Amygdala and nucleus accumbens activation to emotional facial expressions in children and adolescents at risk for major depression.

OBJECTIVE: Offspring of parents with major depressive disorder face a threefold higher risk for major depression than offspring without such family histories. Although major depression is a significant cause of morbidity and mortality, neural correlates of risk for major depression remain poorly understood. This study compares amygdala and nucleus accumbens activation in children and adolescents at high and low risk for major depression under varying attentional and emotional conditions. METHOD: Thirty-nine juveniles, 17 offspring of parents with major depression (high-risk group) and 22 offspring of parents without histories of major depression, anxiety, or psychotic disorders (low-risk group) completed a functional magnetic resonance imaging study. During imaging, subjects viewed faces that varied in intensity of emotional expressions across blocks of trials while attention was unconstrained (passive viewing) and constrained (rate nose width on face, rate subjective fear while viewing face). RESULTS: When attention was unconstrained, high-risk subjects showed greater amygdala and nucleus accumbens activation to fearful faces and lower nucleus accumbens activation to happy faces (small volume corrected for the amygdala and nucleus accumbens). No group differences emerged in amygdala or nucleus accumbens activation during constrained attention. Exploratory analysis showed that constraining attention was associated with greater medial prefrontal cortex activation in the high-risk than in the low-risk group. CONCLUSIONS: Amygdala and nucleus accumbens responses to affective stimuli may reflect vulnerability for major depression. Constraining attention may normalize emotion-related neural function possibly by engagement of the medial prefrontal cortex; face-viewing with unconstrained attention may engage aberrant processes associated with risk for major depression.

Lifetime criminality among boys with attention deficit hyperactivity disorder: a prospective follow-up study into adulthood using official arrest records.

This study investigates the relationship between childhood attention deficit hyperactivity disorder (ADHD) and later criminality. White boys (n=207, ages 6-12) with ADHD, free of conduct disorder, were assessed at ages 18 and 25 by clinicians who were blind to childhood status. A non-ADHD group served as comparisons. Lifetime arrest records were obtained when subjects were 38 years old for subjects who resided in New York State throughout the follow-up interval (93 probands, 93 comparisons). Significantly more ADHD probands than comparisons had been arrested (47% vs. 24%), convicted (42% vs. 14%), and incarcerated (15% vs. 1%). Rates of felonies and aggressive offenses also were significantly higher among probands. Importantly, the development of an antisocial or substance use disorder in adolescence completely explained the increased risk for subsequent criminality. Results suggest that even in the absence of comorbid conduct disorder in childhood, ADHD increases the risk for developing antisocial and substance use disorders in adolescence, which, in turn, increases the risk for criminal behavior in adolescence and adulthood.

Stress responsivity and HPA axis activity in juveniles: results from a home-based CO2 inhalation study.

OBJECTIVE: A previous laboratory-based study found elevated cortisol levels in anxious children susceptible to CO(2)-induced panic, but the effects of parent diagnosis were not considered. The current home-based study tested the hypothesis that parental panic disorder and offspring response to CO(2) are associated with elevated cortisol levels in juvenile offspring. METHOD: A total of 131 offspring (ages 9-19) of parents with panic disorder, major depression, and no mental disorder underwent CO(2) inhalation. Parent and child diagnoses were assessed. Salivary cortisol was assayed before and after CO(2) inhalation. RESULTS: Neither parents with panic disorder, parents with major depression, or offspring anxiety predicted offspring cortisol levels. Independent of parent and child diagnoses, anxiety response to CO(2) predicted elevated cortisol levels in offspring. CONCLUSIONS: As in adults, anxiety response to CO(2) in juveniles is associated with elevated cortisol levels, but elevated cortisol levels are not related to parent or child diagnoses.

Response to 5% carbon dioxide in children and adolescents: relationship to panic disorder in parents and anxiety disorders in subjects.

