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1.
Drug Chem Toxicol ; 43(2): 192-199, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30025480

RESUMO

The potential genotoxic effect of venlafaxine hydrochloride (venlafaxine), an antidepressant drug-active ingredient, was investigated by using in vitro chromosome aberrations (CAs) and cytokinesis-block micronucleus (CBMN) assays in human peripheral blood lymphocytes (PBLs). Mitotic index (MI) and cytokinesis-block proliferation index (CBPI) were also calculated to determine the cytotoxicity of this active drug. For this aim, the human PBLs were treated with 25, 50, and 100 µg/ml venlafaxine for 24 h and 48 h. The results of this study showed that venlafaxine significantly induced the formation of structural CA and MN for all concentrations (25, 50, and 100 µg/ml) and treatment periods (24 h and 48 h) when compared with the negative and the solvent control (except 25 µg/ml at 48 h for MN). In addition, the increases in the percentage of structural CA and MN were concentration-dependent for both treatment times. With regard to cell cycle kinetics, venlafaxine significantly decreased the MI at all concentrations, and also CBPI at the higher concentrations for both treatment times as compared to the control groups. The present results indicate for the first time that venlafaxine had significant clastogenic and cytotoxic effects at the tested concentrations (25, 50, and 100 µg/ml) in the human PBLs, in vitro; therefore, its excessive and careless use may pose a potential risk to human health.


Assuntos
Linfócitos/efeitos dos fármacos , Mutagênicos/toxicidade , Inibidores da Recaptação de Serotonina e Norepinefrina/toxicidade , Cloridrato de Venlafaxina/toxicidade , Adulto , Células Cultivadas , Aberrações Cromossômicas/induzido quimicamente , Relação Dose-Resposta a Droga , Feminino , Humanos , Linfócitos/patologia , Masculino , Testes para Micronúcleos , Índice Mitótico , Mutagênicos/administração & dosagem , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Fatores de Tempo , Cloridrato de Venlafaxina/administração & dosagem , Adulto Jovem
4.
Neuroimage Clin ; 24: 102056, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31795035

RESUMO

INTRODUCTION: Frontal alpha asymmetry (FAA) is a proposed prognostic biomarker in major depressive disorder (MDD), conventionally acquired with electroencephalography (EEG). Although small studies attributed trait-like properties to FAA, a larger sample is needed to reliably asses this characteristic. Furthermore, to use FAA to predict treatment response, determining its stability, including the potential dependency on depressive state or medication, is essential. METHODS: In the international Study to Predict Optimized Treatment in Depression (iSPOT-D), a multi-center, randomized, prospective open-label trial, 1008 MDD participants were randomized to treatment with escitalopram, sertraline or venlafaxine-extended release. Treatment response was established eight weeks after treatment initiation and resting state EEG was measured both at baseline and after eight weeks (n = 453). RESULTS: FAA did not change significantly after eight weeks of treatment (n = 453, p = .234), nor did we find associations with age, sex, depression severity, or change in depression severity. After randomizing females to escitalopram or sertraline, for whom treatment response could be predicted in an earlier study, FAA after eight weeks resulted in equivalent response prediction as baseline FAA (one tailed p = .028). CONCLUSION: We demonstrate that FAA is a stable trait, robust to time, state and pharmacological status. This confirms FAA stability. Furthermore, as prediction of treatment response is irrespective of moment of measurement and use of medication, FAA can be used as a state-invariant prognostic biomarker with promise to optimize MDD treatments.


Assuntos
Ritmo alfa/fisiologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/fisiopatologia , Lobo Frontal/fisiopatologia , Lateralidade Funcional/fisiologia , Adulto , Ritmo alfa/efeitos dos fármacos , Antidepressivos/administração & dosagem , Biomarcadores , Citalopram/administração & dosagem , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Eletroencefalografia , Feminino , Lobo Frontal/efeitos dos fármacos , Lateralidade Funcional/efeitos dos fármacos , Humanos , Masculino , Estudos Prospectivos , Sertralina/administração & dosagem , Sertralina/uso terapêutico , Resultado do Tratamento , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/uso terapêutico
5.
J Clin Psychopharmacol ; 39(6): 583-590, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31688392

