Scoping Review: Transdiagnostic Measurement of Impulsivity Domains in Youth Using the UPPS Impulsive Behavior Scales.

OBJECTIVE: Impulsivity contributes to many clinically relevant behaviors impacting youth. A scoping review was conducted to characterize existing research using the Urgency, Premeditation (lack of), Perseverance (lack of), Sensation Seeking (UPPS) Impulsive Behavior Scale (UPPS) Impulsive Behavior Scales in youth populations, to review the psychometric and validity data of UPPS, and to summarize findings related to sex/gender and diagnostic populations of youth. METHOD: PubMed, Embase, and PsycNET databases were searched from January 1, 2001 (original UPPS publication) through October 2, 2022, according to PRISMA extension for Scoping Reviews guidelines. Articles were reviewed for inclusion/exclusion by 2 authors. Original research articles in English using any UPPS version or subscale in persons aged ≤21 years were included. RESULTS: Inclusion criteria were met by 45 articles, with low bias and moderate-to-high quality. Most were cross-sectional studies; studies investigated diverse community and clinical samples. The UPPS demonstrated consistent factor structure, good reliability, and good external validity with other measures of impulsive behaviors and conditions associated with impaired impulse control. Some studies observed differences in UPPS domain scores between sex/gender groups or differential patterns in relations between UPPS domains and clinical variables. UPPS subscale scores often differed in youth with attention-deficit/hyperactivity disorder, conduct disorders, substance use, and excess weight/obesity compared with control youth. UPPS domains commonly had interactions with sex/gender, sociodemographic, and diagnosis-related variables. CONCLUSION: The current literature suggests that the UPPS has utility in measuring distinct components of impulsivity in clinical and nonclinical populations of youth. Specificity in discriminating diagnostic groups and predicting risk currently remains uncertain. Further research is needed to integrate UPPS measures with experimental models and additional neurobiological methods and to assess longitudinal developmental trajectories.

A pilot spectroscopy study of adversity in adolescents.

Background: Childhood adversity is a global health problem affecting 25-50% of children worldwide. Few prior studies have examined the underlying neurochemistry of adversity in adolescents. This cross-sectional study examined spectroscopic markers of trauma in a cohort of adolescents with major depressive disorder (MDD) and healthy controls. We hypothesized that historical adversity would have a negative relationship with spectroscopic measures of glutamate metabolites in anterior cingulate cortex. Methods: Adolescent participants (aged 13-21) underwent a semi-structured diagnostic interview and clinical assessment, which included the self-report Childhood Trauma Questionnaire (CTQ), a 28-item assessment of childhood adversity. Proton magnetic resonance spectroscopy (1H-MRS) scans at 3 Tesla of an anterior cingulate cortex (ACC) voxel (8 cm3) encompassing both hemispheres were collected using a 2-dimensional J-averaged sequence to assess N-acetylaspartate (NAA), Glx (glutamate+glutamine) and [NAA]/[Glx] concentrations. Generalized linear models assessed the relationships between CTQ scores and metabolite levels in ACC. Results: Thirty-nine participants (17 healthy controls, 22 depressed participants) underwent 1H-MRS and completed the CTQ measures. There were decrements in [NAA]/[Glx] ratio in the ACC of participants with childhood adversity while no significant relationship between CTQ total score and any of the ACC metabolites was found in the combined sample. Exploratory results revealed a positive association between Glx levels and CTQ scores in depressed participants. Conversely the [NAA]/[Glx] ratio had a negative association with total CTQ scores in the depressed participants. Emotional Abuse Scale showed a significant negative relationship with [NAA]/[Glx] ratio in the combined sample when adjusted for depression severity. Conclusions: Our findings suggest that childhood adversity may impact brain neurochemical profiles. Further longitudinal studies should examine neurochemical correlates of childhood adversity throughout development and in populations with other psychiatric disorders.

A systematic review of microbiome changes and impact of probiotic supplementation in children and adolescents with neuropsychiatric disorders.