BACKGROUND: Carbon dioxide (CO(2)) sensitivity is postulated to be a familial risk marker of panic disorder (PD). Exaggerated responses to CO(2) inhalation have been reported in adults with PD and their unaffected adult relatives, as well as in clinic-referred children with anxiety disorders. OBJECTIVE: To test in a family-based design whether CO(2) hypersensitivity is a familial risk marker for PD and associated with current anxiety disorders in children and adolescents. SETTING AND PARTICIPANTS: One hundred forty-two offspring (aged 9-19 years) of parents with PD, major depressive disorder, or no disorder. Forty-five (32%) had a current anxiety disorder, excluding specific phobia. DESIGN AND MAIN OUTCOME MEASURES: Parents and offspring received diagnostic assessments. Offspring underwent 5% CO(2) inhalation at home. Panic symptoms and panic attacks were rated with the Acute Panic Inventory at baseline, while anticipating CO(2) delivery ("threat"), and during CO(2) inhalation. Respiratory rate and volume were measured with spirometry. RESULTS: No group differences were found in Acute Panic Inventory ratings at baseline or in respiratory measures during threat. Risk for PD was not associated with CO(2) sensitivity (panic symptoms and respiratory physiologic response). During CO(2) inhalation, offspring with anxiety disorders, relative to offspring without anxiety disorders, experienced significantly more panic symptoms and panic attacks, as well as elevated respiratory rates. During threat, panic symptoms were significantly and independently associated with both parental PD and offspring anxiety disorders. CONCLUSIONS: No support was obtained for CO(2) hypersensitivity as a familial risk marker for PD in children and adolescents. Links between childhood anxiety disorders and CO(2) sensitivity were replicated. Familial risk for PD in children and adolescents may be associated with vulnerability to anticipatory anxiety.

Face-emotion processing in offspring at risk for panic disorder.

OBJECTIVE: Panic disorder (PD) has been linked to perturbed processing of threats. This study tested the hypotheses that offspring of parents with PD and offspring with anxiety disorders display relatively greater sensitivity and attention allocation to fear provocation. METHOD: Offspring of adults with PD, major depressive disorder (MDD), or no disorder (ages 9-19) viewed computer-presented face photographs depicting angry, fearful, and happy faces. Offspring rated (1) subjectively experienced fear level, (2) how hostile the face appeared, and (3) nose width. Attention allocation was indexed by latency to perform ratings. RESULTS: Compared with offspring of parents without PD (n = 79), offspring of PD parents (n = 65) reported significantly more fear and had slower reaction times to rate fear, controlling for ongoing anxiety disorder in the offspring. Offspring with an anxiety disorder (n = 65) reported significantly more fear than offspring without an anxiety disorder but not when parental PD was controlled. Social phobia but no other anxiety disorder in offspring was associated with slower reaction times for fear ratings (but not greater fear ratings). Parental PD and offspring social phobia independently predicted slower reaction time. CONCLUSIONS: Results support an association between parental PD and offspring responses to fear provocation. Social phobia in children may have a specific relationship to allocation of attention to subjective anxiety during face viewing.

Relationship between separation anxiety disorder, parental panic disorder, and atopic disorders in children: a controlled high-risk study.

OBJECTIVE: To test the hypotheses that rates of atopic disorders are elevated in offspring of parents with panic disorder (PD) and in children with separation anxiety disorder (SAD). METHOD: Rates of atopic disorders were assessed in 343 offspring (aged 6-17 years) of parents with PD, nonpanic psychiatric disorders, and no psychiatric disorder. Lifetime history of atopic disorders was determined by parental responses to a clinician-administered questionnaire assessing medical treatment for asthma and allergies. Logistic regression analyses assessed the association between atopic disorders and parental PD, and between atopic disorders and probable or definite childhood SAD. Analyses controlled for age, sex, socioeconomic status, and treatment for other medical illnesses. RESULTS: Increased rates of atopic disorders were found in offspring of parents with PD (odds ratio [OR] = 2.56, 95% confidence interval [CI] = 1.27-5.16, p = .009) and in children with SAD (OR = 2.71, 95% Cl = 1.22-6.03, p = .015). Associations remained significant when both parental PD and SAD were included in the model, suggesting that each contributed independently to increased rates of atopy. The interaction of parental PD and child SAD was not significant. CONCLUSIONS: Atopic disorders in children are associated with parental PD and with childhood SAD. Results do not appear to support that having both childhood SAD and a parent with PD confers increased risk for atopic disorders above and beyond either condition alone.

