Clinical Focus

  • Psychiatry, Child and Adolescent
  • Child and Adolescent Psychiatry

Academic Appointments

Professional Education

  • Fellowship:Stanford University School of Medicine (1998) CA
  • Residency:University of Cincinnati (1996) OH
  • Internship:University of Cincinnati (1994) OH
  • Medical Education:Tufts University (1993) MA

Research & Scholarship

Current Research and Scholarly Interests

As Director of the Pediatric Bipolar Disorders Program, Dr. Chang conducts research into various facets of bipolar disorder. He is currently conducting phenomenologic, biologic, pharmacologic, and genetic studies of bipolar disorder in adults and children. These studies include brain imaging (MRI, MRS, fMRI) and medication and therapy trials. He is particularly interested in detecting prodromal bipolar disorder in children who might then be treated to prevent the development of full bipolar disorder. To do this, he has been studying children of parents with bipolar disorder who are at high risk for developing the disorder themselves.

As Director of PANS Psychiatry Research, Dr. Chang is investigating underlying causes for the acute neuropsychiatric symptoms in these children. In conjunction with the PANS Clinic at LPCH, he is collecting phenomenological, immunologic, and brain imaging data, the first study ever to investigate this illness in this way.


2014-15 Courses


Journal Articles

  • Preliminary study of anxiety symptoms, family dysfunction, and the brain-derived neurotrophic factor (BDNF) Val66Met genotype in offspring of parents with bipolar disorder. Journal of psychiatric research Park, M., Chang, K. D., Hallmayer, J., Howe, M. E., Kim, E., Hong, S. C., Singh, M. K. 2015; 61: 81-88


    Several genetic and environmental factors place youth offspring of parents with bipolar disorder (BD) at high risk for developing mood and anxiety disorders. Recent studies suggest that anxiety symptoms, even at subclinical levels, have been associated with an increased risk for developing BD. The brain-derived neurotrophic factor (BDNF) gene has been implicated in the pathophysiology of both BD and anxiety disorders. We aimed to explore whether anxiety in BD offspring was associated with the BDNF Val66Met polymorphism. 64 BD offspring (mean age: 13.73 (S.D. 3.45) M = 30, F = 34) and 51 HC (mean age: 13.68 (S.D. 2.68) M = 23, F = 28) were compared on presence of the met allele and on scores from the Multidimensional Anxiety Scale for Children (MASC). To assess family function, we used the Family Adaptability and Cohesion Evaluation Scales (FACES-IV). The Baron & Kenny method was the statistical approach used to examine the moderating effects between variables. BD offspring showed higher levels of overall anxiety than did the HC group. BD offspring with the val/val genotype showed higher levels of anxiety than BD offspring with other genotypes. No significant levels of anxiety or its association with BDNF genotype were found in the HC group. BD offspring group showed significantly more family dysfunction when compared with the HC group and the family dysfunction moderated the association between the BDNF genotype and anxiety symptoms. This study demonstrated the potential interplay of three factors: BD offspring, anxiety symptoms and family dysfunction.

    View details for DOI 10.1016/j.jpsychires.2014.11.013

    View details for PubMedID 25498133

  • Multidisciplinary clinic dedicated to treating youth with pediatric acute-onset neuropsychiatric syndrome: presenting characteristics of the first 47 consecutive patients. Journal of child and adolescent psychopharmacology Frankovich, J., Thienemann, M., Pearlstein, J., Crable, A., Brown, K., Chang, K. 2015; 25 (1): 38-47


