RESUMO
INTRODUCTION: Major Depressive Disorder (MDD) is a common mental health disorder marked by sadness, hopelessness, and anhedonia. Various therapies exist, but their effectiveness is limited. Dextromethorphan hydrobromide combined with bupropion hydrochloride (Auvelity®) is a recently approved alternative for treating this condition in adults. AREAS COVERED: This review summarizes the neurobiology of major depression and delves into the pharmacology, efficacy, safety, and tolerability of dextromethorphan plus bupropion in adult patients. It is based on observational studies, clinical trials, and other secondary studies obtained through systematic literature searches. EXPERT OPINION: The combination of bupropion and dextromethorphan as a new pharmacotherapy for mental health is an interesting addition to the treatment options that can be used for MDD. The combination can be used in a range of scenarios, including as a first line therapy, as a second option when a patient has failed to achieve remission with a serotonin targeting agent, and for treatment resistant depression. Further research for other indications, including addiction disorders, may provide exciting results. Although a new combination, clinicians will be very familiar with both agents, increasing their acceptability. This pharmacotherapy also may bring increased impetus for discovering other combinations that may have beneficial synergistic effects.
Assuntos
Bupropiona , Transtorno Depressivo Maior , Dextrometorfano , Humanos , Bupropiona/uso terapêutico , Bupropiona/farmacologia , Dextrometorfano/uso terapêutico , Dextrometorfano/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Quimioterapia Combinada , Antidepressivos de Segunda Geração/uso terapêutico , Combinação de MedicamentosRESUMO
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 objective of this study was to assess the benefits and potential risks associated with different physical exercise modalities for managing symptoms in adults with major depressive disorder who were not receiving second-generation antidepressants or cognitive behavioral therapy. A systematic review and meta-analysis of randomized controlled trials (RCTs) were conducted. The search included multiple databases: Medline, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, PsycInfo, Web of Science, Clinical Trials repository, gray literature, and manual search. No language restrictions were applied. Eligible studies involved RCTs of adults with major depressive disorder who were not on antidepressants or receiving psychological therapy, comparing various exercise modalities with second-generation antidepressants or cognitive behavioral therapy, body-mind exercise, or no exercise interventions. Nine RCTs involving 678 adults were analyzed. The pooled results indicated a small clinical effect favoring exercise in reducing depressive symptoms, although the difference was not statistically significant (SMD = 0.27, 95% CI [- 0.58, 0.04], P = 0.09). Subgroup analyses suggested that intervention duration, frequency, intensity, supervision, age, overweight/obesity status, and diagnosis of depression could influence treatment outcomes. A sensitivity analysis was conducted for studies with controls without exercise interventions and a low risk of bias in the domains related to the randomization process and deviations from the intended interventions. The results showed that there are no statistically significant differences when interventions are compared with medication and body-mind exercise (p = 0.12, I2 = 78%). Furthermore, the analysis showed a moderate effect size favoring exercise, but no statistically significant difference between groups (p = 0.05), with high heterogeneity (I2 = 85%). The evidence quality was generally low to very low, and methodological limitations compromised the certainty of the findings. Adverse events associated with exercise were manageable. The study emphasizes the need for well-designed RCTs to provide clearer insights into the potential benefits of exercise in managing major depressive disorder symptoms. Caution is warranted in interpreting these results due to the limitations of the included studies.Systematic review registration: PROSPERO CRD42022356741.
Assuntos
Antidepressivos de Segunda Geração , Terapia Cognitivo-Comportamental , Transtorno Depressivo Maior , Adulto , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Antidepressivos/uso terapêutico , Antidepressivos de Segunda Geração/uso terapêutico , Exercício FísicoRESUMO
El manejo farmacológico del episodio depresivo en contexto del trastorno bipolar constituye un desafío para el clínico tanto en psiquiatría adultos como infantoadolescente. El presente trabajo tiene por objetivo actualizar y sintetizar la evidencia disponible respecto al manejo farmacológico para la depresión bipolar en población pediátrica. Metodología: Se realizó una búsqueda de las publicaciones de los últimos 5 años en bases de datos. Resultados: La evidencia muestra como primera línea el uso de antipsicóticos de segunda generación por sobre los estabilizadores del ánimo en este grupo etario; demostrando lurasidona y lanzapina/fluoxetina eficacia similares. Lurasidona es una opción con mejor perfil de seguridad por asociarse a menos efectos adversos y mejor adherencia. El uso de antidepresivos debe considerarse dentro de los pasos iniciales del manejo, asociado a un antipsicótico de segunda generación. Conclusiones: Se destaca la importancia de la sospecha, evaluación y diagnóstico adecuado para guiar la decisión de manejo integral. A pesar de los riesgos y consideraciones existentes, es importante considerar el uso en primera línea de antipsicóticos de segunda generación y de antidepresivos en el manejo de un cuadro depresivo en contexto de la enfermedad bipolar. La escasez de estudios en el tratamiento farmacológico de la depresión bipolar en general y especialmente en población pediátrica limita la generalización y extrapolación de los resultados a la realidad local.
