Journal of child and adolescent psychopharmacology最新文献

Background: Risperidone and, to a lesser extent, paliperidone are metabolized by CYP2D6; however, there are limited data related to variation in CYP2D6 phenotypes and the tolerability of these medications in children and adolescents. Furthermore, the impact of CYP2D6 on the association of risperidone and paliperidone with hyperprolactinemia in youth is not well understood. Methods: A retrospective chart review was performed in psychiatrically hospitalized children and adolescents prescribed risperidone (n = 263, age = 3-18 years, mean age = 13 ± 3 years, 49% female) or paliperidone (n = 124, age = 5-18 years, mean age = 15 ± 2 years, 44% female) who had CYP2D6 genotyping performed as part of routine care. CYP2D6 phenotypes were determined based on Clinical Pharmacogenetics Implementation Consortium guidelines and CYP2D6 inhibitors causing phenoconversion. Adverse effects were obtained from a review of the electronic health record, and patients were selected, in part, to enrich non-normal metabolizers. Results: Among risperidone-treated patients, 45% experienced an adverse effect, whereas 36% of paliperidone-treated patients experienced adverse effects. Discontinuation of risperidone due to lack of efficacy was more frequent in the CYP2D6 normal metabolizers and ultrarapid metabolizers compared with intermediate metabolizers (IMs) and phenoconverted poor metabolizers (pPMs) (54.5% vs. 32.7%, p < 0.001). Discontinuation due to weight gain was more common among risperidone- than paliperidone-treated patients (17% vs. 7%, p = 0.011). Among those taking paliperidone, CYP2D6 was associated with discontinuation due to side effects (p = 0.008), and youth with slower CYP2D6 metabolism (i.e., pPMs and IMs) were more likely to discontinue. Hyperprolactinemia was found in 10% of paliperidone-treated patients and 5% of risperidone-treated patients, and slower CYP2D6 metabolizers required higher risperidone doses to cause hyperprolactinemia (p = 0.011). Conclusions: CYP2D6 phenotype is associated with discontinuation of risperidone due to lack of efficacy and the dose of risperidone that induced hyperprolactinemia, as well as discontinuation of paliperidone due to adverse effects. Future studies should evaluate exposure-response and toxicity relationships in risperidone- and paliperidone-treated youth.

Background: Clinical practice guidelines recommend the use of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), as a first-line pharmacotherapy for major depressive disorder (MDD) and obsessive compulsive disorder (OCD) in children and adolescents. However, response and tolerability to fluoxetine varies from child to child, which may in part, be a result of interindividual differences in fluoxetine metabolism. In this study, we examined whether genotype-predicted activity scores of cytochrome P450 enzymes were associated with patient-reported symptom improvement and side effects in children and adolescents treated with fluoxetine. Methods: Ninety children and adolescents aged 7-18 with a MDD or OCD diagnosis and a history of fluoxetine treatment were recruited from Western Canada. For each participant, fluoxetine dose and duration information were collected, as well as questions about adherence, side effects, and symptom improvement. DNA was extracted from a saliva sample and genotyped for CYP2D6, CYP2C19, CYP2C9, CYP3A4, and CYP3A5. Logistic regression models were fitted to assess the impact of activity scores on symptom improvement and side effects. Results: Increased CYP2D6 activity score was significantly associated with reduced odds of symptom improvement (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.23-0.91, p = 0.028) as well as a trend association with reduced side effects (OR = 0.49, 95% CI = 0.22-1.07, p = 0.072), after adjusting for age, sex, diagnosis, dose, duration, adherence, and activity scores of the other assessed CYP enzymes. No associations with symptom improvement or side effects were detected for the other CYP enzymes examined. Conclusions: Our results suggest that an increase in the genotype-predicted CYP2D6 activity score was associated with a decrease in the odds of reporting symptom improvement among children and adolescents treated with fluoxetine. These findings will contribute to future updates of pharmacogenetic-based SSRI prescribing guidelines and if replicated, could inform fluoxetine treatment in children and adolescents with MDD or OCD. Clinical Trial Registration: NCT04797364.

Objective: To evaluate the efficacy and safety of escitalopram (ESC) in a 48-week relapse prevention study in Japanese adolescents with major depressive disorder (MDD). Methods: This was a 48-week multicenter randomized double-blind placebo-controlled parallel-group study of patients aged 12-17 years with MDD. Patients received ESC for 12 weeks as an open-label treatment period (open-label period). Patients who achieved criteria for remission or response in the open-label period received either ESC or placebo for 36 weeks as a double-blind treatment period (double-blind period). The primary endpoint was the time to relapse during the double-blind period. Safety was evaluated in terms of type, incidence, and severity of adverse events. Results: Of the 128 patients who entered the open-label period, 80 patients entered the double-blind period, all of whom were in the primary analysis population. The primary endpoint, time to relapse, was marginally less than statistically significant between the ESC and placebo groups (p = 0.051, log-rank test). In the Cox proportional hazards model, the estimated hazard ratio [two-sided 95% confidence interval] for relapse in the placebo group versus the ESC group was 2.96 [0.94, 9.30]. There were statistically significant differences between the ESC and placebo groups in several secondary endpoints (change in Children's Depression Rating Scale-Revised, change in Clinical Global Impressions-Severity Scale, etc.). No notable safety/tolerability issues were observed in this study compared with the results of studies in Japanese adults with MDD. Conclusions: Superiority of ESC over placebo for relapse prevention in Japanese adolescents aged 12-17 years with MDD could not be verified with time to relapse evaluated by log-rank test. However, secondary endpoint results and a post hoc analysis of time to relapse suggest that ESC may be effective in preventing MDD relapse. No notable safety/tolerability issues were observed compared with the results of studies in Japanese adults with MDD. Study Registry Number: jRCT2080224520.

