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Although both pediatric and adult patients with anxiety disorders exhibit similar neural responding to threats, age-related differences have been found in some functional MRI (fMRI) studies. To reconcile disparate findings, the authors compared brain function in youths and adults with and without anxiety disorders while rating fear and memory of ambiguous threats.Two hundred medication-free individuals ages 8-50 were assessed, including 93 participants with an anxiety disorder. Participants underwent discriminative threat conditioning and extinction in the clinic. Approximately 3 weeks later, they completed an fMRI paradigm involving extinction recall, in which they rated their levels of fear evoked by, and their explicit memory for, morph stimuli with varying degrees of similarity to the extinguished threat cues.Age moderated two sets of anxiety disorder findings. First, as age increased, healthy subjects compared with participants with anxiety disorders exhibited greater amygdala-ventromedial prefrontal cortex (vmPFC) connectivity when processing threat-related cues. Second, age moderated diagnostic differences in activation in ways that varied with attention and brain regions. When rating fear, activation in the vmPFC differed between the anxiety and healthy groups at relatively older ages. In contrast, when rating memory for task stimuli, activation in the inferior temporal cortex differed between the anxiety and healthy groups at relatively younger ages.In contrast to previous studies that demonstrated age-related similarities in the biological correlates of anxiety disorders, this study identified age differences. These findings may reflect this study's focus on relatively late-maturing psychological processes, particularly the appraisal and explicit memory of ambiguous threat, and inform neurodevelopmental perspectives on anxiety.

The Journal’s 175th anniversary combined with recent advances in research provides an ideal opportunity to present a neurodevelopmental roadmap for understanding, preventing, and treating psychiatric disorders. Such a roadmap is particularly relevant for early childhood onset neurodevelopmental conditions, which emerge when experience-dependent neuroplasticity is at its peak. Employing a novel developmental specification approach, this review places recent neurodevelopmental research on early childhood disruptive behavior within the historical context of The Journal. We highlight irritability and callous behavior as two core exemplars of early disruptive behavior. Both phenotypes can be reliably differentiated from normative variation as early as the first years of life. Both link to discrete pathophysiology: irritability with disruptions in prefrontal regulation of emotion, and callous behavior with abnormal fear processing. Each phenotype also possesses clinical and predictive utility. Based on a nomologic net of evidence, we conclude that early disruptive behavior is neurodevelopmental in nature, and should be reclassified as an early childhood-onset neurodevelopmental condition in DSM 5. Rapid translation from neurodevelopmental discovery to clinical application has transformative potential for psychiatric approaches of the millennium.

National Institute of Developmental Psychiatry for Children and Adolescents, Sao Paulo Sao Paulo Research Foundation] Brazilian National Council for Scientific and Technological Development Shire Eli Lilly Janssen Novartis Sao Paulo Research Foundation Wellcome Trust U.K. National Institutes of Health Research University College London Johnson Johnson Objective: Previous studies have implicated aberrant reward processing in the pathogenesis of adolescent depression. However, no study has used functional connectivity within a distributed reward network, assessed using resting-state functional MRI (fMRI), to predict the onset of depression in adolescents. This study used reward network-based functional connectivity at baseline to predict depressive disorder at follow-up in a community sample of adolescents. Method: A total of 637 children 6-12 years old underwent resting-state fMRI. Discovery and replication analyses tested intrinsic functional connectivity (iFC) among nodes of a putative reward network. Logistic regression tested whether striatal node strength, a measure of reward-related iFC, predicted onset of a depressive disorder at 3-year follow-up. Further analyses investigated the specificity of this prediction. Results: Increased left ventral striatum node strength predicted increased risk for future depressive disorder (odds ratio=1.54, 95% CI=1.09-2.18), even after excluding participants who had depressive disorders at baseline (odds ratio=1.52, 95% CI=1.05-2.20). Among 11 reward-network nodes, only the left ventral striatum significantly predicted depression. Striatal node strength did not predict other common adolescent psychopathology, such as anxiety, attention deficit hyperactivity disorder, and substance use. Conclusions: Aberrant ventral striatum functional connectivity specifically predicts future risk for depressive disorder. This finding further emphasizes the need to understand how brain reward networks contribute to youth depression. Univ Fed Sao Paulo, Dept Psychiat, Lab Interdisciplinar Neurociencias Clin, Sao Paulo, Brazil NIMH, Mood Brain & Dev Unit, Emot & Dev Branch, Bethesda, MD 20892 USA Univ Fed ABC, Ctr Math Comp & Cognit, Santo Andre, Brazil Univ Fed Rio Grande do Sul, Dept Psychiat, Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil Univ Sao Paulo, Dept & Inst Psychiat, Sao Paulo, Brazil NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA NIMH, Sect Mood Dysregulat & Neurosci, Emot & Dev Branch, Bethesda, MD 20892 USA Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Psychosis Studies, London, England Univ Fed Sao Paulo, Dept Psychiat, Sao Paulo, Brazil Univ Fed Sao Paulo, Dept Psychiat, Lab Interdisciplinar Neurociencias Clin, Sao Paulo, Brazil Univ Fed Sao Paulo, Dept Psychiat, Sao Paulo, Brazil FAPESP: 2014/50917-0 FAPESP: 2013/08531-5 CNPq: 465550/2014-2 Web of Science

