Search

Antidepressants are standardly used to treat moderate to severe symptoms of depression and/or anxiety in youth but may also be associated with rare but serious psychiatric adverse events such as irritability, agitation, aggression, or suicidal ideation. Adverse events are especially common in youth with a family history of bipolar disorder (BD) who are at heightened risk for dysfunction in neurobiological systems that regulate emotion and arousal. To further understand this phenomenon, this study will examine (a) baseline risk factors associated with dysfunctional arousal in a sample of youth at high-risk for BD treated with or without an antidepressant, (b) whether antidepressant-related changes in arousal are mediated by changes in prefrontal-limbic circuitry, and (c) whether pharmacogenetic factors influence antidepressant-related changes in arousal. High-risk youth (aged 12-17 years with moderate to severe depressive and/or anxiety symptoms and at least one first-degree relative with bipolar I disorder) will be randomized to receive psychotherapy plus escitalopram or psychotherapy plus placebo. Neuroimaging and behavioral measures of arousal will be collected prior to randomization and at 4 weeks. Samples for pharmacogenetic analysis (serum escitalopram concentration, CYP2C19 metabolizer phenotype, and HTR2A and SLC6A4 genotypes) will be collected at 8 weeks. Youth will be followed for up to 16 weeks to assess change in arousal measures.

Background: Youth with a family history of bipolar disorder (BD) may be at increased risk for mood disorders and for developing side effects after antidepressant exposure. The neurobiological basis of these risks remains poorly understood. We aimed to identify biomarkers underlying risk by characterizing abnormalities in the brain connectome of symptomatic youth at familial risk for BD. Methods: Depressed and/or anxious youth (n = 119, age = 14.9 ± 1.6 years) with a family history of BD but no prior antidepressant exposure and typically developing controls (n = 57, age = 14.8 ± 1.7 years) received functional magnetic resonance imaging (fMRI) during an emotional continuous performance task. A generalized psychophysiological interaction (gPPI) analysis was performed to compare their brain connectome patterns, followed by machine learning of topological metrics. Results: High‐risk youth showed weaker connectivity patterns that were mainly located in the default mode network (DMN) (network weight = 50.1%) relative to controls, and connectivity patterns derived from the visual network (VN) constituted the largest proportion of aberrant stronger pairs (network weight = 54.9%). Global local efficiency (Elocal, p =.022) and clustering coefficient (Cp, p =.029) and nodal metrics of the right superior frontal gyrus (SFG) (Elocal: p <.001; Cp: p =.001) in the high‐risk group were significantly higher than those in healthy subjects, and similar patterns were also found in the left insula (degree: p =.004; betweenness: p =.005; age‐by‐group interaction, p =.038) and right hippocampus (degree: p =.003; betweenness: p =.003). The case–control classifier achieved a cross‐validation accuracy of 78.4%. Conclusions: Our findings of abnormal connectome organization in the DMN and VN may advance mechanistic understanding of risk for BD. Neuroimaging biomarkers of increased network segregation in the SFG and altered topological centrality in the insula and hippocampus in broader limbic systems may be used to target interventions tailored to mitigate the underlying risk of brain abnormalities in these at‐risk youth. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of fish oil (FO), a source of the omega‐3 polyunsaturated fatty acids (n‐3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on emotion‐generated corticolimbic functional connectivity in depressed youth at high risk for developing bipolar I disorder. Methods: Thirty‐nine antidepressant‐free youth with a current depressive disorder diagnosis and a biological parent with bipolar I disorder were randomized to 12‐week double‐blind treatment with FO or placebo. At baseline and endpoint, fMRI (4 Tesla) scans were obtained while performing a continuous performance task with emotional and neutral distractors (CPT‐END). Seed‐to‐voxel functional connectivity analyses were performed using bilateral orbitofrontal cortex (OFC) and amygdala (AMY) seeds. Measures of depression, mania, global symptom severity, and erythrocyte fatty acids were obtained. Results: Erythrocyte EPA+DHA composition increased significantly in the FO group (+47%, p ≤ 0.0001) but not in the placebo group (−10%, p = 0.11). Significant group by time interactions were found for functional connectivity between the left OFC and the left superior temporal gyrus (STG) and between the right AMY and right inferior temporal gyrus (ITG). OFC‐STG connectivity increased in the FO group (p = 0.0001) and decreased in the placebo group (p = 0.0019), and AMY‐ITG connectivity decreased in the FO group (p = 0.0014) and increased in the placebo group (p < 0.0001). In the FO group, but not placebo group, the decrease in AMY‐ITG functional connectivity correlated with decreases in Childhood Depression Rating Scale‐Revised and Clinical Global Impression‐Severity Scale scores. Conclusions: In depressed high‐risk youth FO supplementation alters emotion‐generated corticolimbic functional connectivity which correlates with changes in symptom severity ratings. [ABSTRACT FROM AUTHOR]

Aims: To investigate the mechanism of action of N‐acetylcysteine (NAC) in depressive symptoms in young individuals at familial risk for bipolar disorder. Methods: We conducted an 8‐week open label clinical trial of NAC 2400 mg/days in 15–24 years old depressed offspring of a bipolar I disorder parent, with baseline and endpoint proton magnetic resonance spectroscopy acquired within the left ventrolateral prefrontal cortex (VLPFC). Results: Nine participants were enrolled and finished the study. NAC significantly improved depressive and anxiety symptom scores, and clinical global impression (all p <.001). There was a non‐significant reduction in glutamate levels in the left VLPFC. Reduction in depressive symptom scores was positively associated with reduction in glutamate levels in the left VLPFC (p =.007). Conclusions: This pilot study suggests that NAC might be efficacious for depressive symptoms in at‐risk youth, and that its mechanism of action involves the modulation of glutamate in the left VLPFC. [ABSTRACT FROM AUTHOR]