Prospective Follow-Up of Adolescents With and at Risk for Depression: Protocol and Methods of the Identifying Depression Early in Adolescence Risk Stratified Cohort Longitudinal Assessments.

Objective: To present the protocol and methods for the prospective longitudinal assessments-including clinical and digital phenotyping approaches-of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo) study, which comprises Brazilian adolescents stratified at baseline by risk of developing depression or presence of depression. Method: Of 7,720 screened adolescents aged 14 to 16 years, we recruited 150 participants (75 boys, 75 girls) based on a composite risk score: 50 with low risk for developing depression (LR), 50 with high risk for developing depression (HR), and 50 with an active untreated major depressive episode (MDD). Three annual follow-up assessments were conducted, involving clinical measures (parent- and adolescent-reported questionnaires and psychiatrist assessments), active and passive data sensing via smartphones, and neurobiological measures (neuroimaging and biological material samples). Retention rates were 96% (Wave 1), 94% (Wave 2), and 88% (Wave 3), with no significant differences by sex or group (p > .05). Participants highlighted their familiarity with the research team and assessment process as a motivator for sustained engagement. Discussion: This protocol relied on novel aspects, such as the use of a WhatsApp bot, which is particularly pertinent for low- to-middle-income countries, and the collection of information from diverse sources in a longitudinal design, encompassing clinical data, self-reports, parental reports, Global Positioning System (GPS) data, and ecological momentary assessments. The study engaged adolescents over an extensive period and demonstrated the feasibility of conducting a prospective follow-up study with a risk-enriched cohort of adolescents in a middle-income country, integrating mobile technology with traditional methodologies to enhance longitudinal data collection.

This article details the study protocol and methods used in the longitudinal assessment of 150 Brazilian teenagers with depression and at risk for depression as part of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo). Over 3 years, the authors collected clinical and digital data using innovative mobile technology, including a WhatsApp bot. Most adolescents participated in all the study phases, showing feasibility of prospective follow-up in a middle-income country. This approach allowed for a deeper understanding of depression in young populations, particularly in areas where mental health research is scarce.

A magnetic resonance imaging-based morphometric and structural covariance network study of Brazilian adolescents stratified by depression risk

Objectives: To explore differences in regional cortical morphometric structure between adolescents at risk for depression or with current depression. Methods: We analyzed cross-sectional structural neuroimaging data from a sample of 150 Brazilian adolescents classified as low-risk (LR) (n=50) or high-risk (HR) for depression (n=50) or with current depression (n=50) through a vertex-based approach with measurements of cortical volume (CV), surface area (SA), and cortical thickness (CT). Differences between groups in subcortical volume and in the organization of networks of structural covariance were also explored. Results: No significant differences in brain structure between groups were observed in whole-brain vertex-wise CV, SA, or CT. Also, no significant differences in subcortical volume were observed between risk groups. In relation to the structural covariance network, there was an indication of an increase in the hippocampus betweenness centrality index in the HR group network compared to the LR and current depression group networks. However, this result was only statistically significant when applying false discovery rate correction for nodes within the affective network. Conclusion: In an adolescent sample recruited using an empirically based composite risk score, no major differences in brain structure were detected according to the risk and presence of depression.

Sex-specific inflammatory markers of risk and presence of depression in adolescents.

BACKGROUND: Associations between inflammatory markers and depression are reported among adults; however, less is known in adolescent depression in particular whether these associations are sex-specific. We aimed to identify inflammatory markers of increased risk and presence of depression in adolescence and their association with severity of depressive symptoms in the entire cohort and separately in boys and girls. METHODS: We measured serum cytokines using a Meso Scale Discovery electrochemiluminescence V-PLEX assay in a cohort of 150 adolescents stratified for risk/presence of depression. Risk group and sex-specific differences in inflammatory markers were assessed with 2-way mixed ANOVA, and sex-moderated associations between inflammatory markers and the severity of depressive symptoms were assessed with moderated multiple hierarchical regression analyses. RESULTS: We found a significant interaction between biological sex and the risk group, where boys showed higher interleukin (IL)-2 levels among the depressed group compared with the low-risk group. The severity of depressive symptoms was associated with elevated levels of IL-2 in boys, and of IL-6 in girls. There was a significant moderating effect of sex on the relationship between IL-2 and the severity of depressive symptoms but not for IL-6. LIMITATIONS: The cross-sectional design means that we cannot be certain about the direction of the associations. CONCLUSIONS: Our findings suggest sex-specific associations between inflammatory markers and the development of adolescent depression, where IL-2 may increase risk for depression and severity of depressive symptoms in boys, but not in girls. However, IL-6 may increase risk for more severe depressive symptoms in girls.