The pharmacological management of the depressive episode in the context of bipolar disorder constitutes a challenge for the clinician both in adult and child-adolescent population. The objective of this paper is to update and synthesize the available evidence regarding the pharmacological management of bipolar depression in the pediatric population. Methodology: A search of the publications of the last 5 years in databases was carried out. Results: The evidence shows the use of second generation antipsychotics over mood stabilizers as the first line in this age group; demonstrating similar efficacy. Results: The evidence shows the use of second generation antipsychotics over mood stabilizers as the first line in this age group; demonstrating similar efficacy lurasidone and lanzapine/fluoxetine. Lurasidone is an option with a better safety profile as it is associated with fewer adverse effects and better adherence. The use of antidepressants should be considered within the initial steps of management, associated with a second generation antipsychotic. Conclusions: The importance of suspicion, evaluation and adequate diagnosis to guide the decision of comprehensive management is highlighted. Despite the existing risks and considerations, it is important to consider the first-line use of second-generation antipsychotics and antidepressants in the management of a depressive episode in the context of bipolar illness. The scarcity of studies on the pharmacological treatment of bipolar depression in general and especially in the pediatric population limits the generalization and extrapolation of the results to the local reality.
Assuntos
Humanos , Criança , Adolescente , Transtorno Bipolar/tratamento farmacológico , Antidepressivos de Segunda Geração/uso terapêutico , Depressão/tratamento farmacológico , Antipsicóticos/uso terapêutico , Cloridrato de Lurasidona/uso terapêutico , Olanzapina/uso terapêuticoRESUMO
Fluoxetine is the foremost prescribed antidepressant. Drugs acting on monoaminergic system may also regulate glutamatergic system. Indeed, the investigation of proteins associated with this system, such as Narp (neuronal activity-dependent pentraxin) and GluA4 subunit of AMPA receptor may reveal poorly explored modulations triggered by conventional antidepressants. This study aimed to uncover neurochemical mechanisms underlying the chronic fluoxetine treatment, mainly by evaluating these protein targets in the prefrontal cortex and in the hippocampus. Mice received a daily administration of fluoxetine (0.1, 1 or 10 mg/kg, p.o.) or potable water (vehicle group) for 21 days. These animals were submitted to the forced swim test (FST) to verify antidepressant-like responses and the open-field test (OFT) to assess locomotor activity. Modulation of signaling proteins was analyzed by western blot. Chronic treatment with fluoxetine (1 and 10 mg/kg) was effective, since it reduced the immobility time in the FST, without altering locomotor activity. Fluoxetine 10 mg/kg increased CREB phosphorylation and BDNF expression in the prefrontal cortex and hippocampus. Noteworthy, in the hippocampus fluoxetine also promoted Akt activation and augmented Narp expression. In the prefrontal cortex, a significant decrease in the expression of the GluA4 subunit and Narp were observed following fluoxetine administration (10 mg/kg). The results provide evidence of novel molecular targets potentially involved in the antidepressant effects of fluoxetine, since in mature rodents Narp and GluA4 are mainly expressed in the GABAergic parvalbumin-positive (PV+) interneurons. This may bring new insights into the molecular elements involved in the mechanisms underlying the antidepressant effects of fluoxetine.
