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1.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299103

RESUMO

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 Wistar
2.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062902

RESUMO

Currently utilized antidepressants have limited effectiveness and frequently incur undesired effects. Most antidepressants are thought to act via the inhibition of monoamine reuptake; however, direct binding to monoaminergic receptors has been proposed to contribute to both their clinical effectiveness and their side effects, or lack thereof. Among the target receptors of antidepressants, α1­adrenergic receptors (ARs) have been implicated in depression etiology, antidepressant action, and side effects. However, differences in the direct effects of antidepressants on signaling from the three subtypes of α1-ARs, namely, α1A-, α1B- and α1D­ARs, have been little explored. We utilized cell lines overexpressing α1A-, α1B- or α1D-ARs to investigate the effects of the antidepressants imipramine (IMI), desipramine (DMI), mianserin (MIA), reboxetine (REB), citalopram (CIT) and fluoxetine (FLU) on noradrenaline-induced second messenger generation by those receptors. We found similar orders of inhibition at α1A-AR (IMI < DMI < CIT < MIA < REB) and α1D­AR (IMI = DMI < CIT < MIA), while the α1B-AR subtype was the least engaged subtype and was inhibited with low potency by three drugs (MIA < IMI = DMI). In contrast to their direct antagonistic effects, prolonged incubation with IMI and DMI increased the maximal response of the α1B-AR subtype, and the CIT of both the α1A- and the α1B-ARs. Our data demonstrate a complex, subtype-specific modulation of α1-ARs by antidepressants of different groups.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Receptores Adrenérgicos alfa 1/genética , Animais , Antidepressivos/classificação , Citalopram/farmacologia , Depressão/etiologia , Depressão/genética , Depressão/patologia , Desipramina/farmacologia , Fluoxetina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imipramina/farmacologia , Mianserina/farmacologia , Camundongos , Células PC12 , Ratos , Reboxetina/farmacologia , Transdução de Sinais/efeitos dos fármacos
3.
J Affect Disord ; 292: 733-745, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34161892

RESUMO

Doxycycline (DOXY) is a second-generation tetracycline with anti-inflammatory and neuroprotective effects. A proinflammatory profile seems to predict the severity of depressive symptoms. In the present study, we aimed at determining whether the anti-inflammatory action of subantimicrobial-dose doxycycline (SDD) (DOXY, 10mg/kg), alone or combined with the antidepressant escitalopram (ESC), could revert lipopolysaccharide-induced depressive-like alterations in mice. Male Swiss mice received saline or lipopolysaccharide (LPS) for ten consecutive days. From the 6th day of LPS exposure, they were treated with DOXY 10 mg/kg, ESC 4 mg/kg, DOXY 10 mg/kg plus ESC 4 mg/kg (DOXY+ESC), or saline. On the 10th day, we assessed behavioral despair (forced swimming test), anhedonia (sucrose preference test), brain oxidative stress markers, and inflammatory and protective pathways related to depression, such as NF-kB and phospho-CREB. Our results showed that DOXY alone or combined with ESC reduced hippocampal Iba-1 expression and interleukin (IL)-1ß levels. Only DOXY+ESC successfully reversed the LPS-induced increase in NF-kBp65 expression and TNFα levels. DOXY caused a marked increase in the hippocampal expression of phospho-CREB and GSH concentrations. DOXY and DOXY+ESC showed a tendency to modulate the functional status of mitogen-activated kinase p42-44 (Phospho-p44/42 MAPK) and of the phosphorylated form of glycogen synthase kinase 3 beta (GSK3ß), revealing a protective profile against inflammation. In conclusion, SDD, combined with ESC, seems to be a good strategy for reverting inflammatory changes and protecting against depression.


Assuntos
Citalopram , Lipopolissacarídeos , Animais , Citalopram/farmacologia , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Doxiciclina , Hipocampo , Masculino , Camundongos
4.
Invest Ophthalmol Vis Sci ; 62(7): 8, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34096973

