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1.
Nervenarzt ; 95(7): 622-629, 2024 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-38916664

RESUMO

In addition to trauma-focussed psychotherapy, pharmacological treatment is often unavoidable, especially in patients with severe posttraumatic stress disorder (PTSD). As long as comorbid disorders do not dictate the pharmacotherapy approach, sertraline and paroxetine, along with other off-label prescribable substances approved in Germany, can be used for the treatment of PTSD. Venlafaxine, in particular, has shown good effectiveness in studies, whereas risperidone has shown lower effectiveness in augmentation. Overall, only a small to medium effect size is to be expected for all substances. Psychopharmacotherapy plays an important role in addressing sleep disorders, which are highly prevalent in PTSD. Treatment of trauma-related nightmares can be attempted with doxazosin or clonidine. In contrast, there are limited empirical data available for sleep disorders associated with PTSD, but the pharmacological treatment of insomnia can provide some guidance.


Assuntos
Transtornos de Estresse Pós-Traumáticos , Transtornos de Estresse Pós-Traumáticos/terapia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/psicologia , Humanos , Resultado do Tratamento , Sertralina/uso terapêutico , Medicina Baseada em Evidências , Transtornos do Sono-Vigília/tratamento farmacológico , Transtornos do Sono-Vigília/terapia , Paroxetina/uso terapêutico , Terapia Combinada , Distúrbios do Início e da Manutenção do Sono/terapia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico
2.
EBioMedicine ; 104: 105165, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38776596

RESUMO

BACKGROUND: Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. METHODS: We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. FINDINGS: After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. INTERPRETATION: Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. FUNDING: National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.


Assuntos
Transtornos de Ansiedade , Citocromo P-450 CYP2D6 , Paroxetina , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , China , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , População do Leste Asiático , Genótipo , Paroxetina/administração & dosagem , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Resultado do Tratamento
3.
J Pharm Biomed Anal ; 245: 116148, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38652939

RESUMO

Desvenlafaxine (O-desmethylvenlafaxine) and paroxetine are antidepressants that inhibit serotonin reuptake. Despite their relatively safe profiles, several serious side effects, including serotonin syndrome, bleeding, mania, and high blood pressure, are observed. We report the confirmation of the death of a 41-year-old female, with an overdose of desvenlafaxine and paroxetine suspected as the main cause of death. To quantify the level of desvenlafaxine and paroxetine in whole blood and urine, solid phase extraction combined with liquid chromatography-tandem mass spectrometry was developed and validated. Calibration curves were linear with coefficients of determination (r2) >0.999 for desvenlafaxine and paroxetine. The limits of detection and the limits of quantification for both desvenlafaxine and paroxetine were 0.001 µg/mL and 0.02 µg/mL, respectively. Desvenlafaxine and paroxetine were detected in the postmortem samples, along with various psychiatric drugs, and the blood alcohol content level was below 0.010%. The concentrations of desvenlafaxine and paroxetine in the heart blood were 11.0 µg/mL and 2.1 µg/mL, respectively, indicating lethal concentrations. In the urine, the concentrations of desvenlafaxine and paroxetine were 87.7 µg/mL and 3.5 µg/mL, respectively. This is the first report to determine the blood concentration of desvenlafaxine in a fatal intoxication caused by an overdose of desvenlafaxine single formulation.


Assuntos
Succinato de Desvenlafaxina , Overdose de Drogas , Paroxetina , Espectrometria de Massas em Tandem , Humanos , Succinato de Desvenlafaxina/sangue , Paroxetina/sangue , Feminino , Adulto , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodos , Extração em Fase Sólida/métodos , Evolução Fatal , Antidepressivos/intoxicação , Antidepressivos/sangue , Limite de Detecção , Inibidores Seletivos de Recaptação de Serotonina/intoxicação , Inibidores Seletivos de Recaptação de Serotonina/sangue , Inibidores Seletivos de Recaptação de Serotonina/análise
4.
Arch Pharm Res ; 47(5): 481-504, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38664354