Assuntos
Antidepressivos de Segunda Geração/administração & dosagem , Proteína C-Reativa/antagonistas & inibidores , Sistemas de Liberação de Medicamentos/métodos , Fluoxetina/administração & dosagem , Proteínas do Tecido Nervoso/antagonistas & inibidores , Receptores de AMPA/antagonistas & inibidores , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteína C-Reativa/metabolismo , Relação Dose-Resposta a Droga , Masculino , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Receptores de AMPA/metabolismoRESUMO
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention or impulsivity or both, and hyperactivity, which affect children, adolescents, and adults. In some countries, methylphenidate is the first option to treat adults with moderate or severe ADHD. However, evidence on the efficacy and adverse events of immediate-release (IR) methylphenidate in the treatment of ADHD in adults is limited and controversial. OBJECTIVES: To evaluate the efficacy and harms (adverse events) of IR methylphenidate for treating ADHD in adults. SEARCH METHODS: In January 2020, we searched CENTRAL, MEDLINE, Embase, eight additional databases and three trial registers. We also searched internal reports on the European Medicines Agency and the US Food and Drug Administration websites. We checked citations of included trials to identify additional trials not captured by the electronic searches. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing IR methylphenidate, at any dose, with placebo or other pharmacological interventions (including extended-release formulations of methylphenidate) for ADHD in adults. Primary outcomes comprised changes in the symptoms of ADHD (efficacy) and harms. Secondary outcomes included changes in the clinical impression of severity and improvement, level of functioning, depression, anxiety and quality of life. Outcomes could have been rated by investigators or participants. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently on the characteristics of the trials, participants, interventions; outcomes and financial conflict of interests. We resolved disagreements by discussion or consulting a third review author. We obtained additional, unpublished information from the authors of one included trial that had reported efficacy data in a graph. We calculated mean differences (MDs) or standardized MDs (SMDs) with 95% confidence intervals (CIs) for continuous data reported on the same or different scales, respectively. We summarized dichotomous variables as risk ratios (RRs) with 95% CI. MAIN RESULTS: We included 10 trials published between 2001 and 2016 involving 497 adults with ADHD. Three trials were conducted in Europe and one in Argentina; the remaining trials did not report their location. The RCTs compared IR methylphenidate with placebo, an osmotic-release oral system (OROS) of methylphenidate (an extended-release formulation), an extended-release formulation of bupropion, lithium, and Pycnogenol® (maritime pine bark extract). Participants comprised outpatients, inpatients in addiction treatment, and adults willing to attend an intensive outpatient program for cocaine dependence. The duration of the follow-up ranged from 6 to 18 weeks. IR methylphenidate versus placebo We found very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce symptoms of ADHD when measured with investigator-rated scales (MD -20.70, 95% CI -23.97 to -17.43; 1 trial, 146 participants; end scores; Adult ADHD Investigator Symptom Report Scale (AISRS), scored from 0 to 54), but the evidence is uncertain. The effect of IR methylphenidate on ADHD symptoms when measured with participant-rated scales was moderate, but the certainty of the evidence is very low (SMD -0.59, 95% CI -1.25 to 0.06; I2 = 69%; 2 trials, 138 participants; end scores). There is very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce the clinical impression of the severity of ADHD symptoms (MD -0.57, 95% CI -0.85 to -0.28; 2 trials, 139 participants; I2 = 0%; change and end scores; Clinical Global Impression (CGI)-Severity scale (scored from 1 (very much improved) to 7 (very much worse))). There is low-certainty evidence that, compared with placebo, IR methylphenidate may slightly impact the clinical impression of an improvement in symptoms of ADHD (MD -0.94, 95% CI -1.37 to -0.51; 1 trial, 49 participants; end scores; CGI-Improvement scale (scored from 1 (very much improved) to 7 (very much worse))). There is no clear evidence of an effect on anxiety (MD -0.20, 95% CI -4.84 to 4.44; 1 trial, 19 participants; change scores; Hamilton Anxiety Scale (HAM-A; scored from 0 to 56); very low-certainty evidence) or depression (MD 2.80, 95% CI -0.09 to 5.69; 1 trial, 19 participants; change scores; Hamilton Depression Scale (HAM-D; scored from 0 to 52); very low-certainty evidence) in analyses comparing IR methylphenidate with placebo. IR methylphenidate versus lithium Compared with lithium, it is uncertain whether IR methylphenidate increases or decreases symptoms of ADHD (MD 0.60, 95% CI -3.11 to 4.31; 1 trial, 46 participants; end scores; Conners' Adult ADHD Rating Scale (scored from 0 to 198); very low-certainty evidence); anxiety (MD -0.80, 95% CI -4.49 to 2.89; 1 trial, 46 participants; end scores; HAM-A; very low-certainty evidence); or depression (MD -1.20, 95% CI -3.81 to 1.41, 1 trial, 46 participants; end scores; HAM-D scale; very low-certainty evidence). None of the included trials assessed participant-rated changes in symptoms of ADHD, or clinical impression of severity or improvement in participants treated with IR methylphenidate compared with lithium. Adverse events were poorly assessed and reported. We rated all trials at high risk of bias due to selective outcome reporting