Does stimulant treatment place children at risk for adult substance abuse? A controlled, prospective follow-up study.

The sensitization hypothesis posits a neuroadaptation model in which exposure to stimulants results in dopamine system alterations that, in turn, increase sensitivity to the reinforcing effects of the previously experienced drug. This study examines whether stimulant treatment in childhood confers increased risk for substance use and abuse in later life, as the model predicts. Children, ages 7-12 years, with developmental reading disorders but no other psychiatric diagnoses were randomly assigned to methylphenidate treatment (n = 43) or matching placebo (n = 66) for 12-18 weeks. At 16-year follow-up (mean age 26 years), 94% of probands and 129 normal comparisons were evaluated by trained clinicians who were blind to group and treatment status. There were no significant differences between groups on the prevalence of substance use disorder (abuse or dependence) for any of the seven drug categories studied. There were no significant group differences among substance abusers regarding age at onset, duration, or number of episodes of substance abuse and dependence. Significantly more normals (60%) than treated (46%) and untreated probands (41%) ever used stimulants in adolescence or adulthood. Findings from this randomized trial contradict the notion that stimulant treatment in childhood leads to substance use or abuse in later life. The sensitization hypothesis is not supported.

Young adult outcome of children with "situational" hyperactivity: a prospective, controlled follow-up study.

To examine the importance of symptom pervasiveness in ADHD, we conducted a prospective, 12-year follow-up study of boys (ages 6-12) considered hyperactive at school and home (Pervasive ADHD), boys considered hyperactive by teachers but not parents (School Only ADHD), boys considered hyperactive by parents but not teachers (Home Only ADHD), and nonhyperactive comparisons. Follow-up was completed on 82-94% participants. Clinicians interviewed participants and their parents, blind to childhood status. At follow-up, antisocial disorder was significantly more prevalent among Pervasive and School Only ADHD (29% for both) than Home Only ADHD (0%) and comparisons (8%). In a similar manner, severity of behavioral problems distinguished groups (Pervasive, School > Home, comparisons), as did educational attainment and academic performance (poorest for Pervasive and School). These findings stress the validity of teacher reports in the diagnosis of ADHD.

Significance of childhood conduct problems to later development of conduct disorder among children with ADHD: a prospective follow-up study.

This study investigates whether low to moderate levels of childhood oppositional defiant disorder (ODD) and conduct disorder (CD) behaviors contribute to the development of clinically diagnosed CD in adolescence, in children with attention deficit hyperactivity disorder (ADHD). Participants were 207 White boys (ages 6-12) with ADHD free of conduct disorder diagnoses. Parent and teacher ratings were obtained. Participants were assessed at mean age 18 by clinicians blind to childhood status. A non-ADHD group (recruited in adolescence) was also studied. ODD behavior ratings did not predict CD in adolescence, whereas CD behavior ratings did. No single ODD or CD behavior predicted adolescent outcome. ADHD probands with very low ratings (Not at all, Just a little) by parents and teachers on all CD behaviors were still at significantly increased risk for CD in adolescence, compared to non-ADHD controls. The same relationships were found between childhood ODD and CD behaviors, and antisocial personality disorder in adulthood (mean age, 25). We conclude that childhood ADHD is a developmental precursor of later antisocial disorder, even in the absence of comorbid ODD or CD in childhood. However, low levels of CD-type problems are not innocuous, because they predict later CD among children with ADHD without comorbid CD.