RESUMO

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder, social anxiety disorder, generalized anxiety disorder, and panic disorder. Venlafaxine is metabolized to the active metabolite desvenlafaxine mainly by CYP2D6. Genetic polymorphism of CYP2D6 and coadministration with other medications can significantly affect the pharmacokinetics and/or pharmacodynamics of venlafaxine and its active metabolite. This study aimed to establish the PBPK models of venlafaxine and its active metabolite related to CYP2D6 genetic polymorphism and to predict drug-drug interactions (DDIs) with clarithromycin and paroxetine in different CYP2D6 genotypes. Clinical pharmacogenomic data for venlafaxine and desvenlafaxine were collected to build the PBPK model. Physicochemical and absorption, distribution, metabolism, and excretion (ADME) characteristics of respective compounds were obtained from previously reported data, predicted by the PK-Sim® software, or optimized to capture the plasma concentration-time profiles. Model evaluation was performed by comparing the predicted pharmacokinetic parameters and plasma concentration-time profiles to the observed data. Predicted plasma concentration-time profiles of venlafaxine and its active metabolite were visually similar to the observed profiles and all predicted AUC and Cmax values for respective compounds were included in the twofold error range of observed values in non-genotyped populations and different CYP2D6 genotypes. When clarithromycin or clarithromycin plus paroxetine was concomitantly administered, predicted plasma concentration-time profiles of venlafaxine properly captured the observed profiles in two different CYP2D6 genotypes and all predicted DDI ratios for AUC and Cmax were included within the acceptance range. Consequently, the present model successfully captured the pharmacokinetic alterations of venlafaxine and its active metabolite according to CYP2D6 genetic polymorphism as well as the DDIs between venlafaxine and two CYP inhibitors. The present model can be used to predict the pharmacokinetics of venlafaxine and its active metabolite considering different races, ages, coadministered drugs, and CYP2D6 activity of individuals and it can contribute to individualized pharmacotherapy of venlafaxine.


Assuntos
Claritromicina , Citocromo P-450 CYP2D6 , Interações Medicamentosas , Genótipo , Modelos Biológicos , Paroxetina , Cloridrato de Venlafaxina , Cloridrato de Venlafaxina/farmacocinética , Cloridrato de Venlafaxina/administração & dosagem , Claritromicina/farmacocinética , Claritromicina/metabolismo , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Paroxetina/farmacocinética , Paroxetina/metabolismo , Adulto , Masculino , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacocinética , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Inibidores da Recaptação de Serotonina e Norepinefrina/metabolismo , Feminino , Polimorfismo Genético/genética , Adulto Jovem
5.
J Ment Health Policy Econ ; 27(1): 3-12, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38634393

RESUMO

BACKGROUND: Consensus-guidelines for prescribing antidepressants recommend that clinicians should be vigilant to match antidepressants to patient's medical history but provide no specific advice on which antidepressant is best for a given medical history. AIMS OF THE STUDY: For patients with major depression who are in psychotherapy, this study provides an empirically derived guideline for prescribing antidepressant medications that fit patients' medical history. METHODS: This retrospective, observational, cohort study analyzed a large insurance database of 3,678,082 patients. Data was obtained from healthcare providers in the U.S. between January 1, 2001, and December 31, 2018. These patients had 10,221,145 episodes of antidepressant treatments. This study reports the remission rates for the 14 most commonly prescribed single antidepressants (amitriptyline, bupropion, citalopram, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, mirtazapine, nortriptyline, paroxetine, sertraline, trazodone, and venlafaxine) and a category named "Other" (other antidepressants/combination of antidepressants). The study used robust LASSO regressions to identify factors that affected remission rate and clinicians' selection of antidepressants. The selection bias in observational data was removed through stratification. We organized the data into 16,770 subgroups, of at least 100 cases, using the combination of the largest factors that affected remission and selection bias. This paper reports on 2,467 subgroups of patients who had received psychotherapy. RESULTS: We found large, and statistically significant, differences in remission rates within subgroups of patients. Remission rates for sertraline ranged from 4.5% to 77.86%, for fluoxetine from 2.86% to 77.78%, for venlafaxine from 5.07% to 76.44%, for bupropion from 0.5% to 64.63%, for desvenlafaxine from 1.59% to 75%, for duloxetine from 3.77% to 75%, for paroxetine from 6.48% to 68.79%, for escitalopram from 1.85% to 65%, and for citalopram from 4.67% to 76.23%. Clearly these medications are ideal for patients in some subgroups but not others. If patients are matched to the subgroups, clinicians can prescribe the medication that works best in the subgroup. Some medications (amitriptyline, doxepin, nortriptyline, and trazodone) always had remission rates below 11% and therefore were not suitable as single antidepressant therapy for any of the subgroups. DISCUSSIONS: This study provides an opportunity for clinicians to identify an optimal antidepressant for their patients, before they engage in repeated trials of antidepressants. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: To facilitate the matching of patients to the most effective antidepressants, this study provides access to a free, non-commercial, decision aid at http://MeAgainMeds.com. IMPLICATIONS FOR HEALTH POLICIES:  Policymakers should evaluate how study findings can be made available through fragmented electronic health records at point-of-care. Alternatively, policymakers can put in place an AI system that recommends antidepressants to patients online, at home, and encourages them to bring the recommendation to their clinicians at their next visit. IMPLICATIONS FOR FURTHER RESEARCH:  Future research could investigate (i) the effectiveness of our recommendations in changing clinical practice, (ii) increasing remission of depression symptoms, and (iii) reducing cost of care. These studies need to be prospective but pragmatic. It is unlikely random clinical trials can address the large number of factors that affect remission.