RESUMO

PURPOSE/BACKGROUND: The duration of untreated depression is a predictor for poor future prognosis, making rapid dose finding essential. Genetic variation of the CYP2D6 isoenzyme can influence the optimal dosage needed for individual patients. The aim of this study was to determine the effectiveness of CYP2D6 pharmacogenetic screening to accelerate drug dosing in older patients with depression initiating nortriptyline or venlafaxine. METHODS/PROCEDURES: In this randomized controlled trial, patients were randomly allocated to one of the study arms. In the intervention arm (DG-I), the specific genotype accompanied by a standardized dosing recommendation based on the patients' genotype and the prescribed drug was directly communicated to the physician of the participant. In both the deviating genotype control arm (DG-C) and the nonrandomized control arm, the physician of the participants was not informed about the genotype and the associated dosing advise. The primary outcome was the time needed to reach adequate drug levels: (1) blood levels within the therapeutic range and (2) no dose adjustments within the previous 3 weeks. FINDINGS/RESULTS: No significant difference was observed in mean time to reach adequate dose or time to adequate dose between DG-I and DG-C. Compared with the nonrandomized control arm group, adequate drug levels were reached significantly faster in the DG-I group (log-rank test; P = 0.004), and there was a similar nonsignificant trend for the DG-C group (log-rank test; P = 0.087). IMPLICATIONS/CONCLUSIONS: The results of this study do not support pharmacogenetic CYP2D6 screening to accelerate dose adjustment for nortriptyline and venlafaxine in older patients with depression.


Assuntos
Antidepressivos/administração & dosagem , Citocromo P-450 CYP2D6/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Nortriptilina/administração & dosagem , Testes Farmacogenômicos , Cloridrato de Venlafaxina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antidepressivos/farmacocinética , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nortriptilina/farmacocinética , Fatores de Tempo , Cloridrato de Venlafaxina/farmacocinética
7.
Depress Anxiety ; 36(12): 1125-1134, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31682328

RESUMO

OBJECTIVE: The purpose of this study was to examine the influence of comorbid anxiety symptoms on antidepressant treatment remission in older adults with major depressive disorder (MDD). METHOD: In this multisite clinical trial, 468 older adults aged 60 years or older with MDD received open-label protocolized treatment with venlafaxine extended release (ER) titrated to a maximum of 300 mg daily. At baseline, anxiety was assessed with the Anxiety Sensitivity Index, the Brief Symptom Inventory (BSI) anxiety subscale, and the Penn State Worry Questionnaire. To measure treatment response, depressive symptoms and suicidality were assessed every 1-2 weeks with the Montgomery-Asberg Depression Rating Scale and the 19-item Scale for Suicide Ideation; anxiety was assessed with the BSI. Logistic regression and survival analysis were used to evaluate whether anxiety symptoms predicted depression remission. We also examined the relationships between anxiety scores and suicidality at baseline. RESULTS: Baseline anxiety symptoms did not predict remission or time to remission of depressive symptoms. Depressive, worry, and panic symptoms decreased in parallel in patients with high anxiety. Anxiety symptoms were associated with the severity of depression and with suicidality. CONCLUSION: In older adults with MDD, comorbid anxiety symptoms are associated with symptom severity but do not affect antidepressant remission or time to remission.


Assuntos
Antidepressivos/uso terapêutico , Transtornos de Ansiedade/complicações , Ansiedade/complicações , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/tratamento farmacológico , Ideação Suicida , Cloridrato de Venlafaxina/uso terapêutico , Idoso , Antidepressivos/administração & dosagem , Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/tratamento farmacológico , Depressão/complicações , Depressão/tratamento farmacológico , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Cloridrato de Venlafaxina/administração & dosagem
8.
Expert Opin Drug Deliv ; 16(12): 1413-1427, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31694417