of harms and masking of outcome assessors (failure to blind outcome assessor to measure adverse events). Overall, four trials with 203 participants who received IR methylphenidate and 141 participants who received placebo described the occurrence of harms. The use of IR methylphenidate in these trials increased the risk of gastrointestinal complications (RR 1.96, 95% CI 1.13 to 2.95) and loss of appetite (RR 1.77, 95% CI 1.06 to 2.96). Cardiovascular adverse events were reported inconsistently, preventing a comprehensive analysis. One trial comparing IR methylphenidate to lithium reported five and nine adverse events, respectively. We considered four trials to have notable concerns of vested interests influencing the evidence, and authors from two trials omitted information related to the sources of funding and conflicts of interest. AUTHORS' CONCLUSIONS: We found no certain evidence that IR methylphenidate compared with placebo or lithium can reduce symptoms of ADHD in adults (low- and very low-certainty evidence). Adults treated with IR methylphenidate are at increased risk of gastrointestinal and metabolic-related harms compared with placebo. Clinicians should consider whether it is appropriate to prescribe IR methylphenidate, given its limited efficacy and increased risk of harms. Future RCTs should explore the long-term efficacy and risks of IR methylphenidate, and the influence of conflicts of interest on reported effects.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/administração & dosagem , Metilfenidato/administração & dosagem , Adulto , Antidepressivos de Segunda Geração/administração & dosagem , Ansiedade/tratamento farmacológico , Viés , Bupropiona/administração & dosagem , Estimulantes do Sistema Nervoso Central/efeitos adversos , Depressão/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Feminino , Flavonoides/administração & dosagem , Humanos , Compostos de Lítio/administração & dosagem , Masculino , Metilfenidato/efeitos adversos , Pessoa de Meia-Idade , Placebos/administração & dosagem , Extratos Vegetais/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Adulto JovemRESUMO
Elevated frequency of Th17-like cells expressing Toll-like receptors (TLRs) has been recently associated with relapsing-remitting multiple sclerosis (MS) pathogenesis, a chronic inflammatory demyelinating autoimmune disease of the central nervous system. We aimed to investigate the impact of current major depressive disorder (MDD) on the behaviour of these cells following in vitro stimulation with TLR2, TLR4, TLR5 and TLR9 agonists. Here, the level of both cell proliferation and cytokine production related to Th17/Tc17 phenotypes in response to TLR2 (Pam3C) and TLR4 (LPS) ligands was significantly higher in CD4+ and CD8+ T-cell cultures from MS/MDD patients when compared to non-depressed patients. These cytokine levels were positively associated with neurological disabilities in patients. No difference for responsiveness to TLR5 (flagellin) and TLR9 (ODN) agonists was observed. LPS, but not Pam3C, induced significant IL-10 release, mainly in patients without MDD. Interestingly, more intense expression of TLR2 and TLR4 on these cells was observed in MDD patients. Finally, in vitro addition of serotonin and treatment of MDD patients with selective serotonin reuptake inhibitors (SSRIs) reduced the production of Th17/Tc17-related cytokines by CD4+ and CD8+ T cells in response to Pam3C and LPS. However, only SSRI therapy diminished the frequency and intensity of TLR2 and TLR4 expression on circulating CD4+ and CD8+ T cells. In summary, although preliminary, our findings suggest that adverse events that elevate circulating levels of TLR2 and TLR4 ligands can affect MS pathogenesis, particularly among depressed patients.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Fluoxetina/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Esclerose Múltipla Recidivante-Remitente/imunologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Células Th17/efeitos dos fármacos , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Adulto , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/imunologia , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/metabolismo , Fenótipo , Células Th17/imunologia , Células Th17/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
Although serotonin has been extensively studied in many species, there is a lack of information in ruminants, and no research has been evaluated if its precursor, 5-hydroxytryptophan (5-HTP), administered into the abomasum may be used as a means to manipulate serotonin metabolism. Thus, the objective of this study was to evaluate if intra-abomasal infusion of 5-HTP increases circulating serotonin in the steer. Eight Holstein steers (471 ± 8.9 kg) were used in a replicated 4 × 4 Latin Square design experiment. The treatments were intra-abomasal infusion of 5-HTP at 0.5, 1, 2.5, and 5 mg/kg BW. Blood was collected at 0, 2, 4, 6, 8, and 24 h after infusion. The serum concentration of 5-HTP increased quadratically (P = 0.005) with a peak at 2 h after administration. The 5-HTP administration increased (P < 0.05) serum serotonin in comparison with baseline with no difference (P > 0.05) between the doses of 5-HTP. When 5-HTP was dosed at 2.5 mg/kg BW or higher, intake decreased, and there was an altered manure consistency. The serum 5-hydroxyindole acetic acid concentrations followed the same pattern as 5-HTP. Plasma glucose content was not affected (P > 0.05) by 5-HTP dosing. However, free fatty acids concentration in the plasma was lower (P > 0.05) compared with baseline for the infusion levels of 0.5 and 1 mg/kg BW. Intra-abomasal infusion of 5-HTP efficiently increases serum serotonin cattle.