RESUMO

Purpose: Patients that medicate with antidepressants commonly report dryness of eyes. The cause is often attributed to the anticholinergic properties of the drugs. However, regulation of tear production includes a substantial reflex-evoked component and is regulated via distinct centers in the brain. Further, the anticholinergic component varies greatly among antidepressants with different mechanisms of action. In the current study it was wondered if acute administration of antidepressants can disturb production of tears by affecting the afferent and/or central pathway. Methods: Tear production was examined in vivo in anesthetized rats in the presence or absence of the tricyclic antidepressant (TCA) clomipramine or the selective serotonin reuptake inhibitor (SSRI) escitalopram. The reflex-evoked production of tears was measured by challenging the surface of the eye with menthol (0.1 mM) and cholinergic regulation was examined by intravenous injection with the nonselective muscarinic agonist methacholine (1-5 µg/kg). Results: Acute administration of clomipramine significantly attenuated both reflex-evoked and methacholine-induced tear production. However, escitalopram only attenuated reflex-evoked tear production, while methacholine-induced production of tears remained unaffected. Conclusions: This study shows that antidepressants with different mechanisms of action can impair tear production by attenuating reflex-evoked signaling. Further, antimuscarinic actions are verified as a likely cause of lacrimal gland hyposecretion in regard to clomipramine but not escitalopram. Future studies on antidepressants with different selectivity profiles and mechanisms of action are required to further elucidate the mechanisms by which antidepressants affect tear production.


Assuntos
Citalopram/farmacologia , Clomipramina/farmacologia , Síndromes do Olho Seco , Potenciais Evocados Visuais , Aparelho Lacrimal , Lágrimas/fisiologia , Animais , Antidepressivos/farmacologia , Antagonistas Colinérgicos/farmacologia , Síndromes do Olho Seco/induzido quimicamente , Síndromes do Olho Seco/fisiopatologia , Potenciais Evocados Visuais/efeitos dos fármacos , Potenciais Evocados Visuais/fisiologia , Aparelho Lacrimal/efeitos dos fármacos , Aparelho Lacrimal/fisiologia , Cloreto de Metacolina/farmacologia , Mióticos/farmacologia , Ratos
5.
Brain Behav Immun ; 96: 63-72, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34010713

RESUMO

Clinical studies indicate that obese individuals have an increased risk of developing co-morbid depressive illness and that these patients have reduced responses to antidepressant therapy, including selective serotonin reuptake inhibitors (SSRIs). Obesity, a condition of chronic mild inflammation including obesity-induced neuroinflammation, is proposed to contribute to decreases in synaptic concentrations of neurotransmitters like serotonin (5HT) by decreasing 5HT synthesis in the dorsal raphe nucleus (DRN) and/or affecting 5HT reuptake in DRN target regions like the hippocampus. In view of these observations, the goal of the current study was to examine inflammatory markers and serotonergic dynamics in co-morbid obesity and depression. Biochemical and behavioral assays revealed that high-fat diet produced an obesity and depressive-like phenotype in one cohort of rats and that these changes were marked by increases in key pro-inflammatory cytokines in the hippocampus. In real time using fast scan cyclic voltammetry (FSCV), we observed no changes in basal levels of hippocampal 5HT; however responses to escitalopram were significantly impaired in the hippocampus of obese rats compared to diet resistant rats and control rats. Further studies revealed that these neurochemical observations could be explained by increases in serotonin transporter (SERT) expression in the hippocampus driven by elevated neuroinflammation. Collectively, these results demonstrate that obesity-induced increases in neuroinflammation adversely affect SERT expression in the hippocampus of obese rats, thereby providing a potential synaptic mechanism for reduced SSRI responsiveness in obese subjects with co-morbid depressive illness.


Assuntos
Citalopram , Dieta Hiperlipídica , Animais , Citalopram/farmacologia , Hipocampo , Humanos , Obesidade/complicações , Ratos , Inibidores de Captação de Serotonina/farmacologia
6.
J Clin Psychiatry ; 82(3)2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-34000119

RESUMO

OBJECTIVE: Posttraumatic stress disorder and prolonged grief disorder (PGD) arise following major life stressors and may share some overlapping symptomatology. This study aimed to examine the presence and response to treatment of posttraumatic stress symptoms (PTSS) in bereaved adults with a primary diagnosis of PGD. METHODS: A randomized controlled trial of 395 adults with PGD (defined as an Inventory of Complicated Grief score ≥ 30 plus confirmation on structured clinical interview) randomly assigned participants to either complicated grief treatment (CGT) with citalopram, CGT plus placebo, citalopram, or placebo between March 2010 and September 2014. This secondary analysis examined the presence of PTSS (per the Davidson Trauma Scale) at baseline and change in PTSS with treatment using longitudinal mixed-effects regression and examined the role of violent compared to nonviolent deaths (loss type). RESULTS: High levels of PTSS were present at baseline, regardless of loss type, and were associated with increased functional impairment (P < .001). CGT with placebo demonstrated efficacy for PTSS compared to placebo in both threshold (OR = 2.71; 95% CI, 1.13-6.52; P = .026) and continuous (P < .001; effect size d = 0.47) analyses, and analyses were suggestive of a greater effect for CGT plus citalopram compared to citalopram alone (threshold analysis: OR = 2.84; 95% CI, 1.20-6.70; P = .017; continuous analysis: P = .053; d = 0.25). In contrast, citalopram did not differ from placebo, and CGT plus citalopram did not differ from CGT plus placebo. CONCLUSIONS: Bereavement-related PTSS are common in bereaved adults with PGD in the context of both violent and nonviolent death and are associated with poorer functioning. CGT shows efficacy for PTSS, while the antidepressant citalopram does not. TRIAL REGISTRATION: : ClinicalTrials.gov identifier: NCT01179568.


