RESUMO
BACKGROUND: Tobacco smoking rates in depressive patients are higher compared with the general population. Smoking was demonstrated to accelerate the metabolism of different drugs metabolized by CYP1A2, but possibly also by CYP2C19 and CYP3A4. The principle aim of the present investigation from 2015 to 2018 was to determine the differences in the pharmacokinetics of escitalopram between smokers and nonsmokers. METHODS: A group of nonsmokers (n = 88) was compared with smokers (n = 36), both receiving escitalopram, using the Mann-Whitney U test. Linear regression analysis was used to account for the impact of escitalopram dose, age, and sex in addition to smoking on the steady-state serum concentration of escitalopram. RESULTS: Smokers received by mean 17.6% higher doses of escitalopram (P = 0.026) but showed 31.9% lower serum concentrations (P = 0.031). To control for confounders, linear regression analysis showed that dose (P < 0.001), sex (P = 0.03), and smoking tobacco (P = 0.027) did significantly influence serum concentrations of escitalopram with higher levels in women and nonsmokers. CONCLUSIONS: Notwithstanding higher daily doses, smokers had significantly lower serum concentrations of escitalopram. In concordance with previous results, besides CYP1A2, a possible induction of CYP2C19 and CYP3A4 by tobacco smoke, resulting in lower serum concentrations of escitalopram in smokers than in nonsmokers, is suggested. Therefore, to provide personalized therapy, clinicians should consider smoking status and inform patients on the interactions of smoking and escitalopram metabolism.
Assuntos
Citalopram/administração & dosagem , Transtorno Depressivo/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Fumar Tabaco/epidemiologia , Adulto , Idoso , Citalopram/farmacocinética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Fumantes , Fumar Tabaco/metabolismoRESUMO
Therapeutic drug monitoring (TDM) has become a clinical routine in psychiatry. Nevertheless, for bupropion there is only one method available that is suitable for routine use. However, it involves a complex sample clean-up. Owing to the instability of bupropion in serum, the main and active metabolite hydroxybupropion was chosen as the target substance. Therefore, a simple and robust high-performance liquid chromatography method for the quantification of hydroxybupropion in serum was developed and validated. A volume of 30 µL serum was used for easy sample clean-up, based on protein precipitation with acetonitrile followed by online solid-phase extraction. As hydroxybupropion was present in high serum concentrations, UV detection was possible. Owing to the commonly available instrumentation, the method could easily be integrated in routine TDM. The newly developed method was validated following the guidelines for bioanalytical method validation of the European Medicines Agency and US Food and Drug Administration. The lower limit of quantification was 100 ng/mL (0.391 µm) and linearity was shown between 100 and 2500 ng/mL. Intraday and interday precision ranged from 1.17 to 6.79% and from 6.07 to 9.41%, respectively. Intraday and interday accuracy ranged from 89.97 to 110.86% and from 95.05 to 101.2%. The method was shown to be selective, accurate and precise. Additionally, the method was successfully implemented in the therapeutic drug monitoring laboratory of the Department of Psychiatry, Psychosomatics and Psychotherapy at the University Hospital of Würzburg, Germany. Six months of routine analysis showed a rather low correlation between applied dose and serum concentration and therefore the necessity of TDM for dose-individualization in the treatment with bupropion.
Assuntos
Bupropiona/análogos & derivados , Monitoramento de Medicamentos/métodos , Adulto , Idoso , Bupropiona/administração & dosagem , Bupropiona/sangue , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Humanos , Limite de Detecção , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Extração em Fase Sólida/métodos , Adulto JovemRESUMO
BACKGROUND: Epigenetic mechanisms may play a major role in the biological embedding of early-life stress (ELS). One proposed mechanism is that glucocorticoid (GC) release following ELS exposure induces long-lasting alterations in DNA methylation (DNAm) of important regulatory genes of the stress response. Here, we investigate the dynamics of GC-dependent methylation changes in key regulatory regions of the FKBP5 locus in which ELS-associated DNAm changes have been reported. RESULTS: We repeatedly measured DNAm in human peripheral blood samples from 2 independent cohorts exposed to the GC agonist dexamethasone (DEX) using a targeted bisulfite sequencing approach, complemented by data from Illumina 450K arrays. We detected differentially methylated CpGs in enhancers co-localizing with GC receptor binding sites after acute DEX treatment (1 h, 3 h, 6 h), which returned to baseline levels within 23 h. These changes withstood correction for immune cell count differences. While we observed main effects of sex, age, body mass index, smoking, and depression symptoms on FKBP5 methylation levels, only the functional FKBP5 SNP (rs1360780) moderated the dynamic changes following DEX. This genotype effect was observed in both cohorts and included sites previously shown to be associated with ELS. CONCLUSION: Our study highlights that DNAm levels within regulatory regions of the FKBP5 locus show dynamic changes following a GC challenge and suggest that factors influencing the dynamics of this regulation may contribute to the previously reported alterations in DNAm associated with current and past ELS exposure.