RESUMO

Background: Actually, no drugs provide therapeutic benefit to approximately one-third of depressed patients. Depression is predicted to become the first global disease by 2030. So, new therapeutic interventions are imperative.Research design and methods: Venlafaxine-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were surface functionalized with two ligands against transferrin receptor to enhance access to brain. An in vitro blood-brain barrier model using hCMEC/D3 cell line was developed to evaluate permeability. In vivo biodistribution studies were performed using C57/bl6 mice. Particles were administered intranasal and main organs were analyzed.Results: Particles were obtained as a lyophilized powder easily to re-suspend. Internalization and permeability studies showed the following cell association sequence: TfRp-NPs>Tf-NPs>plain NPs. Permeability studies also showed that encapsulated VLF was not affected by P-gP pump efflux increasing its concentration in the basolateral side after 24 h. In vivo studies showed that 25% of plain NPs reach the brain after 30 min of one intranasal administration while less than 5% of functionalized NPs get the target.Conclusions: Plain NPs showed the highest ability to reach the brain vs. functionalized NPs after 30 min by intranasal administration. We suggest plain NPs probably travel via direct nose-to-brian route whereas functionalized NPs reach the brain by receptor-mediated endocytosis.


Assuntos
Antidepressivos , Portadores de Fármacos , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Cloridrato de Venlafaxina , Administração Intranasal , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacocinética , Encéfalo/metabolismo , Linhagem Celular , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Nanopartículas/química , Permeabilidade , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Distribuição Tecidual , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/farmacocinética
9.
Pharmacol Biochem Behav ; 187: 172817, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31655085

RESUMO

INTRODUCTION: Depression is a psychiatric disorder with higher incidence in women. Among the most common and less investigated adverse effects of antidepressants are the female sexual dysfunctions. Up to one third of the patients fail to respond to antidepressants; therefore, more treatment alternatives are necessary. The combination of mirtazapine plus venlafaxine, known as "California Rocket Fuel" has shown to be an option for treatment-resistant depression. However, there are no reports of the effects of this combination in animal models and its action on female sexual behavior is unknown. AIM: To analyze the effect of mirtazapine and venlafaxine alone or combined -given at doses with actions on the forced swim test- on female rat sexual behavior. METHODS: Mirtazapine (10, 20 or 40 mg/kg) and venlafaxine (15, 30 or 60 mg/kg) or their combinations (2.5/3.75, 5/7.5, 10/15 and 20/30 mg/kg mirtazapine and venlafaxine, respectively) were injected to sexually receptive female rats. We evaluated their effect on the forced swim test (FST). The doses that reduced immobility were tested on proceptivity and receptivity. RESULTS: Mirtazapine (40 mg/kg) and venlafaxine (60 mg/kg), administered alone, or combined (mirtazapine, 5, 10 and 20 mg/kg plus venlafaxine, 7.5, 15 and 30 mg/kg) reduced immobility, but affected motor activity. However, the reduced locomotion after the lowest combination (5/7.5 mg/kg) was smaller. Mirtazapine at 40 mg/kg reduced proceptivity and receptivity, while 60 mg/kg venlafaxine only decreased proceptivity. The combination of 5/7.5 mg/kg mirtazapine and venlafaxine did not affect female sexual behavior. CONCLUSIONS: Mirtazapine and venlafaxine exerted an effect in the FST, which was also evident when sub-effective doses of both antidepressants were combined. This combination also lacked adverse effects on female sexual behavior. The results suggest that "California Rocket Fuel" could be an effective antidepressant therapy with no adverse sexual effects in women.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Mirtazapina/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Cloridrato de Venlafaxina/farmacologia , Animais , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/uso terapêutico , Depressão/tratamento farmacológico , Relação Dose-Resposta a Droga , Quimioterapia Combinada/efeitos adversos , Feminino , Locomoção/efeitos dos fármacos , Masculino , Mirtazapina/administração & dosagem , Mirtazapina/uso terapêutico , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Natação , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/uso terapêutico
10.
Pharmacol Rep ; 71(4): 573-582, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31170658