Assuntos
5-Hidroxitriptofano/farmacologia , Antidepressivos de Segunda Geração/farmacologia , Bovinos/fisiologia , Serotonina/biossíntese , Animais , Glicemia , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , MasculinoRESUMO
Venlafaxine (VEN) is a P-glycoprotein (P-gp) substrate, and nifedipine has been described by in vitro and experimental studies as a P-gp inhibitor. The present study aimed to investigate whether nifedipine alters the kinetic disposition of VEN enantiomers and their metabolites in healthy subjects. A crossover study was conducted in 10 healthy subjects phenotyped as extensive metabolizers for cytochrome P450 (CYP) 2D6, CYP2C19, and CYP3A. In phase 1, the subjects received a single oral dose of 150 mg racemic VEN, and in phase 2, a single oral dose of 40 mg nifedipine was administered with the VEN treatment. Plasma concentrations of VEN enantiomers and their metabolites O-desmethylvenlafaxine and N, O- didesmethylvenlafaxine (ODV and DDV, respectively) were evaluated by liquid chromatography with tandem mass spectrometry up to 72 hours after drug administration. Phase 2 was compared with phase 1 using the 90% confidence interval (CI) of the ratio of geometric means for Cmax and area under the curve (AUC). AUC enantiomeric ratios S-(+)/R-(-) were evaluated within each and between phases using the Wilcoxon test (P ≤ .05). The kinetic disposition of VEN was enantioselective (phase 1) with VEN S-(+)/R-(-) AUC ratio median of 2.83 (AUC0-∞ , 526 vs 195 ng·h/mL). However, AUC median did not differ between enantiomers for the metabolites ODV (1971 vs 2226 ng·h/mL) and DDV (199 vs 151 ng·h/mL). The 90%CI of the ratio of geometric means showed that the phases are bioequivalent. A single oral dose of 40 mg nifedipine did not alter VEN enantiomer pharmacokinetics in healthy subjects.
Assuntos
Antidepressivos de Segunda Geração/farmacocinética , Nifedipino/farmacologia , Cloridrato de Venlafaxina/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Cromatografia Líquida , Estudos Cross-Over , Cicloexanóis/sangue , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Succinato de Desvenlafaxina/sangue , Interações Medicamentosas , Humanos , Masculino , Fenótipo , Estereoisomerismo , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
The treatment of a man who attempted suicide after experiencing symptoms of anxiety and aggressiveness associated with the use of androgenic-anabolic steroids (AAS) is described. This report includes 30 days of inpatient treatment and a 6-month follow-up. Regular use of fluoxetine apparently prevented the onset of anxiety, depression, aggressiveness, and suicide ideation, even with the concurrent use of AAS. The urinary concentration of androgens, metabolites of AAS, and fluoxetine were monitored through analysis of urinary samples by the Brazilian Laboratory of Doping Control. Our results are congruent with previous findings describing the risk of suicide prompted by AAS use as well as the efficacy of fluoxetine in the treatment of mood disorders associated with the use of anabolic steroids.
Assuntos
Agressão/efeitos dos fármacos , Antidepressivos de Segunda Geração/uso terapêutico , Ansiedade/prevenção & controle , Fluoxetina/uso terapêutico , Tentativa de Suicídio/prevenção & controle , Congêneres da Testosterona/efeitos adversos , Adulto , Ansiedade/induzido quimicamente , Depressão/prevenção & controle , Humanos , Masculino , Adulto JovemRESUMO
Discovery of the rapid antidepressant effect of ketamine has been considered one of the most important advances in major depressive disorder treatment. Several studies report a significant benefit to patients that lasts up to 19 days after treatment. However, concerns arise from the long-term use of ketamine, thus a safe and effective strategy for maintaining its antidepressant effect is still necessary. To this end, our work assessed the effects of imipramine and fluoxetine after repeated ketamine treatment in male mice. Ketamine (30 mg/kg/day for 14 days) induced an anti-immobility effect in the forced swimming (FS) paradigm, detected 1 and 3 days after treatment. Seven days after the last ketamine injection, mice received imipramine (20 mg/kg) or fluoxetine (30 mg/kg). Imipramine and fluoxetine did not change mice's immobility time, regardless of the pre-treatment (saline or ketamine). Since both drugs' anti-immobility effect was demonstrated in the classical FS test, we can assume that repeated exposure to intermittent stress inhibited the antidepressant drugs' anti-immobility effects. Moreover, pre-exposure to ketamine did not counteract stress-induced changes in mice response to antidepressants. Since exposure to forced swim and i.p. injections are stressful to rodents, each stressor's contribution to the blunted response to antidepressants was investigated. Our data demonstrated that both stressors (FS and i.p. injections) influenced the reported effect. In summary, our results showed that exposure to intermittent repeated stress inhibited the anti-immobility effect of imipramine and fluoxetine in mice and corroborated findings demonstrating that exposure to stress can blunt patients' response to antidepressants.