An MRI-based morphometric and structural covariance network study of Brazilian adolescents stratified by depression risk.

OBJECTIVE: To explore differences in regional cortical morphometric structure between adolescents at risk for depression or with current depression. METHODS: We analyzed cross-sectional structural neuroimaging data from a sample of 150 Brazilian adolescents classified as low-risk (n=50) or high-risk for depression (n=50) or with current depression (n=50) through a vertex-based approach with measurements of cortical volume, surface area and thickness. Differences between groups in subcortical volumes and in the organization of networks of structural covariance were also explored. RESULTS: No significant differences in brain structure between groups were observed in whole-brain vertex-wise cortical volume, surface area or thickness. Also, no significant differences in subcortical volume were observed between risk groups. In relation to the structural covariance network, there was an indication of an increase in the hippocampus betweenness centrality index in the high-risk group network compared to the low-risk and current depression group networks. However, this result was only statistically significant when applying false discovery rate correction for nodes within the affective network. CONCLUSION: In an adolescent sample recruited using an empirically based composite risk score, no major differences in brain structure were detected according to the risk and presence of depression.

Frontolimbic Network Topology Associated With Risk and Presence of Depression in Adolescents: A Study Using a Composite Risk Score in Brazil.

BACKGROUND: There have been significant challenges in understanding functional brain connectivity associated with adolescent depression, including the need for a more comprehensive approach to defining risk, the lack of representation of participants from low- and middle-income countries, and the need for network-based approaches to model connectivity. The current study aimed to address these challenges by examining resting-state functional connectivity of frontolimbic circuitry associated with the risk and presence of depression in adolescents in Brazil. METHODS: Adolescents in Brazil ages 14 to 16 years were classified into low-risk, high-risk, and depressed groups using a clinical assessment and composite risk score that integrates 11 sociodemographic risk variables. After excluding participants with excessive head movement, resting-state functional magnetic resonance imaging data of 126 adolescents were analyzed. We compared group differences in frontolimbic network connectivity using region of interest-to-region of interest, graph theory, and seed-based connectivity analyses. Associations between self-reported depressive symptoms and brain connectivity were also explored. RESULTS: Adolescents with depression showed greater dorsal anterior cingulate cortex (ACC) connectivity with the orbitofrontal cortex compared with the 2 risk groups and greater dorsal ACC global efficiency than the low-risk group. Adolescents with depression also showed reduced local efficiency and a lower clustering coefficient of the subgenual ACC compared with the 2 risk groups. The high-risk group also showed a lower subgenual ACC clustering coefficient relative to the low-risk group. CONCLUSIONS: These findings highlight altered connectivity and topology of the ACC within frontolimbic circuitry as potential neural correlates and risk factors of developing depression in adolescents in Brazil. This study broadens our understanding of the neural connectivity associated with adolescent depression in a global context.

Sleep disturbances, circadian activity, and nocturnal light exposure characterize high risk for and current depression in adolescence.

STUDY OBJECTIVES: Major depressive disorder (MDD) in adolescence is associated with irregularities in circadian rhythms and sleep. The characterization of such impairment may be critical to design effective interventions to prevent development of depression among adolescents. This study aimed to examine self-reported and actimetry-based circadian rhythms and sleep-wake behavior associated with current MDD and high risk (HR) for MDD among adolescents. METHODS: Ninety-six adolescents who took part in the IDEA-RiSCo study were recruited using an empirically developed depression-risk stratification method: 26 classified as low risk (LR), 31 as HR, and 39 as a current depressive episode (MDD). We collected self-report data on insomnia, chronotype, sleep schedule, sleep hygiene as well as objective data on sleep, rest-activity, and light exposure rhythms using actimetry for 10 days. RESULTS: Adolescents with MDD exhibited more severe insomnia, shorter sleep duration, higher social jetlag (SJL), lower relative amplitude (RA) of activity, and higher exposure to artificial light at night (ALAN) compared with the other groups. They also presented poorer sleep hygiene compared with the LR group. The HR group also showed higher insomnia, lower RA, higher exposure to ALAN, and higher SJL compared with the LR group. CONCLUSIONS: HR adolescents shared sleep and rhythm alterations with the MDD group, which may constitute early signs of depression, suggesting that preventive strategies targeting sleep should be examined in future studies. Furthermore, we highlight that actimetry-based parameters of motor activity (particularly RA) and light exposure are promising constructs to be explored as tools for assessment of depression in adolescence.

Handling missing data in rest-activity time series measured by actimetry.

