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1.
J Clin Psychiatry ; 81(5)2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32857933

RESUMO

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics from February 2015 through November 2018. METHODS: Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean ± SD age: 14.8 ± 1.7 years) or placebo (n = 25, mean ± SD age: 14.9 ± 1.6 years) for 8 weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUC0-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes. RESULTS: Escitalopram was superior to placebo for mean ± SD baseline-to-endpoint change in PARS (-8.65 ± 1.3 vs -3.52 ± 1.1, P = .005) and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax (P = .07) and AUC0-24 (P < .05). Vital signs, corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo. CONCLUSIONS: Escitalopram reduces anxiety symptoms, and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02818751.


Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Citalopram/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Adolescente , Área Sob a Curva , Criança , Citalopram/análogos & derivados , Citalopram/sangue , Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Método Duplo-Cego , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/farmacocinética , Resultado do Tratamento
2.
AAPS PharmSciTech ; 21(5): 161, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488427

RESUMO

Development of generic extended-release (ER) formulations is challenging. Especially under fed conditions, the risk of failure in bioequivalence trials is high because of long gastric residence times and susceptibility to food effects. We describe the development of a generic trazodone ER formulation that was aided with a biorelevant dissolution evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both in USP and EMA compliant conditions and in the StressTest device that simulated both physicochemical and mechanical conditions of the gastrointestinal passage. The final formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines. Initially developed formulations dissolved trazodone similarly to the originator under standard conditions (f2 factor above 50), but their dissolution kinetics differed significantly in the biorelevant tests. The formulation was optimized by the addition of low-viscosity hypromellose and mannitol. The final formulation was approved for the bioequivalence trial. Calculated Cmax were 1.92 ± 0.77 and 1.92 ± 0.63 [µg/mL], AUC0-t were 27.46 ± 8.39 and 29.96 ± 9.09 [µg∙h/mL], and AUC0-∞ were 28.22 ± 8.91 and 30.82 ± 9.41 [µg∙h/mL] for the originator and test formulations, respectively. The 90% confidence intervals of all primary pharmacokinetic parameters fell within the 80-125% range. In summary, biorelevant dissolution tests supported successful development of a generic trazodone ER formulation pharmaceutically equivalent with the originator under fed conditions. Employment of biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER formulations.


Assuntos
Desenvolvimento de Medicamentos , Inibidores de Captação de Serotonina/administração & dosagem , Trazodona/administração & dosagem , Adulto , Área Sob a Curva , Química Farmacêutica , Estudos Cross-Over , Preparações de Ação Retardada/farmacocinética , Feminino , Humanos , Masculino , Inibidores de Captação de Serotonina/farmacocinética , Solubilidade , Equivalência Terapêutica , Trazodona/farmacocinética
3.
Lakartidningen ; 1172020 04 21.
Artigo em Sueco | MEDLINE | ID: mdl-32315439

RESUMO

Depression is common during pregnancy, and a considerable proportion of pregnant women take antidepressants. Modern antidepressants (e.g. SSRIs) are fairly safe to use during pregnancy. Several physiological changes occur in the pregnant state, possibly affecting the pharmacokinetics of many drugs. Metabolism via CYP enzymes are important for the elimination of antidepressants. This metabolism may increase, decrease or remain constant throughout pregnancy. The activity of CYP2D6 increases drastically with pregnancy progression, causing decreasing serum concentrations of drugs metabolised via this enzyme. Examples of such drugs are paroxetine and fluoxetine. The field of pregnancy-related pharmacokinetics of antidepressants is still in its early stages. More research will be necessary in the future, to enable evidence-based clinical decisions and optimise antidepressant treatment for pregnant women.


Assuntos
Antidepressivos , Complicações na Gravidez/tratamento farmacológico , Inibidores de Captação de Serotonina , Antidepressivos/farmacocinética , Citocromo P-450 CYP2D6 , Feminino , Fluoxetina , Humanos , Paroxetina , Gravidez , Inibidores de Captação de Serotonina/farmacocinética
4.
Clin Pharmacol Ther ; 107(3): 662-670, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31628858