Assuntos
Sintomas Comportamentais/terapia , Citalopram/farmacologia , Pesar , Avaliação de Resultados em Cuidados de Saúde , Psicoterapia , Inibidores de Captação de Serotonina/farmacologia , Transtornos de Estresse Pós-Traumáticos/terapia , Adulto , Idoso , Sintomas Comportamentais/tratamento farmacológico , Citalopram/administração & dosagem , Terapia Combinada , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Inibidores de Captação de Serotonina/administração & dosagem , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Síndrome
7.
Transl Psychiatry ; 11(1): 268, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947833

RESUMO

Maternal stress has debilitating implications for both mother and child, including increased risk for anxiety. The current COVID-19 pandemic escalates these phenomena, thus, urging the need to further explore and validate feasible therapeutic options. Unlike the protracted nature of clinical studies, animal models could offer swift evidence. Prominent candidates for treatment are selective serotonin reuptake inhibitors (SSRIs) to the mother, that putatively accommodate maternal functioning, and, thereby, also protect the child. However, SSRIs might have deleterious effects. It is important to assess whether SSRIs and other pharmacotherapies can moderate the transference of anxiety by soothing maternal anxiety and to examine the extent of offspring's exposure to the drugs via lactation. To our knowledge, the possibility that antenatal stress exacerbates lactation-driven exposure to SSRIs has not been tested yet. Thirty ICR-outbred female mice were exposed to stress during gestation and subsequently administered with either the SSRI, escitalopram, or the novel herbal candidate, shan-zha, during lactation. Upon weaning, both dams' and pups' anxiety-like behavior and serum escitalopram levels were assessed. The major findings of the current study show that both agents moderated the antenatal stress-induced transgenerational transference of anxiety by ameliorating dams' anxiety. Interestingly though, pups' exposure to escitalopram via lactation was exacerbated by antenatal stress. The latter finding provides a significant insight into the mechanism of lactation-driven exposure to xenobiotics and calls for a further consideration vis-à-vis the administration of other drugs during breastfeeding.


Assuntos
Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Lactação/metabolismo , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/uso terapêutico , Estresse Psicológico/fisiopatologia , Animais , COVID-19 , Citalopram/administração & dosagem , Citalopram/farmacologia , Citalopram/uso terapêutico , Crataegus , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pandemias , Gravidez , Inibidores de Captação de Serotonina/farmacologia , Xenobióticos/metabolismo
8.
Psychiatry Res Neuroimaging ; 312: 111286, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-33857750

RESUMO

Hippocampal volume loss is prominent in first episode schizophrenia (FES) and has been associated with poor clinical outcomes and with BDNF genotype; antidepressants are believed to reverse hippocampal volume loss via release of BDNF. In a 12-month, placebo-controlled add-on trial of the antidepressant, citalopram, during the maintenance phase of FES, negative symptoms were improved with citalopram. We now report results of structural brain imaging at baseline and 6 months in 63 FES patients (34 in citalopram group) from the trial to assess whether protection against hippocampal volume loss contributed to improved negative symptoms with citalopram. Hippocampal volumetric integrity (HVI) did not change significantly in the citalopram or placebo group and did not differ between treatment groups, whereas citalopram was associated with greater volume loss of the right CA1 subfield. Change in cortical thickness was associated with SANS change in 4 regions (left rostral anterior cingulate, right frontal pole, right cuneus, and right transverse temporal) but none differed between treatment groups. Our findings suggest that minimal hippocampal volume loss occurs after stabilization on antipsychotic treatment and that citalopram's potential benefit for negative symptoms is unlikely to result from protection against hippocampal volume loss or cortical thinning.