Assuntos
Citalopram , Trazodona , Humanos , Citalopram/uso terapêutico , Fluoxetina/uso terapêutico , Paroxetina/uso terapêutico , Sertralina/uso terapêutico , Bupropiona/uso terapêutico , Nortriptilina/uso terapêutico , Amitriptilina , Cloridrato de Duloxetina , Cloridrato de Venlafaxina , Succinato de Desvenlafaxina , Escitalopram , Doxepina , Estudos Prospectivos , Estudos de Coortes , Estudos Retrospectivos , Antidepressivos/uso terapêutico , Psicoterapia
6.
Behav Brain Res ; 465: 114972, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38552744

RESUMO

The hippocampal salt-inducible kinase 2 (SIK2)-CREB-regulated transcription co-activator 1 (CRTC1) system has been demonstrated to participate in not only the pathogenesis of depression but also the antidepressant mechanisms of several antidepressant medications including fluoxetine, paroxetine, and mirtazapine. Like fluoxetine, paroxetine is also a widely used selective serotonin (5-HT) reuptake inhibitor (SSRI). Recent studies have indicated that paroxetine also modulates several pharmacological targets other than the 5-HT system. Here, we speculate that paroxetine regulates the hippocampal SIK2-CRTC1 system. Chronic stress models of depression, various behavioral tests, western blotting, co-immunoprecipitation, quantitative real-time reverse transcription PCR, and genetic knockdown were used together in the present study. Our results show that the antidepressant actions of paroxetine in mice models of depression were accompanied by its preventing effects against chronic stress on hippocampal SIK2, CRTC1, and CRTC1-CREB binding. In contrast, genetic knockdown of hippocampal CRTC1 notably abrogated the antidepressant effects of paroxetine in mice. In summary, regulating hippocampal SIK2 and CRTC1 participates in the antidepressant mechanism of paroxetine, extending the knowledge of its pharmacological targets.


Assuntos
Fluoxetina , Paroxetina , Animais , Camundongos , Antidepressivos/farmacologia , Fluoxetina/farmacologia , Hipocampo/metabolismo , Paroxetina/farmacologia , Serotonina/metabolismo
7.
CNS Drugs ; 38(4): 255-265, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38485889

RESUMO

Compulsive sexual behavior disorder (CSBD) has recently been recognized as a psychiatric disorder. Pharmacological treatments for CSBD have received little study and thus have limited empirical support. The main objective of the present work is to review existing literature on the efficacy of different drugs on the symptomatology of CSBD, including the subtype of problematic pornography use (PPU). The main pharmacological approaches to treating CSBD have included opioid antagonists (naltrexone and nalmefene), selective serotonin reuptake inhibitors (paroxetine, citalopram, fluoxetine, and sertraline), mood stabilizers (topiramate), tricyclic antidepressants (clomipramine), serotonin antagonist and reuptake inhibitors (nefazodone), and N-acetylcysteine. Since people with CSBD may experience different co-occurring disorders, these should be considered when choosing the best pharmacological treatment. Pharmacological therapy for CSBD/PPU has been suggested as an adjunct to psychological therapies, which, for the moment, have the most empirical evidence. However, to evaluate the efficacy of most of the drugs presented in this narrative review, data to date have only been available from case studies. Thus, empirical support is scant and generalizability of results is limited, highlighting the need for more research in this area.


Assuntos
Transtorno do Comportamento Sexual Compulsivo , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Paroxetina/uso terapêutico , Sertralina/uso terapêutico , Fluoxetina , Comportamento Compulsivo/tratamento farmacológico , Comportamento Compulsivo/psicologia
8.
Biochem Pharmacol ; 223: 116184, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38556027

