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Background: Changes in the hypothalamic-pituitary-adrenal (HPA) axis, as evidenced by patterns of cortisol secretion, have been of interest in understanding depression and anxiety disorders across the life span. Previous studies of pediatric depression have pointed to the period around sleep onset as a key time point for observing alterations in cortisol secretion associated with affective disorders. Evidence also indicates that pubertal development may influence the expression of HPA dysregulation. We hypothesized that adolescents with depression and youth with anxiety disorders exhibit elevated peri-sleep-onset cortisol., Methods: Plasma cortisol was sampled every 20 min around sleep onset from children and adolescents with major depressive disorder (n = 116), anxiety disorders (n = 32), or no history of psychiatric disorder (control; n = 76). Sleep onset was determined by polysomnography. Classification of participants as children or adolescents was based on Tanner staging of pubertal maturation., Results: Children with anxiety disorders had higher peri-sleep-onset cortisol than children with depression or control children. Adolescents with depression had marginally higher peri-sleep-onset cortisol than control adolescents and significantly higher peri-sleep-onset cortisol than children with depression., Conclusions: Depression and anxiety are associated with altered cortisol secretion around sleep onset, and these changes appear to be influenced by pubertal maturation.

Background: In vivo imaging studies in adult bipolar patients have suggested enlargement of the amygdala. It is not known whether this abnormality is already present early in the illness course or whether it develops later in life. We conducted a morphometric MRI study to examine the size of specific temporal lobe structures in adolescents and young adults with bipolar disorder and healthy control subjects, as well as their relationship with age, to examine possible neurodevelopmental abnormalities., Methods: Subjects included 16 DSM-IV bipolar patients (16 +/- 3 years) and 21 healthy controls (mean age +/- SD = 17 +/- 4 years). Measures of amygdala, hippocampus, temporal gray matter, temporal lobe, and intracranial volumes (ICV) were obtained., Results: There was a trend to smaller left amygdala volumes in patients (mean volumes +/- SD = 1.58 +/- .42 mL) versus control subjects (1.83 +/- .4 mL; F = 3.87, df = 1,32, p = .06). Bipolar patients did not show significant differences in right or left hippocampus, temporal lobe gray matter, temporal lobe, or right amygdala volumes (analysis of covariance, age, gender, and ICV as covariates, p > .05) compared with healthy control subjects. Furthermore, there was a direct correlation between left amygdala volumes and age (r =. 50, p = .047) in patients, whereas in healthy controls there was an inverse correlation (r = -.48, p = .03)., Conclusions: The direct correlation between left amygdala volumes and age in bipolar patients, not present in healthy control subjects, may reflect abnormal developmental mechanisms in bipolar disorder.

Background: The essential symptoms of generalized anxiety disorder (GAD) are intrusive worry about everyday life circumstances and social competence, and associated autonomic hyperarousal. The amygdala, a brain region involved in fear and fear-related behaviors in animals, and its projections to the superior temporal gyrus (STG), thalamus, and to the prefrontal cortex are thought to comprise the neural basis of our abilities to interpret social behaviors. Larger amygdala volumes were previously reported in pediatric GAD; however, the brain regions involved in social intelligence were not examined in this pilot study., Methods: Magnetic resonance imaging (MRI) was used to measure the STG, thalamus, and prefrontal volumes in 13 medically healthy child and adolescent subjects with generalized anxiety disorder (GAD) and 98 comparison subjects, who were at low familial risk for mood and psychotic disorders. Groups were similar in age, gender, height, weight, handedness, socioeconomic status, and full-scale IQ., Results: The total, white matter, and gray matter STG volumes were significantly larger in GAD subjects compared with control subjects. Thalamus and prefrontal lobe volumes did not differ between groups. Findings of significant side-by-diagnosis interactions for STG and STG white matter volumes suggest that there is a more pronounced right > left asymmetry in total and STG white matter volumes in pediatric GAD subjects compared with control subjects. A significant correlation between the STG white matter percent asymmetry index with the child report of the Screen for Child Anxiety Related Emotional Disorders Scale was seen., Conclusions: These data agree with previous work implicating posterior right-hemispheric regions in anxiety disorders and may suggest developmental alterations in pediatric GAD.

Background: The neurodevelopment of childhood anxiety disorders is not well understood. Basic research has implicated the amygdala and circuits related to these nuclei as being central to several aspects of fear and fear-related behaviors in animals., Methods: Magnetic resonance imaging was used to measure amygdala volumes and comparison brain regions in 12 child and adolescent subjects with generalized anxiety disorder and 24 comparison subjects. Groups were matched on age, sex, height, and handedness and were also similar on measures of weight, socioeconomic status, and full scale IQ., Results: Right and total amygdala volumes were significantly larger in generalized anxiety disorder subjects. Intracranial, cerebral, cerebral gray and white matter, temporal lobe, hippocampal, and basal ganglia volumes and measures of the midsagittal area of the corpus callosum did not differ between groups., Conclusions: Although these data are preliminary and from a small sample, the results are consistent with a line of thinking that alterations in the structure and function of the amygdala may be associated with pediatric generalized anxiety disorder.