Assuntos
Antipsicóticos , Esquizofrenia , Antipsicóticos/uso terapêutico , Citalopram/farmacologia , Citalopram/uso terapêutico , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológico
9.
J Affect Disord ; 285: 120-126, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33647579

RESUMO

BACKGROUND: A thorough QT study identified that escitalopram-induced QT prolongation was delayed. This study thus aimed to develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model to characterize the relationship between escitalopram concentrations and the delayed effect on QT prolongation. METHODS: The data of completed subjects who had placebo (n=36) and a single dose of 20 mg escitalopram (n=33) from a previous thorough QT study were used. Population PK/PD analysis was performed by nonlinear mixed-effects modeling. A escitalopram concentration-drug effect model was developed with estimated individual PK and baseline QT parameters. To explain the relationship between escitalopram concentrations and QT prolongation delay, an effect compartment model was utilized. RESULTS: A two-compartment model with first-order absorption and lag time and first-order elimination adequately described the PK of escitalopram. The circadian rhythm of baseline QT interval was best explained by two harmonic cosine functions. A linear model properly characterized escitalopram-induced QT prolongation. The average estimated maximal QT prolongation was 5.4 ms (range: 1.9-7.6 ms). The equilibrium half-life of delayed QT prolongation was 1.9 h. The drug effect of QTc change compared with that at baseline remained relatively constant from 1.3 to 3.5 ms over 24 h, and the maximum QTc change occurred with a 3-h delay after the time to the maximum plasma concentration. LIMITATIONS: We did not include genetic polymorphisms, such as CYP2C19, as potential covariates owing to limited information. CONCLUSIONS: These results may provide useful information on when to monitor electrocardiogram in patients who require intensive care after drug administration.


Assuntos
Citalopram , Síndrome do QT Longo , Grupo com Ancestrais do Continente Asiático , Citalopram/farmacologia , Eletrocardiografia , Frequência Cardíaca , Humanos , Modelos Lineares , Síndrome do QT Longo/induzido quimicamente
10.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572981

RESUMO

The functional suppression of serotonin (5-HT) type 7 receptor (5-HT7R) is forming a basis for scientific discussion in psychopharmacology due to its rapid-acting antidepressant-like action. A novel mood-stabilizing atypical antipsychotic agent, lurasidone, exhibits a unique receptor-binding profile, including a high affinity for 5-HT7R antagonism. A member of a novel class of antidepressants, vortioxetine, which is a serotonin partial agonist reuptake inhibitor (SPARI), also exhibits a higher affinity for serotonin transporter, serotonin receptors type 1A (5-HT1AR) and type 3 (5-HT3R), and 5-HT7R. However, the effects of chronic administration of lurasidone, vortioxetine, and the selective serotonin reuptake inhibitor (SSRI), escitalopram, on 5-HT7R function remained to be clarified. Thus, to explore the mechanisms underlying the clinical effects of vortioxetine, escitalopram, and lurasidone, the present study determined the effects of these agents on thalamocortical glutamatergic transmission, which contributes to emotional/mood perception, using multiprobe microdialysis and 5-HT7R expression using capillary immunoblotting. Acute local administration of a 5-HT7R agonist and antagonist into the mediodorsal thalamic nucleus (MDTN) enhanced and reduced thalamocortical glutamatergic transmission, induced by N-methyl-D-aspartate (NMDA)/glutamate receptor inhibition in the reticular thalamic nucleus (RTN). Acute local administration of a relevant therapeutic concentration of vortioxetine and lurasidone into the MDTN suppressed the thalamocortical glutamatergic transmission via 5-HT7R inhibition, whereas that of escitalopram activated 5-HT7R. Subchronic administration of effective doses of vortioxetine and lurasidone (for 7 days) reduced the thalamocortical glutamatergic transmission, but escitalopram did not affect it, whereas subchronic administration of these three agents attenuated the stimulatory effects of the 5-HT7R agonist on thalamocortical glutamatergic transmission. Subchronic administration of effective doses of vortioxetine, lurasidone, and escitalopram downregulated the 5-HT7R expression of the plasma membrane in the MDTN; the 5-HT7R downregulation induced by vortioxetine and lurasidone was observed at 3 days, but that induced by escitalopram required a longer duration of 7 days. These results indicate that chronic administration of vortioxetine, escitalopram, and lurasidone generate downregulation of 5-HT7R in the thalamus; however, the direct inhibition of 5-HT7R associated with vortioxetine and lurasidone generates more rapid downregulation than the indirect elevation of the extracellular serotonin level via serotonin transporter inhibition by escitalopram.