Anxiety sensitivity among children of parents with anxiety disorders: a controlled high-risk study.

We investigated whether parental anxiety was related to anxiety sensitivity (AS) in offspring. Subjects were 261 offspring (aged 6-17 years) of parents with lifetime DSM-IV anxiety and/or mood disorders, and 79 offspring of parents with no lifetime anxiety, mood, or psychotic disorder. Parents and offspring were interviewed by blind clinicians. Children were administered the Child Anxiety Sensitivity Index (CASI). There were no significant differences between CASI scores of the offspring of parents with anxiety and/or mood disorders, and offspring of comparison parents. We conclude that parental anxiety or mood disorder does not predispose offspring to high anxiety sensitivity.

Persistence of Attention-Deficit/Hyperactivity Disorder into adulthood: what have we learned from the prospective follow-up studies?

OBJECTIVES: Longitudinal studies of children with Attention-Deficit/Hyperactivity Disorder (ADHD) into adolescence have all reported high rates of ADHD. However, findings from studies into adulthood are inconsistent. This article reviews factors that may account for disparate rates found in adult follow-ups, and recommends optimal methodologies for prospective studies of children with ADHD in particular and childhood mental disorders in general. METHOD: Follow-up studies of children with ADHD into adulthood are critically reviewed to identify factors that influence adult ADHD prevalence estimates. RESULTS: Four factors are identified: (1) ascertainment procedure, (2) attrition rate, (3) reporting source, and (4) disorder criteria. CONCLUSIONS: Estimates of the proportion of children with ADHD who will experience symptoms of the childhood syndrome in adulthood are likely to vary considerably, as a function of multiple factors. Several recommendations are made for designing future follow-up investigations.

Carbon dioxide hypersensitivity in separation-anxious offspring of parents with panic disorder.

BACKGROUND: Similar patterns of vulnerability to carbon dioxide (CO(2)) inhalation have been reported in adults with panic disorder (PD) and children with separation anxiety disorder (SAD), suggesting a link between the adult and child conditions. This study examines the influence of familial risk for PD on CO(2) responses in children with SAD. We hypothesized that offspring with SAD of parents with PD would have distinct CO(2) responses. METHODS: Two hundred twelve 9- to 20-year-old offspring of parents with or without PD were exposed to maintained 5% CO(2) inhalation in the participants' homes. Anxiety symptoms, panic attacks, and respiratory physiology (respiratory frequency and tidal volume) were monitored during baseline and 15-min maintained CO(2) breathing. RESULTS: As hypothesized, significant offspring SAD x parent PD interactions were obtained for anxiety symptoms, respiratory frequency, tidal volume, and a panting index during CO(2) inhalation. Offspring with both SAD and parental PD exhibited more anxiety symptoms at termination of 5% CO(2) breathing than the other offspring groups and had the most extreme values on measures of respiratory physiology. CONCLUSIONS: Youth with both SAD and parental PD have respiratory responses to CO(2) similar to adult PD. They might be a subtype of SAD at particularly high risk for adult PD.

Age of methylphenidate treatment initiation in children with ADHD and later substance abuse: prospective follow-up into adulthood.