Assuntos
Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos Tricíclicos/administração & dosagem , Fluoxetina/administração & dosagem , Imipramina/administração & dosagem , Ketamina/administração & dosagem , Estresse Psicológico/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , CamundongosRESUMO
Several attempts have been made to understand the role of cholecalciferol (vitamin D3) in the modulation of neuropsychiatric disorders. Notably, the deficiency of vitamin D3 is considered a pandemic and has been postulated to enhance the risk of major depressive disorder (MDD). Therefore, this study aims to investigate the antidepressant-like effect of cholecalciferol in a mouse model of depression induced by corticosterone, and the possible role of glucocorticoid receptors (GR), NLRP3 and autophagic pathways in this effect. Corticosterone administration (20 mg/kg, p.o., for 21 days) significantly increased the immobility time and grooming latency, as well as reduced the total time spent grooming in mice subjected to the tail suspension test (TST) and splash test (ST), respectively. Importantly, these behavioral alterations were associated with reduced GR immunocontent in the hippocampus of mice. Conversely, the repeated administration of cholecalciferol (2.5 µg/kg, p.o.) in the last 7 days of corticosterone administration was effective to prevent the increased immobility time in the TST and the reduced time spent grooming in the ST, and partially abolished the increase in the grooming latency induced by corticosterone, suggesting its antidepressant-like effect. These behavioral effects were similar to those exerted by fluoxetine (10 mg/kg, p.o.). Moreover, the corticosterone-induced reduction on hippocampal GR immunocontent was not observed in mice treated with cholecalciferol. Additionally, cholecalciferol treatment per se reduced the immunocontent of NLRP3 inflammasome-related proteins ASC, caspase-1, and TXNIP in the hippocampus of mice. No alterations on hippocampal immunocontent of the autophagic-related proteins phospho-mTORC1, beclin-1, and LC3A/B were observed following cholecalciferol treatment and/or corticosterone administration. Collectively, our results provide insights into the effects of cholecalciferol in depression-related behaviors that seem to be related, at least in part, to GR modulation.
Assuntos
Proteína Beclina-1/metabolismo , Colecalciferol/farmacologia , Corticosterona/administração & dosagem , Depressão/prevenção & controle , Hipocampo/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Receptores de Glucocorticoides/efeitos dos fármacos , Animais , Antidepressivos de Segunda Geração/farmacologia , Comportamento Animal/efeitos dos fármacos , Fluoxetina/farmacologia , Hipocampo/metabolismo , Masculino , Camundongos , Receptores de Glucocorticoides/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: Fluoxetine, antidepressant widely-used during pregnancy, is a selective inhibitor for P-glycoprotein (P-gp). Fexofenadine, an in vivo P-gp probe, is an antihistamine drug for seasonal allergic rhinitis and chronic urticaria treatment during pregnancy and it is available as a racemic mixture. This study evaluated the chiral discrimination of P-gp investigating the effect of fluoxetine on maternal-fetal pharmacokinetics of fexofenadine. METHODS: Healthy parturient women received either a single oral dose of 60 mg racemic fexofenadine (Control group; n = 8) or a single oral dose of 40 mg racemic fluoxetine 3 h before a single oral dose of 60 mg racemic fexofenadine (Interaction group; n = 8). Maternal blood and urine samples were collected up to 48 h after fexofenadine administration. At delivery, maternal-placental-fetal blood samples were collected. RESULTS: The maternal pharmacokinetics of fexofenadine was enantioselective (AUC0-∞R-(+)/S-(-) ~ 1.5) in both control and interaction groups. Fluoxetine increased AUC0-∞ (267.7 vs 376.1 ng.h/mL) and decreased oral total clearance (105.1 vs 74.4 L/h) only of S-(-)-fexofenadine, whereas the renal clearance were reduced for both enantiomers, suggesting that the intestinal P-gp-mediated transport of S-(-)-fexofenadine is influenced by fluoxetine to a greater extent that the R-(+)-fexofenadine. However, the transplacental transfer of fexofenadine is low (~16%), non-enantioselective and non-influenced by fluoxetine. CONCLUSIONS: A single oral dose of 40 mg fluoxetine inhibited the intestinal P-gp mediated transport of S-(-)-fexofenadine to a greater extent than R-(+)-fexofenadine in parturient women. However, the placental P-gp did not discriminate fexofenadine enantiomers and was not inhibited by fluoxetine.
