Aim To appraise the current evidence on the efficacy and safety of lamotrigine (LAM) in the treatment of pediatric mood disorders (PMD) (i.e., Major Depressive disorder [MDD], bipolar disorder [BD]). Methods Major databases were searched for randomized controlled trials (RCTs), open‐label trials, and observational studies reporting on pediatric (age < 18 years) patients treated with LAM for mood disorders. Results A total of 3061 abstracts were screened and seven articles were selected for inclusion. Seven studies (319 BD and 43 MDD patients), including one RCT (n = 173), three prospective (n = 105), and three retrospective (n = 84) studies, met the study criteria with a study duration range from 8 to 60.9 weeks. The mean age of this pooled data is 14.6 ± 2.0 years. LAM daily dosage varied from 12.5 to 391.3 mg/day among the studies. In an important finding, the RCT reported favorable outcomes with LAM (HR = 0.46; p = 0.02) in 13‐ to 17‐year‐old age group as compared with 10‐ to 12‐year‐old age group (HR = 0.93; p = 0.88). In addition, time to occurrence of a bipolar event trended toward favoring LAM over placebo. All the studies identified LAM as an effective and safe drug in PMDs especially, BDs. Overall, LAM was well tolerated with no major significant side effects and no cases of Stevens–Johnson syndrome. Conclusions Most studies suggested that LAM was safe and effective in pediatric patients with mood disorders. However, the data regarding the therapeutic range for LAM are lacking. Based on the data, there is inconsistent evidence to make conclusive recommendations on therapeutic LAM dosage for mood improvement in the pediatric population. Further studies including larger sample sizes are required to address this relevant clinical question.

Background Implicit cognitive markers may assist with the prediction of suicidality beyond clinical risk factors. The aim of this study was to investigate neural correlates associated with Death/Suicide Implicit Association Test (DS-IAT) via event-related potentials (ERP) in suicidal adolescents. Methods Thirty inpatient adolescents with suicidal ideations and behaviors (SIBS), and thirty healthy controls from community were recruited. All participants underwent 64-channel electroencephalography, DS-IAT, and clinical assessments. Hierarchical generalized linear models with spatiotemporal clustering were used to identify significant ERPs associated with the behavioral outcome of DS-IAT (D scores) and group differences. Results Behavioral results (D scores) showed that the adolescents with SIBS had stronger implicit associations between “death” and “self” than the healthy group (P=.02). Within adolescents with SIBS, participants with stronger implicit associations between “death” and “self” reported more difficulty in controllability of suicidal ideation in the past 2 weeks based on the Columbia-Suicide Severity Rating Scale (P=.03). For the ERP data, the D scores and N100 component over the left parieto-occipital cortex had significant correlations. Significant group differences without behavioral correlation were observed for a second N100 cluster (P=.01), P200 (P=.02), and late positive potential (5 clusters, all P≤.02). Exploratory predictive models combining both neurophysiological and clinical measures distinguished adolescents with SIBS from healthy adolescents. Conclusions Our results suggest that N100 may be a marker of attentional resources involved in the distinction of stimuli that are congruent or incongruent to associations between death and self. Combined clinical and event-related potential measures may have utility in future refinements of assessment and treatment approaches for adolescents with suicidality.

Background: The cortical silent period (CSP) and long-interval intracortical inhibition (LICI) are putative markers of γ-aminobutyric acid receptor type B (GABAB)-mediated inhibitory neurotransmission. We aimed to assess the association between LICI and CSP in youths. Methods: We analyzed data from three previous studies of youth who underwent CSP and LICI measurements with transcranial magnetic stimulation and electromyography. We assessed CSP and LICI association using Spearman rank correlation tests and multiple linear regression analyses adjusted for demographic and clinical covariates. Results: The sample included 16 healthy participants and 45 participants with depression. The general mean (SD) age was 15.5 (1.7), 14.3 (1.7) for healthy participants, and 15.9 (1.6) years for participants with depression. Measures were nonnormally distributed (Shapiro–Wilk, p < 0.001). CSP and LICI were not correlated at 100-millisecond (ρ = −0.2421, p = 0.06), 150-millisecond (ρ = −0.1612, p = 0.21), or 200-millisecond (ρ = −0.0507, p = 0.70) interstimulus intervals using Spearman rank correlation test. No correlations were found in the multiple regression analysis (p = 0.35). Conclusions: Although previous studies suggest that cortical silent period and long-interval intracortical inhibition measure GABAB receptor-mediated activity, these biomarkers were not associated in our sample of youths. Future studies should focus on the specific physiologic and pharmacodynamic properties assessed by CSP and LICI in younger populations.

Background Suicide is a leading cause of death in adolescents worldwide. Previous research findings suggest that suicidal adolescents with depression have pathophysiological dorsolateral prefrontal cortex (DLPFC) deficits in γ-aminobutyric acid neurotransmission. Interventions with transcranial magnetic stimulation (TMS) directly address these underlying pathophysiological deficits in the prefrontal cortex. Theta burst stimulation (TBS) is newer dosing approach for TMS. Accelerated TBS (aTBS) involves administering multiple sessions of TMS daily as this dosing may be more efficient, tolerable, and rapid acting than standard TMS. Materials and methods This is a randomized, double-blind, sham-controlled trial of sequential bilateral aTBS in adolescents with major depressive disorder (MDD) and suicidal ideation. Three sessions are administered daily for 10 days. During each session, continuous TBS is administered first to the right DPFC, in which 1,800 pulses are delivered continuously over 120 seconds. Then intermittent TBS is applied to the left DPFC, in which 1,800 pulses are delivered in 2-second bursts and repeated every 10 seconds for 570 seconds. The TBS parameters were adopted from prior research, with 3-pulse, 50-Hz bursts given every 200 ms (at 5 Hz) with an intensity of 80% active motor threshold. The comparison group will receive 3 daily sessions of bilateral sham TBS treatment for 10 days. All participants will receive the standard of care for patients with depression and suicidal ideation including daily psychotherapeutic skill sessions. Long-interval intracortical inhibition (LICI) biomarkers will be measured before and after treatment. Exploratory measures will be collected with TMS and electroencephalography for biomarker development. Discussion This is the first known randomized controlled trial to examine the efficacy of sequential bilateral aTBS for treating suicidal ideation in adolescents with MDD. Results from this study will also provide opportunities to further understand the neurophysiological and molecular mechanisms of suicidal ideation in adolescents. Trial registration Investigational device exemption (IDE) Number: G200220, ClinicalTrials.gov (ID: NCT04701840). Registered August 6, 2020. https://clinicaltrials.gov/ct2/show/NCT04502758?term=NCT04701840&draw=2&rank=1.

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