RESUMO

BACKGROUND: Macrophages, involved in the pathogenesis of pain, express a variety of receptors enabling responsiveness to certain medications, including adjuvant analgesics (AAs), that are effective in neuropathic pain and include drugs not primarily indicated for pain treatment, such as anticonvulsants or antidepressants. Their analgesic effects are likely associated with immunomodulatory activity, that remain undefined. Thus, current research aimed at examining the impact of AAs on morphine-induced effects exerted on mouse immunity. METHODS: Macrophages from mice treated with morphine with or without gabapentin, amitriptyline or venlafaxine, were either subjected to phagocytosis assay, cultured to evaluate the generation of cytokines, or were pulsed with either corpuscular antigen or hapten and transferred to naive recipients to induce humoral or cellular response, respectively. Active contact hypersensitivity was also elicited in drug-treated mice. RESULTS: We observed that repeatedly administered morphine and AAs reduced antigen phagocytosis by macrophages. Further, amitriptyline with morphine enhanced basal secretion of cytokines by macrophages, and all drugs tended to decrease LPS-stimulated release of pro-inflammatory cytokines. Morphine and AAs impacted the expression of phagocytosis and antigen-presentation markers on macrophages, which led to the reduced ability of morphine-affected macrophages to induce B-cell secretion of specific antibodies, and the addition of AAs strengthened this effect. Finally, gabapentin and venlafaxine suppressed the contact hypersensitivity reaction, while amitriptyline seemed to have the opposite effect. CONCLUSIONS: Our study demonstrated a significant anti-inflammatory activity of AAs across a broad spectrum of macrophage immune functions, which is likely critical to their analgesic activity supporting the beneficial effect of morphine.


Assuntos
Adjuvantes Farmacêuticos/farmacologia , Analgésicos Opioides/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Morfina/farmacologia , Fagocitose/efeitos dos fármacos , Adjuvantes Farmacêuticos/administração & dosagem , Amitriptilina/administração & dosagem , Amitriptilina/farmacologia , Analgésicos Opioides/administração & dosagem , Animais , Apresentação do Antígeno/efeitos dos fármacos , Citocinas/metabolismo , Gabapentina/administração & dosagem , Gabapentina/farmacologia , Imunidade Humoral/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Masculino , Camundongos Endogâmicos CBA , Morfina/administração & dosagem , Fagocitose/imunologia , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/farmacologia
11.
Chronobiol Int ; 36(9): 1194-1207, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31198056

RESUMO

The circadian system regulates sleep/wake cycles, metabolism, mood, and other functions. It also influences medication efficacy. In this study, we studied the chronopharmacological profiles of antidepressants with various modes of action. We also investigated the effects of dosing time on the pharmacological activity of several antidepressants acting on serotonergic, noradrenergic, and/or dopaminergic neurons. C57BL/6 mice were intraperitoneally administered fluoxetine, imipramine, venlafaxine, or bupropion at 08:00 h (morning), 14:00 h (mid-day), 20:00 h (evening), or 02:00 h (mid-night). Antidepressant activity was evaluated by the tail suspension test. All antidepressants reduced immobility, and their activities varied according to the dosing time. Fluoxetine and imipramine induced relatively strong rhythms with high amplitudes. Their maximal effects were observed in the morning and evening, respectively. Venlafaxine and bupropion induced weak rhythms with maximal effects in the evening and dawn, respectively. These results suggest that the antidepressant activity is associated with circadian fluctuation, and antidepressants with different modes of action have different chronopharmacological profiles. They affect locomotor activity in animals placed in novel (unfamiliar) environments. Fluoxetine, imipramine, and venlafaxine reduced locomotor activity, whereas bupropion increased it. The effects on locomotor activity also vary with circadian rhythm, and the tested drugs showed a maximal effect during the light phase. The peak time was different from that in TST. Plasma and brain levels of all drugs were slightly higher in the morning than in the evening. The dosing time dependency of the antidepressant activity did not correlate with the sedative/stimulatory activity or tissue drug level. Therefore, these latter two factors may have only a small impact on circadian antidepressant activity fluctuations. The relative activity of the serotonergic, noradrenergic, and dopaminergic systems may determine the chronopharmacological profiles of each drug. These results suggest the possibility that drug therapy be optimized by considering the dosing time when the antidepressant activity is high and other pharmacological activities leading to adverse effects are low. Further studies using animal models of depression and in clinical settings are necessary to confirm the effects of dosing time on depressed subjects.


