Association between poor tolerability of antidepressant treatment and brain functional activation in youth at risk for bipolar disorder

Objective: To investigate whether poor antidepressant tolerability is associated with functional brain changes in children and adolescents of parents with bipolar I disorder (at-risk youth). Methods: Seventy-three at-risk youth (ages 9-20 years old) who participated in a prospective study and had an available baseline functional magnetic resonance imaging (fMRI) scan were included. Research records were reviewed for the incidence of adverse reactions related to antidepressant exposure during follow-up. The sample was divided among at-risk youth without antidepressant exposure (n=21), at-risk youth with antidepressant exposure and no adverse reaction (n=12), at-risk youth with antidepressant-related adverse reaction (n=21), and healthy controls (n=20). The fMRI task was a continuous performance test with emotional distracters. Region-of-interest mean activation in brain areas of the fronto-limbic emotional circuit was compared among groups. Results: Right amygdala activation in response to emotional distracters significantly differed among groups (F3,66 = 3.1, p = 0.03). At-risk youth with an antidepressant-related adverse reaction had the lowest amygdala activation, while at-risk youth without antidepressant exposure had the highest activation (p = 0.004). Conclusions: Decreased right amygdala activation in response to emotional distracters is associated with experiencing an antidepressant-related adverse reaction in at-risk youth. Further studies to determine whether amygdala activation is a useful biomarker for antidepressant-related adverse events are needed.

Medication exposure and predictors of first mood episode in offspring of parents with bipolar disorder: a prospective study

Objectives: To prospectively investigate whether baseline clinical characteristics and medication exposure predict development of major depressive disorder or bipolar disorder in offspring of parents with bipolar disorder. Methods: Youth aged 9-20 years with at least one biological parent with bipolar disorder and no prior history of mood or psychotic episodes (n=93) were prospectively evaluated and treated naturalistically during the study. Participants were divided into two groups: converters, defined as those who met DSM-IV criteria for a mood episode during follow-up (n=19); or non-converters (n=74). Logistic regression models were used to investigate associations between baseline clinical variables and medication exposure during follow-up and risk of developing a first mood episode (conversion). Results: Multivariate regression analyses showed that baseline anxiety disorders and subsyndromal mood disorders were associated with increased risk of conversion during follow-up. Adding medication exposure to the multivariate model showed that exposure to antidepressants during follow-up was associated with increased risk of conversion. Conclusions: Caution should be used when treating bipolar offspring with anxiety and/or emerging depressive symptoms using antidepressant agents, given the increased risk of developing a major mood disorder.

Association between poor tolerability of antidepressant treatment and brain functional activation in youth at risk for bipolar disorder.

OBJECTIVE: To investigate whether poor antidepressant tolerability is associated with functional brain changes in children and adolescents of parents with bipolar I disorder (at-risk youth). METHODS: Seventy-three at-risk youth (ages 9-20 years old) who participated in a prospective study and had an available baseline functional magnetic resonance imaging (fMRI) scan were included. Research records were reviewed for the incidence of adverse reactions related to antidepressant exposure during follow-up. The sample was divided among at-risk youth without antidepressant exposure (n=21), at-risk youth with antidepressant exposure and no adverse reaction (n=12), at-risk youth with antidepressant-related adverse reaction (n=21), and healthy controls (n=20). The fMRI task was a continuous performance test with emotional distracters. Region-of-interest mean activation in brain areas of the fronto-limbic emotional circuit was compared among groups. RESULTS: Right amygdala activation in response to emotional distracters significantly differed among groups (F3,66 = 3.1, p = 0.03). At-risk youth with an antidepressant-related adverse reaction had the lowest amygdala activation, while at-risk youth without antidepressant exposure had the highest activation (p = 0.004). CONCLUSIONS: Decreased right amygdala activation in response to emotional distracters is associated with experiencing an antidepressant-related adverse reaction in at-risk youth. Further studies to determine whether amygdala activation is a useful biomarker for antidepressant-related adverse events are needed.

Medication exposure and predictors of first mood episode in offspring of parents with bipolar disorder: a prospective study.