RESUMO

Treatment of major depressive disorder remains a major unmet clinical need. Given the advantages of intranasal administration for targeted brain delivery, the present study aimed at investigating the pharmacokinetics of paroxetine, after its intranasal instillation and assessing its potential therapeutic effect on female and male mice subjected to unpredictable chronic mild stress (UCMS) protocol. IN administration revealed direct nose-to-brain paroxetine delivery but dose- and sex-dependent differences. Pharmacokinetics was nonlinear and paroxetine concentrations were consistently higher in plasma and brain of male mice. Additionally, UCMS decreased animal preference for sucrose in both male and female mice following acute (p < 0.01) and chronic stress (p < 0.05), suggesting anhedonia. Both male and female mice exhibited depressive-like behavior in the forced swimming test. UCMS females displayed a significantly longer immobility time and shorter climbing time than the control group (p < 0.05), while no differences were found between male mice. Two weeks of paroxetine intranasal administration reduced immobility time and lengthened climbing and swimming time, approaching values similar to those observed in the healthy control group. The therapeutic effect was stronger on female mice. Importantly, melatonin plasma levels were significantly decreased in female mice following UCMS (p < 0.05), while males exhibited heightened corticosterone levels. On the other hand, treatment with IN paroxetine significantly increased corticosterone and melatonin levels in both sexes compared to healthy mice (p < 0.05). Intranasal paroxetine delivery undoubtedly ameliorated the behavioral despair, characteristic of depressive-like animals. Despite its efficiency in male and female mice subjected to UCMS, females were more prone to this novel therapeutic strategy.


Assuntos
Transtorno Depressivo Maior , Melatonina , Feminino , Camundongos , Masculino , Animais , Paroxetina/uso terapêutico , Administração Intranasal , Caracteres Sexuais , Corticosterona , Melatonina/uso terapêutico , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Estresse Psicológico/tratamento farmacológico
9.
J Affect Disord ; 355: 200-209, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38513773

RESUMO

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 , Paroxetina , Humanos , Paroxetina/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/induzido quimicamente , Frequência Cardíaca , Método Duplo-Cego , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
J Affect Disord ; 355: 422-425, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38537756

RESUMO

BACKGROUND: Patients with major depression often suffer from excessive interpersonal sensitivity, although it is not typically measured in antidepressant clinical trials. Preliminary evidence suggests selective serotonin reuptake inhibitors have the capacity to reduce interpersonal sensitivity. METHODS: This was a pooled analysis of data from 1709 patients in three randomized, double-blind, placebo-controlled trials of fluoxetine and paroxetine for acute major depressive disorder. Depressive symptoms were assessed with the Hamilton Depression Rating Scale. A factor from the Symptom Checklist was used to assess interpersonal sensitivity. Our outcome of interest was change from baseline scores at the last assessment (up to 8 or 12 weeks, depending on the trial). RESULTS: Both medications produced significantly greater reductions in interpersonal sensitivity relative to placebo. The effect of medication remained significant after controlling for depression improvement, which explained 18.5% of the variation in interpersonal sensitivity improvement among those treated with active medication. The effect of medication on depressive symptoms, relative to placebo, was not influenced by baseline interpersonal sensitivity. LIMITATIONS: The outcome measured interpersonal sensitivity over the last week, and the results do not necessarily reflect changes in long-standing, trait-like patterns of interpersonal sensitivity. Only two medications were studied. CONCLUSIONS: Selective serotonin reuptake inhibitors are effective at treating interpersonal sensitivity in acutely depressed patients. This appears to be a unique drug effect that is not only the result of depression improvement. Future clinical trials might benefit from assessing interpersonal sensitivity more routinely.


Assuntos
Transtorno Depressivo Maior , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Depressão , Antidepressivos/uso terapêutico , Paroxetina/uso terapêutico , Fluoxetina/uso terapêutico , Método Duplo-Cego , Resultado do Tratamento
11.
J Affect Disord ; 354: 152-159, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38479501

RESUMO

BACKGROUND: Preclinical studies suggested that drugs that functionally inhibit acid sphingomyelinase (FIASMA)may enhance immune cell longevity and potentially offer protection against infections. Many antidepressants have shown FIASMA activity. METHODS: We conducted a cohort study using primary-care data from the UK-based Clinical Practice Research Datalink (2000-2021). We assessed the association of composite diagnosed acute infections in new users of fluoxetine, sertraline, paroxetine, or venlafaxine aged 18-80 years compared to citalopram. We compared SARS-CoV-2 infections between groups in a secondary analysis. We estimated incidence rates (IR) and IR ratios (IRR) of acute infections in four pairwise comparisons using negative binomial regression. We applied propensity score (PS) fine stratification to control for confounding. RESULTS: In the PS-weighted cohorts, we included 353,138 fluoxetine, 222,463 sertraline, 69,963 paroxetine, 32,608 venlafaxine, and between 515,996 and 516,583 new citalopram users. PS-weighted IRs ranged between 76.8 acute infections /1000 person-years (py) (sertraline) and 98.9 infections/1000 py (citalopram). We observed PS-weighted IRRs around unity for paroxetine (0.97, 95 % CI, 0.95-1.00), fluoxetine (0.94, 95 % CI, 0.92-0.95), and venlafaxine (0.90, 95 % CI, 0.87-0.94) vs citalopram. Reduced IRR for sertraline vs citalopram (0.84, 95 % CI, 0.82-0.85), became null within subgroups by cohort entry date. In the analysis of SARS-CoV-2 infection, no statistically relevant risk reduction was seen. LIMITATIONS: Analysis not limited to patients with diagnosed depression, possible underestimation of infection incidence, and unclear FIASMA activity of citalopram. CONCLUSIONS: Fluoxetine, sertraline, paroxetine, and venlafaxine were not associated with a reduced risk of acute infection when compared with the presumably weak FIASMA citalopram.


