Adolescent experience predicts longevity: evidence from historical epidemiology.

Human development reportedly includes critical and sensitive periods during which environmental stressors can affect traits that persist throughout life. Controversy remains over which of these periods provides an opportunity for such stressors to affect health and longevity. The elaboration of reproductive biology and its behavioral sequelae during adolescence suggests such a sensitive period, particularly among males. We test the hypothesis that life expectancy at age 20 among males exposed to life-threatening stressors during early adolescence will fall below that among other males. We apply time-series methods to cohort mortality data in France between 1816 and 1919, England and Wales between 1841 and 1919, and Sweden between 1861 and 1919. Our results indicate an inverse association between cohort death rates at ages 10-14 and cohort life expectancy at age 20. Our findings imply that better-informed and more strategic management of the stressors encountered by early adolescents may improve population health.

Why do anxious children become depressed teenagers? The role of social evaluative threat and reward processing.

BACKGROUND: Depression is a leading cause of worldwide disability. Adolescence represents a key developmental window in which rates of this disorder increase markedly. Children with an anxiety disorder show a particular risk of developing depression during adolescence. METHOD: We present and review evidence for a developmental model that considers the intersection of two vulnerabilities relevant to the trajectory from anxiety to depression: difficulties in response to potential social evaluation and changes in reward processing at puberty. RESULTS: Evidence suggests that these vulnerabilities (a) have been associated with depression, (b) are likely to be problematic in many, but not all, anxious youth, and (c) may be exacerbated by maturational processes that occur around pubertal development in ways that can create a negative spiral into a depressive disorder. CONCLUSIONS: We discuss the possibility that early intervention strategies targeting key aspects of these vulnerabilities could alter the trajectory away from depression for many anxious youth.

A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity.

Recent studies have indicated that a newly identified second isoform of the tryptophan hydroxylase gene (TPH2) is preferentially involved in the rate-limiting synthesis of neuronal serotonin. Genetic variation in the human TPH2 gene (hTPH2) has been associated with altered in vitro enzyme activity as well as increased risk for mood disorders. Here, we provide the first in vivo evidence that a relatively frequent regulatory variant (G(-844)T) of hTPH2 biases the reactivity of the amygdala, a neural structure critical in the generation and regulation of emotional behaviors.

Amygdala response to fearful faces in anxious and depressed children.

BACKGROUND: Alterations in amygdala function have been implicated in the pathophysiological characteristics of adult anxiety and depressive disorders. Studies with healthy adults and children, as well as with adults who have amygdala lesions, have found facial expressions of emotion to be useful probes of amygdala activity. Our study examined the amygdala response to fearful and neutral facial expressions in healthy, anxious, and depressed children. We hypothesized that children with anxiety and depression may show atypical amygdala responses to emotional stimuli. METHODS: Twelve children (8-16 years of age) with generalized anxiety or panic disorder and 12 healthy comparison children underwent noninvasive functional magnetic resonance imaging while viewing photographs of fearful and neutral facial expressions. In a second comparison, 5 girls with major depressive disorder were compared with 5 anxious and 5 healthy girls from the previous sample. RESULTS: Children with anxiety disorders showed an exaggerated amygdala response to fearful faces compared with healthy children, whereas depressed children showed a blunted amygdala response to these faces. In addition, the magnitude of the amygdala's signal change between fearful and neutral faces was positively correlated with the severity of everyday anxiety symptoms. CONCLUSIONS: Our results suggest that amygdala function is affected in both anxiety and depression during childhood and adolescence. Moreover, this disruption appears to be specific to the child's own rating of everyday anxiety.

Amygdala response to facial expressions in children and adults.

BACKGROUND: The amygdala plays a central role in the human response to affective or emotionally charged stimuli, particularly fear-producing stimuli. We examined the specificity of the amygdala response to facial expressions in adults and children. METHODS: Six adults and 12 children were scanned in a 1.5-T scanner during passive viewing of fearful and neutral faces using an EPI BOLD sequence. All scans were registered to a reference brain, and analyses of variance were conducted on the pooled data to examine interactions with age and gender. RESULTS: Overall, we observed predominantly left amygdala and substantia innominata activity during the presentation of nonmasked fearful faces relative to fixation, and a decrease in activation in these regions with repeated exposure to the faces. Adults showed increased left amygdala activity for fearful faces relative to neutral faces. This pattern was not observed in the children who showed greater amygdala activity with neutral faces than with fearful faces. For the children, there was an interaction of gender and condition whereby boys but not girls showed less activity with repeated exposure to the fearful faces. CONCLUSIONS: This is the first study to examine developmental differences in the amygdala response to facial expressions using functional magnetic resonance imaging.

