a new miR-34a-mediated regulatory mechanism of 5-HT2C expression in the dorsal raphe and implicate it in eliciting the behavioral responses to chronic fluoxetine treatment.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Núcleo Dorsal da Rafe/efeitos dos fármacos , Fluoxetina/farmacologia , Locomoção/efeitos dos fármacos , MicroRNAs/efeitos dos fármacos , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Núcleo Dorsal da Rafe/metabolismo , Locomoção/genética , Camundongos , Camundongos Knockout , MicroRNAs/genética , Receptor 5-HT2C de Serotonina/genética , Regulação para CimaRESUMO
Depression is a psychiatric disorder with several comorbidities that has a complicated pathophysiology. Multiple mechanisms such as abnormal hypothalamic-pituitary adrenal (HPA) axis activity, neurotransmission (namely serotonin), and immune-inflammatory responses are involved in the pathophysiology of disease. In this study, we hypothesized that applying exercise (running wheel (RW) and treadmill (TM)) or fluoxetine (FLX) during adolescence could protect adult rats against the negative impact of early-life stress. To do this, we applied maternal separation stress (MS) to neonatal rats from postnatal day (PND) 2 to 14 and at PND 28, rats were divided into 8 experimental groups and were subjected to TM or RW or FLX treatment. After four weeks of physical activity or FLX treatment, at PND 64, behaviors were assessed by applying forced swimming test, sucrose preference test, open-field test, and elevated plus maze test. Serum cortiscosterone (CORT) levels and expression of genes associated with inflammatory factors (Il1ß, Hmgb1, and Il6) and serotonergic systems (5-ht2c and 5-ht3a) were studies in the hippocampus (HIPP) and prefrontal cortex (PFC). Our results revealed that RW and FLX treatment during adolescence are capable of attenuating MS-induced depressive- and anxiety-like disorders in adult male rats. These effects were accompanied by the normalization of both serum CORT and the expression of genes in the HIPP and PFC. TM exercise in adolescence showed anxiolytic effects but failed to produce antidepressant-like effects. Results of this study suggest that voluntary physical activity during adolescence can reduce the negative effects of early-life stress through different mechanisms.