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: Emotional problems have been associated with substance use, yet longitudinal research examining this relationship during childhood and adolescence in large, diverse, community-based samples remains limited. Aims: This study investigates the prospective associations between three emotional problems—hopelessness, depression, and suicide attempts—before ages 9–10 and the subsequent initiation of tobacco and marijuana use before ages 14–15, using data from the Adolescent Brain Cognitive Development (ABCD) study. Methods: Data from the ABCD study were analyzed. Baseline emotional problems, including hopelessness, depression, and suicide attempts, were assessed at ages 9–10 through structured parent interviews. Substance use outcomes (tobacco and marijuana initiation) were tracked from baseline to follow-up at ages 14–15 using structured self-report measures. Structural Equation Modeling (SEM) was employed to assess the predictive roles of these early-life emotional problems, controlling for potential confounders such as demographic factors and family and neighborhood socioeconomic status. Results: Baseline hopelessness, depression, and suicide attempts at ages 9–10 were significant predictors of tobacco and marijuana use initiation at ages 14–15. These associations remained robust after adjusting for confounders, indicating the independent effects of early emotional problems on adolescent substance use initiation. Conclusions: Emotional problems in early childhood, including hopelessness, depression, and suicidal behavior, are critical predictors of substance use initiation during adolescence. These findings underscore the importance of early identification and targeted mental health interventions to reduce the risk of substance use among vulnerable youth.

Major depressive disorder is characterized, among other symptoms, by depressed mood and anhedonia associated with a high rate of suicidal ideation. In recent years, research has shown reduced expression of the brain-derived neurotrophic factor (BDNF) in limbic areas of individuals with depression. This reduction of BDNF is reversed by antidepressants in animal models of stress. Stress is one of the main triggers of mood disorders such as depression. Also, administration of BDNF increases the number of serotonergic fibers and serotonergic innervation, indicating an increase of serotonin in the synaptic cleft by this neurotrophin. Thus, BDNF appears to be one of the targets of antidepressant drugs for the increase of monoamines and remission of symptoms of major depression. The purpose of this review was to show the evidence that indicates BDNF as a molecular substrate for vulnerability to depression and the response of this substrate to the antidepressants.