Assuntos
Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Citalopram/farmacologia , Cloridrato de Lurasidona/farmacologia , Receptores de Serotonina/metabolismo , Vortioxetina/farmacologia , Animais , Antidepressivos/administração & dosagem , Antipsicóticos/administração & dosagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Citalopram/administração & dosagem , Ácido Glutâmico/metabolismo , Cloridrato de Lurasidona/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Tálamo/metabolismo , Vortioxetina/administração & dosagem
11.
Artigo em Inglês | MEDLINE | ID: mdl-33607327

RESUMO

BACKGROUND: Psychiatric medication that has a soothing effect on limbic responses to affective stimuli could improve affective instability symptoms as observed in borderline personality disorder (BPD). The objective of this study was to investigate whether citalopram versus placebo reduces the response of the affective neural circuitry during an emotional challenge. METHODS: A total of 30 female individuals with a BPD diagnosis participated in a placebo-controlled, double-blind crossover trial design. Three hours after oral drug intake, individuals with BPD viewed affective pictures while undergoing functional magnetic resonance imaging. Blood oxygen level-dependent responses to images of negative affective scenes and faces showing negative emotional expressions were assessed in regions of interest (amygdala, anterior cingulate cortex, anterior insula, dorsolateral prefrontal cortex). Blood perfusion at rest was assessed with arterial spin labeling. RESULTS: The neural response to pictures showing negative affective scenes was not significantly affected by citalopram (n = 23). Citalopram significantly reduced the amygdala response to pictures of faces with negative affective expressions (n = 25, treatment difference left hemisphere: -0.06 ± 0.16, p < .05; right hemisphere: -0.06 ± 0.17, p < .05). We observed no significant effects of citalopram on the other regions. The drug did not significantly alter blood perfusion at rest. CONCLUSIONS: Citalopram can alter the amygdala response to affective stimuli in BPD, which is characterized by overly responsive affective neural circuitry.


Assuntos
Transtorno da Personalidade Borderline , Citalopram , Tonsila do Cerebelo , Transtorno da Personalidade Borderline/tratamento farmacológico , Citalopram/farmacologia , Emoções , Feminino , Humanos , Imageamento por Ressonância Magnética
12.
Can J Microbiol ; 67(8): 599-612, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33481681

RESUMO

Bacterial resistance has become one of the most serious public health problems, globally, and drug repurposing is being investigated to speed up the identification of effective drugs. The aim of this study was to investigate the repurposing of escitalopram oxalate and clonazepam drugs individually, and in combination with the antibiotics ciprofloxacin and sulfamethoxazole-trimethoprim, to treat multidrug-resistant (MDR) microorganisms and to evaluate the potential chemical nuclease activity. The minimum inhibitory concentration, minimum bactericidal concentration, fractional inhibitory concentration index, and tolerance level were determined for each microorganism tested. In vitro antibacterial activity was evaluated against 47 multidrug-resistant clinical isolates and 11 standard bacterial strains from the American Type Culture Collection. Escitalopram oxalate was mainly active against Gram-positive bacteria, and clonazepam was active against both Gram-positive and Gram-negative bacteria. When associated with the two antibiotics mentioned, they had a significant synergistic effect. Clonazepam cleaved plasmid DNA, and the mechanisms involved were oxidative and hydrolytic. These results indicate the potential for repurposing these non-antibiotic drugs to treat bacterial infections. However, further studies on the mechanism of action of these drugs should be performed to ensure their safe use.


Assuntos
Ciprofloxacina , Bactérias Gram-Negativas , Antibacterianos/farmacologia , Ciprofloxacina/farmacologia , Citalopram/farmacologia , Clonazepam/farmacologia , DNA , Reposicionamento de Medicamentos , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Positivas , Humanos , Testes de Sensibilidade Microbiana , Plasmídeos/genética , Sulfametoxazol/farmacologia , Trimetoprima/farmacologia
13.
J Psychosom Res ; 141: 110351, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33412422

RESUMO

INTRODUCTION: Momentary ecological assessment indicated alleviated abdominal pain in escitalopram treatment of irritable bowel syndrome (IBS) with comorbid panic disorder. Hitherto, little is known about symptom formation, i.e., how psychological impact physical symptoms, and vice versa, and about the effect of SSRI-treatment on symptom formation. OBJECTIVE: To investigate how psychological and somatic symptoms co-vary over time in IBS patients with comorbid panic disorder and how they are affected by escitalopram treatment. METHODS: Experience sampling data from 14 IBS patients with panic disorder were obtained from a single-centre, double-blind, parallel-group, randomized controlled trial on escitalopram versus placebo. At baseline, after three and six months, multilevel time-lagged linear regression analysis was used to construct symptom networks. Network connections represented coefficients between various affect and gastrointestinal items. RESULTS: Connectivity increased up to 3 months in both groups. Between 3 and 6 months, connectivity decreased for placebo and further increased in the escitalopram group. Additionally, a steep increase in node strength for negative affect nodes was observed in the escitalopram network and the opposite for positive affect nodes. Over time, group symptom networks became increasingly different from each other. Anxious-anxious and enthusiastic-relaxed became significantly different between groups at 6 months. The connection that changed significantly in all analyses was anxious-anxious. CONCLUSIONS: Escitalopram treatment was associated with changes in the symptom networks in IBS patients with panic disorder. While mood and physical symptoms improve over time, mainly connectivity between mood nodes changed, possibly pointing towards a healthier emotion regulation resulting in alleviation of physical symptoms.


