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


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: identifier: NCT02818751.

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
J Child Adolesc Psychopharmacol ; 30(4): 267-272, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31825249


Objective: To examine the potential effectiveness and tolerability of cariprazine in pediatric bipolar and psychotic disorders. Methods: We retrospectively reviewed the electronic health records of patients <21 years of age prescribed cariprazine to treat bipolar and psychotic disorders. Adverse effects, tolerability, therapeutic response (Clinical Global Impression-Improvement [CGI-I]), and severity of illness (Clinical Global Impression-Severity [CGI-S]) were determined through manual chart review. Results: We identified 16 patients aged 6-20 years who were treated with cariprazine (initial dose: 1.5 mg/day, interquartile range [IQR], 1.5-1.5; endpoint dose: 3 mg/day, IQR, 1.5-4.5). No serious adverse events were reported, but the most commonly reported side effect was weight gain (n = 3, 19%). Of the 14 patients for whom baseline and endpoint body mass index (BMI) data were available, neither changes in BMI (p = 0.391; 0.54 kg/m2, IQR, -0.33 to 1.38) nor BMI percentile (p = 0.71; 0.36%, IQR, -0.49 to 3.97) significantly differed between baseline and endpoint. However, patients receiving ≥4.5 mg/day had a significantly greater BMI increases during the course of treatment compared with those receiving ≤3 mg/day (p = 0.034; -1.14 kg/m2, IQR, -3.65 to 0.53 vs. 1.01 kg/m2, IQR, 0.17-4.88). CGI-S scores (p = 0.016; 4.5, IQR, 4-5 vs. 4, IQR, 3-4) significantly differed from baseline to endpoint. The response rate was 44% (n = 7/16), with responders being prescribed higher doses (p = 0.005; 6 mg/day, IQR, 4.875-6 vs. 3 mg/day, IQR, 3-4.125). Conclusions: Cariprazine may be well tolerated and effective for pediatric bipolar and psychotic disorders; however, compared with higher doses, total daily doses ≤3 mg/day appear to be more tolerable. Prospective controlled studies to further evaluate cariprazine in youth are needed.

J Child Adolesc Psychopharmacol ; 29(5): 348-361, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31066578


Objective: To determine whether genetic variants in a pharmacokinetic gene (the number of CYP2C19 reduced function alleles [RFAs]), and in pharmacodynamic genes (HTR2A, SLC6A4, and GRIK4) influence sertraline tolerability and response in a cohort of pediatric patients with anxiety and depressive disorders. Methods: A retrospective analysis was performed using the electronic medical record data of 352 patients <19 years of age being treated for anxiety and/or depressive disorders with sertraline and who underwent routine clinical CYP2C19 genotyping. Additional genotyping and analysis of variants in HTR2A, SLC6A4, and GRIK4 were conducted for 249 patients. Multivariate regression models testing for associations with CYP2C19 were adjusted for concomitant use of interacting medications. Combinatorial classification and regression tree (CART) analyses containing all pharmacokinetic and pharmacodynamic genes and clinical factors were performed. Results: The maximum sertraline dose during the initial titration period of sertraline was inversely associated with the number of CYP2C19 RFAs and sertraline dose at 60 (p = 0.025) and 90 days (p = 0.025). HTR2A rs6313 was associated with sertraline dose (p = 0.011) and time to the average maximum sertraline dose (p = 0.039). Regarding efficacy, the number of CYP2C19 RFAs was not associated with the sertraline dose at the time of response (p = 0.22), whereas for the pharmacodynamic genes, only HTR2A rs6313 was associated with response dose (p = 0.022). An association was observed between predicted expression levels of SLC6A4 and the duration on sertraline (p = 0.025). Combinatorial CART and multivariate regression analyses implicated that pharmacodynamic genes and clinical factors influence the maximum sertraline dose and response dose. The total number of side effects was not associated with any of the variants tested. Conclusion: Both pharmacokinetic and pharmacodynamic factors, in addition to clinical and demographic components, influence sertraline dose, response, and tolerability, thereby necessitating further research to assess for the validity of these pharmacogenetic associations in children and adolescents.

Antidepressivos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Citocromo P-450 CYP2C19/genética , Transtorno Depressivo/tratamento farmacológico , Farmacogenética , Receptor 5-HT2A de Serotonina/genética , Receptores de Ácido Caínico/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Sertralina/uso terapêutico , Adolescente , Transtornos de Ansiedade/genética , Criança , Transtorno Depressivo/genética , Feminino , Genótipo , Humanos , Masculino , Estudos Retrospectivos
J Child Adolesc Psychopharmacol ; 29(5): 340-347, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30817183


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.

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
Front Pharmacol ; 10: 99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30837874


In pediatric patients, the selective serotonin reuptake inhibitors (SSRIs) escitalopram and citalopram (es/citalopram) are commonly prescribed for anxiety and depressive disorders. However, pharmacogenetic studies examining CYP2C19 metabolizer status and es/citalopram treatment outcomes have largely focused on adults. We report a retrospective study of electronic medical record data from 263 youth < 19 years of age with anxiety and/or depressive disorders prescribed escitalopram or citalopram who underwent routine clinical CYP2C19 genotyping. Slower CYP2C19 metabolizers experienced more untoward effects than faster metabolizers (p = 0.015), including activation symptoms (p = 0.029) and had more rapid weight gain (p = 0.018). A larger proportion of slower metabolizers discontinued treatment with es/citalopram than normal metabolizers (p = 0.007). Meanwhile, faster metabolizers responded more quickly to es/citalopram (p = 0.005) and trended toward less time spent in subsequent hospitalizations (p = 0.06). These results highlight a disparity in treatment outcomes with es/citalopram treatment in youth with anxiety and/or depressive disorders when standardized dosing strategies were used without consideration of CYP2C19 metabolizer status. Larger, prospective trials are warranted to assess whether tailored dosing of es/citalopram based on CYP2C19 metabolizer status improves treatment outcomes in this patient population.