OBJECTIVES: To prospectively investigate whether baseline clinical characteristics and medication exposure predict development of major depressive disorder or bipolar disorder in offspring of parents with bipolar disorder. METHODS: Youth aged 9-20 years with at least one biological parent with bipolar disorder and no prior history of mood or psychotic episodes (n=93) were prospectively evaluated and treated naturalistically during the study. Participants were divided into two groups: converters, defined as those who met DSM-IV criteria for a mood episode during follow-up (n=19); or non-converters (n=74). Logistic regression models were used to investigate associations between baseline clinical variables and medication exposure during follow-up and risk of developing a first mood episode (conversion). RESULTS: Multivariate regression analyses showed that baseline anxiety disorders and subsyndromal mood disorders were associated with increased risk of conversion during follow-up. Adding medication exposure to the multivariate model showed that exposure to antidepressants during follow-up was associated with increased risk of conversion. CONCLUSIONS: Caution should be used when treating bipolar offspring with anxiety and/or emerging depressive symptoms using antidepressant agents, given the increased risk of developing a major mood disorder.

A randomized, placebo-controlled study of duloxetine for the treatment of children and adolescents with generalized anxiety disorder.

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of the selective serotonin norepinephrine inhibitor duloxetine in children and adolescents with generalized anxiety disorder (GAD). METHOD: Youth aged 7 through 17 years with a primary diagnosis of GAD were treated with flexibly dosed duloxetine (30-120 mg daily, n = 135) or placebo (n = 137) for 10 weeks, followed by open-label duloxetine (30-120mg daily) for 18 weeks. Efficacy measures included the Pediatric Anxiety Rating Scale (PARS), Clinical Global Impression-Severity (CGI-Severity) scale, and Children's Global Assessment Scale (CGAS). Safety measures included the Columbia-Suicide Severity Rating Scale (C-SSRS) as well as vital signs and electrocardiographic and laboratory monitoring. RESULTS: On the primary efficacy measure (PARS severity for GAD), mean improvement from baseline to 10 weeks was statistically significantly greater for duloxetine (-9.7) compared with placebo (-7.1, p ≤ .001, Cohen's d: 0.5). Symptomatic response (50% improvement on the PARS severity for GAD), remission (PARS severity for GAD ≤8), and functional remission (CGAS >70) rates for the duloxetine group (59%, 50%, 37%, respectively) were statistically significantly greater than for the placebo group (42%, 34%, 24%, respectively, p ≤ .05) during acute treatment. Changes in systolic and diastolic blood pressure and discontinuation because of adverse events did not statistically differ between the duloxetine and placebo groups, although gastrointestinal-related adverse events, oropharyngeal pain, dizziness, cough, and palpitations were reported with a statistically significantly greater incidence for the duloxetine group compared with the placebo group. Mean changes in pulse and weight for the duloxetine group (+6.5 beats/min, -0.1 kg, respectively) were statistically different from the placebo group (+2.0 beats/min, +1.1 kg, respectively, p ≤ .01). CONCLUSION: In this study, duloxetine was superior to placebo on the primary efficacy analysis of mean change from baseline to week 10 on the PARS severity for GAD score, and safety results were consistent with the known safety profile of duloxetine in pediatric and adult patients. Clinical trial registration information-A Study in Pediatric Participants With Generalized Anxiety Disorder; http://clinicaltrials.gov; NCT01226511.

Sexual abuse is associated with obese children and adolescents admitted for psychiatric hospitalization.

OBJECTIVE: To determine the relationship between a history of child abuse and obesity among children admitted for psychiatric hospitalization. STUDY DESIGN: The charts of 1434 youth consecutively admitted to an inpatient psychiatric facility during a 10-month period were retrospectively analyzed. Rates of physical and sexual abuse, as well as other factors believed to increase the risk of obesity, were compared between children whose body mass index (BMI) percentiles were between 5 and 80 and whose BMI percentiles were >85. RESULTS: After correcting for age, race, gender, and antipsychotic usage, we found that a reported history of sexual abuse was associated with increased probability of being overweight/obese (BMI percentile 85-99) compared with being of typical BMI (aOR 1.41). Reported physical abuse neither increased the risk of obesity nor moderated the association between sexual abuse and increased weight. Antipsychotic treatment and female gender also were associated with increased BMI percentiles, with antipsychotic usage being the only variable associated with increased risk of a BMI percentile >99. CONCLUSIONS: Among youth with significant psychiatric illness, a history of sexual abuse increases the risk of being overweight or obese, an association that warrants further study regarding the temporal relationship between sexual abuse and obesity and may inform future obesity prevention and intervention programs in children.