Assuntos
Antidepressivos/farmacologia , Ritmo Circadiano , Depressão/tratamento farmacológico , Animais , Antidepressivos/administração & dosagem , Comportamento Animal , Bupropiona/administração & dosagem , Dopamina/administração & dosagem , Fluoxetina/administração & dosagem , Imipramina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Movimento , Norepinefrina/administração & dosagem , Fatores de Tempo , Cloridrato de Venlafaxina/administração & dosagem
12.
Eur J Clin Pharmacol ; 75(8): 1109-1116, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30968172

RESUMO

PURPOSE: To assess in a large naturalistic sample, whether clinical response to a treatment with venlafaxine is associated with different patterns of plasma concentrations of active moiety, AM (sum of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN)). METHODS: Applying a regression model, plasma concentrations and plasma concentrations corrected-by-dosage (C/D) for AM were included as independent variable with Clinical Global Impressions-Improvement (CGI-I) scale ratings as dependent variable. Moreover, AM, VEN, and ODVEN were compared between treatment responders and non-responders, defining response as much or very much improved on the CGI-I scale based on the non-parametric Mann-Whitney U (M-W-U) test with a significance level of 0.05. RESULTS: No correlations were found between AM and C/D AM plasma concentrations and CGI-I ratings (regression coefficient 0.0, CI 0.000, 0.001, p = 0.492 for AM and 0.047, CI - 0.065, 0.159, p = 0.408 for C/D AM). Venlafaxine daily dosage did not differ between responders and non-responders (217.7 ± 76.9 vs. 222.0 ± 72.7 mg/day, p = 0.45 for M-W-U). Responders displayed lower ODVEN (p = 0.033) and AM (p = 0.031) plasma concentrations than non-responders (p = 0.033 and 0.031, respectively for M-W-U). No other differences were detected. Using a cut-off level of 400 ng/mL for AM concentrations, a higher percentage of responders was reported in the group of patients with AM < 400 ng/mL (13.04%) compared to patients with AM > 400 ng/mL (8%) (p = 0.038). CONCLUSIONS: Higher ODVEN and AM concentrations in non-responders than in responders indicate that treatment escalation above upper thresholds of therapeutic reference ranges of venlafaxine is not promising. Hence, the therapeutic reference range for venlafaxine can help in improving outcomes in a measurement-based care model that takes advantage of therapeutic drug monitoring.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacocinética , Cloridrato de Venlafaxina/farmacocinética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtorno Bipolar/sangue , Transtorno Bipolar/diagnóstico , Bases de Dados Factuais/estatística & dados numéricos , Succinato de Desvenlafaxina/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Estudos Retrospectivos , Esquizofrenia/sangue , Esquizofrenia/diagnóstico , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Resultado do Tratamento , Cloridrato de Venlafaxina/administração & dosagem , Adulto Jovem
13.
J Clin Psychopharmacol ; 39(3): 220-225, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30932945

RESUMO

BACKGROUND: The neurotrophic hypothesis of depression has been mostly studied with a focus on brain-derived neurotrophic factor (BDNF) leading to lack of data on non-BDNF neurotrophins (NTs). The aim of this study was to evaluate the effect of antidepressant drugs on changes in serum nerve growth factor (NGF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). METHODS: A prospective cohort study was conducted on 105 patients with depression who were subgrouped to the group 1 (mild and moderate depression without somatic syndrome treated with sertraline), group 2 (mild and moderate depression with somatic syndrome treated with dosulepin), and group 3 (severe depression without psychotic symptoms treated with venlafaxine). At baseline, the severity of depression (Montgomery-Asberg Depression Rating Scale [MADRS]), serum NGF, NT-3, and NT-4 were estimated. Thirty-five healthy volunteers were recruited as controls for a baseline comparison of NTs. All patients were followed up after 6 weeks to evaluate the changes in NT levels and correlate it with the change in MADRS scores. RESULTS: At baseline, NT levels were significantly lower in patients with depression in comparison with healthy control. In group 1, serum NGF, NT-3, and NT-4 level were found to increase significantly after treatment, whereas changes in groups 2 and 3 were statistically not significant. Montgomery-Asberg Depression Rating Scale score and serum NGF at baseline had an inverse relation (r = -0.648), whereas the change in MADRS score in sertraline group had a positive correlation (r = 0.86) with the change of serum NGF. CONCLUSIONS: Monotherapy with sertraline increased the level of non-BDNF NTs; however, treatment with dosulepin and venlafaxine did not produce any significant changes in patients with depression.