Assuntos
Antidepressivos de Segunda Geração/administração & dosagem , Fluoxetina/administração & dosagem , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacocinética , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Parto , Terfenadina/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Antidepressivos de Segunda Geração/efeitos adversos , Estudos de Casos e Controles , Interações Medicamentosas , Feminino , Sangue Fetal/metabolismo , Fluoxetina/efeitos adversos , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Antagonistas não Sedativos dos Receptores H1 da Histamina/sangue , Humanos , Mucosa Intestinal/metabolismo , Troca Materno-Fetal , Circulação Placentária , Gravidez , Terfenadina/administração & dosagem , Terfenadina/sangue , Terfenadina/farmacocinética , Adulto JovemRESUMO
Objective: We investigated whether single nucleotide polymorphisms (SNPs) associated with neuroplasticity and activity of monoamine neurotransmitters, such as the brain-derived neurotrophic factor (BDNF, rs6265), the serotonin transporter (SLC6A4, rs25531), the tryptophan hydroxylase 1 (TPH1, rs1800532), the 5-hydroxytryptamine receptor 2A (HTR2A, rs6311, rs6313, rs7997012), and the catechol-O-methyltransferase (COMT, rs4680) genes, are associated with efficacy of transcranial direct current stimulation (tDCS) in major depression. Methods: Data from the Escitalopram vs. Electrical Current Therapy for Treating Depression Clinical Study (ELECT-TDCS) were used. Participants were antidepressant-free at baseline and presented with an acute, moderate-to-severe unipolar depressive episode. They were randomized to receive escitalopram/tDCS-sham (n=75), tDCS/placebo-pill (n=75), or placebo-pill/sham-tDCS (n=45). General linear models assessed the interaction between treatment group and allele-wise carriers. Additional analyses were performed for each group and each genotype separately. Results: Pairwise group comparisons (tDCS vs. placebo, tDCS vs. escitalopram, and escitalopram vs. placebo) did not identify alleles associated with depression improvement. In addition, exploratory analyses also did not identify any SNP unequivocally associated with improvement of depression in any treatment group. Conclusion: Larger, combined datasets are necessary to identify candidate genes for tDCS response.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Adulto Jovem , Citalopram/uso terapêutico , Antidepressivos de Segunda Geração/uso terapêutico , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/terapia , Estimulação Transcraniana por Corrente Contínua , Catecol O-Metiltransferase/genética , Método Duplo-Cego , Resultado do Tratamento , Terapia Combinada , Fator Neurotrófico Derivado do Encéfalo/genética , Polimorfismo de Nucleotídeo Único , Receptor 5-HT2A de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Oxigenases de Função Mista/genética , Pessoa de Meia-Idade , Antidepressivos/uso terapêuticoRESUMO
OBJECTIVE: We investigated whether single nucleotide polymorphisms (SNPs) associated with neuroplasticity and activity of monoamine neurotransmitters, such as the brain-derived neurotrophic factor (BDNF, rs6265), the serotonin transporter (SLC6A4, rs25531), the tryptophan hydroxylase 1 (TPH1, rs1800532), the 5-hydroxytryptamine receptor 2A (HTR2A, rs6311, rs6313, rs7997012), and the catechol-O-methyltransferase (COMT, rs4680) genes, are associated with efficacy of transcranial direct current stimulation (tDCS) in major depression. METHODS: Data from the Escitalopram vs. Electrical Current Therapy for Treating Depression Clinical Study (ELECT-TDCS) were used. Participants were antidepressant-free at baseline and presented with an acute, moderate-to-severe unipolar depressive episode. They were randomized to receive escitalopram/tDCS-sham (n=75), tDCS/placebo-pill (n=75), or placebo-pill/sham-tDCS (n=45). General linear models assessed the interaction between treatment group and allele-wise carriers. Additional analyses were performed for each group and each genotype separately. RESULTS: Pairwise group comparisons (tDCS vs. placebo, tDCS vs. escitalopram, and escitalopram vs. placebo) did not identify alleles associated with depression improvement. In addition, exploratory analyses also did not identify any SNP unequivocally associated with improvement of depression in any treatment group. CONCLUSION: Larger, combined datasets are necessary to identify candidate genes for tDCS response.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Citalopram/uso terapêutico , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/terapia , Estimulação Transcraniana por Corrente Contínua , Adolescente , Adulto , Idoso , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Catecol O-Metiltransferase/genética , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptor 5-HT2A de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Resultado do Tratamento , Triptofano Hidroxilase/genética , Adulto JovemRESUMO
BACKGROUND: Major depressive disorder (MDD) has been linked to episodic memory deficits that may be improved after pharmacological treatment, but it is unclear whether there is a class of antidepressants that is more effective than others to ameliorate these deficits in MDD. In addition, the possible effects of clinical and sociodemographic variables on the improvement of MDD memory deficits after pharmacological treatment are currently unknown. Our aims are to study the possible neuropsychological effects of second-generation antidepressant classes on the episodic memory of MDD patients and to study the potential effects of clinical and demographic variables as moderators of the effects of antidepressants on the memory of depressed patients through a meta-analysis approach. PROCEDURES: Nine articles were included in our study. A structural equation model meta-analysis was performed. RESULTS: Our results suggest that selective serotonin reuptake inhibitors and serotonine-noradrenaline reuptake inhibitors would bring about a substantial improvement in the memory of depressed patients, whereas other antidepressant classes would cause rather modest effects. Our results also suggest that clinical and demographic variables play a very important role as mediators of memory improvement after MDD treatment. Thus, a relatively low level of symptom severity, a high degree of clinical improvement, a younger age, and more years of education were positively related to memory improvement after MDD treatment. CONCLUSIONS: Although antidepressant class is an important variable linked to memory improvement in MDD, overall, the degree of memory amelioration in depression is very closely related to clinical and demographic variables of patients with depression.