Understanding the neural processes tied to the adult outcome of childhood attention deficit hyperactivity disorder (ADHD) could guide novel interventions to improve its clinical course. It has been argued that normalization of prefrontal cortical activity drives remission from ADHD, while anomalies in subcortical processes are "fixed," present even in remission. Using multimodal neuroimaging of inhibitory processes, the authors tested these hypotheses in adults followed since childhood, contrasting remitted against persistent ADHD.Adult participants (persistent ADHD, N=35; remit-ted ADHD, N=47; never affected, N=99) were scanned with functional MRI (fMRI) (N=85), magnetoencephalography (N=33), or both (N=63) during a response inhibition task.In fMRI analyses, during inhibition, right caudate anomalies reflected a childhood ADHD history and were present even among those who remitted. By contrast, differences related to adult outcome emerged in cortical (right inferior frontal and inferior parietal/precuneus) and cerebellar regions. The persistent ADHD group showed under-activation, whereas the remitted ADHD group did not differ significantly from the never-affected group. Magnetoencephalography showed that the association between adult symptom severity and prefrontal neuronal activity was confined to the time window covering the act of inhibition (300 ms-350 ms). Group differences in cerebellar and parietal neuronal activity occurred during the time window of performance monitoring processes (500 ms-600 ms).By combining fMRI and magnetoencephalography, the location and time window of neuronal activity that underpins the adult outcome of ADHD was pinpointed. Thus, the cortico-cerebellar processes tied to the clinical course of ADHD are separated from the subcortical processes that are not.

Although irritability is among the most common reasons that children and adolescents are brought for psychiatric care, there are few effective treatments. Developmentally sensitive pathophysiological models are needed to guide treatment development. In this review, the authors present a mechanistic model of irritability that integrates clinical and translational neuroscience research. Two complementary conceptualizations of pathological irritability are proposed: 1) aberrant emotional and behavioral responding to frustrative nonreward, mediated by reward-system dysfunction; and 2) aberrant approach responding to threat, mediated by threat-system dysfunction. The authors review the pathophysiological literature, including animal studies, as well as experimental psychology and clinical studies. Data suggest that, relative to healthy children, irritable children have deficient reward learning and elevated sensitivity to reward receipt and omission. These deficits are associated with dysfunction in the prefrontal cortex, striatum, and amygdala. Youths with irritability also show maladaptive orienting to, interpreting, and labeling of potential threats, associated with prefrontal cortical and amygdalar dysfunction. Abnormalities in reward and threat processing potentiate one another. Future work should test pathophysiological hypotheses and novel interventions targeting reward- and threat-related dysfunction to improve treatment for severe irritability in youths.