Background: Ecological momentary assessment (EMA) captures naturalistic experience in real time and holds promise to improve our understanding and treatment of youth psychopathology. While psychometric evaluation of EMA methods is crucial, particularly for use as a tool in clinical trials, research examining the reliability and validity of EMA items in youth is lacking. Method: This study evaluates EMA responses from 204 child and adolescent participants (M age = 12.54, 60.8% female), including 131 participants with an anxiety disorder and 73 participants with no psychiatric diagnosis. We assessed the within- and between-person variability, internal consistency, test-retest reliability, and convergent and discriminant validity of two EMA items probing anxiety symptoms; one positive affect item served as a comparison. Results: All psychometric properties of the anxiety items were at least satisfactory in youth with anxiety disorders. However, there was restricted variability and poor test-retest reliability in youth with no diagnosis. Discussion: These results might facilitate future clinical trials using EMA to investigate pediatric anxiety. Results also suggest that unique EMA items might be needed to reliably track anxiety in healthy youth. Future work should continue to examine the psychometric properties of EMA protocols before implementation in clinical trials. ClinicalTrials.gov identifier: NCT00018057.

Objective: The efficacy and safety of long-acting injectable (LAI) antipsychotics in the pediatric population is not well established due to limited evidence. This case series aims to describe off-label use of aripiprazole lauroxil (AL) LAI in adolescent inpatients, including findings on safety and readmission trends. Methods: This was a retrospective chart review of patients who were initiated on AL LAI while admitted at a county-based adolescent psychiatric unit between March 2021 and March 2023. Data comprised sociodemographic and clinical characteristics, such as psychiatric diagnoses, prior antipsychotic trials, and history of nonadherence. Other observations of interest included tolerability of AL LAI and time to readmission. Results: This analysis identified 12 adolescents who received AL LAI within a 2-year period. The mean age was 16 ± 1 years, and seven (58%) patients were female. There were varying primary psychiatric diagnoses, with the most common being bipolar disorder (25%), schizophrenia (17%), major depressive disorder with psychotic features (17%), and unspecified mood disorder (17%). Eleven (92%) patients had previously trialed at least one antipsychotic, with seven (58%) having exposure to oral aripiprazole before admission. Nonadherence was the driving factor for LAI consideration in all but one patient. AL LAI was well tolerated short term; one patient reported experiencing injection site pain, and one patient discontinued the LAI after discharge due to anxiety. Time to readmission ranged from 15 to 658 days for seven patients who were hospitalized again; two of the readmissions occurred within 1 month. Conclusion: This is the first case series to describe initiation of AL LAI at an inpatient adolescent psychiatric unit. Our study illustrates that AL LAI may hold potential as an acceptably tolerated treatment in adolescents with varying psychiatric diagnoses. Further studies are needed to evaluate long-term safety and effectiveness of AL LAI in youth.

Objective: To review the current state of the literature regarding anxiety symptoms and anxiety disorders in chronic tic disorder (CTD). Results: We conducted a literature search on anxiety and tic disorders. Anxiety symptoms and anxiety disorders are common in youth with CTD, with ∼30%-50% of youth with CTD having at least one co-occurring anxiety disorder. Tics often improve by young adulthood but anxiety symptoms tend to persist, or worsen, over time. Anxiety and tics are closely related, but the exact nature of their relationship is poorly understood. We discuss some potential ways in which anxiety and tics are linked with an emphasis on the underlying brain circuitry involved. The relationship between anxiety and tics may be related to the premonitory urge. In addition, stress hormones may link anxiety and tics. Individuals with CTD have greater activation of their hypothalamic-pituitary-adrenal system in response to acute stress. We also review the impact of anxiety on youth with CTD and approaches to management of anxiety in youth. Conclusions: Anxiety is common in youth with CTD, is associated with more severe CTD, and can adversely affect a child's function. Thus, it is important to identify anxiety disorders in CTD and manage them appropriately.

Objective: Irritability in children with autism spectrum disorder (ASD) is prominent and often leads to distress to both autistic children and their families. However, the nature of irritability in autism and the difference from nonautistic children have rarely been examined. This study aimed to investigate the clinical characteristics of irritability in autism, and to compare the symptom profiles with those of disruptive mood dysregulation disorder (DMDD) in nonautistic children. Methods: Fifty-six children aged 7-17 years (mean age 10.36 ± 3.05) were recruited into this study (21 with DMDD, 21 with high-functioning autism [hfASD], and 14 healthy volunteers [HV]). Their parents completed the Aberrant Behavior Checklist-Irritability (ABC-I) subscale and the Strengths and Difficulties Questionnaire (SDQ) parent report form. The ABC-I subscale was analyzed as a whole and broken into subsets (ABC-I-Irritability, ABC-I-Agitation, and ABC-I-Crying). The symptom profiles of irritability and the association with psychosocial difficulties were compared between groups. Results: The ABC-I-Irritability scores of children with hfASD closely matched to those of children with DMDD. In addition, both DMDD and hfASD groups could be differentiated from HV group in five of the six items except "depressed mood." However, in the ABC-I-Agitation scale, children with DMDD, but not hfASD, had higher scores in "Aggressive to other patients and staff" and "Stamps feet while banging objects or slamming doors" than HV. Regarding psychosocial outcomes, irritability in children with DMDD and hfASD were associated with emotional problems as measured by the SDQ. Moreover, irritability in DMDD was associated with conduct problems, and the hfASD group exhibited the similar trend. Conclusions: Symptom profiles of irritability and the associated emotional and conduct problems in children with hfASD were similar to those of DMDD in the nonautistic population. Future studies are warranted to explore the underlying neurophysiological mechanisms of irritability between autistic and nonautistic children for further insight into the nature of irritability in autism.