OBJECTIVES: In recent decades, the diagnostic and therapeutic implications of the microbiome changes and the impact of probiotic supplementation have increased rapidly. However, the potential for clinical translation of microbiome research for children and adolescents with psychiatric disorders is unclear. This review examined available evidence related to gut microbiota as well as the impact of probiotic supplementation on psychiatric disorders in the pediatric population reported to date. METHODS: We performed a literature search for the gut microbiota in child and adolescent population (0-18 years old) with mental health disorders from July 1999 through July 2019 in several databases: ClinicalTrials.gov, Ovid EBM Reviews, Ovid Embase, Ovid Medline, Ovid PsycINFO, Scopus, and Web of Science. RESULTS: A total of 7 studies met inclusion criteria consisting of randomized controlled trials and cohort studies that examined various associations between psychiatric disorders and gut microbiota in youth. Six studies examined the effects of various treatment interventions such as probiotic supplementation on microbiota composition and behaviors. One study showed an increase in prosocial behavior in children with Autism Spectrum Disorder (ASD) and an increase in the Lachnospiraceae family following prebiotic supplementation. Another study suggested that prebiotic supplementation increased bifidobacterial populations for ASD and healthy controls. A study evaluating infant supplementation of prebiotics showed both a decreased likelihood of developing Attention Deficit Hyperactivity Disorder (ADHD) or ASD and decreased gut Bifidobacterium. One study did not find significant differences in microbiome composition after micronutrient treatment. CONCLUSION: The main goal of this systematic review was to comprehensively examine and summarize the current evidence focused on the potential effect of the relationship between microbiota gut composition as well as the effects of probiotic supplementation on psychiatric disorders in children and adolescents. This is a relatively new area of research and the number of included studies is limited. More studies are needed to determine whether gut dysbiosis leads to the development and/or contributes to the severity of mental disorders or whether gut dysbiosis is a result of other processes that accompany mental disorders. CLINICAL SIGNIFICANCE: A better understanding of the specific bacteria contributions, gut-brain pathways, and role in pathophysiological mechanisms in neuropsychiatric disorders in the child and adolescent populations can possibly provide alternative tools for a clinical psychiatrist. Moreover, it may ultimately aid the clinician with intervention strategies, or detect populations at risk for developing neuropsychiatric disorders.

Glutamatergic Correlates of Bipolar Symptoms in Adolescents.

Objectives: Prior studies demonstrate elevated cortical glutamate (Glu) in patients with bipolar disorder (BD). Studies assessing neurochemistry in early stages of bipolar illness before the emergence of manic symptoms are lacking. This study aimed to examine neurochemical correlates measured by proton magnetic resonance spectroscopy (1H-MRS) and a dimensional measure of bipolarity in a sample of depressed adolescents. Methods: Adolescent participants (aged 13-21 years) underwent a semistructured diagnostic interview and clinical assessment, which included the General Behavior Inventory Parent Version (P-GBI), a 73-item, parent-rated assessment of symptoms and behaviors. 1H-MRS scans of a left dorsolateral prefrontal cortex (L-DLPFC) voxel (8 cm3) were collected using a two-dimensional J-averaged sequence to assess N-acetylaspartate (NAA), Glu, Glx (glutamate + glutamine), and NAA/Glx concentrations. We used generalized linear models to assess the relationships between P-GBI scores and metabolite levels in L-DLPFC. Results: Thirty-six participants (17 healthy controls, 19 depressed) underwent 1H-MRS scans and clinical evaluation with the P-GBI. There was a significant negative relationship between P-GBI score and L-DLPFC NAA/Glx in the whole sample. However, the magnitude of the effect was small and statistical significance was lost after correcting for multiple comparisons. Conclusions: These preliminary results suggest that NAA/Glx may have utility as a marker of bipolar traits in healthy and depressed adolescents. If replicated, 1H-MRS measures of glutamatergic metabolism anomalies might have a role in identifying depressed adolescents at risk for mixed symptom presentations or BD. Identifying bipolarity in the early stages of the disease would have a significant impact on treatment planning and prognosis. Further longitudinal studies should examine neurochemical correlates of mood state during the developmental emergence of BD.