    Abrupt, dramatic onset obsessive-compulsive disorder (OCD) and/or eating restriction with at least two coinciding symptoms (anxiety, mood dysregulation, irritability/aggression/oppositionality, behavioral regression, cognitive deterioration, sensory or motor abnormalities, or somatic symptoms) defines pediatric acute-onset neuropsychiatric syndrome (PANS). Descriptions of clinical data in such youth are limited.We reviewed charts of 53 consecutive patients evaluated in our PANS Clinic; 47 met PANS symptom criteria but not all met the requirement for "acute onset." Patients meeting full criteria for PANS were compared with patients who had a subacute/insidious onset of symptoms.Nineteen of 47 (40%) patients in the study had acute onset of symptoms. In these patients, autoimmune/inflammatory diseases and psychiatric disorders were common in first-degree family members (71% and 78%, respectively). Most acute-onset patients had a relapsing/remitting course (84%), prominent sleep disturbances (84%), urinary issues (58%), sensory amplification (66%), gastrointestinal symptoms (42%), and generalized pain (68%). Inflammatory back pain (21%) and other arthritis conditions (28%) were also common. Suicidal and homicidal thoughts and gestures were common (44% and 17%, respectively) as were violent outbursts (61%). Group A streptococcus (GAS) was the most commonly identified infection at onset (21%) and during flares (74%). Rates of the abovementioned characteristics did not differ between the acute-onset group and the subacute/insidious-onset groups. Low levels of immunoglobulins were more common in the subacute/insidious-onset group (75%) compared with the acute-onset group (22%), but this was not statistically significant (p=0.06).In our PANS clinic, 40% of patients had acute onset of symptoms. However, those with and without acute onset of symptoms had similar symptom presentation, rates of inflammatory conditions, somatic symptoms, and violent thoughts and behaviors. GAS infections were the most commonly identified infection at onset and at symptom flares. Because of the wide variety of medical and psychiatric symptoms, youth with PANS may require a multidisciplinary team for adequate care management.

    View details for DOI 10.1089/cap.2014.0081

    View details for PubMedID 25695943

  • Clinical Evaluation of Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): Recommendations from the 2013 PANS Consensus Conference. Journal of child and adolescent psychopharmacology Chang, K., Frankovich, J., Cooperstock, M., Cunningham, M. W., Latimer, M. E., Murphy, T. K., Pasternack, M., Thienemann, M., Williams, K., Walter, J., Swedo, S. E. 2015; 25 (1): 3-13


    On May 23 and 24, 2013, the First PANS Consensus Conference was convened at Stanford University, calling together a geographically diverse group of clinicians and researchers from complementary fields of pediatrics: General and developmental pediatrics, infectious diseases, immunology, rheumatology, neurology, and child psychiatry. Participants were academicians with clinical and research interests in pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) in youth, and the larger category of pediatric acute-onset neuropsychiatric syndrome (PANS). The goals were to clarify the diagnostic boundaries of PANS, to develop systematic strategies for evaluation of suspected PANS cases, and to set forth the most urgently needed studies in this field. Presented here is a consensus statement proposing recommendations for the diagnostic evaluation of youth presenting with PANS.

    View details for DOI 10.1089/cap.2014.0084

    View details for PubMedID 25325534

  • Five youth with pediatric acute-onset neuropsychiatric syndrome of differing etiologies. Journal of child and adolescent psychopharmacology Frankovich, J., Thienemann, M., Rana, S., Chang, K. 2015; 25 (1): 31-37


    Pediatric acute-onset neuropsychiatric syndrome (PANS) is diagnosed by the abrupt onset of new obsessive compulsive disorder (OCD) or food-restricting symptoms, and at least two of a variety of other neuropsychiatric symptoms. Detailed clinical presentation of youth with this condition has not yet been provided in the literature.We review the clinical charts of five youth meeting criteria for PANS in our PANS Clinic. These five patients were selected for differing underlying causes thought to be driving an inflammatory response that appeared to impact psychiatric symptoms.Five youth with varying potential etiologies impacting neuropsychiatric symptoms were identified. These youth were from 8 to 18 years old at the onset of their PANS illness, and had bacterial, autoimmune, and unknown etiologies. Treatment directed at presumed etiologies ranged from antibiotics to intravenous gamma globulin (IVIG) to other immunomodulatory regimens, and appeared to improve the psychiatric illness.Youth with PANS may present in differing ways, with psychiatric and physical symptoms overlapping with inflammatory or infectious diseases, pain syndromes, and other psychiatric diagnoses. Patients' psychiatric symptoms may respond to treatments targeting the underlying cause of physical illness. Faced with a pediatric patient demonstrating the abrupt onset or exacerbation of psychiatric and physical symptoms, clinicians should consider PANS in their differential diagnosis.