Assuntos
Paroxetina , Sertralina , Humanos , Sertralina/efeitos adversos , Paroxetina/efeitos adversos , Fluoxetina , Citalopram , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Cloridrato de Venlafaxina , Estudos de Coortes , Antidepressivos/efeitos adversos
12.
J Affect Disord ; 352: 201-213, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38346646

RESUMO

OBJECTIVES: Selective serotonin reuptake inhibitors (SSRIs) are the first-line anti-depressants. Unfortunately, about 30 % depressed patients do not effectively respond to SSRIs. It is still unclear that the gastrointestinal characteristics of responders and non-responders, and the differences. METHODS: Herein, we characterized gut microbiome and metabolome of depressed rats with differential responses to Paroxetine (PX) by 16S rRNA sequencing and 1H NMR-based metabolomics, respectively. On top of this, we constructed both inter- and inner-layer networks, intuitively showing the correlations among behavioral indicators, immune factors, intestinal bacteria, and differential metabolites. RESULTS: Consequently, we found that depressed rats differently responded to PX, which could be divided into PX responsive (PX-R) and non-responsive (PX-N) groups. Firstly, the depressive behaviors of PX-R rats and PX-N rats significantly differed. Meanwhile, inflammatory balance was also characterized for depressed rats with different responses to PX. Overall, PX-R rats and PX-N rats exhibited differential gut microbiome and metabolome, including intestinal structures, intestinal functions, metabolic profiles, metabolites, and metabolic pathways. LIMITATIONS: Metabolites that identified by metabolomics based on 1H NMR are not comprehensive enough. CONCLUSIONS: Taken together, our study demonstrated that gut microbiome and metabolome, as well as related functions, are of significance in differential responses of depressed rats to PX, which might be novel insights in uncovering the mechanisms of differences in efficacies of antidepressants.


Assuntos
Microbiota , Paroxetina , Humanos , Ratos , Animais , Paroxetina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , RNA Ribossômico 16S/genética , Metaboloma , Metabolômica
13.
Hum Genomics ; 18(1): 11, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38303026

RESUMO

BACKGROUND: Individual assessment of CYP enzyme activities can be challenging. Recently, the potato alkaloid solanidine was suggested as a biomarker for CYP2D6 activity. Here, we aimed to characterize the sensitivity and specificity of solanidine as a CYP2D6 biomarker among Finnish volunteers with known CYP2D6 genotypes. RESULTS: Using non-targeted metabolomics analysis, we identified 9152 metabolite features in the fasting plasma samples of 356 healthy volunteers. Machine learning models suggested strong association between CYP2D6 genotype-based phenotype classes with a metabolite feature identified as solanidine. Plasma solanidine concentration was 1887% higher in genetically poor CYP2D6 metabolizers (gPM) (n = 9; 95% confidence interval 755%, 4515%; P = 1.88 × 10-11), 74% higher in intermediate CYP2D6 metabolizers (gIM) (n = 89; 27%, 138%; P = 6.40 × 10-4), and 35% lower in ultrarapid CYP2D6 metabolizers (gUM) (n = 20; 64%, - 17%; P = 0.151) than in genetically normal CYP2D6 metabolizers (gNM; n = 196). The solanidine metabolites m/z 444 and 430 to solanidine concentration ratios showed even stronger associations with CYP2D6 phenotypes. Furthermore, the areas under the receiver operating characteristic and precision-recall curves for these metabolic ratios showed equal or better performances for identifying the gPM, gIM, and gUM phenotype groups than the other metabolites, their ratios to solanidine, or solanidine alone. In vitro studies with human recombinant CYP enzymes showed that solanidine was metabolized mainly by CYP2D6, with a minor contribution from CYP3A4/5. In human liver microsomes, the CYP2D6 inhibitor paroxetine nearly completely (95%) inhibited the metabolism of solanidine. In a genome-wide association study, several variants near the CYP2D6 gene associated with plasma solanidine metabolite ratios. CONCLUSIONS: These results are in line with earlier studies and further indicate that solanidine and its metabolites are sensitive and specific biomarkers for measuring CYP2D6 activity. Since potato consumption is common worldwide, this biomarker could be useful for evaluating CYP2D6-mediated drug-drug interactions and to improve prediction of CYP2D6 activity in addition to genotyping.