RESUMO

We previously reported that testis-specific Y-encoded-like protein (TSPYLs) are transcription regulators for CYP3A4, CYP2C9, and CYP2C19. Here, we observed dual roles for TSPYLs in mediating serotonin transport and the metabolism of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD). The widely prescribed SSRIs, citalopram, and escitalopram are metabolized mainly by CYP2C19. The TSPYL1 rs3828743 single nucleotide polymorphism (SNP), which decreases its suppression of CYP2C19 expression, was associated with rapid escitalopram metabolism and worse treatment response in the Mayo PGRN-AMPS clinical trial. We also found that TSPYLs can regulate expression of the serotonin transporter protein, SLC6A4, and, in turn, serotonin transport into cells. The SNPs in tight linkage disequilibrium with the TSPYL1 rs10223646 SNP were significantly correlated with baseline severity of depression in patients with MDD in the Sequenced Treatment Alternatives to Relieve Depression and International SSRI Pharmacogenomics Consortium clinical trials. Our findings suggest that genetic variation in TSPYL genes may be novel indicators for baseline severity of depression and SSRI poor response.


Assuntos
Citalopram/administração & dosagem , Citocromo P-450 CYP2C19/genética , Transtorno Depressivo Maior/tratamento farmacológico , Proteínas Nucleares/genética , Inibidores de Captação de Serotonina/administração & dosagem , Células CACO-2 , Citalopram/farmacocinética , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/fisiopatologia , Células Hep G2 , Humanos , Desequilíbrio de Ligação , Farmacogenética , Polimorfismo de Nucleotídeo Único , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores de Captação de Serotonina/farmacocinética , Índice de Gravidade de Doença
6.
J Clin Psychopharmacol ; 39(5): 485-488, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31343441

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 de Captação 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 de Captação de Serotonina/farmacocinética , Fumantes , Fumar Tabaco/metabolismo
7.
J Neurochem ; 151(5): 642-655, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31325179

RESUMO

As selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications in autism, we aimed to determine whether targets for SSRIs are differentially affected in three cortical areas in children and adults with autism compared to neurotypical individuals. Utilizing a large cohort of postmortem brain tissue (n = 14-19 per group), saturation ligand binding assays were conducted on sections from the anterior cingulate cortex (ACC), posterior cingulate cortex, and fusiform gyrus (FG). Specific binding to the 5-HT transporter (5-HTT) as well as to 5-HT2 and 1A receptors (5-HT2, 5-HT1A ) was quantified in superficial and deep layers of each region using the ligands [3 H]-citalopram (5-HTT), [3 H]-ketanserin (5-HT2 ), and [3 H]-8-OH-DPAT (5-HT1A ). A Welch's t-test was utilized to compare receptor densities (Bmax ), revealing a statistically significant decrease in 5-HTT within the ACC of the entire autism cohort. There was also a decrease in 5-HT2 receptor density in the ACC in the adult cohort, but not in child postmortem autism cases as compared to controls. Comparing linear regression lines of Bmax values plotted against age, shows a significantly lower intercept for 5-HTT in autism (p = 0.025). 5-HT2 density increases with age in control cases, whereas in autism there is a decrease with age and significantly different slopes between regression lines (p = 0.032). This suggests a deficit in 5-HTT within the ACC in individuals with autism, while decreases in 5-HT2 density are age-dependent. There were no differences in receptor densities in the posterior cingulate cortex or FG in autism and no differences in ligand affinity (KD ) across all regions and ligands examined.


Assuntos
Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacocinética , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Adulto Jovem
8.
Am J Emerg Med ; 37(10): 1993.e5-1993.e6, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31257122

RESUMO

INTRODUCTION: Citalopram is a selective serotonin reuptake inhibitor used for treatment of depression. Metabolism is primarily through CYP3A4 and CYP2C19; activity of the latter can vary depending on genetics. Although rare after single agent exposure, large citalopram ingestions can lead to serotonin syndrome. We report a case of citalopram overdose in an intermediate CYP2C19 metabolizer complicated by severe serotonin syndrome. CASE DETAILS: A 25-year-old female presented after intentional citalopram overdose with seizures, tachycardia, persistent neuromuscular findings, and severe hyperthermia requiring aggressive sedation and cooling. Protracted symptoms required critical care services throughout a 14 day hospital stay despite traditional treatment of serotonin syndrome. Pharmacogenomic studies revealed intermediate CYP2C19 metabolism which reduces citalopram inactivation and may cause increased levels and toxicity. DISCUSSION: In the majority of serotonin syndrome cases, symptoms resolve rapidly after treatment initiation and discontinuation of the offending agents. Severe cases are typically associated with ingestion of multiple serotonergic agents. Our patient had severe toxicity after single agent ingestion. Pharmacogenetic testing identified abnormal CYP2C19 activity and previous cases have associated enzyme dysfunction and citalopram toxicity. CONCLUSION: Citalopram overdose may be associated with severe serotonin syndrome and further investigation is warranted to understand the impact of enzyme genotype on toxicity.