Assuntos
Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Dotiepina/administração & dosagem , Sertralina/administração & dosagem , Cloridrato de Venlafaxina/administração & dosagem , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Depressão/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Neural/sangue , Fatores de Crescimento Neural/sangue , Neurotrofina 3 , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Adulto Jovem
14.
J Clin Psychopharmacol ; 39(3): 258-260, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30932946

RESUMO

PURPOSE: The time course of adverse events is an important factor for patient management. Clinicians are better able to prepare patients for specific adverse events, which leads to better treatment adherence. METHODS: Adverse events were followed longitudinally for 6 months during the open-label phase of a relapse prevention trial with 264 patients with generalized anxiety disorder. Adverse events were assessed at each treatment visit using a 21-item checklist. Logistic regression modeling, continuation ratio modeling, and hierarchical linear modeling were used to determine whether adverse events led to early attrition and whether adverse events decreased in enrolled patients over time. FINDINGS: Adverse events were found to have decreased highly significantly during treatment. A highly significant race effect was found in that whites had a significantly higher adverse event rate than did nonwhites. Early attrition rates were predicted by presence of nausea and fatigue, late attrition by dizziness, nervousness, and sexual dysfunction. IMPLICATIONS: Our findings provide information for clinicians on the course of adverse events over treatment, useful to prepare patients for treatment adherence.


Assuntos
Antidepressivos de Segunda Geração/administração & dosagem , Transtornos de Ansiedade/tratamento farmacológico , Cloridrato de Venlafaxina/administração & dosagem , Antidepressivos de Segunda Geração/efeitos adversos , Preparações de Ação Retardada , Feminino , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Fatores de Tempo , Cloridrato de Venlafaxina/efeitos adversos
15.
Saudi Med J ; 40(4): 339-346, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30957126

RESUMO

OBJECTIVES: To investigate the effects of venlafaxine (VEN) on the relapse of methamphetamine (METH)-induced conditioned place preference (CPP) in rats. METHODS: This study was conducted at the Department of Pharmacology and Toxicology, and the Addiction and Neuroscience Research Unit, College of Pharmacy, Taif University, Taif, Kingdom of Saudi Arabia between May  2017 and October 2018. A total of 32 male Wistar rats were used in this study. Rats were divided to receive either METH or saline during the conditioning phase. Following the acquisition of METH-induced CPP, the animals were randomly divided to receive saline or VEN for 21 days instead of METH during the extinction training. The reinstatement was initiated by re-exposure to a single dose of METH to test any anti-reinstatement effects of VEN. Results: Two-way repeated measures Analysis of Variance (ANOVA) (time × chamber) was used to analyze time spent in conditioning chambers, while distance traveled was analyzed using one-way ANOVA. Saline or VEN, when administered alone, did not affect CPP or locomotor activity results. A priming intraperitoneal injection of METH reinstated CPP in the animals treated with saline during the extinction phase. Interestingly, VEN treatment blocked METH-induced CPP. CONCLUSION: Venlafaxine effects on the reinstatement of METH-induced CPP are not likely due to nonspecific effects on locomotor activity. This beneficial effect of VEN on relapse to METH-induced CPP could be due to its antidepressant effects. Venlafaxine can thus be a potential therapeutic option in the treatment of relapse to METH-seeking behaviors.


Assuntos
Antidepressivos de Segunda Geração , Comportamento Aditivo/tratamento farmacológico , Metanfetamina , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/psicologia , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/farmacologia , Animais , Condicionamento Clássico , Infusões Parenterais , Masculino , Atividade Motora/efeitos dos fármacos , Ratos Wistar , Recidiva
16.
J Clin Neurosci ; 63: 27-31, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30837110

RESUMO

Narcolepsy is a life-long neurological disorder characterized by excessive daytime sleepiness (EDS) and cataplexy. At present, Sodium oxybate, modafinil, methylphenidate and other stimulants are recommended first-line therapies for narcolepsy but are difficult to obtain in China. One hundred forty-eight patients with narcolepsy were treated with antidepressants and administered the Epworth Sleepiness Scale (ESS) and the Maintenance of Wakefulness Test (MWT) before and after treatment from August 2012 to August 2017. The subjects were followed for 1-6 years after treatment. Improvement in sleepiness, cataplexy, cataplexy-like episodes, and antidepressant side effects were assessed. There were significant differences in the mean sleep latency (MSL) and sleep onset rapid eye movement periods (SOREMPs) in MWT and ESS scores, cataplexy and cataplexy-like episodes before and after treatment (p < 0.01). Venlafaxine demonstrated significantly greater improvements in MSL in the MWT (p < 0.01). Early awakenings and dry mouth were the most common adverse effects.