Novel pharmacological treatments for generalized anxiety disorder: Pediatric considerations.

BACKGROUND: Pediatric anxiety disorders such as generalized anxiety disorder (GAD) are common, impairing, and often undertreated. Moreover, many youth do not respond to standard, evidence-based psychosocial or psychopharmacologic treatment. An increased understanding of the gamma-aminobutyric acid (GABA) and glutamate neurotransmitter systems has created opportunities for novel intervention development for pediatric GAD. METHODS: This narrative review examines potential candidates for pediatric GAD: eszopiclone, riluzole, eglumegad (LY354740), pimavanserin, agomelatine. RESULTS: The pharmacology, preclinical data, clinical trial findings and known side effects of eszopiclone, riluzole, eglumegad (LY354740), pimavanserin, agomelatine, are reviewed, particularly with regard to their potential therapeutic relevance to pediatric GAD. CONCLUSION: Notwithstanding numerous challenges, some of these agents represent potential candidate drugs for pediatric GAD. Further treatment development studies of agomelatine, eszopiclone, pimavanserin and riluzole for pediatric GAD also have the prospect of informing the understanding of GABAergic and glutamatergic function across development.

Altered anterior cingulate glutamatergic metabolism in depressed adolescents with current suicidal ideation.

The anterior cingulate cortex (ACC) is involved in emotion regulation and salience processing. Prior research has implicated ACC dysfunction in suicidal ideation (SI) and suicidal behavior. This study aimed to quantify ACC glutamatergic concentrations and to examine relationships with SI in a sample of healthy and depressed adolescents. Forty adolescents underwent clinical evaluation and proton magnetic resonance spectroscopy (1H-MRS) at 3 T, utilizing a 2-dimensional J-averaged PRESS sequence sampling a medial pregenual ACC voxel. Cerebrospinal fluid-corrected ACC metabolite concentrations were compared between healthy control (HC, n = 16), depressed without SI (Dep/SI-, n = 13), and depressed with SI (Dep/SI+, n = 11) youth using general linear models covarying for age, sex, and psychotropic medication use. Relationships between ACC metabolites and continuous measures of SI were examined using multiple linear regressions. ROC analysis was used to determine the ability of glutamate+glutamine (Glx) and the N-acetylaspartate (NAA)/Glx ratio to discriminate Dep/SI- and Dep/SI+ adolescents. Dep/SI+ adolescents had higher Glx than Dep/SI- participants (padj = 0.012) and had lower NAA/Glx than both Dep/SI- (padj = 0.002) and HC adolescents (padj = 0.039). There were significant relationships between SI intensity and Glx (pFDR = 0.026), SI severity and NAA/Glx (pFDR = 0.012), and SI intensity and NAA/Glx (pFDR = 0.004). ACC Glx and NAA/Glx discriminated Dep/SI- from Dep/SI+ participants. Uncoupled NAA-glutamatergic metabolism in the ACC may play a role in suicidal ideation and behavior. Longitudinal studies are needed to establish whether aberrant glutamatergic metabolism corresponds to acute or chronic suicide risk. Glutamatergic biomarkers may be promising targets for novel risk assessment and interventional strategies for suicidal ideation and behavior.

Improvement in hypersomnia with high frequency repetitive transcranial magnetic stimulation in depressed adolescents: Preliminary evidence from an open-label study.