Affect regulation, brain development, and behavioral/emotional health in adolescence.

This paper addresses the importance of affect regulation (AR) in relation to a broad range of behavioral and emotional health problems that emerge during adolescence. AR is defined as the adaptive modulation of emotional experience to serve a goal or purpose. This conceptualization of AR emphasizes the use of cognitive skills to guide, inhibit, or modify emotion and behavior, including the expression of emotional responses, in learned, strategic ways-skills that ultimately underpin adult levels of social maturity and the ability to show "responsible" behavior across a range of emotional situations. Neurobehavioral systems that subserve these AR skills include areas of the inferior and orbital prefrontal cortex (PFC), with rich interconnections to several limbic structures and other cortical areas, including the dorsolateral PFC. Adolescence represents an important developmental period in the functional maturation of adult AR skills; it is also a critical time in the development of clinical disorders of AR (eg, rates of depression increase dramatically and gender differences in depression emerge). Maturational changes in AR that occur during adolescence-particularly with respect to the role of emotions influencing responsible decision making-are also relevant to understanding key aspects of the developmental pathways of some behavioral health problems, such as alcohol use and nicotine dependence. A strong case is made for developmental research in affective neuroscience aimed at this important maturational period, particularly the kind of transdisciplinary research leading toward mechanistic understanding of the development of adolescent-onset disorders. Improving understanding in these areas could ultimately lead to the development of early interventions in targeted high-risk populations, and has enormous clinical and social policy relevance.

Parent-child bonding and family functioning in depressed children and children at high risk and low risk for future depression.

OBJECTIVE: To evaluate parent-child bonding and familial functioning in depressed children, children at high risk for depression, and low-risk controls. METHOD: Diagnoses of children and their relatives were obtained via structured interviews with all available informants. Depressed children (n = 54) received a diagnosis of current major depressive disorder (MDD). The high-risk children (n = 21) had no lifetime diagnoses of mood disorders, but at least one first-degree relative with a lifetime history of depression. The low-risk controls (n = 23) had no lifetime psychiatric disorders and no first-degree relative with a lifetime history of mood disorders. Parent-child bonding was evaluated with the child's report on the Parental Bonding Instrument (PBI). Familial functioning was evaluated with each parent answering the Family Assessment Device (FAD). RESULTS: Significant differences were found between the MDD and low-risk children on most parameters of the PBI and FAD. The children with MDD reported significantly elevated maternal overprotection, and their fathers scored significantly lower on the FAD scales of Behavioral Control and General Functioning, compared with the high-risk children. Mothers of high-risk children had significantly lower scores on the Roles and Affective Involvement dimensions of the FAD compared with mothers of low-risk children. Current maternal depression had a deleterious effect on the child's perception of maternal protection and paternal care, mother's report on all FAD scales, and father's report on most FAD scales, whether interacting with the child's depression or existing even if the child was not depressed. CONCLUSION: Maternal depression and its interaction with the child's depression appear to have negative consequences for parent-child bonding and family functioning.

Low growth hormone response to growth hormone-releasing hormone in child depression.

BACKGROUND: This study examined growth hormone (GH) response to growth hormone-releasing hormone (GHRH) in a large sample of depressed children compared with normal control children. Within-subject comparisons were also performed in control subjects to examine test-retest reliability and in depressed children comparing episode versus clinical recovery. METHODS: The sample included depressed children (n = 82) and normal control children (n = 55) group-matched for age, gender, and pubertal status; the mean ages were 11.2 +/- 1.7 and 11.2 +/- 1.8 years, respectively. We gave GHRH (0.1 mcg/Kg) at 9 AM, and serum GH levels were determined every 15 min from -30 min through +90 min of the GHRH infusion. A subgroup of normal control subjects (n = 11) repeated the protocol for test-retest reliability within a 2-month interval. A subgroup of depressed children (n = 20) were restudied off all medications following full clinical remission from depression. RESULTS: The mean GH response to GHRH was significantly lower in the depressed group (8.7 ng/mL +/- SEM 0.9) compared with normal control children [12.2 ng/mL +/- SEM 1.3; t(135) = 2.59, p =.01 effect size 0.44]. The test-retest reliability of GH response to GHRH was stable (intraclass correlation =.93 for mean post-GH). The GH response to GHRH remained low in subjects restudied during clinical remission from depression. CONCLUSIONS: Depressed children show low GH response to GHRH. The measure appears to be reliable, and the low GH response continues following clinical remission. Further studies are needed to explore the mechanism and relative specificity of this finding.