Assuntos
Citalopram/uso terapêutico , Avaliação Momentânea Ecológica/normas , Síndrome do Intestino Irritável/psicologia , Transtorno de Pânico/complicações , Transtorno de Pânico/psicologia , Inibidores de Captação de Serotonina/uso terapêutico , Adolescente , Adulto , Idoso , Citalopram/farmacologia , Comorbidade , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Inibidores de Captação de Serotonina/farmacologia , Adulto Jovem
14.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33374959

RESUMO

Previous studies suggest that depression may be associated with reactive oxygen species overproduction and disorders of the tryptophan catabolites pathway. Moreover, one-third of patients do not respond to conventional pharmacotherapy. Therefore, the study investigates the molecular effect of escitalopram on the expression of Cat, Gpx1/4, Nos1/2, Tph1/2, Ido1, Kmo, and Kynu and promoter methylation in the hippocampus, amygdala, cerebral cortex, and blood of rats exposed to CMS (chronic mild stress). The animals were exposed to CMS for two or seven weeks followed by escitalopram treatment for five weeks. The mRNA and protein expression of the genes were analysed using the TaqMan Gene Expression Assay and Western blotting, while the methylation was determined using methylation-sensitive high-resolution melting. The CMS caused an increase of Gpx1 and Nos1 mRNA expression in the hippocampus, which was normalised by escitalopram administration. Moreover, Tph1 and Tph2 mRNA expression in the cerebral cortex was increased in stressed rats after escitalopram therapy. The methylation status of the Cat promoter was decreased in the hippocampus and cerebral cortex of the rats after escitalopram therapy. The Gpx4 protein levels were decreased following escitalopram compared to the stressed/saline group. It appears that CMS and escitalopram influence the expression and methylation of the studied genes.


Assuntos
Encéfalo/efeitos dos fármacos , Citalopram/farmacologia , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Estresse Psicológico/fisiopatologia , Triptofano/metabolismo , Animais , Antidepressivos de Segunda Geração/farmacologia , Encéfalo/metabolismo , Catalase/genética , Catalase/metabolismo , Doença Crônica , Depressão/genética , Depressão/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Nitrosativo , Estresse Oxidativo , Ratos Wistar , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
15.
Arch Environ Contam Toxicol ; 79(4): 478-487, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33151376

RESUMO

Selective serotonin reuptake inhibitors (SSRIs) are psychotropic pharmaceuticals used as antidepressants. SSRIs are commonly found in surface waters in populated areas across the globe. They exert their effect by blocking the serotonin re-uptake transporter in the presynaptic nerve ending. The present study examined whether behavioural effects to exposure to SSRI citalopram depend on personality and sex in the stickleback (Gasterosteus aculeatus). Three aspects of stickleback behaviour are examined: feeding behaviour, aggression, and boldness. We exposed sticklebacks to 350-380 ng/l citalopram for 3 weeks. Feeding and aggressive behaviour were recorded before and after exposure, whereas scototaxis behaviour was tested after exposure. The results show treatment effects in feeding and aggressive behaviour. Feeding is suppressed only in the male group (χ2 = 20.4, P < 0.001) but not in the females (χ2 = 0.91, P = 0.339). Aggressive behaviour was significantly affected by treatment (χ2 = 161.9, P < 0.001), sex (χ2 = 86.3, P < 0.001), and baseline value (χ2 = 58.8, P < 0.001). Aggressiveness was suppressed by citalopram treatment. In addition, the fish showed no change in aggression and feeding behaviour over time regardless of sex and treatment, which indicate personality traits. Only females are affected by treatment in the scototaxis test. The exposed females spent significantly (χ2 = 5.02, P = 0.050) less time in the white zone than the female controls.


Assuntos
Citalopram/toxicidade , Inibidores de Captação de Serotonina/toxicidade , Smegmamorpha/fisiologia , Poluentes Químicos da Água/toxicidade , Agressão/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Citalopram/farmacologia , Comportamento Alimentar , Feminino , Masculino , Inibidores de Captação de Serotonina/farmacologia , Coluna Vertebral
16.
Anal Chem ; 92(21): 14676-14684, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33086792