STUDY OBJECTIVES: Sleep disruption is a significant symptom of major depressive disorder (MDD). To our knowledge, no prior work has examined the impact of repetitive transcranial magnetic stimulation (rTMS) on sleep disturbances in adolescents with MDD. METHODS: Seventeen adolescents with treatment-resistant depression received 30 daily sessions of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex (L-DLPFC). Clinical symptoms were assessed at baseline; after 10, 20, and 30 treatments; and at a 6-month follow-up visit. Insomnia was measured with a 3-item subscale of the Quick Inventory of Depressive Symptomatology-Adolescent (17 Item)-Self Report (QIDS-A17-SR). Hypersomnia was measured with a single QIDS-A17-SR item. Depression severity was rated with the Children's Depression Rating Scale, Revised (CDRS-R). The effect of rTMS on sleep was examined via linear mixed model analyses, with fixed effects of time (as a proxy of treatment), depression severity, age, and hypnotic medication use. RESULTS: No significant main effect of time was observed on the insomnia subscale (F4,43.442 = 1.078, p = 0 .379). However, there was a significant main effect of time on the QIDS-A17-SR hypersomnia score (F4,46.124 = 2.733, p = 0 .040), with significant improvement from baseline to treatment 10 (padj = 0.019) and from baseline to 6-month follow-up (padj = 0.044). In exploratory sensitivity analyses, response/nonresponse to rTMS for overall depressive symptoms had no significant effect on sleep outcomes. CONCLUSIONS: rTMS may have intrinsic effects on hypersomnia apart from its antidepressant effects in depressed adolescents. Future work should utilize sham controls and objective, quantitative measurements of sleep architecture to assess effects of rTMS in depressed adolescents. CLINICAL TRIAL REGISTRY: Clinicaltrials.gov identifiers are NCT00587639, NCT01502033, NCT01804270.

Accelerated TMS for Depression: A systematic review and meta-analysis.

Repetitive transcranial magnetic stimulation (TMS) is now widely available for the clinical treatment of depression, but the associated financial and time burdens are problematic for patients. Accelerated TMS (aTMS) protocols address these burdens and attempt to increase the efficiency of standard TMS. This systematic review and meta-analysis aimed to examine accelerated TMS studies for depressive disorders in accordance with PRISMA guidelines. Inclusion criteria consisted of studies with full text publications available in English describing more than one session of TMS (repetitive or theta burst stimulation) per day. Studies describing accelerated TMS protocols for conditions other than depression or alternative neuromodulation methods, preclinical studies, and neurophysiology studies regarding transcranial stimulation were excluded. Eighteen articles describing eleven distinct studies (seven publications described overlapping samples) met eligibility criteria. A Hedges' g effect size and confidence intervals were calculated. The summary analysis of three suitable randomized control trials revealed a cumulative effect size of 0.39 (95% CI 0.005-0.779). A separate analysis including open-label trials and active arms of suitable RCTs revealed a g of 1.27 (95% CI 0.902-1.637). Overall, the meta-analysis suggested that aTMS improves depressive symptom severity. In general, study methodologies were acceptable, but future efforts could enhance sham techniques and blinding.

Preliminary evidence of an association between increased cortical inhibition and reduced suicidal ideation in adolescents treated for major depression.

BACKGROUND: Suicide is a leading cause of death among youth. Prior research using transcranial magnetic stimulation (TMS) has implicated deficits in GABAergic cortical inhibition in adolescent suicidal behavior, yet no studies have assessed whether cortical inhibition varies over time in conjunction with changes in suicidal ideation (SI). This study examined dynamic changes in long-interval intracortical inhibition (LICI), a TMS measure of GABAB-mediated inhibition, and their relationship with changes in SI in a small sample of adolescents undergoing pharmacologic treatment for depression. METHODS: Ten depressed adolescents (aged 13-17) underwent clinical assessment and TMS testing at baseline and again at follow-up. All were treated with antidepressant medication in the interim. SI was measured with the Columbia Suicide Severity Rating Scale (C-SSRS) Intensity of Ideation subscale. LICI was measured at interstimulus intervals of 100 and 150 ms. RESULTS: There was a significant partial correlation, controlling for change in depression severity, between ΔLICI-100 and change in SI as measured by ΔC-SSRS (ρ = .746, df = 7, p = .021), which remained after also controlling for time to follow-up assessment (ρ = .752, df = 6, p = .032). No significant correlation was observed between ΔLICI-150 and change in SI. LIMITATIONS: Sample size; variable follow-up interval; inability to control for age, sex, and potential treatment effects. CONCLUSIONS: These data offer preliminary signal of an association between increases in GABAB-mediated cortical inhibition and reduction in SI over time in adolescents treated for depression. Further studies are warranted to explore the role of cortical inhibition in adolescent suicidal ideation and behavior.