ABSTRACT
Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level as well as the therapeutic serum reference range in this age group. Within a large naturalistic observational prospective multicenter clinical trial ("TDM-VIGIL"), a transdiagnostic sample of children and adolescents (n = 138; mean age, 15; range, 7-18 years; 24.6% males) was treated with fluoxetine (10-40 mg/day). Analyses of both the last timepoint and all timepoints (n = 292 observations), utilizing (multiple) linear regressions, linear mixed-effect models, and cumulative link (mixed) models, were used to test the associations between dose, serum concentration, outcome, and potential predictors. The receiver operating curve and first to third interquartile methods, respectively, were used to examine concentration cutoff and reference values for responders. A strong positive relationship was found between dose and serum concentration of fluoxetine and its metabolite. Higher body weight was associated with lower serum concentrations, and female sex was associated with lower therapeutic response. The preliminary reference ranges for the active moiety (fluoxetine+norfluoxetine) were 208-328 ng/mL (transdiagnostically) and 201.5-306 ng/mL (depression). Most patients showed marked (45.6%) or minimal (43.5%) improvements and reported no adverse effects (64.9%). This study demonstrated a clear linear dose-serum level relationship for fluoxetine in youth, with the identified reference range being within that established for adults.
ABSTRACT
BACKGROUND: Although there is good evidence to support the effectiveness of cognitive behavioral therapy (CBT) for the outpatient treatment of adolescent major depressive disorder (MDD), evidence-based manuals for the inpatient setting are lacking. This pilot study sought to (i) adapt an existing CBT manual (treatment of adolescent depression; TADS) to an inpatient setting (TADS-in), (ii) test its effectiveness at symptom reduction and remission of MDD in a pre-post design, and (iii) assess the strengths and limitations of the manual via a focus-group with clinicians. METHODS: Twenty nine adolescents aged 12-17 years with a primary ICD-10 diagnosis of MDD being treated as inpatients at a psychiatric clinic were included. Embedded in the regular inpatient treatment course (8 weeks), patients received 12 sessions of the TADS-in manual. Quantitative assessment of symptom reduction and remission of MDD was conducted using a non-controlled pre-post design. The quantitative results were supplemented by a focus group with participating psychotherapists. RESULTS: Of the 29 patients included in the study at the beginning, 19 (65.5%) remained in the study at week 8. Symptoms of depression were statistically significantly lower at the end of treatment than at baseline according to self- (d = 1.38; mean change = 19.88; 95% CI = 12.48-27.28) and other reports (d = 0.64, mean change = 0.35; 95% CI = 0.08-0.62). Clinicians ratings of improvement (CGI-I) suggested that at the end of treatment, 15.8% were very much improved, 68.4% much improved, and 15.8% were minimally improved. According to diagnostic interviews with patients conducted at the end of treatment, 73.3% were in remission. The qualitative analysis showed that on the whole, the TADS-in manual is suitable for the inpatient setting. However, clinicians believed the effectiveness of TADS-in was limited by patient comorbidity and the fact that the inpatients were unable to practice incorporating techniques learnt into everyday life. CONCLUSIONS: This study is the first to adapt the TADS manual to the inpatient setting. The sample of depressed adolescents showed reduced symptomology following treatment, although these findings require replicating in a randomized controlled trial before effects can be attributed to the TADS-in manual specifically. This pilot study informs further development of the manual as well as representing an important first step in the evaluation of the inpatient treatment of adolescent depression.The study was retrospectively registered (DRKS00017308) and received no external funding.