Assuntos
Citocromo P-450 CYP2D6 , Diosgenina , Estudo de Associação Genômica Ampla , Humanos , Citocromo P-450 CYP2D6/genética , Paroxetina/farmacologia , Biomarcadores , Genótipo
14.
Pathog Dis ; 822024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38204138

RESUMO

Infections caused by Cryptococcus gattii mainly affect immunocompetent individuals and the treatment presents important limitations. This study aimed to validate the efficacy of selective serotonin reuptake inhibitors (SSRI), fluoxetine hydrochloride (FLH), and paroxetine hydrochloride (PAH) in vitro against C. gattii. The antifungal activity of SSRI using the microdilution method revealed a minimal inhibitory concentration (MIC) of 31.25 µg/ml. The combination of FLH or PAH with amphotericin B (AmB) was analyzed using the checkerboard assay and the synergistic effect of SSRI in combination with AmB was able to reduce the SSRI or AmB MIC values 4-8-fold. When examining the effect of SSRI on the induced capsules, we observed that FLH and PAH significantly decreased the size of C. gattii capsules. In addition, the effects of FLH and PAH were evaluated in biofilm biomass and viability. The SSRI were able to reduce biofilm biomass and biofilm viability. In conclusion, our results indicate the use of FLH and PAH exhibited in vitro anticryptococcal activity, representing a possible future alternative for the cryptococcosis treatment.


Assuntos
Cryptococcus gattii , Cryptococcus neoformans , Humanos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antifúngicos/farmacologia , Anfotericina B/farmacologia , Testes de Sensibilidade Microbiana , Fluoxetina/farmacologia , Paroxetina/farmacologia , Biofilmes
15.
Biol Pharm Bull ; 47(1): 328-333, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38296462

RESUMO

Alzheimer's disease (AD) is accompanied by behavioral and psychological symptoms of dementia (BPSD), which is often alleviated by treatment with psychotropic drugs, such as antidepressants, hypnotics, and anxiolytics. If these drugs also inhibit acetylcholinesterase (AChE) activity, they may contribute to the suppression of AD progression by increasing brain acetylcholine concentrations. We tested the potential inhibitory effects of 31 antidepressants, 21 hypnotics, and 12 anxiolytics on recombinant human AChE (rhAChE) activity. At a concentration of 10-4 M, 22 antidepressants, 19 hypnotics, and 11 anxiolytics inhibited rhAChE activity by <20%, whereas nine antidepressants (clomipramine, amoxapine, setiptiline, nefazodone, paroxetine, sertraline, citalopram, escitalopram, and mirtazapine), two hypnotics (triazolam and brotizolam), and one anxiolytic (buspirone) inhibited rhAChE activity by ≥20%. Brotizolam (≥10-6 M) exhibited stronger inhibition of rhAChE activity than the other drugs, with its pIC50 value being 4.57 ± 0.02. The pIC50 values of the other drugs were <4, and they showed inhibitory activities toward rhAChE at the following concentrations: ≥3 × 10-6 M (sertraline and buspirone), ≥10-5 M (amoxapine, nefazodone, paroxetine, citalopram, escitalopram, mirtazapine, and triazolam), and ≥3 × 10-5 M (clomipramine and setiptiline). Among these drugs, only nefazodone inhibited rhAChE activity within the blood concentration range achievable at clinical doses. Therefore, nefazodone may not only improve the depressive symptoms of BPSD through its antidepressant actions but also slow the progression of cognitive symptoms of AD through its AChE inhibitory actions.


Assuntos
Amoxapina , Ansiolíticos , Triazolam , Humanos , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Acetilcolinesterase , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Sertralina , Clomipramina , Mirtazapina , Paroxetina , Citalopram , Escitalopram , Buspirona , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico
16.
Sci Total Environ ; 917: 170405, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38280602

RESUMO

The functional conservation of important selective serotonin reuptake inhibitor (SSRI) targets in non-target organisms raises concerns about their potential adverse effects on the ecosystems. Although the environmental levels of SSRIs like paroxetine (PAR) have risen, the knowledge regarding the effects of long-term exposure to PAR is limited. This study investigated the impact of sub-chronic exposure (21 days) to two sub-lethal concentrations of PAR (40 and 400 µg/L) on the behaviour of adult zebrafish in different scenarios: basal activity (under dark and light conditions), stress response (evoked by sudden light transitions) and stress response recovery. A new framework was employed for the integrative study of fish's swimming performance based on their innate ability to respond to light shifts. Several swimming-associated parameters (e.g., total swimming distance, time of inactivity, swimming angles) and thigmotaxis were monitored for an integrated analysis in each scenario. Data revealed reduced swimming activity, impaired behavioural response to stress and alterations in stress recovery of PAR-exposed fish. An anxiolytic effect was particularly noticeable in fish basal swimming activity in the dark at 400 µg/L and in the behavioural response to stress (from dark to light) and stress recovery (from light to dark) for organisms exposed to 40 µg/L. The detected PAR-induced behavioural modifications suggest a disruption of brain glucocorticoid signalling that may have implications at the individual level (e.g., changing behavioural responses to predators), with potential repercussions on the population and community levels. Therefore, the applied protocol proved sensitive in detecting behavioural changes induced by PAR.