Bipolar disorder and disruptive mood dysregulation disorder (DMDD) are clinically and pathophysiologically distinct, yet irritability can be a clinical feature of both illnesses. The authors examine whether the neural mechanisms mediating irritability differ between bipolar disorder and DMDD, using a face emotion labeling paradigm because such labeling is deficient in both patient groups. The authors hypothesized that during face emotion labeling, irritability would be associated with dysfunctional activation in the amygdala and other temporal and prefrontal regions in both disorders, but that the nature of these associations would differ between DMDD and bipolar disorder.During functional MRI acquisition, 71 youths (25 with DMDD, 24 with bipolar disorder, and 22 healthy youths) performed a labeling task with happy, fearful, and angry faces of varying emotional intensity.Participants with DMDD and bipolar disorder showed similar levels of irritability and did not differ from each other or from healthy youths in face emotion labeling accuracy. Irritability correlated with amygdala activity across all intensities for all emotions in the DMDD group; such correlation was present in the bipolar disorder group only for fearful faces. In the ventral visual stream, associations between neural activity and irritability were found more consistently in the DMDD group than in the bipolar disorder group, especially in response to ambiguous angry faces.These results suggest diagnostic specificity in the neural correlates of irritability, a symptom of both DMDD and bipolar disorder. Such evidence of distinct neural correlates suggests the need to evaluate different approaches to treating irritability in the two disorders.

Disruption of executive function is present in many neuropsychiatric disorders. However, determining the specificity of executive dysfunction across these disorders is challenging given high comorbidity of conditions. Here the authors investigate executive system deficits in association with dimensions of psychiatric symptoms in youth using a working memory paradigm. The authors hypothesize that common and dissociable patterns of dysfunction would be present.The authors studied 1,129 youths who completed a fractal n-back task during functional magnetic resonance imaging at 3-T as part of the Philadelphia Neurodevelopmental Cohort. Factor scores of clinical psychopathology were calculated using an item-wise confirmatory bifactor model, describing overall psychopathology as well as four orthogonal dimensions of symptoms: anxious-misery (mood and anxiety), behavioral disturbance (attention deficit hyperactivity disorder and conduct disorder), psychosis-spectrum symptoms, and fear (phobias). The effect of psychopathology dimensions on behavioral performance and executive system recruitment (2-back0-back) was examined using both multivariate (matrix regression) and mass-univariate (linear regression) analyses.Overall psychopathology was associated with both abnormal multivariate patterns of activation and a failure to activate executive regions within the cingulo-opercular control network, including the frontal pole, cingulate cortex, and anterior insula. In addition, psychosis-spectrum symptoms were associated with hypoactivation of the left dorsolateral prefrontal cortex, whereas behavioral symptoms were associated with hypoactivation of the frontoparietal cortex and cerebellum. In contrast, anxious-misery symptoms were associated with widespread hyperactivation of the executive network.These findings provide novel evidence that common and dissociable deficits within the brain's executive system are present in association with dimensions of psychopathology in youth.

This study examined the long-term effects of fluoxetine administered to juvenile rhesus monkeys who, as young adults, were imaged with positron emission tomography for two serotonergic markers: serotonin transporter (SERT) and serotonin 1A (5-HT1A) receptor. An equal number of monkeys separated from their mothers at birth-an animal model of human childhood stress-were also studied.At birth, 32 male rhesus monkeys were randomly assigned to either maternal separation or normal rearing conditions. At age 2, half (N=8) of each group was randomly assigned to fluoxetine (3 mg/kg) or placebo for 1 year. To eliminate the confounding effects of residual drug in the brain, monkeys were scanned at least 1.5 years after drug discontinuation. Social interactions were assessed both during and after drug administration.Fluoxetine persistently upregulated SERT, but not 5-HT1A receptors, in both the neocortex and the hippocampus. Whole-brain voxel-wise analysis revealed that fluoxetine had a significant effect in the lateral temporal and cingulate cortices. In contrast, neither maternal separation by itself nor the rearing-by-drug interaction was significant for either marker. Fluoxetine had no significant effect on the behavioral measures.Fluoxetine administered to juvenile monkeys upregulates SERT into young adulthood. Implications regarding the efficacy or potential adverse effects of SSRIs in patients cannot be directly drawn from this study. Its purpose was to investigate effects of SSRIs on brain development in nonhuman primates using an experimental approach that randomly assigned long-term SSRI treatment or placebo.