RESUMO

Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is an established tool in drug development, which enables visualization of drugs and drug metabolites at spatial localizations in tissue sections from different organs. However, robust and accurate quantitation by MALDI-MSI still remains a challenge. We present a quantitative MALDI-MSI method using two instruments with different types of mass analyzers, i.e., time-of-flight (TOF) and Fourier transform ion cyclotron resonance (FTICR) MS, for mapping levels of the in vivo-administered drug citalopram, a selective serotonin reuptake inhibitor, in mouse brain tissue sections. Six different methods for applying calibration standards and an internal standard were evaluated. The optimized method was validated according to authorities' guidelines and requirements, including selectivity, accuracy, precision, recovery, calibration curve, sensitivity, reproducibility, and stability parameters. We showed that applying a dilution series of calibration standards followed by a homogeneously applied, stable, isotopically labeled standard for normalization and a matrix on top of the tissue section yielded similar results to those from the reference method using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The validation results were within specified limits and the brain concentrations for TOF MS (51.1 ± 4.4 pmol/mg) and FTICR MS (56.9 ± 6.0 pmol/mg) did not significantly differ from those of the cross-validated LC-MS/MS method (55.0 ± 4.9 pmol/mg). The effect of in vivo citalopram administration on the serotonin neurotransmitter system was studied in the hippocampus, a brain region that is the principal target of the serotonergic afferents along with the limbic system, and it was shown that serotonin was significantly increased (2-fold), but its metabolite 5-hydroxyindoleacetic acid was not. This study makes a substantial step toward establishing MALDI-MSI as a fully quantitative validated method.


Assuntos
Encéfalo/efeitos dos fármacos , Ciclotrons , Análise de Fourier , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/instrumentação , Animais , Encéfalo/metabolismo , Calibragem , Cromatografia Líquida , Citalopram/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Reprodutibilidade dos Testes , Serotonina/metabolismo
17.
Neurology ; 95(19): e2658-e2665, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913021

RESUMO

OBJECTIVE: To determine whether treatment with escitalopram compared with placebo would lower CSF ß-amyloid 42 (Aß42) levels. RATIONALE: Serotonin signaling suppresses Aß42 in animal models of Alzheimer disease (AD) and young healthy humans. In a prospective study in older adults, we examined dose and treatment duration effects of escitalopram. METHODS: Using lumbar punctures to sample CSF levels before and after a course of escitalopram treatment, cognitively normal older adults (n = 114) were assigned to placebo, 20 mg escitalopram × 2 weeks, 20 mg escitalopram × 8 weeks, or 30 mg escitalopram × 8 weeks; CSF sampled pretreatment and posttreatment and within-subject percent change in Aß42 was used as the primary outcome in subsequent analyses. RESULTS: An overall 9.4% greater reduction in CSF Aß42 was found in escitalopram-treated compared with placebo-treated groups (p < 0.001, 95% confidence interval [CI] 4.9%-14.2%, d = 0.81). Positive baseline Aß status (CSF Aß42 levels <250 pg/mL) was associated with smaller Aß42 reduction (p = 0.006, 95% CI -16.7% to 0.5%, d = -0.52) compared with negative baseline amyloid status (CSF Aß42 levels >250 pg/mL). CONCLUSIONS: Short-term longitudinal doses of escitalopram decreased CSF Aß42 in cognitively normal older adults, the target group for AD prevention. CLINICALTRIALSGOV IDENTIFIER: NCT02161458. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for cognitively normal older adults, escitalopram decreases CSF Aß42.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Citalopram/administração & dosagem , Duração da Terapia , Fragmentos de Peptídeos/líquido cefalorraquidiano , Inibidores de Captação de Serotonina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/efeitos dos fármacos , Citalopram/farmacologia , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/efeitos dos fármacos , Estudos Prospectivos , Inibidores de Captação de Serotonina/farmacologia
18.
Neurology ; 95(19): e2666-e2674, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913022

RESUMO

BACKGROUND: Several neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into ß-amyloid (Aß). Serotonin signaling through a subset of serotonin receptors suppresses Aß generation. We proposed that escitalopram, the most specific selective serotonin reuptake inhibitor (SSRI) that inhibits the serotonin transporter SERT, would suppress Aß levels in mice. OBJECTIVES: We hypothesized that acute treatment with escitalopram would reduce Aß generation, which would be reflected chronically with a significant reduction in Aß plaque load. METHODS: We performed in vivo microdialysis and in vivo 2-photon imaging to assess changes in brain interstitial fluid (ISF) Aß and Aß plaque size over time, respectively, in the APP/presenilin 1 mouse model of Alzheimer disease treated with vehicle or escitalopram. We also chronically treated mice with escitalopram to determine the effect on plaques histologically. RESULTS: Escitalopram acutely reduced ISF Aß by 25% by increasing α-secretase cleavage of APP. Chronic administration of escitalopram significantly reduced plaque load by 28% and 34% at 2.5 and 5 mg/d, respectively. Escitalopram at 5 mg/kg did not remove existing plaques, but completely arrested individual plaque growth over time. CONCLUSIONS: Escitalopram significantly reduced Aß in mice, similar to previous findings in humans treated with acute dosing of an SSRI.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Citalopram/farmacologia , Fragmentos de Peptídeos/efeitos dos fármacos , Placa Amiloide/patologia , Inibidores de Captação de Serotonina/farmacologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Líquido Extracelular , Microscopia Intravital , Camundongos , Microdiálise , Microscopia de Fluorescência por Excitação Multifotônica , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/metabolismo , Presenilina-1/genética
19.
J Clin Psychiatry ; 81(6)2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32991792