Assuntos
Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Variantes Farmacogenômicos/genética , Síndrome da Serotonina/genética , Inibidores de Captação de Serotonina/farmacocinética , Tentativa de Suicídio , Adulto , Citalopram/envenenamento , Overdose de Drogas , Feminino , Genótipo , Humanos , Inibidores de Captação de Serotonina/envenenamento , Resultado do Tratamento
9.
Expert Opin Drug Metab Toxicol ; 15(8): 619-631, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31271537

RESUMO

Introduction: The comorbidity between obsessive-compulsive disorder (OCD) and bipolar disorders (BDs) is a frequent and severe condition characterized by a chronic course, high suicidal risk and tendency towards chronicity and treatment non-response. It represents a real challenge to psychiatrists, while requiring a careful and appropriate therapeutic management consisting in the combination of serotonergic antidepressants (ADs), such as serotonin reuptake inhibitors (SRIs), with mood stabilizers. This combination, like any other, raises the problems related to drug interactions that may lead to pharmacokinetic and pharmacodynamic changes, resulting in the modification of the pharmacologic effect and safety profile of a given compound. Areas covered: The aim of the present paper was to review the literature on the pharmacokinetic and pharmacodynamic changes resulting from the interactions of the different drugs prescribed in the OCD-BD comorbidity. Expert opinion: The literature data on pharmacokinetic and pharmacodynamic changes due to interactions of drugs commonly prescribed in the treatment of the OCD-BD comorbidity are extremely limited, and the information is inferred by findings gathered in psychiatric patients suffering from other disorders. This represents a gap in psychopharmacology that should be filled by specific studies on this important topic.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Antimaníacos/administração & dosagem , Antimaníacos/farmacocinética , Antimaníacos/farmacologia , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Transtorno Bipolar/complicações , Interações Medicamentosas , Humanos , Transtorno Obsessivo-Compulsivo/complicações , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacocinética , Inibidores de Captação de Serotonina/farmacologia
10.
Eur Neuropsychopharmacol ; 29(6): 711-719, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31076187

RESUMO

Pharmacological imaging of the effects of selective serotonin reuptake inhibitors (SSRI) may aid the clarification of their mechanism of action and influence treatment of highly prevalent neuropsychiatric conditions if the detected effects could be related to patient outcomes. In a randomized double-blind design, 38 healthy participants received a constant infusion of 8 mg citalopram or saline during either their first or second of two PET/MR scans. Resting-state functional MRI (fMRI) was acquired simultaneously with PET data on the binding of serotonin transporters (5-HTT) using [11C]DASB. Three different approaches for modeling of pharmacological fMRI response were tested separately. These relied on the use of regressors corresponding to (1) the drug infusion paradigm, (2) time courses of citalopram plasma concentrations and (3) changes in 5-HTT binding measured in each individual, respectively. Furthermore, the replication of results of a widely used model-free analysis method was attempted which assesses the deviation of signal in discrete time bins of fMRI data acquired after start of drug infusion. Following drug challenge, average 5-HTT occupancy was 69±7% and peak citalopram plasma levels were 111.8 ±â€¯21.1 ng/ml. None of the applied methods could detect significant differences in the pharmacological response between SSRI and placebo scans. The failed replication of SSRI effects reported in the literature despite a threefold larger sample size highlights the importance of appropriate correction for family-wise error in order to avoid spurious results in pharmacological imaging. This calls for the development of analysis methods which take regional specialization and the dynamics of brain activity into account.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Citalopram/farmacologia , Imagem por Ressonância Magnética/métodos , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Inibidores de Captação de Serotonina/farmacologia , Adolescente , Adulto , Encéfalo/metabolismo , Citalopram/farmacocinética , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacocinética , Adulto Jovem
11.
Anal Chem ; 91(13): 8062-8069, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31074958