Atypical symptoms of depression in a sample of depressed child and adolescent outpatients.

OBJECTIVE: To examine the presence of symptoms of atypical depression among children and adolescents with a major depressive disorder (MDD). METHOD: One thousand forty-six youths (aged 6-19 years) meeting DSM-III-R criteria for MDD were included in the study. All subjects had presented at an outpatient clinic seeking treatment and were identified as having MDD via clinical interviews using the semistructured Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present Episode (K-SADS-P) with the youngster themselves and a parent/guardian. A diagnosis of atypical depression was derived from the symptoms of depression assessed in the K-SADS-P and required the presence of mood reactivity and at least one the following symptoms: hypersomnia, increased appetite, weight gain, or psychomotor retardation (substituted for leaden paralysis). RESULTS: One hundred sixty-two (15.5%) of the depressed youths met criteria for atypical depression. The symptoms of atypical depression were found to correlate marginally, and the diagnosis of atypical depression had marginal construct validity for both children and adolescents. CONCLUSIONS: The findings from this large sample of depressed children and adolescents suggest that atypical features of depression occur in this age group. However, the diagnosis of atypical depression appears to have only marginal construct validity for both children and adolescents.

Growth hormone secretion in children and adolescents at high risk for major depressive disorder.

BACKGROUND: Decreased growth hormone (GH) response to pharmacologic stimulation has been found in children and adolescents during an episode of major depressive disorder and after recovery. In this study, we sought to determine whether GH secretion is similarly altered in children and adolescents who had never experienced depression but were at high risk of developing depression. METHODS: Subjects were 8 through 16 years of age and selected for high- and low-risk status according to familial loading for mood disorders. Sixty-four high-risk and 55 low-risk healthy subjects participated in the study, which assessed the following GH measures: (1) GH before growth hormone-releasing hormone (GHRH) infusion, every 15 minutes for 30 minutes; (2) GH response after intravenous infusion of GHRH (0.1 microg/kg), every 15 minutes for 90 minutes; and (3) nocturnal GH every 20 minutes from 9 PM until morning awakening. RESULTS: After stimulation with GHRH, the high-risk subjects secreted significantly less GH compared with the low-risk healthy controls (effect sizes for mean and peak GH, 0.52 [P =.007] and 0.40 [P =.04], respectively). In contrast, there were no between-group differences in the pre-GHRH and nocturnal GH secretion levels. Exposure to recent stressors was not associated with GH secretion. CONCLUSIONS: Taken together with previous evidence of decreased GH after GHRH infusion in acutely depressed and recovered children, these results indicate that the decreased GH response found in high-risk subjects may represent a trait marker for depression in children and adolescents.

A pilot study of amygdala volumes in pediatric generalized anxiety disorder.

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.

Nocturnal growth hormone secretion studies in adolescents with or without major depression re-examined: integration of adult clinical follow-up data.

BACKGROUND: Early sleep is associated with an increased secretion of human growth hormone (GH) through muscarinic inhibition of somatostatin, a GH suppressant. A clinical follow-up was performed approximately 1 decade after depressed and psychiatrically "normal" control adolescents, who were now young adults, had undergone baseline serial GH measurements over a 24-hour period on the third night of sleep polysomnography studies. METHODS: The study population consisted of 77 young adults who had received a diagnosis of adolescent major depressive disorder and had participated in the adolescent sleep and neuroendocrine studies. Alternatively, the young adult subjects were assessed as normal adolescent control subjects free of any psychiatric diagnosis. Blood samples had been collected for GH every 20 min during the 24-hour period coinciding with the third consecutive night of sleep electroencephalography. Subjects, now in young adulthood, were relocated and blindly reinterviewed using the Schedule for Affective Disorders and Schizophrenia (lifetime version). The original adolescent nocturnal GH data were analyzed in light of the information obtained regarding clinical course into adulthood. RESULTS: A substantial proportion of the nominally normal control group developed at least one episode of major depression or dysthymia during the follow-up period. "Latent" depressive subjects differed from depression-free control subjects by having exhibited a significantly more rapid increase of adolescent nocturnal GH secretion following sleep onset. Of the subjects who had experienced at least one lifetime major depressive episode during the follow-up, the subgroup who would go on to make suicide attempts secreted significantly greater amounts of GH during the first 4 hours of sleep. Adults with lifetime depression exhibited significantly reduced levels of GH in the 100 min preceding sleep onset during adolescence. CONCLUSIONS: Assignment of subjects based on longitudinal clinical follow-up into adulthood revealed that the sleep-related GH secretion paradigm has predictive value for future depressive episodes and future suicide attempts. Dysfunction of complex sleep-onset mechanisms may be a premorbid marker of depression and suicidal behavior.

