Major depressive disorder (MDD) is a significant psychiatric condition, with many affected individuals not gaining remission from conventional treatments, leading to classification as treatment-resistant depression (TRD). This study aimed to investigate the potential of intravenous (IV) ketamine, particularly the S-enantiomer esketamine in nasal spray form, for treating patients with TRD and associated comorbidities. We report three cases of patients with diverse psychiatric and medical backgrounds whom all reported significant symptomatic relief from depressive episodes and suicidal ideation (SI) following esketamine administration. Additionally, esketamine seemed to proffer benefits beyond the primary depressive symptoms, positively impacting other comorbid conditions, such as agitation, self-injurious behavior (SIB), and chronic pain. The goal of this paper is to highlight that while esketamine's primary utility is in addressing TRD, its therapeutic potential may extend to a variety of associated conditions. However, it is crucial to underscore the heterogeneity of MDD, emphasizing the necessity for individualized therapeutic approaches and further research into esketamine's broader applications.

Background: Adolescence is a critical developmental stage for the emergence of major depressive disorder (MDD). Structural and diffusion neuroimaging studies have highlighted the anterior cingulate cortex (ACC) as a key region implicated in emotion regulation, stress reactivity, and mood processing. However, few studies have examined whether microstructural characteristics of the ACC, reflected by mean diffusivity (MD) within gray matter–white matter (GM–WM) contrast regions, are associated with depression in early adolescence. Objective: To examine whether mean diffusivity (MD) within the GM–WM contrast of the left caudal anterior cingulate cortex (ACC) is associated with a past diagnosis of MDD among adolescents in the Adolescent Brain Cognitive Development (ABCD) Study, after accounting for demographic, socioeconomic, and adversity-related factors. Methods: Data were drawn from adolescents with diffusion MRI–derived mean diffusivity measures and diagnostics. The independent variable was mean diffusivity (MD) of the GM–WM contrast in the left caudal ACC. The primary outcome was past MDD diagnosis based on structured psychiatric assessments. Covariates included age, sex, socioeconomic status (SES), and exposure to adverse childhood experiences (ACEs). Logistic regression models tested the association between ACC MD and past MDD. A secondary model evaluated the relationship between ACC MD and past suicide attempt. Results: Mean diffusivity of the left caudal ACC was associated with the odds of past MDD, independent of age, sex, SES, and adversity exposure. In contrast, ACC mean diffusivity was not associated with a history of suicide attempt. Conclusions: Increased mean diffusivity in the caudal ACC may indicate microstructural alterations associated with depressive vulnerability in adolescence. ACC tissue integrity may serve as a sensitive neural correlate of early-onset depression.

Background: Sexual and gender minority (SGM) youth are at elevated risk for adverse mental health and substance use outcomes. Stressors such as family conflict, discrimination, and trauma have been suggested as possible mediators of these disparities. Aims: This study examined whether family conflict, discrimination, and trauma mediate the associations between SGM identity and adverse outcomes, including suicide attempt, major depressive disorder (MDD), nicotine use, and marijuana use. Methods: Participants were children from the Adolescent Brain Cognitive Development (ABCD) study. SGM identity was reported at baseline, while outcomes included past MDD and suicide attempts as well as future nicotine and marijuana use. Structural equation modeling (SEM) was used to test both direct and indirect pathways linking SGM identity to mental health and behavioral outcomes. Results: No significant mediation was found through family conflict, discrimination, or trauma. Instead, effects of SGM identity were primarily direct: SGM youth had higher odds of past suicide attempts and MDD, as well as future marijuana use, but not future nicotine use. Stressor variables, however, were independently associated with outcomes. Discrimination predicted all outcomes; trauma was positively associated with suicide, nicotine, and marijuana use but not MDD; and family conflict predicted all outcomes except MDD. Conclusion: Family conflict, discrimination, and trauma did not mediate SGM disparities in mental health and substance use, but each emerged as an independent predictor of risk. These findings highlight the complexity of mechanisms underlying SGM-related disparities and suggest the need for future research to explore additional pathways and contextual influences.

Background: The sensory-motor network is essential for integrating sensory input with motor function and higher-order cognition. Resting-state functional connectivity (rsFC) within this network undergoes significant developmental changes, and disruptions in these connections have been linked to behavioral and psychiatric outcomes. However, the relationship between sensory-motor connectivity, early-life adversity, and later health behaviors remains understudied. Objective: This study examines the associations between rsFC within the sensory-motor network (mouth and hand regions) and key social, psychological, and behavioral factors, including baseline and past socioeconomic status (SES), trauma exposure, family conflict, impulsivity, major depressive disorder (MDD), and future substance use. Methods: Data were drawn from the Adolescent Brain Cognitive Development (ABCD) Study, a national sample of U.S. children. Resting-state fMRI data were used to assess functional connectivity within the sensory-motor network. Bivariate analyses examined associations between rsFC in the sensory-motor mouth and hand regions and baseline SES, past SES, childhood trauma exposure, family conflict, impulsivity, and MDD. Longitudinal analyses assessed whether baseline rsFC predicted future substance use. Results: Greater rsFC between the sensory-motor mouth and hand regions was significantly associated with lower SES, higher trauma exposure, and greater family conflict. Increased connectivity was also correlated with older age and more advanced puberty status. Higher rsFC between the sensory-motor mouth and hand regions was linked to greater impulsivity, lower cognitive function, an increased likelihood of MDD, and future marijuana use. Conclusion: These findings suggest that sensory-motor connectivity is sensitive to socioeconomic and psychosocial stressors, with potential long-term implications for mental health and substance use risk. The results highlight the importance of early-life environmental factors in shaping neurodevelopmental trajectories and emphasize the need for targeted interventions to mitigate the effects of adversity on brain function and behavior. Future research should further explore the role of sensory-motor network alterations in behavioral health outcomes as a function of environmental stressors.