RESUMO

Drug monitoring is crucial for providing accurate and effective care; however, current methods (e.g., blood draws) are inconvenient and unpleasant. We aim to develop a non-invasive method for the detection and monitoring of drugs via human skin. The initial development toward this aim required information about which drugs, taken orally, can be detected via the skin. Untargeted liquid chromatography-mass spectrometry (LC-MS) was used as it was unclear if drugs, known drug metabolites, or other transformation products were detectable. In accomplishing our aim, we analyzed samples obtained by swabbing the skin of 15 kidney transplant recipients in five locations (forehead, nasolabial area, axillary, backhand, and palm), bilaterally, on two different clinical visits. Untargeted LC-MS data were processed using molecular networking via the Global Natural Products Social Molecular Networking platform. Herein, we report the qualitative detection and location of drugs and drug metabolites. For example, escitalopram/citalopram and diphenhydramine, taken orally, were detected in forehead, nasolabial, and hand samples, whereas N-acetyl-sulfamethoxazole, a drug metabolite, was detected in axillary samples. In addition, chemicals associated with environmental exposure were also detected from the skin, which provides insight into the multifaceted chemical influences on our health. The proof-of-concept results presented support the finding that the LC-MS and data analysis methodology is currently capable of the qualitative assessment of the presence of drugs directly via human skin.


Assuntos
Monitoramento de Medicamentos/métodos , Absorção Cutânea , Pele/metabolismo , Administração Oral , Cromatografia Líquida/métodos , Citalopram/administração & dosagem , Citalopram/farmacocinética , Difenidramina/administração & dosagem , Difenidramina/farmacocinética , Humanos , Espectrometria de Massas/métodos , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacocinética , Medicamentos Indutores do Sono/administração & dosagem , Medicamentos Indutores do Sono/farmacocinética
12.
Clin Pharmacol Ther ; 106(4): 855-865, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31012492

RESUMO

We set out to determine whether machine learning-based algorithms that included functionally validated pharmacogenomic biomarkers joined with clinical measures could predict selective serotonin reuptake inhibitor (SSRI) remission/response in patients with major depressive disorder (MDD). We studied 1,030 white outpatients with MDD treated with citalopram/escitalopram in the Mayo Clinic Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS; n = 398), Sequenced Treatment Alternatives to Relieve Depression (STAR*D; n = 467), and International SSRI Pharmacogenomics Consortium (ISPC; n = 165) trials. A genomewide association study for PGRN-AMPS plasma metabolites associated with SSRI response (serotonin) and baseline MDD severity (kynurenine) identified single nucleotide polymorphisms (SNPs) in DEFB1, ERICH3, AHR, and TSPAN5 that we tested as predictors. Supervised machine-learning methods trained using SNPs and total baseline depression scores predicted remission and response at 8 weeks with area under the receiver operating curve (AUC) > 0.7 (P < 0.04) in PGRN-AMPS patients, with comparable prediction accuracies > 69% (P ≤ 0.07) in STAR*D and ISPC. These results demonstrate that machine learning can achieve accurate and, importantly, replicable prediction of SSRI therapy response using total baseline depression severity combined with pharmacogenomic biomarkers.


Assuntos
Citalopram/farmacocinética , Transtorno Depressivo Maior , Adulto , Algoritmos , Biomarcadores Farmacológicos/sangue , Regras de Decisão Clínica , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Aprendizado de Máquina , Masculino , Testes Farmacogenômicos/métodos , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Indução de Remissão , Inibidores de Captação de Serotonina/farmacocinética
13.
J Child Adolesc Psychopharmacol ; 29(5): 340-347, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30817183