Assuntos
Antidepressivos/uso terapêutico , Modafinila/uso terapêutico , Narcolepsia/tratamento farmacológico , Cloridrato de Venlafaxina/uso terapêutico , Adulto , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modafinila/administração & dosagem , Modafinila/efeitos adversos , Estudos Prospectivos , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/efeitos adversos
17.
BMC Psychiatry ; 19(1): 24, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642308

RESUMO

BACKGROUND: Patients with Major Depressive Disorder (MDD) who are non-improvers after two weeks of antidepressant treatment have a high risk of treatment failure. Recently, we did not find differences in outcomes in non-improvers randomized to an early medication change (EMC) strategy compared to treatment as usual (TAU). This secondary analysis investigated possible predictors of higher remission rates in the EMC strategy. METHODS: Of 192 non-improvers (i.e. decrease of ≤20% on the HAMD-17 depression scale) after a two-week treatment with escitalopram, n = 97 were randomized to EMC (immediate switch to high doses of venlafaxine XR) and n = 95 to TAU (continued escitalopram until day 28 with non-responders switched to venlafaxine XR). We first analyzed patient characteristics, psychopathological features and subtypes of MDD by logistic regression analyses as possible predictors of remission rates. In a second investigation, we analyzed the predictors, which showed a significant association in the first analysis before Bonferroni-Holm correction by chi-squared tests separated for treatment groups. All analyses were corrected by Bonferroni-Holm method. RESULTS: The first analyses yielded no statistically significant results after correction for multiple testing. In the second analyses, however, patients with prior medication at study entry showed higher remission rates in EMC than in TAU (24.2% versus 8.6%, p = 0.017; Bonferroni-Holm corrected significance level: p = 0.025.). Furthermore, patients with a recurrent course of MDD benefited less from treatment as usual (p = 0.009; Bonferroni-Holm corrected significance level: p = 0.025). Age, sex, age of onset, psychiatric or somatic comorbidities, and other subtypes of MDD did not predict remission rates. CONCLUSIONS: Although in our first analysis we found statistically non-significant results, the second analysis showed significant differences in remission rates between patients with or without previous medication and in patients with recurrent MDD or the first depressive episode. It would therefore be valuable to examine in larger and prospective studies whether remission rates can be increased by quick escalation of treatment in certain subgroups of patients. Promising subgroups to be tested are patients who were previously medicated, and who show a recurrent course of MDD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00974155 . Registered at the 10th of September 2009. Retrospectively registered.


Assuntos
Antidepressivos/administração & dosagem , Citalopram/administração & dosagem , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Substituição de Medicamentos/tendências , Cloridrato de Venlafaxina/administração & dosagem , Adulto , Comorbidade , Transtorno Depressivo Maior/psicologia , Substituição de Medicamentos/psicologia , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Recidiva , Estudos Retrospectivos , Falha de Tratamento , Resultado do Tratamento
18.
Int J Neuropsychopharmacol ; 22(4): 278-285, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649319

RESUMO

BACKGROUND: The in vivo binding of clinical dose of venlafaxine on norepinephrine transporter has been questioned because venlafaxine has higher in vitro affinity to serotonin transporter than that to norepinephrine transporter. Although serotonin transporter occupancy of clinically relevant doses of venlafaxine has been reported, there has been no report of norepinephrine transporter occupancy in the human brain. METHODS: This was an open-label, single center, exploratory positron emission tomography study. Twelve major depressive disorder patients who had responded to venlafaxine extended-release and 9 control subjects were recruited. Each subject participated in one positron emission tomography measurement with [18F]FMeNER-D2. Binding potential in brain was quantified by the area under the curve ratio method with thalamus as target and white matter as reference regions. The difference of binding potential values between control and patient groups divided to 2 dose ranges were evaluated. Norepinephrine transporter occupancy (%) for all the major depressive disorder patients was calculated using mean binding potential of control subjects as baseline. The relationships between dose or plasma concentration of total active moiety and occupancies of norepinephrine transporter were also estimated. RESULTS: The binding potential of the patient group with 150 to 300 mg/d was significantly lower than that in the control subjects group (P = .0004 < .05/2). The norepinephrine transporter occupancy (8-61%) increased in a dose-dependent manner although a clear difference beyond 150 mg/d was not observed. CONCLUSIONS: This study demonstrates that clinically relevant doses of venlafaxine extended-release block the norepinephrine transporter of the major depressive disorder patient's brain. The data support the notion that the antidepressant effect of venlafaxine involves a combination of serotonin transporter and norepinephrine transporter blockades.