RESUMO

OBJECTIVE: There is a paucity of data on the effects of coprescribed benzodiazepines on treatment response variability and adherence to antidepressant pharmacotherapy for depression and anxiety in late life. The objective of this transdiagnostic analysis was to examine the effect of benzodiazepines on treatment outcomes in older patients with generalized anxiety disorder (GAD) or major depressive disorder (MDD). METHODS: Secondary analyses of data from 2 clinical trials of antidepressant pharmacotherapy for GAD (escitalopram vs placebo, 2006-2009) or MDD (open treatment with venlafaxine, 2009-2014) were conducted. Participants included 640 adults aged 60+ years with DSM-IV-defined GAD (n = 177) or MDD (n = 463). Benzodiazepine data were collected at baseline. Adherence and treatment response were assessed over 12 weeks. The analysis addressed whether coprescribed benzodiazepines are associated with treatment response, antidepressant medication adherence, dropout, final dose of antidepressant medication, and report of antidepressant-related adverse effects. RESULTS: Participants with GAD and coprescribed benzodiazepines were treated with a lower mean dosage of escitalopram and were less likely to complete the trial; there was no difference in adherence or treatment response. Participants with MDD and coprescribed benzodiazepines were less likely to tolerate a therapeutic dose of venlafaxine and reported more medication-related adverse effects; there was no difference in adherence, dropout, or treatment response. CONCLUSIONS: Coprescription of benzodiazepines was associated with increased dropout in older patients with GAD and more medication-related adverse effects in older patients with MDD. However, with the systematic clinical attention offered in a clinical trial, they do not impede treatment response. Clinicians should be aware that a coprescribed benzodiazepine may be a marker of a more challenging treatment course. Trial Registration: Data analyzed were from studies with ClinicalTrials.gov identifiers NCT00892047 and NCT00105586.


Assuntos
Envelhecimento , Antidepressivos de Segunda Geração/farmacologia , Transtornos de Ansiedade/tratamento farmacológico , Benzodiazepinas/farmacologia , Citalopram/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Cloridrato de Venlafaxina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/efeitos adversos , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Citalopram/administração & dosagem , Citalopram/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/efeitos adversos
20.
Mol Biol Rep ; 47(10): 8273-8278, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32914264

RESUMO

Neuropeptides are important, multifunctional regulatory factors of the nervous system, being considered as a novel, atypical sites of antidepressants action. It has already been proven that some of them, such as selective serotonin reuptake inhibitors (SSRI), are able to affect peptidergic pathways in various brain regions. Despite these reports, there is so far no reports regarding the effect of treatment with SSRIs on brain proopiomelanocortin (POMC), kisspeptin, Kiss1R and MCHR1 gene expression. In the current study we examined POMC, kisspeptin, Kiss1R and MCHR1 mRNA expression in the selected brain structures (hypothalamus, hippocampus, amygdala, striatum, cerebellum and brainstem) of rats chronically treated with a 10 mg/kg dose of escitalopram using quantitative Real-Time PCR. Long-term treatment with escitalopram led to the upregulation of MCHR1 expression in the rat amygdala. Kisspeptin mRNA level was also increased in the amygdala, but Kiss1R mRNA expressions were elevated in the hippocampus, hypothalamus and cerebellum. POMC mRNA expressions were in turn decreased in the hippocampus, amygdala, cerebellum and brainstem. These results may support the hypothesis that these neuropeptides may be involved in the site-dependent actions of SSRI antidepressants. This is the first report of the effects of escitalopram on POMC, kisspeptin, Kiss1R and MCHR1 in animal brain. Our findings shed a new light on the pharmacology of SSRIs and may contribute to a better understanding of the alternative, neuropeptide-dependent modes of antidepressant action.


Assuntos
Encéfalo/metabolismo , Citalopram/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Kisspeptinas/biossíntese , Pró-Opiomelanocortina/biossíntese , Receptores de Kisspeptina-1/biossíntese , Receptores de Somatostatina/biossíntese , Animais , Masculino , Ratos , Ratos Sprague-Dawley
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