RESUMO

Objective: Cytochrome P4502C19 (CYP2C19) is a highly polymorphic gene that encodes an enzyme that metabolizes escitalopram and sertraline, two selective serotonin reuptake inhibitors (SSRIs) that are FDA approved for pediatric use and commonly used to treat anxiety and depressive disorders in youth. Using pharmacokinetic (PK) models in adolescents, we sought to (1) model SSRI dosing across CYP2C19 phenotypes to compare SSRI exposure (area under curve, AUC) and maximum concentration (Cmax), (2) evaluate the impact of b.i.d. dosing (in rapid metabolizers [RM] and ultrarapid metabolizers [UM]) on SSRI exposure and Cmax, and (3) determine pharmacogenomically-informed dosing strategies to provide similar exposure across CYP2C19 phenotypes in adolescents. Methods: Using PK parameters in CYP2C19 phenotype groups and previously reported pediatric PK data for escitalopram and sertraline, we modeled exposure (AUC0-24) and Cmax and determined CYP2C19-guided dosing strategies. Results: Compared with normal CYP2C19 metabolizers treated with either escitalopram or sertraline, Cmax and AUC0-24 were higher in slower metabolizers and lower in patients with increased CYP2C19 activity, although the magnitude of these differences was more pronounced for escitalopram than for sertraline. For escitalopram, poor metabolizers (PMs) require 10 mg/day and UMs require 30 mg/day to achieve an exposure that is equivalent to 20 mg/day in a normal metabolizer (NM). For sertraline, to achieve AUC0-24 and Cmax similar to NMs receiving 150 mg/day, PMs require 100 mg/day, whereas a dose of 200 mg/day was required in rapid and UMs. For UMs, b.i.d. escitalopram dosing was necessary to achieve comparable trough levels and exposure to NMs. Conclusions: This simulation study raises the possibility that achieving similar escitalopram and sertraline plasma concentrations could require dose adjustments in CYP2C19 poor metabolizers and UMs, although the magnitude of these differences were more pronounced for escitalopram than for sertraline. However, prospective trials of pharmacogenomically guided dosing in the pediatric population are needed to extend the findings of these modeling studies.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Transtorno Depressivo Maior/tratamento farmacológico , Inibidores de Captação de Serotonina/farmacocinética , Sertralina/farmacocinética , Adolescente , Citalopram/uso terapêutico , Feminino , Humanos , Masculino , Testes Farmacogenômicos , Fenótipo , Polimorfismo Genético , Inibidores de Captação de Serotonina/uso terapêutico , Sertralina/uso terapêutico
14.
Handb Exp Pharmacol ; 250: 135-144, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30838457

RESUMO

The first antidepressants were created by chance but brought the idea that central serotonin agonism produced an antidepressant effect. SSRIs were the first class of psychotropic medications to be rationally designed, meaning that researchers intended to utilize a specific mechanism of action while avoiding adverse effects. In this way, SSRIs were created to be safer and more tolerable than previous antidepressants. SSRIs share many similarities, but differ in terms of pharmacokinetics and effects on CYP450 enzymes, which is detailed in this chapter. Further information will be provided regarding safety, clinical indications/uses, and dosing recommendations.


Assuntos
Antidepressivos , Inibidores de Captação de Serotonina , Antidepressivos/farmacocinética , Inibidores de Captação de Serotonina/farmacocinética , Inibidores de Captação de Serotonina/farmacologia
15.
Exp Clin Psychopharmacol ; 27(5): 413-432, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30869982

RESUMO

Selective serotonin reuptake inhibitors (SSRIs) are the first-line drugs in the treatment of depression. Investigations of the effects of SSRIs in healthy individuals is a useful model to understand the mechanisms of SSRI action and potentially the underlying pathophysiology of depression. We conducted an updated systematic review of all randomized multiple-dose, placebo-controlled trials on the effect of intervention with SSRI for ≥ 7 days in healthy nonpsychiatric subjects. Tables were drawn for characteristics of the trial, quality assessment, outcome measures, and the effect of intervention with SSRI. The search strategy identified a total of 51 placebo-controlled randomized trials investigating seven different SSRIs and 249 different outcome measures. Among trials, using the same outcome measure, most associations were either contradictory or statistically nonsignificant. Replication of statistically significant findings in two or more trials showed that SSRIs compared with placebo decreased divided attention, sustained attention network, negative affects, hostility, sleep quality, and platelet 5-HT content and further increased activity in the amygdala in relation to happy faces. Factors such as age, gender, family history of psychiatric disorder, and drug level influenced the findings but were rarely systematically investigated. The newly published retrieved trials fulfilled more criteria according to the CONSORT statement. This systematic review points to effects of SSRIs increasing positive emotional processing and decreasing divided and sustained attention besides physiological effects decreasing sleep quality and platelet 5-HT content in healthy subjects. Larger studies with a translational medicines approach with improved methodology are needed on the effects of SSRIs in healthy subjects. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Inibidores de Captação de Serotonina/uso terapêutico , Emoções/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Avaliação de Resultados em Cuidados de Saúde , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Inibidores de Captação de Serotonina/farmacocinética , Inibidores de Captação de Serotonina/farmacologia , Sono/efeitos dos fármacos
16.
Expert Opin Drug Metab Toxicol ; 15(4): 261-273, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30793987

