Thyroid Function Screening in Children and Adolescents With Mood and Anxiety Disorders.

OBJECTIVE: To determine the prevalence of abnormal thyroid-stimulating hormone (TSH) measures in youth with severe mood and anxiety disorders and to examine clinical and demographic predictors of abnormal TSH measures. METHODS: We retrospectively examined screening TSH concentrations in psychiatrically hospitalized children and adolescents (3-19 years) with mood/anxiety disorders (DSM-IV and DSM-5 criteria) at a large, urban, pediatric hospital between September 2013 and April 2017. Symptoms were extracted from the medical record using adaptive natural language processing algorithms, and the utility of demographic, clinical, and treatment variables as predictors of abnormal TSH measures was evaluated using logistic regression. RESULTS: In this sample (N = 1,017, mean ± SD age = 14.7 ± 2.24 years), 62 patients had a TSH concentration > 3.74 µIU/mL (5.3% [n = 6] of patients < 12 years of age and 6.2% [n = 56] of patients ≥ 12 years of age), and 7 patients had a TSH concentration < 0.36 µIU/mL. Elevated TSH concentrations were associated with a recent weight gain (odds ratio [OR] = 3.60; 95% CI, 1.13-9.61; P = .017), a history of thyroid disease (OR = 6.88; 95% CI, 2.37-10.7; P ≤ .0001), abnormal menstrual bleeding/menometrorrhagia (OR = 2.03; CI, 1.04-3.63; P = .024), and benzodiazepine treatment (OR = 2.29; 95% CI, 1.07-4.52; P = .02). No association was observed for sex, age, or body mass index z score. Among patients with elevated TSH measures, 12.9% (n = 8, mean ± SD age = 16.5 ± 1.5 years, 87.5% female) had an abnormal free/total thyroxine (T4) level or other biochemical findings consistent with thyroid disease. Patients with thyroid disease (compared to those patients with elevated TSH and normal active thyroid hormone concentrations) were older (16.5 ± 1.5 vs 14.6 ± 2.3 years, P = .020) but did not differ in sex distribution (87.5% vs 63.6% female, P = .444). CONCLUSIONS: TSH concentrations are abnormal in approximately 6% of psychiatrically hospitalized youth, although thyroid disease was present in < 1% of the total sample. Targeted screening should focus on patients with recent weight gain, those treated with benzodiazepines, and girls with a history of abnormal uterine bleeding/menometrorrhagia.

Pharmacogenetics of Sertraline Tolerability and Response in Pediatric Anxiety and Depressive Disorders.

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.

Influence of CYP2C19 Metabolizer Status on Escitalopram/Citalopram Tolerability and Response in Youth With Anxiety and Depressive Disorders.

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.