A handling procedure of off-wrist episodes in actimetry time series of motor activity is presented using two records (regular vs. irregular sleep-wake cycle and daytime activity) of 14 consecutive days sampled in 1-minute epochs. We generated single missing value (NA) intervals of 1 h, 2 h, 4 h, 6 h, 12 h, and 24 h as well as random NA episodes following probabilistic rules to simulate real-life off-wrist episodes. Then, we replaced these episodes with "zeroes" (i.e., the default of immobility records), mean or median of the remaining 13 days corresponding to the missing bins. Single missing episodes of up to 12 h resulted in less than 5% variation from the original values. The irregular series showed higher variability in acrophase, MESOR, L5, M10 and RA compared to the regular series. Random missing allocation simulating real-life off-wrist episodes resulted in significant changes in most parameters, and the imputation of zeroes significantly increased the variance; however, replacing NA with mean or median resulted in patterns similar to those of NA. We recommend replacing 'zeroes' with NA whenever possible, given the risk of inflating invariance using zeroes. If the parameters cannot be computed in the presence of NA, we recommend using the weekly mean of corresponding timepoints.

Reward- and threat-related neural function associated with risk and presence of depression in adolescents: a study using a composite risk score in Brazil.

BACKGROUND: Neuroimaging studies on adolescents at risk for depression have relied on a single risk factor and focused on adolescents in high-income countries. Using a composite risk score, this study aims to examine neural activity and connectivity associated with risk and presence of depression in adolescents in Brazil. METHODS: Depression risk was defined with the Identifying Depression Early in Adolescence Risk Score (IDEA-RS), calculated using a prognostic model that included 11 socio-demographic risk factors. Adolescents recruited from schools in Porto Alegre were classified into a low-risk (i.e., low IDEA-RS and no lifetime depression), high-risk (i.e., high IDEA-RS and no lifetime depression), or clinically depressed group (i.e., high IDEA-RS and depression diagnosis). One hundred fifty adolescents underwent a functional MRI scan while completing a reward-related gambling and a threat-related face-matching task. We compared group differences in activity and connectivity of the ventral striatum (VS) and amygdala during the gambling and face-matching tasks, respectively, and group differences in whole-brain neural activity. RESULTS: Although there was no group difference in reward-related VS or threat-related amygdala activity, the depressed group showed elevated VS activity to punishment relative to high-risk adolescents. The whole-brain analysis found reduced reward-related activity in the lateral prefrontal cortex of patients and high-risk adolescents compared with low-risk adolescents. Compared with low-risk adolescents, high-risk and depressed adolescents showed reduced threat-related left amygdala connectivity with thalamus, superior temporal gyrus, inferior parietal gyrus, precentral gyrus, and supplementary motor area. CONCLUSIONS: We identified neural correlates associated with risk and presence of depression in a well-characterized sample of adolescents. These findings enhance knowledge of the neurobiological underpinnings of risk and presence of depression in Brazil. Future longitudinal studies are needed to examine whether the observed neural patterns of high-risk adolescents predict the development of depression.

The Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo): Rationale, Methods, and Baseline Characteristics.

Background: The characterization of adolescents at high risk for developing depression has traditionally relied on the presence or absence of single risk factors. More recently, the use of composite risk scores combining information from multiple variables has gained attention in prognostic research in the field of mental health. We previously developed a sociodemographic composite score to estimate the individual level probability of depression occurrence in adolescence, the Identifying Depression Early in Adolescence Risk Score (IDEA-RS). Objectives: In this report, we present the rationale, methods, and baseline characteristics of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo), a study designed for in-depth examination of multiple neurobiological, psychological, and environmental measures associated with the risk of developing and with the presence of depression in adolescence, with a focus on immune/inflammatory and neuroimaging markers. Methods: Using the IDEA-RS as a tool for risk stratification, we recruited a new sample of adolescents enriched for low (LR) and high (HR) depression risk, as well as a group of adolescents with a currently untreated major depressive episode (MDD). Methods for phenotypic, peripheral biological samples, and neuroimaging assessments are described, as well as baseline clinical characteristics of the IDEA-RiSCo sample. Results: A total of 7,720 adolescents aged 14-16 years were screened in public state schools in Porto Alegre, Brazil. We were able to identify individuals at low and high risk for developing depression in adolescence: in each group, 50 participants (25 boys, 25 girls) were included and successfully completed the detailed phenotypic assessment with ascertainment of risk/MDD status, blood and saliva collections, and magnetic resonance imaging (MRI) scans. Across a variety of measures of psychopathology and exposure to negative events, there was a clear pattern in which either the MDD group or both the HR and the MDD groups exhibited worse indicators in comparison to the LR group. Conclusion: The use of an empirically-derived composite score to stratify risk for developing depression represents a promising strategy to establish a risk-enriched cohort that will contribute to the understanding of the neurobiological correlates of risk and onset of depression in adolescence.