Assuntos
Paroxetina , Poluentes Químicos da Água , Animais , Paroxetina/toxicidade , Peixe-Zebra , Ecossistema , Comportamento Animal , Inibidores Seletivos de Recaptação de Serotonina , Natação , Poluentes Químicos da Água/toxicidade
17.
J Affect Disord ; 345: 394-403, 2024 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-38190276

RESUMO

BACKGROUND: Depressive disorder in adolescents is a major health problem with inadequate treatment. Omega-3 (ω3) polyunsaturated fatty acids are a promising adjuvant therapy in adult depression. The primary objective of this study was to investigate the efficacy of adjuvant ω3 treatment on depressive symptoms in adolescent depression. Secondarily, we explored the effects of ω3 on cognitive function and memory and niacin skin flushing response (NSFR), as their robust associations with adolescent depression. METHODS: A total of 71 adolescents with depression (aged 13-24; 59.2 % female) were randomly assigned to receive ω3 plus Paxil (n = 34) or Paxil alone (n = 37) for 12 weeks. Primary outcome was depression severity according to scores on Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes were cognitive function and memory, and NSFR. RESULTS: Significant improvements in depressive symptoms over time (p = 0.00027 at week 12) were observed in the ω3 + Paxil group compared with Paxil group. Additionally, in the ω3 + Paxil group, significant improvements in memory over time, and greater cognitive function and NSFR were also observed compared with the Paxil group; the NSFR was negatively correlated with MADRS scores at baseline. LIMITATIONS: The trial was open label; thus, the outcome measures should be viewed as preliminary since inherent bias in outcomes due to the potential of a placebo effect. CONCLUSIONS: Our results demonstrate that adjuvant ω3 treatment is effective for reducing depressive symptoms as well as improving cognitive function, memory and the NSFR; these results suggest ω3 is a promising adjuvant treatment for adolescent depression.


Assuntos
Niacina , Adulto , Adolescente , Feminino , Humanos , Masculino , Depressão/tratamento farmacológico , Paroxetina , Cognição , Suplementos Nutricionais
18.
Curr Neuropharmacol ; 22(4): 749-805, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37533247

RESUMO

Antidepressants are a commonly used, easily accessible, and overall safe treatment option for post-traumatic stress disorder (PTSD). The present review aims to evaluate the efficacy and safety of antidepressants in treating sleep disturbances in patients with PTSD. PubMed and the Cochrane Library were searched (July 2022) for systematic reviews and meta-analyses on the treatment of PTSD. Moreover, PubMed and ClinicalTrials.gov were searched for individual trials investigating the antidepressant treatment of PTSD (up to September 2022), and reference lists of all possibly relevant identified studies were screened. Sleep-related outcomes, i.e., total sleep time, sleep quality, dreams/ nightmares, insomnia, and somnolence, were extracted independently by at least two reviewers. Metaanalytic evaluations were performed wherever possible. 39 randomised controlled trials (RCTs) were identified; data from pooled analyses, reviews, and observational studies were used for antidepressants with a weak evidence base or when their findings were deemed important. Overall, scarce data exist on the effects of antidepressants on sleep outcomes among patients with PTSD. Some evidence may support the use of amitriptyline, nefazodone, paroxetine, and sertraline for improving sleep in patients with PTSD. Τhere was a meta-analytical trend indicating improvement of nightmares with fluoxetine, less insomnia with amitriptyline and more with brofaromine, as well as more somnolence with paroxetine vs. placebo, respectively. However, data from more than 1 RCT with a considerable number of patients were only available for paroxetine. Evidence is insufficient to draw safe conclusions. More and better-designed RCTs, with consistent reporting of sleep-related outcomes, are needed.