RESUMO

INTRODUCTION: Although the treatment of obsessive-compulsive disorder (OCD), a common, chronic, and disabling psychiatric condition, has significantly improved in the last decades, with the demonstration of the specific effectiveness of serotonin reuptake inhibitors (SRIs), a large proportion of patients still show high relapse rates. In addition, pharmacological treatments should be maintained for years, so that the clinicians should take into account the pharmacokinetic changes in the long-term, which may be responsible for dangerous side effects or interactions. Areas covered: The aim of this paper was to review the literature on the pharmacokinetics of SSRIs and clomipramine, and on their pharmacokinetic parameters in OCD patients. Expert opinion: Although the literature on the pharmacokinetics of both clomipramine and SSRIs is consistent, data on pharmacokinetic parameters in OCD patients are very few. Given the impact of OCD, its chronicity requiring long-term treatments, together with the need to increase the clinical response rate, more studies in this field are urgently required.


Assuntos
Clomipramina/administração & dosagem , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Inibidores de Captação de Serotonina/administração & dosagem , Clomipramina/efeitos adversos , Clomipramina/farmacocinética , Humanos , Transtorno Obsessivo-Compulsivo/fisiopatologia , Inibidores de Captação de Serotonina/farmacocinética , Fatores de Tempo
17.
Int J Neuropsychopharmacol ; 22(4): 286-291, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753467

RESUMO

BACKGROUND: Selective serotonin reuptake inhibitors are often used in alcohol use disorders. Clinical trials with selective serotonin reuptake inhibitors for alcohol use disorders, however, have yielded mixed results. The goal of this project was to assess whether a single i.v. dose of a selective serotonin reuptake inhibitor reduces craving for alcohol and/or simultaneously increases striatal dopamine concentration in individuals with alcohol dependence. METHODS: Alcohol-dependent (DSM-IV-TR criteria) volunteers and matched controls (n = 10/group) underwent a double-blind, placebo-controlled, within-subjects study. Participants received i.v. citalopram (40 mg) or saline (counter-balanced) followed by a cue-induced craving assessment and [18F]-fallypride positron emission tomography scanning. RESULTS: In the alcohol-dependent individuals, the citalopram (compared with saline) resulted in decreased cue-induced craving for alcohol. For the whole study group, cue-induced alcohol craving was inversely correlated with thalamic (but not striatal) dopamine D2/3 receptor availability. CONCLUSIONS: Acute serotonin reuptake inhibition reduces cue-induced alcohol craving. Furthermore, thalamic dopamine abnormalities and the striatal hyperdopaminergic hypothesis of alcohol use disorder are supported.


Assuntos
Alcoolismo/tratamento farmacológico , Citalopram/farmacocinética , Corpo Estriado/efeitos dos fármacos , Fissura/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D3/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacocinética , Tálamo/efeitos dos fármacos , Administração Intravenosa , Adulto , Benzamidas , Citalopram/administração & dosagem , Sinais (Psicologia) , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Pirrolidinas , Inibidores de Captação de Serotonina/administração & dosagem
18.
Basic Clin Pharmacol Toxicol ; 124(3): 285-297, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30220109

RESUMO

Therapeutic drug monitoring (TDM) is used to determine the concentration of drug in plasma/serum to adjust the dose of the therapeutic drug. Selective and sensitive analytical methods are used to determine drug and metabolite levels for the successful application of TDM. The aim of the study was to develop and validate using LC-MS/MS to analyse quantitative assay of escitalopram (S-CT) and metabolites in human plasma samples. In order to provide a convenient and safe treatment dose, it was aimed to determine the levels of S-CT and its metabolites in the patients' plasma. A new method with short sample preparation and analysis time was developed and validated using LC-MS/MS to analyse quantitative assay of S-CT and its metabolites in plasma. Also, plasma samples of 30 patients using 20 mg S-CT between the ages of 18 and 65 years were analysed by the validated method. The mean values of S-CT, demethyl escitalopram and didemethyl escitalopram in plasma of patients were 27.59, 85.52 and 44.30 ng/mL, respectively. At the end of the analysis, the metabolic ratio of S-CT and metabolites was calculated. It is considered that the method for the quantitative analysis of S-CT and its metabolites in human plasma samples may contribute to the literature on account of its sensitive and easy application. Additionally, the use of our data by physicians will contribute to the effective drug treatment for their patients who take S-CT.