In recent years, increasing numbers of children have been diagnosed with bipolar disorder. In some cases, children with unstable mood clearly meet current diagnostic criteria for bipolar disorder, and in others, the diagnosis is unclear. Severe mood dysregulation is a syndrome defined to capture the symptomatology of children whose diagnostic status with respect to bipolar disorder is uncertain, that is, those who have severe, nonepisodic irritability and the hyperarousal symptoms characteristic of mania but who lack the well-demarcated periods of elevated or irritable mood characteristic of bipolar disorder. Levels of impairment are comparable between youths with bipolar disorder and those with severe mood dysregulation. An emerging literature compares children with severe mood dysregulation and those with bipolar disorder in longitudinal course, family history, and pathophysiology. Longitudinal data in both clinical and community samples indicate that nonepisodic irritability in youths is common and is associated with an elevated risk for anxiety and unipolar depressive disorders, but not bipolar disorder, in adulthood. Data also suggest that youths with severe mood dysregulation have lower familial rates of bipolar disorder than do those with bipolar disorder. While youths in both patient groups have deficits in face emotion labeling and experience more frustration than do normally developing children, the brain mechanisms mediating these pathophysiologic abnormalities appear to differ between the two patient groups. No specific treatment for severe mood dysregulation currently exists, but verification of its identity as a syndrome distinct from bipolar disorder by further research should include treatment trials.

For decades, researchers have considered the hypothesis that dysfunction in circadian rhythms and the sleep-wake cycle, rather than simply being symptoms of mood disorders, play a causal role in their pathophysiology. Three studies in this month's Journal continue that line of research. First, Frank et al. (1) reported that patients with bipolar disorder who receive acute treatment with interpersonal and social rhythm therapy show faster improvement in occupational function than do those assigned to intensive clinical management. Second, in a 2-year study of 351 adults ages 60 or older, Cho et al. (2) reported that sleep disturbance predicts the onset of depression, even after the effect of other depressive symptoms is controlled. Finally, Parry et al. (3) reported that levels of the circadian marker melatonin are significantly higher in depressed pregnant women than in euthymic pregnant women, but lower in depressed postpartum women than in euthymic postpartum women.

Extensive work implicates abnormal amygdala activation in emotional facial expression processing in adults with callous-unemotional traits. However, no research has examined amygdala response to emotional facial expressions in adolescents with disruptive behavior and callous-unemotional traits. Moreover, despite high comorbidity of callous-unemotional traits and attention deficit hyperactivity disorder (ADHD), no research has attempted to distinguish neural correlates of pediatric callous-unemotional traits and ADHD.Participants were 36 children and adolescents (ages 10-17 years); 12 had callous-unemotional traits and either conduct disorder or oppositional defiant disorder, 12 had ADHD, and 12 were healthy comparison subjects. Functional MRI was used to assess amygdala activation patterns during processing of fearful facial expressions. Patterns in the callous-unemotional traits group were compared with those in the ADHD and comparison groups.In youths with callous-unemotional traits, amygdala activation was reduced relative to healthy comparison subjects and youths with ADHD while processing fearful expressions, but not neutral or angry expressions. Functional connectivity analyses demonstrated greater correlations between the amygdala and the ventromedial prefrontal cortex in comparison subjects and youths with ADHD relative to those with callous-unemotional traits. Symptom severity in the callous-unemotional traits groups was negatively correlated with connectivity between amygdala and ventromedial prefrontal cortex.This is the first study to demonstrate reduced amygdala responsiveness in youths with callous-unemotional traits. These findings support the contention that callous and unemotional personality traits are associated with reduced amygdala response to distress-based social cues.