    View details for DOI 10.1089/cap.2014.0056

    View details for PubMedID 25695942

  • Changes in brain activation following psychotherapy for youth with mood dysregulation at familial risk for bipolar disorder PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Garrett, A. S., Miklowitz, D. J., Howe, M. E., Singh, M. K., Acquaye, T. K., Hawkey, C. G., Glover, G. H., Reiss, A. L., Chang, K. D. 2015; 56: 215-220
  • Distinguishing Bipolar Disorder From Other Psychiatric Disorders in Children CURRENT PSYCHIATRY REPORTS Singh, M. K., Ketter, T., Chang, K. D. 2014; 16 (12)
  • Early signs of anomalous neural functional connectivity in healthy offspring of parents with bipolar disorder BIPOLAR DISORDERS Singh, M. K., Chang, K. D., Kelley, R. G., Saggar, M., Reiss, A. L., Gotlib, I. H. 2014; 16 (7): 678-689

    View details for DOI 10.1111/bdi.12221

    View details for Web of Science ID 000344373100002

  • Reward Processing in Healthy Offspring of Parents With Bipolar Disorder JAMA PSYCHIATRY Singh, M. K., Kelley, R. G., Howe, M. E., Reiss, A. L., Gotlib, I. H., Chang, K. D. 2014; 71 (10): 1148-1156
  • Neurobiological Clues of Risk for Bipolar Disorder Development PSYCHIATRIC ANNALS Chang, K. D., Garrett, A., Singh, M. 2014; 44 (10): 466-470
  • Prospective neurochemical characterization of child offspring of parents with bipolar disorder. Psychiatry research Singh, M. K., Jo, B., Adleman, N. E., Howe, M., Bararpour, L., Kelley, R. G., Spielman, D., Chang, K. D. 2013; 214 (2): 153-160


    We wished to determine whether decreases in N-acetyl aspartate (NAA) and increases in myoinositol (mI) concentrations as a ratio of creatine (Cr) occurred in the dorsolateral prefrontal cortex (DLPFC) of pediatric offspring of parents with bipolar disorder (BD) and a healthy comparison group (HC) over a 5-year period using proton magnetic resonance spectroscopy ((1)H-MRS). Paticipants comprised 64 offspring (9-18 years old) of parents with BD (36 with established BD, and 28 offspring with symptoms subsyndromal to mania) and 28 HCs, who were examined for group differences in NAA/Cr and mI/Cr in the DLPFC at baseline and follow-up at either 8, 10, 12, 52, 104, 156, 208, or 260 weeks. No significant group differences were found in metabolite concentrations at baseline or over time. At baseline, BD offspring had trends for higher mI/Cr concentrations in the right DLPFC than the HC group. mI/Cr concentrations increased with age, but no statistically significant group differences were found between groups on follow-up. It may be the case that with intervention youth at risk for BD are normalizing otherwise potentially aberrant neurochemical trajectories in the DLPFC. A longer period of follow-up may be required before observing any group differences.

    View details for DOI 10.1016/j.pscychresns.2013.05.005

    View details for PubMedID 24028795

  • Associations Among Obesity, Acute Weight Gain, and Response to Treatment with Olanzapine in Adolescent Schizophrenia JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Kemp, D. E., Correll, C. U., Tohen, M., DelBello, M. P., Ganocy, S. J., Findling, R. L., Chang, K. 2013; 23 (8): 522-530