Assuntos
Afeto/efeitos dos fármacos , Antidepressivos de Segunda Geração/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Memória Episódica , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Adulto , Idoso , Antidepressivos de Segunda Geração/efeitos adversos , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores da Recaptação de Serotonina e Norepinefrina/efeitos adversos , Resultado do TratamentoRESUMO
Fluoxetine (FLX) is a selective serotonin reuptake inhibitor (SSRI) antidepressant widely used in clinics and very often found in environmental samples of urban aquatic ecosystems in concentrations ranging from ng/L to µg/L. Fish populations might be especially susceptible to FLX due to the presence of conserved cellular receptors of serotonin. Neurotoxic effects on fish biota of polluted water bodies may be expected, but there are no sufficient studies in the current literature to elucidate this hypothesis. Batteries of embryo larval assays with zebrafish were performed to evaluate the potential effects of FLX exposure, including environmentally relevant concentrations. Evaluated parameters included survival, development, behaviour and neuronal biochemical markers. Regarding acute toxicity, a 168â¯h-LC50 value of 1.18â¯mg/L was obtained. Moreover, hatching delay and loss of equilibrium were observed, but at a concentration level much higher than FLX measured environmental concentrations (>100⯵g/L). On the other hand, effects on locomotor and acetylcholinesterase activity (≥0.88 and 6⯵g/L, respectively) were found at levels close to the maximum reported FLX concentration in surface waters. Altogether, these results suggest that FLX is neurotoxic to early life stages of zebrafish, in a short period of time causing changes in important ecological attributes which can probably be linked from molecular to population level.
Assuntos
Comportamento Animal/efeitos dos fármacos , Inibidores da Colinesterase/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Fluoxetina/toxicidade , Proteínas do Tecido Nervoso/antagonistas & inibidores , Poluentes Químicos da Água/toxicidade , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Antidepressivos de Segunda Geração/efeitos adversos , Biomarcadores/metabolismo , Resistência a Medicamentos , Embrião não Mamífero/enzimologia , Larva/efeitos dos fármacos , Larva/enzimologia , Larva/crescimento & desenvolvimento , Dose Letal Mediana , Proteínas do Tecido Nervoso/metabolismo , Concentração Osmolar , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Especificidade da Espécie , Testes de Toxicidade Aguda , Peixe-Zebra/embriologia , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/metabolismoRESUMO
OBJECTIVE: To determine the frequency of paroxetine use in adolescent patients under 20 years of age enrolled in the Colombian Health System. MATERIAL AND METHODS: Cross-sectional study, based on a population database of people enrolled in the Colombian Health System between January 1, 2011 and December 31, 2015. The sample included patients under 20 years of age who had received any presentation of paroxetine. For data analysis, frequencies and proportions were established. RESULTS: 777 subjects were prescribed with paroxetine during the five years of evaluation, with an average age of 53.8 ± 16.2 years. Only 36 patients under 20 received it, especially men (n=24, 64.8%) with a mean age of 17.7 ± 1.8 years. Most of them were being treated in the city of Bogotá (58.3%), followed by Medellín (16.7%) and Cartagena (8.3%). CONCLUSIONS: A low proportion of adolescents are receiving paroxetine in Colombia, which reduces the risk that this drug may pose on them.
OBJETIVO: Determinar la frecuencia de uso de paroxetina en pacientes adolescentes menores de 20 años afiliados al sistema de salud colombiano. MÉTODOS: Estudio de corte transversal, a partir de una base de datos poblacional de personas afiliadas al Sistema General de Seguridad Social en Colombia entre primero de enero 2011 y 31 diciembre 2015 buscando los pacientes menores de 20 años que hubiesen recibido cualquier presentación de paroxetina. Para el análisis de datos se establecieron frecuencias y proporciones. RESULTADOS: Se hallaron 777 sujetos prescritos con paroxetina durante los cinco años de evaluación, con edad promedio de 53,8±16, dos años Solo 36 pacientes menores de 20 años lo recibían, especialmente hombres (n=24; 64,8%) con edad media de 17,7±1,8 años. La mayoría estaban siendo tratados en la ciudad de Bogotá (58,3%), seguidos de Medellín (16,7%) y Cartagena (8,3%). CONCLUSIONES: Una baja proporción de adolescentes están recibiendo paroxetina en Colombia lo que reduce el riesgo que puede representar este fármaco para ellos.