Assuntos
Metilação de DNA/efeitos dos fármacos , Glucocorticoides/farmacologia , Estresse Psicológico/genética , Proteínas de Ligação a Tacrolimo/genética , Adulto , Estudos de Coortes , Dexametasona/efeitos adversos , Epigênese Genética/efeitos dos fármacos , Feminino , Glucocorticoides/agonistas , Glucocorticoides/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Análise de Sequência de DNA , Estresse Psicológico/metabolismo , Adulto JovemRESUMO
Smoking is common among psychiatric patients and has been shown to accelerate the metabolism of different drugs. We aimed to determine the effect of smoking on the serum concentrations of psychopharmacological drugs in a naturalistic clinical setting. Dose-corrected, steady-state serum concentrations of individual patients were analyzed retrospectively by linear regression including age, sex, and smoking for amitriptyline (n=503), doxepin (n=198), mirtazapine (n=572), venlafaxine (n=534), clozapine (n=106), quetiapine (n=182), and risperidone (n=136). Serum levels of amitriptyline (P=0.038), clozapine (P=0.02), and mirtazapine (P=0.002) were significantly lower in smokers compared with nonsmokers after correction for age and sex. In addition, the ratios of nortriptyline/amitriptyline (P=0.001) and nordoxepin/doxepin (P=0.014) were significantly higher in smokers compared with nonsmokers. Smoking may not only induce CYP1A2, but may possibly also affect CYP2C19. Furthermore, CYP3A4, UGT1A3, and UGT1A4 might be induced by tobacco smoke. Hence, a different dosing strategy is required among smoking and nonsmoking patients. Nevertheless, the clinical relevance of the results remained unclear.
Assuntos
Antidepressivos/sangue , Antipsicóticos/sangue , Fumar/sangue , Fumar/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Amitriptilina/sangue , Clozapina/análogos & derivados , Clozapina/sangue , Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A , Succinato de Desvenlafaxina/sangue , Doxepina/análogos & derivados , Doxepina/sangue , Monitoramento de Medicamentos , Feminino , Glucuronosiltransferase , Humanos , Masculino , Pessoa de Meia-Idade , Mirtazapina/sangue , Nortriptilina/sangue , Palmitato de Paliperidona/sangue , Fumarato de Quetiapina/sangue , Estudos Retrospectivos , Risperidona/sangue , Cloridrato de Venlafaxina/sangueRESUMO
123I-metaiodobenzylguanidine (123I-MIBG) has independent prognostic value for risk stratification among heart failure patients, but the use of concomitant medication should not affect its quantitative information. We evaluated whether the 4 classes of antidepressants currently most prescribed as first-line treatment for major depressive disorder (MDD) have the potential to alter 123I-MIBG imaging results. Methods: The inhibition effect of desipramine, escitalopram, venlafaxine, and bupropion on 131I-MIBG uptake was assessed by in vitro uptake assays using human neuroblastoma SK-N-SH cells. The half-maximal inhibitory concentration of tracer uptake was determined from dose-response curves. To evaluate the effect of intravenous pretreatment with desipramine (1.5 mg/kg) and escitalopram (2.5 or 15 mg/kg) on 123I-MIBG cardiac uptake, in vivo planar 123I-MIBG scanning of healthy New Zealand White rabbits was performed. Results: The half-maximal inhibitory concentrations of desipramine, escitalopram, venlafaxine, and bupropion on 131I-MIBG cellular uptake were 11.9 nM, 7.5 µM, 4.92 µM, and 12.9 µM, respectively. At the maximum serum concentration (as derived by previous clinical trials), the inhibition rates of 131I-MIBG uptake were 90.6% for desipramine, 25.5% for venlafaxine, 11.7% for bupropion, and 0.72% for escitalopram. A low inhibition rate for escitalopram in the cell uptake study triggered investigation of an in vivo rabbit model: with a dosage considerably higher than used in clinical practice, the noninhibitory effect of escitalopram was confirmed. Furthermore, pretreatment with desipramine markedly reduced cardiac 123I-MIBG uptake. Conclusion: In the present in vitro binding assay and in vivo rabbit study, the selective serotonin reuptake inhibitor escitalopram had no major impact on neuronal cardiac 123I-MIBG uptake within therapeutic dose ranges, whereas other types of first-line antidepressants for MDD treatment led to a significant decrease. These preliminary results warrant further confirmatory clinical trials regarding the reliability of cardiac 123I-MIBG imaging, in particular, if the patient's neuropsychiatric status would not tolerate withdrawal of a potentially norepinephrine-interfering antidepressant.
Assuntos
3-Iodobenzilguanidina/metabolismo , Antidepressivos/farmacologia , Artefatos , Saúde , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Animais , Antidepressivos/uso terapêutico , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Feminino , Coração/diagnóstico por imagem , Humanos , CoelhosRESUMO
BACKGROUND: Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear. RESULTS: We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 % (110/353) of these CpGs and transcription in 81.7 % (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias. CONCLUSIONS: Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.