    Abstract Objective: The purpose of this study was to investigate associations between body weight and illness characteristics, including weight gain and therapeutic efficacy, in adolescents with schizophrenia. Methods: Adolescents ages 13-17 years (n=107) with American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) schizophrenia enrolled in a 6 week, double-blind, placebo-controlled trial comparing olanzapine and placebo. Therapeutic response was assessed by the Brief Psychiatric Rating Scale for Children (BPRS-C). Secondary outcomes included the Clinical Global Impressions-Severity (CGI-S) scale and Positive and Negative Syndrome Scale (PANSS). Obesity was defined as sex-/age-adjusted body mass index (BMI)≥95th percentile. Linear regression was used to analyze the relationship between weight gain and psychiatric symptom improvement; logistic regression was conducted to identify predictors of baseline obesity. Results: Weight gain was significantly correlated with greater BPRS-C reduction among olanzapine-treated subjects (r=-0.31, p<0.01), whereas a trend was observed among placebo-treated subjects (r=-0.31, p=0.08). However, this relationship became nonsignificant when analyses were controlled for duration of olanzapine treatment (p=0.12), and a treatment by weight gain interaction did not emerge in a repeated-measures mixed model analysis that included time in the study (t=1.27, p=0.21). Additionally, weight gain ≥7% was not significantly associated with response or remission. Among 17 adolescents (16%) with obesity at study entry, obesity was not significantly associated with endpoint BPRS-C illness severity. However, girls (p=0.03), individuals hospitalized within the past year (p=0.02), and those with less severe overall (p=0.03) and negative symptoms (p=0.003) according to the CGI-S and PANSS negative subscale, respectively, were more likely to be obese at baseline. Conclusion: Baseline obesity was associated with lower illness severity, which could be mediated by greater treatment adherence, leading to more weight gain. Olanzapine-related weight gain was not independently associated with symptomatic outcome when controlling for treatment duration. Additional studies are needed to extend these findings to other disorders and medications.

    View details for DOI 10.1089/cap.2012.0099

    View details for Web of Science ID 000336520200003

    View details for PubMedID 24111982

  • Bipolar disorder and attention-deficit/hyperactivity disorder comorbidity in children and adolescents: evidence-based approach to diagnosis and treatment. journal of clinical psychiatry Miller, S., Chang, K. D., Ketter, T. A. 2013; 74 (6): 628-629

    View details for DOI 10.4088/JCP.13ac08565

    View details for PubMedID 23842014

  • Socio-emotional processing and functioning of youth at high risk for bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Whitney, J., Howe, M., Shoemaker, V., Li, S., Sanders, E. M., Dijamco, C., Acquaye, T., Phillips, J., Singh, M., Chang, K. 2013; 148 (1): 112-117


    The goal of this study was to investigate differences in socio-emotional processing and functioning in children and adolescents at high risk for bipolar disorder (BD) and healthy control participants.Children and adolescents with a parent with bipolar disorder, who had mood dysregulation but not fully syndromal BD (high risk, HR, n=24), were compared to participants with no personal or family history of psychopathology (healthy control, HC, n=27) across several neuropsychological domains. Social reciprocity was measured by the Social Responsiveness Scale, theory of mind was measured by use of the NEPSY, and affect recognition was measured by the NEPSY and the Diagnostic Test of Nonverbal Accuracy 2 (DANVA).The HR group demonstrated significant impairment in social reciprocity, including impairments in social awareness, social cognition, social communication, social motivation, and autistic mannerisms. There were no significant group differences in performance on theory of mind or affect recognition tasks.Lack of impairment in tasks associated with theory of mind or affect recognition indicate that social functioning difficulties are not likely due to impairments in these areas, or that the measures employed were not sufficiently sensitive to detect group differences.Youth at high risk for BD demonstrated impairments in numerous social domains, which may be due to innate differences in brain development governing socio-emotional functioning or may be due to disruptions in normal development caused by mood regulation difficulties.

    View details for DOI 10.1016/j.jad.2012.08.016

    View details for Web of Science ID 000318563000016

    View details for PubMedID 23123133

  • Early Intervention for Symptomatic Youth at Risk for Bipolar Disorder: A Randomized Trial of Family-Focused Therapy JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Miklowitz, D. J., Schneck, C. D., Singh, M. K., Taylor, D. O., George, E. L., Cosgrove, V. E., Howe, M. E., Dickinson, L. M., Garber, J., Chang, K. D. 2013; 52 (2): 121-131