Background: Few studies have examined the involvement of the central dopaminergic system in the pathophysiology of mood disorders. The study of prolactin (PRL) secretion may be an informative indirect method for the assessment of the dopaminergic system in children with major depressive disorder (MDD)., Methods: Plasma PRL concentrations were measured at 20-min intervals over a 24-hr period in 40 pre-pubertal children with MDD, 18 with non-affective psychiatric disorders (PC), and 6 normal controls (NC). A subgroup of depressed children (n = 21) was restudied after recovery., Results: There was no significant differences in either the amount or the pattern of PRL secretion between the MDD, PC, and NC groups. Children who recovered from their depression secreted less PRL during sleep and more while awake compared to when they were acutely depressed., Conclusions: Overall, there were no differences in baseline PRL secretion between children with MDD, NC and psychiatric control. These results suggest that the dopaminergic system as measured by baseline PRL blood levels is not compromised in children with MDD.

Background: This investigation examined the relationship between trauma, psychiatric symptoms and urinary free cortisol (UFC) and catecholamine (epinephrine [EPI], norepinephrine [NE], dopamine [DA]) excretion in prepubertal children with posttraumatic stress disorder (PTSD) secondary to past child maltreatment experiences (n = 18), compared to non-traumatized children with overanxious disorder (OAD) (n = 10) and healthy controls (n = 24)., Methods: Subjects underwent comprehensive psychiatric and clinical assessments and 24 hour urine collection for measurements of UFC and urinary catecholamine excretion. Biological and clinical measures were compared using analyses of variance., Results: Maltreated subjects with PTSD excreted significantly greater concentrations of urinary DA and NE over 24 hours than OAD and control subjects and greater concentrations of 24 hour UFC than control subjects. Post hoc analysis revealed that maltreated subjects with PTSD excreted significantly greater concentrations of urinary EPI than OAD subjects. Childhood PTSD was associated with greater co-morbid psychopathology including depressive and dissociative symptoms, lower global assessment of functioning, and increased incidents of lifetime suicidal ideation and attempts. Urinary catecholamine and UFC concentrations showed positive correlations with duration of the PTSD trauma and severity of PTSD symptoms., Conclusions: These data suggest that maltreatment experiences are associated with alterations of biological stress systems in maltreated children with PTSD. An improved psychobiological understanding of trauma in childhood may eventually lead to better treatments of childhood PTSD.

Sleep measures were obtained in 16 depressed and 21 control adolescents following 1 week of adherence to a uniformly imposed and strictly enforced sleep/wake schedule. Three nights of baseline electroencephalographic (EEG) sleep on the same 10:00 PM to 7:00 AM schedule revealed prolonged sleep latency and reduced rapid eye movement (REM) latency in the depressed adolescents. Following baseline measures, sleep was restricted for 2 nights (10:00 PM-4:00 AM) and measures of recovery sleep were obtained showing further sleep latency differences. There was no evidence for delta sleep changes or sleep continuity differences in depressed adolescents. These results suggest that control over sleep/wake schedules is an important methodological issue in adolescent sleep studies. Furthermore, the findings are consistent with a larger body of evidence indicating that dysregulation near sleep onset represents a primary psychobiological change in early-onset depression.

Dexamethasone Suppression Test (DST) studies conducted in children and adolescents are reviewed, together with factors hypothesized to explain discrepancies in rates of DST nonsuppression across studies. These factors are then examined in a controlled study of 27 adolescents with major depressive disorder (MDD) and 34 normal controls (NC). Subjects were given 1 mg of dexamethasone at 11:00 PM, and the following day serum samples for cortisol were collected each hr from 8 AM to 11 PM through an indwelling catheter. There were no significant differences found between the MDD and NC subjects on any postdexamethasone cortisol measure. Further, cortisol suppressors and nonsuppressors were not distinguished by any of the hypothesized factors identified from the review, including inpatient status, presence of suicidality, endogenous features, psychotic symptoms, or prior history of MDD. Questions about the appropriateness of the 1 mg dose of dexamethasone (currently the standard dose used with adolescents) are raised, together with a discussion of the effects of stress on DST findings.

Levels of the melatonin metabolite, 6-hydroxymelatonin sulfate, were measured in overnight urine from 31 prepubertal children with major depressive disorder and 15 normal control children with very low family loading for affective disorder. The two groups did not differ with regard to their nocturnal excretion of this compound, nor was any depressive subgroup identified whose 6-hydroxymelatonin sulfate excretion differed from that of the control group. Previous studies of pineal function in depression are reviewed and discussed in the context of the present investigation.