Event-Related Potential Markers of Suicidality in Adolescents.

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 the 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 30 healthy controls from the 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 ERP measures may have utility in future refinements of assessment and treatment approaches for adolescents with suicidality.

Efficacy and safety of lamotrigine in pediatric mood disorders: A systematic review.

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.

A Systematic Review of the Safety and Tolerability of Theta Burst Stimulation in Children and Adolescents.

OBJECTIVES: Theta burst stimulation (TBS) is often used in clinical practice and research protocols for adults with neuropsychiatric disorders. There are substantial knowledge gaps related to the application of TBS in children and adolescents. This systematic review examined the safety and tolerability of TBS in children and adolescents. MATERIALS AND METHODS: A systematic review of human TBS studies in children and adolescents was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following inclusion criteria were applied: 1) articles in English language only; 2) studies that included child and adolescent participants (up to 21 years of age); 3) studies that administered intermittent TBS or continuous TBS or both to participants; 4) studies that had an outcome measure; and 5) availability of full text material. The primary outcome measures were tolerability and safety. When feasible, the clinical effects were reviewed. RESULTS: Twenty relevant articles met the criteria for inclusion. The reported adverse events were mild and similar to what is noted in adult studies. The most common symptom was headache. One case report described a seizure induced by TBS. Collectively, the studies were heterogeneous but the methodologic quality of randomized trials was high. CONCLUSIONS: TBS interventions in children may have similar safety, tolerability, and feasibility as compared to adults. However, long-term, follow-up studies of TBS are lacking. Future dose-ranging studies with systematic assessment of adverse events will be important in the translation of findings with TBS from adults to youth.

A retrospective, naturalistic study of deep brain stimulation and vagal nerve stimulation in young patients.

INTRODUCTION: Invasive neuromodulation interventions such as deep brain stimulation (DBS) and vagal nerve stimulation (VNS) are important treatments for movement disorders and epilepsy, but literature focused on young patients treated with DBS and VNS is limited. This retrospective study aimed to examine naturalistic outcomes of VNS and DBS treatment of epilepsy and dystonia in children, adolescents, and young adults. METHODS: We retrospectively assessed patient demographic and outcome data that were obtained from electronic health records. Two researchers used the Clinical Global Impression scale to retrospectively rate the severity of neurologic and psychiatric symptoms before and after patients underwent surgery to implant DBS electrodes or a VNS device. Descriptive and inferential statistics were used to examine clinical effects. RESULTS: Data from 73 patients were evaluated. Neurologic symptoms improved for patients treated with DBS and VNS (p < .001). Patients treated with DBS did not have a change in psychiatric symptoms, whereas psychiatric symptoms worsened for patients treated with VNS (p = .008). The frequency of postoperative complications did not differ between VNS and DBS groups. CONCLUSION: Young patients may have distinct vulnerabilities for increased psychiatric symptoms during treatment with invasive neuromodulation. Child and adolescent psychiatrists should consider a more proactive approach and greater engagement with DBS and VNS teams that treat younger patients.

A Dose-Finding, Biomarker Validation, and Effectiveness Study of Transcranial Magnetic Stimulation for Adolescents With Depression.

OBJECTIVE: Research and clinical application of transcranial magnetic stimulation (TMS) for adolescents with major depressive disorder (MDD) has advanced slowly. Significant gaps persist in our understanding of optimized, age-specific protocols and dosing strategies. This study aimed to compare the clinical effects of 1 Hz versus 10 Hz TMS regimens and examine a biomarker-informed treatment approach with glutamatergic intracortical facilitation (ICF). METHOD: Participants with moderate-to-severe symptoms of MDD were randomized to 30 sessions of left prefrontal 1 Hz or 10 Hz TMS, stratified by baseline ICF measures. The primary clinical outcome measure was the Children's Depression Rating Scale, Revised (CDRS-R). The CDRS-R and ICF biomarker were collected weekly. RESULTS: Forty-one participants received either 1 Hz (n = 22) or 10 Hz (n = 19) TMS treatments. CDRS-R scores improved compared to baseline in both 1 Hz and 10 Hz groups. For participants with low ICF at baseline, the overall least squares means of CDRS-R scores over the 6-week trial showed that depressive symptom severity was lower for the group treated with 1 Hz TMS than for those who received 10 Hz TMS. There were no significant changes in weekly ICF measurements across the 6 weeks of TMS treatment. CONCLUSION: Low ICF may reflect optimal glutamatergic N-methyl-d-aspartate (NMDA) receptor activity that facilitates the therapeutic effect of 1 Hz TMS through long-term depression-like mechanisms on synaptic plasticity. The stability of ICF suggests that it is a tonic, trait-like measure of NMDA receptor-mediated neurotransmission, with potential utility to inform parameter selection for therapeutic TMS in adolescents with MDD.

Evidence for Altered Electroencephalography Coherence in Depressed Adolescents with Suicidal Ideation and Behaviors.

Introduction: Major depressive disorder (MDD) is a primary risk factor for suicide, which is one of the leading causes of death among adolescents worldwide. Understanding the heterogeneity of suicidality in adolescents with MDD is critical for suicide prevention and intervention discovery. Quantitative electroencephalography (EEG) is a promising tool to address the knowledge gaps related to the neurophysiological characteristics of depression and suicidality. This study sought to examine resting-state EEG coherence differences in adolescents with MDD and suicidal ideation (SI)/behaviors (SB) and healthy controls (HC) to assess the utility of coherence as a biomarker of suicide. Methods: Twenty-six adolescents with MDD who were hospitalized for suicidality and 30 HC were recruited. The clinical sample was divided into SI (n = 9) and SB (n = 19) subgroups. Eyes closed resting-state EEG were recorded, and coherence was calculated. Depression severity and suicidality were assessed with the Children's Depression Rating Scale Revised and the Columbia Suicide Severity Rating Scale, respectively. Results: There were intrahemispheric differences in the right hemisphere across multiple electrode pairs. Delta, alpha, and beta coherence were higher in the SB group over the right prefrontofrontal and left parietooccipital electrode pairs, while alpha coherence was higher in the HC group over the right centroparietal electrode pair. There were no significant differences between HC and SI groups in any electrode pair. Conclusions: Patients with recent SB showed increased coherence in right frontal regions compared with patients with SI, suggesting altered cognitive states between those with SB and SI. These findings may have implications for suicide prevention in adolescents and could serve as useful biomarkers in clinical settings, but larger studies are needed to confirm the results.

Long-Interval Intracortical Inhibition and the Cortical Silent Period in Youth.

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.

Sequential bilateral accelerated theta burst stimulation in adolescents with suicidal ideation associated with major depressive disorder: Protocol for a randomized controlled trial.

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.