Assuntos
Citalopram/sangue , Transtornos Mentais/sangue , Adolescente , Adulto , Idoso , Cromatografia Líquida/métodos , Citalopram/administração & dosagem , Citalopram/farmacocinética , Monitoramento de Medicamentos/métodos , Humanos , Transtornos Mentais/tratamento farmacológico , Pessoa de Meia-Idade , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/sangue , Inibidores de Captação de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacocinética , Espectrometria de Massas em Tandem/métodos , Adulto Jovem
19.
Int J Legal Med ; 133(2): 353-363, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30173302

RESUMO

Depression is known to be a risk factor for suicide. Currently, the most used antidepressants are selective serotonin reuptake inhibitors (SSRIs). Not all users, however, benefit from them. In such cases, treatment failure can be explained in part by genetic differences. In this study, we investigated the role of pharmacogenetic factors in citalopram-positive completed suicides (n = 349). Since citalopram is metabolized by CYP2C19 and CYP2D6 enzymes, the study population was genotyped for clinically relevant CYP2C19 and CYP2D6 polymorphisms and CYP2D6 copy number variation. To assess genetic differences between suicide cases and Finns in general, Finnish population samples (n = 855) were used as controls. Also, the role of drug interactions among suicide cases was evaluated. We found enrichment of a combined group of genetically predicted poor and ultrarapid metabolizer phenotypes (gMPs) of CYP2C19 among suicide victims compared to controls 0.356 [0.31-0.41] vs. 0.265 [0.24-0.30] (p = 0.0065). In CYP2D6 gMPs, there was no difference between cases and controls when the study population was analyzed as a whole. However, there were significantly more poor metabolizers among females who committed suicide by poisoning compared to female controls. In 8% of all drug poisoning deaths, lifetime drug-drug interaction was evaluated having a contribution to the fatal outcome. From clinical perspective, pharmacogenetic testing prior to initiation of SSRI drug could be beneficial. It may also be useful in medico-legal settings as it may elucidate obscure poisoning cases. Also, the possibility of unintentional drug interactions should be taken into account in drug poisoning deaths.


Assuntos
Citalopram/envenenamento , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Genótipo , Variantes Farmacogenômicos/genética , Inibidores de Captação de Serotonina/envenenamento , Suicídio , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Citalopram/farmacocinética , Variações do Número de Cópias de DNA , Interações Medicamentosas/genética , Feminino , Finlândia , Toxicologia Forense , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Inibidores de Captação de Serotonina/farmacocinética
20.
J Affect Disord ; 246: 62-68, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578947

RESUMO

BACKGROUND: The purpose of this study was to identify specific pharmacokinetic (PK) and pharmacodynamics (PD) factors that affect the likelihood of treatment remission with a serotonin norepinephrine reuptake inhibitor (SNRI) in depressed patients whose initial selective serotonin reuptake inhibitor (SSRI) failed. METHODS: Multiple logistic regression modeling of PK and PD variation hypothesized to contribute to SNRI (i.e. duloxetine or venlafaxine) treatment remission in prior SSRI (i.e. citalopram or escitalopram) failure was conducted on 139 subjects from the Pharmacogenomics Research Network (PGRN) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies. Depressive symptoms were assessed with the Quick Inventory of Depressive Symptomatology Clinician-rated (QIDS-C16). RESULTS: Venlafaxine-XR remission was associated with a significant interaction between CYP2D6 ultra-rapid metabolizer (URM) phenotype and SLC6A4 5-HTTLPR L/L genotype. A similar significant interaction effect was observed between CYP2D6 URM and SLC6A2 G1287A GA genotype. Stratifying by transporter genotypes, venlafaxine-XR remission was associated with CYP2D6 URM in patients with SLC6A4 L/L (p = 0.001) and SLC6A2 G1287A GA genotypes. LIMITATIONS: The primary limitation of this post hoc study was small sample size. CONCLUSION: Our results suggest that CYP2D6 ultra-rapid metabolizer status contributes to venlafaxine-XR treatment remission in MDD patients; in particular, there is a PK-PD interaction with treatment remission associated with CYP2D6 URM phenotype and SLC6A4 5-HTTLPR L/L or SLC6A2 G1287A G/A genotype, respectively. These preliminary data are encouraging and support larger pharmacogenomics studies differentiating treatment response to mechanistically different antidepressants in addition to further PK-PD interactive analyses.


Assuntos
Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico , Adulto , Antidepressivos/farmacocinética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Fenótipo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores de Captação de Serotonina/farmacocinética , Falha de Tratamento , Cloridrato de Venlafaxina/farmacocinética
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