Further studies on periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder.

Fourteen consecutive children who were newly diagnosed with attention-deficit hyperactivity disorder (ADHD) and who had never been exposed to stimulants and 10 control children without ADHD underwent polysomnographic studies to quantify Periodic Limb Movements in Sleep (PLMS) and arousals. Parents commonly gave both false-negative and false-positive reports of PLMS in their children, and a sleep study was necessary to confirm their presence or absence. The prevalence of PLMS on polysomnography was higher in the children with ADHD than in the control subjects. Nine of 14 (64%) children with ADHD had PLMS at a rate of >5 per hour of sleep compared with none of the control children (p <0.0015). Three of 14 children with ADHD (21%) had PLMS at a rate of >20 per hour of sleep. Many of the PLMS in the children with ADHD were associated with arousals. Historical sleep times were less for children with ADHD. The children with ADHD who had PLMS chronically got 43 minutes less sleep at home than the control subjects (p = 0.0091). All nine children with ADHD who had a PLMS index of >5 per hour of sleep had a long-standing clinical history of sleep onset problems (>30 minutes) and/or maintenance problems (more than two full awakenings nightly) thus meeting the criteria for Periodic Limb Movement Disorder (PLMD). None of the control children had a clinical history of sleep onset or maintenance problems. The parents of the children with ADHD were more likely to have restless legs syndrome (RLS) than the parents of the control children. Twenty-five of 28 biologic parents of the children with ADHD and all of the biologic parents of the control children were reached for interview. Eight of twenty-five parents of the children with ADHD (32%) had symptoms of RLS as opposed to none of the control parents (p = 0.011). PLMS may directly lead to symptoms of ADHD through the mechanism of sleep disruption. Alternative explanations for the association between ADHD and RLS/PLMS are that they are genetically linked, they share a common dopaminergic deficit, or both.

Factors associated with the development of substance use disorder in depressed adolescents.

OBJECTIVE: To document rates of substance use disorders (SUD) in adolescents with unipolar major depressive disorder and to examine demographic, clinical, and biological factors associated with the development of SUD. METHOD: Twenty-eight adolescents with unipolar major depression and no SUD history and 35 group-matched normal controls who participated in a cross-sectional sleep polysomnography and neuroendocrine study were reassessed clinically 7 years later. RESULTS: The risk for SUD was high in both groups (34.6% in the depressed group and 24.2% in the controls). Depressed adolescents had earlier onset of SUD than controls. Depressed adolescents who developed SUD had more significant psychosocial impairment than depressed adolescents who did not develop SUD. More anxiety traits and elevated cortisol secretion near sleep onset were associated with SUD in depressed teenagers, whereas less emotional responsiveness to exciting stimuli and higher density of eye movements during REM sleep were related to depression without SUD. CONCLUSIONS: Depressed adolescents who have anxiety traits and whose hypothalamic-pituitary-adrenal axis is active when the system is normally quiescent may be at risk for developing SUD. Co-occurrence of depression and SUD is associated with serious psychosocial morbidity. Identification of risk factors for SUD in depressed teenagers may be helpful in developing more effective treatment and prevention programs.

Importance of sleep in the management of pediatric pain.

This article outlines several aspects of sleep regulation relevant to pediatric pain management. A broad range of connections between sleep and pain are described: (1) pain can interfere with the quality and quantity of children's sleep; (2) insufficient sleep (quality or quantity) can cause daytime sequelae (behavioral and emotional changes) that interfere with the coping skills necessary for effective pain management; (3) fear and anxiety often have a negative impact on both pain and sleep; (4) feelings of safety and control frequently have a positive effect on both sleep and pain symptoms; (5) adequate sleep seems to promote both physiological (tissue repair) and psychological (transient cessation of the perception of pain signals) processes relevant to recovery from pain, injury, and illness; and (6) treatment approaches to pediatric sleep and pain problems show considerable overlap with respect to many pharmacological as well as cognitive-behavioral interventions. Given these multiple links, a better understanding of sleep--and its importance in physical and mental health--is likely to be of value to clinicians and researchers working in areas of pediatric pain management. One specific hypothesis to be addressed is the possible contribution of sleep disruption as a step in the progression to some chronic pain syndromes.