Researchers disagree as to whether irritability is a diagnostic indicator for pediatric mania in bipolar disorder. The authors compared the behavioral and psychophysiological correlates of irritability among children with severe mood dysregulation (i.e., nonepisodic irritability and hyperarousal without episodes of euphoric mood) and narrow-phenotype bipolar disorder (i.e., a history of at least one manic or hypomanic episode with euphoric mood) as well as those with no diagnosis (i.e., healthy comparison children).Subjects with severe mood dysregulation (N=21) or narrow-phenotype bipolar disorder (N=35) and comparison subjects (N=26) completed the affective Posner task, an attentional task that manipulated emotional demands and induced frustration. Mood response, behavior (reaction time and accuracy), and brain activity (event-related potentials) were measured.The severe mood dysregulation and narrow-phenotype bipolar disorder groups both reported significantly more arousal than comparison subjects during frustration, but behavioral and psychophysiological performance differed between the patient groups. In the frustration condition, children with narrow-phenotype bipolar disorder had lower P3 amplitude than children with severe mood dysregulation or comparison subjects, reflecting impairments in executive attention. Regardless of emotional context, children with severe mood dysregulation had lower N1 event-related potential amplitude than comparison subjects or children with narrow-phenotype bipolar disorder, reflecting impairments in the initial stages of attention. Post hoc analyses demonstrated that the N1 deficit in children with severe mood dysregulation is associated with oppositional defiant disorder symptom severity.Results indicate that while irritability is an important feature of severe mood dysregulation and narrow-phenotype bipolar disorder, the pathophysiology of irritability may differ among the groups and is influenced by oppositional defiant disorder severity.

The authors suggest criteria for a range of narrow to broad phenotypes of bipolar disorder in children, differentiated according to the characteristics of the manic or hypomanic episodes, and present methods for validation of the criteria.Relevant literature describing bipolar disorder in both children and adults was reviewed critically, and the input of experts was sought.Areas of controversy include whether the diagnosis of bipolar disorder should require clearly demarcated affective episodes and, if so, of what duration, and whether specific hallmark symptoms of mania should be required for the diagnosis. The authors suggest a phenotypic system of juvenile mania consisting of a narrow phenotype, two intermediate phenotypes, and a broad phenotype. The narrow phenotype is exhibited by patients who meet the full DSM-IV diagnostic criteria for hypomania or mania, including the duration criterion, and also have hallmark symptoms of elevated mood or grandiosity. The intermediate phenotypes include 1) hypomania or mania not otherwise specified, in which the patient has clear episodes and hallmark symptoms, but the episodes are between 1 and 3 days in duration, and 2) irritable hypomania or mania, in which the patient has demarcated episodes with irritable, but not elevated, mood. The broad phenotype is exhibited by patients who have a chronic, nonepisodic illness that does not include the hallmark symptoms of mania but shares with the narrower phenotypes the symptoms of severe irritability and hyperarousal.The presence of distinct episodes and hallmark symptoms can be used to differentiate clinical phenotypes of juvenile mania. The utility and validity of this system can be tested in subsequent research.