Assuntos
Distúrbios do Início e da Manutenção do Sono , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Paroxetina/efeitos adversos , Amitriptilina/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Sonolência , Revisões Sistemáticas como Assunto , Antidepressivos/uso terapêutico
19.
Andrology ; 12(3): 655-673, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37675929

RESUMO

BACKGROUND: Paroxetine, a selective serotonin reuptake inhibitor (SSRI) antidepressant, has caused male sexual dysfunction; however, the paroxetine mechanisms of action in testes are still unclear. OBJECTIVES: Paroxetine serotonergic effects in testes were evaluated, focusing on steroidogenesis and the correlation between macrophages population and possible TNF-α-derived oxidative stress. We also verified whether the changes are reversible following treatment interruption. MATERIALS AND METHODS: Adult rats received paroxetine (PG35 and PG65) or tap water (CG) for 35 days. PG65 was maintained without treatment for 30 more days. Intratesticular testosterone (IT), nitrite, and malondialdehyde concentrations were measured. To confirm serotonergic and estrogenic effects, Htr1b and Esr1 expressions were analyzed. The daily sperm production (DSP), frequency of abnormal seminiferous tubules (ST), SC number, ST area, and Leydig cells nuclear area (LCnu) were evaluated. TUNEL+ germ cells, M1 (CD68+ ), and M2 (Perls+ ) macrophages were quantified. 17ß-HSD7, CYP19A1, NDRG2, oxytocin, TNF-α, and iNOS were evaluated by immunoreactions. Oxytocin and NDRG2 protein levels as well as Tnfa mRNA expression were also analyzed. RESULTS: The Htr1b downregulation in testes confirmed the paroxetine serotonergic effect. The testicular sections showed abnormal ST frequency, ST atrophy and reduction of DSP, LCnu, SC number and Perls+ macrophages. TUNEL+ germ cells and LC were associated with strong NDRG2 immunoexpression. Paroxetine reduced IT levels and 17ß-HSD7 immunoexpression in parallel to increased CYP19A1, oxytocin, TNF-α and iNOS. Esr1 and Tnfa overexpression and increased number of CD68+ macrophages were also observed together with high nitrite and malondialdehyde levels. Most parameters were not recovered in PG65. CONCLUSIONS: Paroxetine serotonergic effect impairs LC steroidogenesis, via aromatization, increasing estrogen/testosterone ratio, which in turn upregulate NDRG2, promoting apoptosis, and impairing sperm production. Serotonin-estrogen pathways may be responsible for M2/M1 polarization, Tnfa upregulation, and induction of oxidative stress. The unrecovered testicular changes after treatment discontinuation are due to persistent paroxetine serotonin/estrogen effects.


Assuntos
Paroxetina , Testículo , Masculino , Ratos , Animais , Testículo/metabolismo , Paroxetina/farmacologia , Paroxetina/metabolismo , Serotonina , Fator de Necrose Tumoral alfa/metabolismo , Ocitocina , Nitritos/metabolismo , Nitritos/farmacologia , Sêmen , Testosterona/farmacologia , Estrogênios/metabolismo , Macrófagos , Malondialdeído/metabolismo , Malondialdeído/farmacologia
20.
J Am Board Fam Med ; 36(6): 1071-1086, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37704392

RESUMO

INTRODUCTION: Existing guidelines for primary care clinicians (PCCs) on the detection and management of perinatal depression (PD) contain important gaps. This review aims to provide PCCs with a summary of clinically relevant evidence in the field. METHODS: A narrative literature review was conducted by searching PubMed and PsycINFO for articles published between 2010 to 2023. Guidelines, systematic reviews, clinical trials, and/or observational studies were all examined. RESULTS: Screening with the Edinburgh Postnatal Depression Scale or Patient Health Questionnaire-9 followed by a diagnostic evaluation for major depressive disorder in probable cases can enhance PD detection. At-risk individuals and mild to moderate PD should be referred for cognitive behavioral therapy or interpersonal psychotherapy when available. Selective serotonin reuptake inhibitors should be used for moderate to severe PD, with sertraline, escitalopram, or citalopram being preferred first. Using paroxetine or clomipramine in pregnancy, and fluoxetine or doxepin during lactation is generally not preferred. Gestational antidepressant use is associated with a small increase in risk of reduced gestational age at birth, low birth weight, and lower APGAR scores, though whether these links are causal is unclear. Sertraline and paroxetine have the lowest rate of adverse events during lactation. Consequences of untreated PD can include maternal and offspring mortality, perinatal complications, poor maternal-infant attachment, child morbidity and maltreatment, less breastfeeding, and offspring developmental problems. CONCLUSIONS: These clinically relevant data can support the delivery of high-quality care by PCCs. Risks and benefits of PD treatments and the consequences of untreated PD should be discussed with patients to support informed decision making.


Assuntos
Transtorno Depressivo Maior , Paroxetina , Gravidez , Recém-Nascido , Feminino , Criança , Humanos , Paroxetina/efeitos adversos , Sertralina/uso terapêutico , Depressão/tratamento farmacológico , Atenção Primária à Saúde
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