Assuntos
Encéfalo/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/efeitos dos fármacos , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Cloridrato de Venlafaxina/farmacologia , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Preparações de Ação Retardada , Transtorno Depressivo Maior/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas , Tomografia por Emissão de Pósitrons , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Cloridrato de Venlafaxina/administração & dosagem , Adulto Jovem
19.
Depress Anxiety ; 36(1): 63-71, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30311742

RESUMO

BACKGROUND: There is a need to identify biomarkers of treatment outcomes for major depressive disorder (MDD) that can be disseminated. We investigated the predictive utility of pretreatment heart rate variability (HRV) for outcomes of antidepressant medication in MDD, with pretreatment anxious depression as a hypothesized moderator of HRV effects. METHODS: A large, randomized, multicenter practical trial (International Study to Predict Optimized Treatment in Depression) in patients with current nonpsychotic MDD (N = 1,008; 722 completers) had three arms: escitalopram, sertraline, and venlafaxine-extended release. At pretreatment, patients were defined as having anxious (N = 309) versus nonanxious (N = 413) depression and their resting high-frequency HRV (root mean square of successive differences) was assessed. Patients' usual treating clinicians managed medication. At 8 weeks, primary outcomes were clinician-rated depressive symptom response and remission; secondary outcomes were self-reported response and remission. RESULTS: Pretreatment HRV predicted antidepressant outcomes as a function of anxious versus nonanxious depression. In anxious depression, patients with higher HRV had better outcomes, whereas patients with lower HRV had poorer outcomes. In nonanxious depression, patients with lower HRV had better outcomes, whereas patients with higher HRV had poorer outcomes. Some simple effects were not significant. Results did not differ by treatment arm and remained significant when controlling for important covariates. CONCLUSIONS: These findings inform a precision medicine approach in which clinical and biological assessments may be integrated to facilitate treatment outcome prediction. Knowing about HRV may help determine which patients with anxious depression could benefit from antidepressants and which patients may require a different treatment approach.


Assuntos
Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ansiedade/complicações , Ansiedade/tratamento farmacológico , Biomarcadores , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Frequência Cardíaca/efeitos dos fármacos , Adolescente , Adulto , Idoso , Ansiedade/fisiopatologia , Citalopram/uso terapêutico , Depressão/diagnóstico , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Depressão/psicologia , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Sertralina/uso terapêutico , Resultado do Tratamento , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/uso terapêutico , Adulto Jovem
20.
Br J Clin Pharmacol ; 85(1): 194-201, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30312494

RESUMO

AIMS: CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. METHODS: A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores. RESULTS: MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P < 0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35-0.61) in carriers of CYP2D6*1/null (n = 269), CYP2D6*9-10/null (n = 17), CYP2D6*41/null (n = 30) and CYP2D6null/null (n = 95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10. CONCLUSIONS: CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.


Assuntos
Antidepressivos de Segunda Geração/farmacocinética , Citocromo P-450 CYP2D6/metabolismo , Monitoramento de Medicamentos/estatística & dados numéricos , Cloridrato de Venlafaxina/farmacocinética , Idoso , Alelos , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/sangue , Cicloexanóis/administração & dosagem , Cicloexanóis/sangue , Cicloexanóis/farmacocinética , Citocromo P-450 CYP2D6/genética , Succinato de Desvenlafaxina/administração & dosagem , Succinato de Desvenlafaxina/sangue , Succinato de Desvenlafaxina/farmacocinética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Noruega , Estudos Retrospectivos , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/sangue
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