Little is known about the pathophysiology of postpartum depression. While the same can be said for many (if not most) psychiatric illnesses, in the case of postpartum depression the need for pathophysiological studies to guide the development of novel treatments is particularly pressing because the illness affects not only the woman who experiences it, but also her newborn and other members of her family (1). But while pathophysiological studies of postpartum depression are particularly important, they are also very difficult to conduct, given the biological and logistical complexities that characterize the postpartum period. Therefore, the study by Moses-Kolko et al. (2) in this issue of the Journal is a welcome addition to the literature. The authors used functional magnetic resonance imaging (fMRI) to study 16 healthy women and 14 unmedicated unipolar depressed women within 12 weeks of giving birth. While being scanned, subjects completed a task that included shape and face matching blocks, with the latter including angry and sad faces. This task is designed to probe between-group differences in amygdala activity. Previous fMRI studies using similar tasks in patients with depression demonstrate abnormalities in amygdala activity and amygdala-medial prefrontal cortex connectivity in response to negatively valenced emotional faces (3). However, the precise nature of those abnormalities, and the extent to which they differ in unipolar versus bipolar depression, remains unclear. Given the previous literature, Moses-Kolko et al. focused their analysis on activity in the amygdala and the medial prefrontal cortex. Their major finding was a group-by-condition interaction in the dorsomedial prefrontal cortex (the finding was specifically in Brodmann’s area 32). While both depressed and comparison mothers activated this region more in response to faces than to shapes, depressed mothers activated more in response to shapes than comparison mothers, and comparison mothers activated more in response to faces than depressed mothers. As discussed below, the dorsomedial prefrontal cortex is known to mediate important aspects of social cognition. Therefore, it is notable that depressed mothers, relative to comparison mothers, show decreased activation in this region in response to the social stimulus of a face. Moses-Kolko et al.’s finding indicates that it is important to focus research and treatment strategies not only on a mother’s depression, but also on her ability to engage affectively with her infant. A hallmark of depression is increased self-focus, particularly in the form of self-referential negative thoughts; research suggests that this symptom may be mediated by the dorsomedial prefrontal cortex. For example, Johnson et al. (4) found associations between activity in the dorsomedial prefrontal cortex (as well as posterior medial prefrontal cortex), rumination, and difficulty disengaging from self-referential thoughts in subjects with major depressive disorder. There is an extensive body of literature indicating that the dorsomedial prefrontal cortex is activated when subjects are asked to perform “theory of mind” or “mentalizing” tasks (5). These tasks require subjects to focus not on their own thoughts but instead on the thoughts, beliefs, or feelings of other individuals. As any parent who has tried to calm a fussy baby can attest, parenting a preverbal child is arguably the ultimate challenge to one’s mentalizing abilities. Considerable research documents the elegant interplay that occurs within healthy infant-mother dyads as they communicate using mutual gaze, vocalizations, and nonverbal expressions of affect (6). Observational studies of mother-child interactions show that, on average, depressed mothers demonstrate less positive affect toward their child than nondepressed mothers, engage with their child less often, and are less sensitive to the child’s cues (1). Further, such parenting difficulties are associated with subsequent deficits in the infant’s social engagement and emotion regulation abilities (1). In a depressed mother, are difficulties interacting with her infant mediated by dorsomedial prefrontal cortex dysfunction? The design of the study by Moses-Kolko et al. does not provide an answer to this question, and it is clearly an important topic for further work. Future studies could use paradigms that assess depressed and comparison mothers’ neural responses to verbal or auditory cues from their own infant (versus that of other infants and noninfant stimuli) and could correlate such neural responses with observational measures of mother-infant interactions. A few fMRI studies in healthy mothers have tested neural responses to their infant’s cues, but results have been inconsistent because of differences in paradigms and analytic strategies as well as small sample sizes (even in healthy women, postpartum studies are challenging). However, activation in Brodmann’s area 32 has been noted when healthy mothers hear their infant cry (7) or watch a video of their infant crying after separation (8). Ultimately, research on the circuitry mediating postpartum depression and/or maternal-child interactions in healthy and depressed women will have the greatest impact if it suggests new treatment strategies for the illness. When testing treatments for postpartum depression, both the mother’s depressive symptoms and adverse mother-infant interactions should be considered important targets for intervention. Importantly, we do not know whether successfully treating a mother’s depression will necessarily improve parenting interactions, although preliminary evidence suggests that it may not (9). Psychopharmacologic studies in postpartum depression tend to assess the impact of treatment on the mother’s depression but not on mother-infant interactions (10, 11). Several trials of interpersonal psychotherapy have used depressive symptoms as the primary outcome but have also assessed the impact of treatment on parenting. However, parenting assessment has been accomplished with self-report scales, which provide less detail (and perhaps less reliability) than observational measures (e.g., 12, 13). One study found that parenting classes are less effective than interpersonal psychotherapy for the symptoms of postpartum depression (14), but the impact of the parenting classes on mother-infant interactions was not assessed. The most effective strategies for treatment development in postpartum depression would therefore combine expertise in clinical trials, observational studies of mother-infant interactions, and neuroimaging. fMRI, in combination with carefully designed behavioral paradigms, could be used to delineate the neural mechanisms that compromise a depressed mother’s ability to respond to her baby optimally. For example, investigators could test whether infant-related stimuli are less emotionally salient for depressed mothers than for nondepressed mothers, with emotional salience assessed by behavioral measures (e.g., reaction times) and the degree to which such stimuli engage “bottom-up” attentional circuitry, including the amygdala and ventral prefrontal cortex. Also, given the anhedonia characteristic of major depression, one could test the hypothesis that women with postpartum depression would be less likely than unaffected women to experience interactions with their infant as rewarding, with the latter assessed by self-report, behavioral measures, and striatal activation. The degree to which attentional versus reward-based deficits contribute to parenting difficulties can inform the development of new psychotherapeutic approaches and thus has direct treatment implications. Parenting a newborn is a challenging endeavor, even for mothers (and fathers) not burdened by the pain and symptoms of acute depression. For those with depressive illness, parenting an infant can be quite daunting. Our obligation is to both relieve the suffering of women with postpartum depression and to support their ability to parent lovingly and effectively. To fulfill that goal, we need to learn much more about the pathophysiology of postpartum depression and about how to treat this devastating illness effectively.