Prolactin secretion in depressed children.

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.

Depressed adolescents grown up.

CONTEXT: Major depressive disorder (MDD) that arises in adolescence impairs functioning and is associated with suicide risk, but little is known about its continuity into adulthood. OBJECTIVE: To describe the clinical course of adolescent-onset MDD into adulthood. DESIGN AND PARTICIPANTS: Prospective case-control study. Seventy-three subjects had onset of MDD based on systematic clinical assessment during adolescence (Tanner stage III-V) and 37 controls had no evidence of past or current psychiatric disorders, and also were assessed in adolescence (assessment years: 1977-1985). Follow-up was conducted 10 to 15 years after the initial assessment by an independent team without knowledge of initial diagnosis (follow-up years: 1992-1996). SETTING: Cases were identified at Columbia Presbyterian Hospital, New York City, NY; controls were recruited from the community. MAIN OUTCOME MEASURES: Suicide and suicide attempts, psychiatric diagnoses, treatment utilization, and social functioning. RESULTS: Clinical outcomes of adolescent-onset MDD into adulthood compared with control subjects without psychiatric illness include a high rate of suicide (7.7%); a 5-fold increased risk for first suicide attempt; a 2-fold increased risk of MDD, but not other psychiatric disorders; an increased occurrence of psychiatric and medical hospitalization; and impaired functioning in work, social, and family life. Thirty-seven percent of those with adolescent MDD survived without an episode of MDD in adulthood vs 69% of the control participants (relative risk, 2.2 [95% confidence interval, 1.0-4.7; P<.05]). CONCLUSION: There is substantial continuity, specificity, morbidity, and potential mortality from suicide into adulthood in adolescent-onset MDD patients. Now that empirically based guides to their treatment are becoming available, early identification and treatment seems warranted.

Children with prepubertal-onset major depressive disorder and anxiety grown up.

BACKGROUND: The continuity in adulthood of major depressive disorder (MDD) first arising before puberty is largely unknown. This information could guide early treatment and clarify the appropriateness of including children with MDD in genetic studies. METHODS: Eighty-three subjects with onset of MDD, 44 subjects with anxiety disorder and no MDD, and 91 subjects with no evidence of past or current psychiatric disorders were assessed by two psychiatrists before puberty (Tanner stage < III) and were evaluated 10 to 15 years later as adults by an independent team without knowledge of the initial diagnosis. RESULTS: The clinical outcome of children with prepubertal-onset MDD in adulthood includes a high risk of suicide attempts (nearly 3-fold compared with normal controls and 2-fold compared with children with anxiety) and bipolar disorder. Compared with controls, both the children with MDD and those with anxiety went on to have increased risk of substance abuse and conduct disorder but not other disorders, increased use of longterm psychiatric and medical services, and overall impaired functioning. Children with prepubertal-onset MDD with a recurrence of MDD during follow-up had higher rates of MDD in their first-degree relatives. CONCLUSIONS: There is high morbidity in clinically referred children with prepubertal-onset MDD and anxiety, but continuity and specificity of MDD or anxiety disorder in adulthood is less clear. Caution is warranted in selecting clinically referred children with prepubertal-onset MDD for inclusion in genetic studies unless they have a family history of MDD and recurrence of MDD over time.

Serotonergic functioning in depressed abused children: clinical and familial correlates.

BACKGROUND: The goal of this study was to examine serotonergic functioning and concomitant clinical and familial correlates in depressed abused children. METHODS: L-5-Hydroxytryptophan (L-5-HTP) (0.8 mg/kg) was administered intravenously to 10 depressed abused (MDD-AB), 10 depressed nonabused (MDD-NA), and 10 normal control nonabused (NC-NA) children. The children in the two nonabused cohorts represent a small matched subset of children from a larger interlocking study of the psychobiology of depression. Blood samples for prolactin and cortisol were collected from 30 min before to 2.5 hours after L-5-HTP infusion. RESULTS: The MDD-AB children secreted significantly more prolactin post-L-5-HTP than the children in the other two groups. There were no differences in baseline prolactin or any of the cortisol measures. Total prolactin post-L-5-HTP was significantly correlated with clinical ratings of aggressive behavior (rho = .48). In addition, children with a family history positive for suicide attempt (MDD-AB: n = 7; MDD-NA: n = 5; NC-NA: n = 2) secreted significantly more prolactin post-L-5-HTP than children with no family history of suicide. CONCLUSIONS: Dysregulation in the serotonergic system in abused children appears to be related to both familial and experiential factors.