Depression and insulin resistance are becoming increasingly prevalent in younger populations. The origin and consequence of insulin resistance in depressed youth may, in part, be rooted in exposure to environmental stressors, such as early life abuse, that may lead to aberrant brain motivational networks mediating maladaptive food-seeking behaviors and insipient insulin resistance. In this paper, we aimed to investigate the impact of early life abuse on the development of insulin resistance in depressed and overweight youth aged 9 to 17 years. We hypothesized that youth with the greatest burden of early life abuse would have the highest levels of insulin resistance and corresponding aberrant reward network connectivities. To test this hypothesis, we evaluated sixty-nine depressed and overweight youth aged 9 to 17, using multimodal assessments of early life abuse, food-seeking behavior, and insulin resistance. Based on results of the Childhood Trauma Questionnaire (CTQ), we separated our study participants into two groups: 35 youth who reported high levels of the sum of emotional, physical, or sexual abuse and 34 youth who reported insignificant or no levels of any abuse. Results of an oral glucose tolerance test (OGTT) and resting state functional connectivity (RSFC), using the amygdala, insula, and nucleus accumbens (NAcc) as seed-based reward network regions of interest, were analyzed for group differences between high abuse and low abuse groups. High abuse youth exhibited differences from low abuse youth in amygdala-precuneus, NAcc-paracingulate gyrus, and NAcc-prefrontal cortex connectivities, that correlated with levels of abuse experienced. The more different their connectivity from of that of low abuse youth, the higher were their fasting glucose and glucose at OGTT endpoint. Importantly, level of abuse moderated the relation between reward network connectivity and OGTT glucose response. In contrast, low abuse youth showed hyperinsulinemia and more insulin resistance than high abuse youth, and their higher OGTT insulin areas under the curve correlated with more negative insula-precuneus connectivity. Our findings suggest distinct neural and endocrine profiles of youth with depression and obesity based on their histories of early life abuse.

KEYWORDS: antidepressant-induced mania, family history of bipolar disorder, pediatric depression and anxiety, pharmacotherapy, psychotherapy, treatment | C A S E"John" is a 14-year-old boy who presents with symptoms of depressed mood and anxiety. His mother describes him as a sociable child who participates in several extracurricular activities. However, over the past 2 years, he has become increasingly socially withdrawn. In the past 6 months, other symptoms developed, including difficulties falling asleep, academic decline, and feelings of worthlessness. During this time, John's family reports significant psychosocial stressors: John's brother is diagnosed with schizophrenia, and his father, who has lived with bipolar I disorder for years, is hospitalized for a suicide attempt.Indeed, John's symptoms significantly interfere with his social and academic functioning. With these concerns, he initially presents to his pediatrician seeking treatment for sustained depressive symptoms lasting at least 2 weeks for most of the day, every day.He shares with his pediatrician that he had been experiencing daily challenges trying to fall asleep due to low mood and worries, some anhedonia, decreased energy, difficulty concentrating in school, and psychomotor retardation. He also reports several weeks of hypersomnia, increased appetite, and eating, especially during times of stress, like studying for exams. Though he endorses passive suicidal thoughts in dark moments of hopelessness, he denies any specific plans, means, or intent to harm himself, and does not report a history of any prior suicide attempts or self-injurious behaviors.Importantly, John denies any current or lifetime manic or psychotic symptoms. After being diagnosed with major depressive disorder, it is recommended that he receive psychotherapy to address his mood symptoms. John completes 4 months of family focused therapy (FFT) for youth at risk for bipolar disorder, after which he reported mild improvement in anxiety but no significant improvement of his mood symptoms. His baseline and 4-month depression and mania severity scores are as follows: Children's Depression Rating Scale-Revised Raw score went from 59 to 52 and the Young Mania Rating Scale score went from 1 to 0.Given the persistence of his mood symptoms in spite of FFT, John's therapist recommends that he speak to his pediatrician about the possibility of starting an antidepressant. After reviewing risks, benefits, and alternatives, his pediatrician starts John on 5 mg of escitalopram. Within hours, John notices that his mood had improved.However, on the third day of treatment on 5 mg of escitalopram, John's experiences increased anxiety to a level of a full-blown panic attack. While he was sitting in class, he reports suddenly feeling restless, a sense of doom, and palpitations. He worries that these intense symptoms were due to escitalopram so he discontinues the medication the next day with full resolution of his anxiety and agitation. A life chart illustrating his transition from psychotherapy t...

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