OBJECTIVE: Animal studies have shown that age at stimulant exposure is positively related to later drug sensitivity. The purpose of this study was to examine whether age at initiation of stimulant treatment in children with attention deficit hyperactivity disorder (ADHD) is related to the subsequent development of substance use disorders. METHOD: The authors conducted a prospective longitudinal study of 176 methylphenidate-treated Caucasian male children (ages 6 to 12) with ADHD but without conduct disorder. The participants were followed up at late adolescence (mean age=18.4 years; retention rate=94%) and adulthood (mean age=25.3; retention rate=85%). One hundred seventy-eight comparison subjects also were included. All subjects were diagnosed by blinded clinicians. The Cox proportional hazards model included the following childhood predictor variables: age at initiation of methylphenidate treatment, total cumulative dose of methylphenidate, treatment duration, IQ, severity of hyperactivity, socioeconomic status, and lifetime parental psychopathology. Separate models tested for the following four lifetime outcomes: any substance use disorder, alcohol use disorder, non-alcohol substance use disorder, and stimulant use disorder. Other outcomes included antisocial personality, mood, and anxiety disorders. RESULTS: There was a significant positive relationship between age at treatment initiation and non-alcohol substance use disorder. None of the predictor variables accounted for this association. Post hoc analyses showed that the development of antisocial personality disorder explained the relationship between age at first methylphenidate treatment and later substance use disorder. Even when controlling for substance use disorder, age at stimulant treatment initiation was significantly and positively related to the later development of antisocial personality disorder. Age at first methylphenidate treatment was unrelated to mood and anxiety disorders. CONCLUSIONS: Early age at initiation of methylphenidate treatment in children with ADHD does not increase the risk for negative outcomes and may have beneficial long-term effects.

Memory deficits in children with and at risk for anxiety disorders.

There are limited data on the neurocognitive correlates of childhood anxiety disorders. The objective of this study was to examine whether visual and verbal memory deficits of nonemotional stimuli are (1) a shared feature of three common childhood anxiety disorders (social phobia, separation anxiety disorder, and generalized anxiety disorder) or whether these deficits are restricted to specific anxiety disorders, and (2) present in offspring who possess at least one of the following established risk factors for anxiety disorders, parental history of panic disorder (PD), or major depressive disorder (MDD). One hundred and sixty offspring, ages 9-20 years, were recruited from parents with lifetime diagnoses of PD, MDD, PD plus MDD, or neither illness. Different clinicians blindly administered semistructured diagnostic interviews to offspring and parents. Verbal and visual memory subtests of the Wide Range Assessment of Memory and Learning were administered to offspring. The results showed that offspring with ongoing social phobia demonstrated reduced visual but not verbal memory scores compared to those without social phobia when controlling for offspring IQ, separation anxiety disorder, and generalized anxiety disorder. No other offspring anxiety disorder predicted memory performance. Neither parental PD nor parental MDD was associated with offspring memory performance. These findings are relevant to understanding the phenomenology of childhood anxiety disorders and may provide insights into the neural circuits underlying these disorders.

Face-memory and emotion: associations with major depression in children and adolescents.

BACKGROUND: Studies in adults with major depressive disorder (MDD) document abnormalities in both memory and face-emotion processing. The current study used a novel face-memory task to test the hypothesis that adolescent MDD is associated with a deficit in memory for face-emotions. The study also examines the relationship between parental MDD and memory performance in offspring. METHODS: Subjects were 152 offspring (ages 9-19) of adults with either MDD, anxiety disorders, both MDD and anxiety, or no disorder. Parents and offspring were assessed for mental disorders. Collection of face-memory data was blind to offspring and parent diagnosis. A computerized task was developed that required rating of facial photographs depicting 'happy,"fearful,' or 'angry' emotions followed by a memory recall test. Recall accuracy was examined as a function of face-emotion type. RESULTS: Age and gender independently predicted memory, with better recall in older and female subjects. Controlling for age and gender, offspring with a history of MDD (n = 19) demonstrated significant deficits in memory selectively for fearful faces, but not happy or angry faces. Parental MDD was not associated with face-memory accuracy. DISCUSSION: This study found an association between MDD in childhood or adolescence and perturbed encoding of fearful faces. MDD in young individuals may predispose to subtle anomalies in a neural circuit encompassing the amygdala, a brain region implicated in the processing of fearful facial expressions. These findings suggest that brain imaging studies using similar face-emotion paradigms should test whether deficits in processing of fearful faces relate to amygdala dysfunction in children and adolescents with MDD.