Objective: The purpose ofthis article is to review the literature concerninggender differences In the course ofbipolar illness and discuss issues relevant to the treatment ofwomen with the illness. Method: The literature concerning the following topics is reviewed: gender differences in the course ofbipolar illness; effects ofthe female reproductive cycle on the course of bipolar illness; special considerations in the treatment of bipolar women (focusing on the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-thyroid axes); and hypotheses to explain the greater prevalence of rapid cycling among bipolar women than among bipolar men. �yj(�: Data clearly indicate that rapid cycling is more common among bipolar women. Data also suggest that bipolar women may have more depressive episodes (and fewer manic episodes) and may be more likely to suffer from mixed (as opposed to pure) mania than bipolar men. While it is clear that bipolar women are at high risk for postpartum episodes, the effects ofother reproductive system events (i.e., puberty, menstrual cycle, pregnancy, menopause, use oforal contraceptives or hormone replacement therapy) on the course or treatment of bipolar illness have received little systematic study. It is unclear whether women are at higher risk than men for developing lithium-induced hypothyroidism. Higher rates ofhypothyroidism, greater use of antidepressants, and gonadal steroid effects are possible explanations for the greater prevalence ofrapid cycling among bipolar women. Conclusions: Gender differences in bipolar illness and the effects of the female reproductive system on the course and treatment of the illness deserve more study. The importance of a longitudinal approach to these questions is emphasized. (AmJ Psychiatry 1996; 153:163-173)

Objective and Method: Using data from the APA ‘s 1 988-1 989 Professional Activities Survey, the authors compared male and female psychiatrists on demographic characteristics, training, practice patterns, and income. Results: In keeping with previous studies’ findings, female respondents on the average were younger than male respondents and more likely to have taken a residency or fellowship in child or adolescent psychiatry, worked fewer hours per week, allocated their working hours differently among types of activities, saw fewer patients per week, and worked in somewhat different settings. Multiple regression analysis showed that women had significantly lower mean net annual income than men after the effects of those predictors were statistically controlled. Conclusions: Differences in age, training, hours worked in specific settings, and numbers ofpatients do not completely account for the gender gap in psychiatrists ‘ annual incomes. (Am J Psychiatry 1 994; 151:96-101)

Objective: Deficits in motor inhibition may contribute to impulsivity and irritability in children with bipolar disorder. Studies of the neural circuitry engaged during failed motor inhibition in pediatric bipolar disorder may increase our understanding of the pathophysiology of the illness. The authors tested the hypothesis that children with bipolar disorder and comparison subjects would differ in ventral prefrontal cortex, striatal, and anterior cingulate activation during unsuccessful motor inhibition. They also compared activation in medicated versus unmedicated children with bipolar disorder and in children with bipolar disorder and attention deficit hyperactivity disorder (ADHD) versus those with bipolar disorder without ADHD. Method: The authors conducted an event-related functional magnetic resonance imaging study comparing neural activation in children with bipolar disorder and healthy comparison subjects while they performed a motor inhibition task. The study group included 26 children with bipolar disorder (13 unmedicated and 15 with ADHD) and 17 comparison subjects matched by age, gender, and IQ. Results: On failed inhibitory trials, comparison subjects showed greater bilateral striatal and right ventral prefrontal cortex activation than did patients. These deficits were present in unmedicated patients, but the role of ADHD in mediating them was unclear. Conclusions: In relation to comparison subjects, children with bipolar disorder may have deficits in their ability to engage striatal structures and the right ventral prefrontal cortex during unsuccessful inhibition. Further research should ascertain the contribution of ADHD to these deficits and the role that such deficits may play in the emotional and behavioral dysregulation characteristic of bipolar disorder.