    Depression and brief periods of (hypo)mania are linked to an increased risk of progression to bipolar I or II disorder (BD) in children of bipolar parents. This randomized trial examined the effects of a 4-month family-focused therapy (FFT) program on the 1-year course of mood symptoms in youth at high familial risk for BD, and explored its comparative benefits among youth in families with high versus low expressed emotion (EE).Participants were 40 youth (mean 12.3±2.8 years, range 9-17) with BD not otherwise specified, major depressive disorder, or cyclothymic disorder who had a first-degree relative with BD I or II and active mood symptoms (Young Mania Rating Scale [YMRS]>11 or Child Depression Rating Scale>29). Participants were randomly allocated to FFT-High Risk version (FFT-HR; 12 sessions of psychoeducation and training in communication and problem-solving skills) or an education control (EC; 1-2 family sessions).Youth in FFT-HR had more rapid recovery from their initial mood symptoms (hazard ratio = 2.69, p = .047), more weeks in remission, and a more favorable trajectory of YMRS scores over 1 year than youth in EC. The magnitude of treatment effect was greater among youth in high-EE (versus low-EE) families.FFT-HR may hasten and help sustain recovery from mood symptoms among youth at high risk for BD. Longer follow-up will be necessary to determine whether early family intervention has downstream effects that contribute to the delay or prevention of full manic episodes in vulnerable youth.

    View details for DOI 10.1016/j.jaac.2012.10.007

    View details for Web of Science ID 000314430000004

    View details for PubMedID 23357439

  • Brain structural response in individuals at familial risk for bipolar disorder: a tale of two outcomes. Biological psychiatry Singh, M. K., Chang, K. D. 2013; 73 (2): 109-110

    View details for DOI 10.1016/j.biopsych.2012.11.005

    View details for PubMedID 23245951

  • Bipolar Depression in Pediatric Populations Epidemiology and Management PEDIATRIC DRUGS Cosgrove, V. E., Roybal, D., Chang, K. D. 2013; 15 (2): 83-91


    Depression in children and adolescents with bipolar disorder is more commonly observed than mania or hypomania, and is associated with significant functional disability in multiple environmental realms. Optimal management of pediatric bipolar depression is often defined by its multimodal nature with emphasis on both psychopharmacological and psychosocial treatment. This article provides a brief overview of the epidemiology and clinical course of pediatric bipolar depression, a clinically-oriented guide to the evidence-based psychopharmacological and psychosocial management of bipolar depression in youth, and suggestions on how best to integrate medication and therapy. Recommended treatment for bipolar depression in pediatric populations usually includes both medication and psychosocial interventions given a paucity of double-blind, placebo-controlled psychopharmacological studies. Lithium and lamotrigine are feasible and tentatively efficacious options; however, treatment with quetiapine monotherapy may be no better than placebo. Furthermore, some youth may be at heightened risk for developing manic symptoms after treatment with selective serotonin reuptake inhibitors (SSRIs). Psychotherapy, either alone or adjunctively with medications, provides practitioners with a safe and feasible alternative. Interpersonal and Social Rhythm Therapy for Adolescents (IPSRT-A), Child- and Family-Focused Cognitive Behavioral Therapy (CFF-CBT), Dialectical Behavior Therapy for Adolescents (DBT-A), family psychoeducation, and Family Focused Therapy for Adolescents (FFT-A) are evidence-based treatments available to clinicians treating youth with bipolar depression.

    View details for DOI 10.1007/s40272-013-0022-8

    View details for Web of Science ID 000318532000002

    View details for PubMedID 23529869

  • Reward Processing in Adolescents With Bipolar I Disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Singh, M. K., Chang, K. D., Kelley, R. G., Cui, X., Sherdell, L., Howe, M. E., Gotlib, I. H., Reiss, A. L. 2013; 52 (1): 68-83


    Bipolar disorder (BD) is a debilitating psychiatric condition that commonly begins in adolescence, a developmental period that has been associated with increased reward seeking. Because youth with BD are especially vulnerable to negative risk-taking behaviors, understanding the neural mechanisms by which dysregulated affect interacts with the neurobehavioral processing of reward is clearly important. One way to clarify how manic symptoms evolve in BD is to "prime" the affect before presenting rewarding stimuli. The objective of this study was to investigate the neural effects of an affective priming task designed to positively induce mood before reward processing in adolescents with and without BD.Neural activity and behaviors during the anticipation of and response to monetary reward and loss after an affective prime were compared using functional magnetic resonance imaging in 13- to 18-year-old adolescents with a recent onset of BD-I (n = 24) and demographically matched healthy comparison youth (n = 24).Compared with the healthy control youth, youth with BD had speeded reaction times and showed decreased activation in the thalamus and inferior temporal gyrus while anticipating gains after priming but increased activations in the middle frontal gyrus and parietal cortices while anticipating losses after priming. Youth with BD also showed less activation in the inferior parietal lobule, thalamus, and superior frontal gyrus while receiving losses after priming.Aberrant prefrontal and subcortical activations during reward processing suggest mechanisms that may underlie disordered self-awareness during goal pursuit and motivation in BD. Longitudinal studies are needed to examine whether this pattern of neural activation predicts a poorer long-term outcome.

    View details for DOI 10.1016/j.jaac.2012.10.004

    View details for Web of Science ID 000313143400008

  • The Neural Effects of Psychotropic Medications in Children and Adolescents CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA Singh, M. K., Chang, K. D. 2012; 21 (4): 753-?


    Little is known about the neurobiological effects of psychotropic medications used in the treatment of children and adolescents diagnosed with a psychiatric disorder. This review provides a synopsis of the literature demonstrating the neural effects associated with exposure to psychotropic medication in youth using multimodal neuroimaging. The article concludes by illustrating how, taken together, these studies suggest that pharmacological interventions during childhood do indeed affect brain structure and function in a detectable manner, and the effects appear to be ameliorative.

    View details for DOI 10.1016/j.chc.2012.07.010

    View details for Web of Science ID 000311194100005

    View details for PubMedID 23040900

  • Health-related quality of life as measured by the child health questionnaire in adolescents with bipolar disorder treated with olanzapine COMPREHENSIVE PSYCHIATRY Olsen, B. T., Ganocy, S. J., Bitter, S. M., Findling, R. L., Case, M., Chang, K., Tohen, M., DelBello, M. P. 2012; 53 (7): 1000-1005


    To examine health-related quality of life (HRQoL) in adolescents with bipolar disorder before and after double-blind treatment with olanzapine or placebo.Parents or legal guardians of 160 adolescents with a manic or mixed episode associated with bipolar I disorder were asked to rate their child's health using the Child Health Questionnaire-Parental Form 50 at baseline, before receiving medication, and then again at the end of participation in a 3-week double-blind placebo-controlled study of olanzapine.Adolescents in both treatment groups began and ended the study with significantly lower scores than normalized values of healthy peers on several HRQoL subscales (lower ratings indicate more impaired functioning), especially those assessing psychosocial factors. However, participants receiving olanzapine exhibited greater improvement than those in the placebo group across multiple HRQoL subscales, including the Behavior, Family activities, and Mental health subscales. Reduction in manic symptoms was associated with improvement in HRQoL values.As expected, manic adolescents with bipolar disorder exhibit abnormalities in psychosocial, rather than physical factors associated with HRQoL. Treatment with olanzapine had a greater effect on multiple domains of psychosocial functioning compared with placebo, suggesting that in addition to improving manic symptoms, pharmacologic interventions may lessen some of psychosocial deficits experienced by adolescents with bipolar disorder. However, following 3 weeks of treatment, adolescents with bipolar disorder continued to exhibit deficits in several aspects of psychosocial functioning, indicating that additional pharmacologic and psychosocial interventions may be necessary to further improve functional outcome.

    View details for DOI 10.1016/j.comppsych.2012.03.010

    View details for Web of Science ID 000309437200014

    View details for PubMedID 22520085

  • Volumetric reductions in the subgenual anterior cingulate cortex in adolescents with bipolar I disorder BIPOLAR DISORDERS Singh, M. K., Chang, K. D., Chen, M. C., Kelley, R. G., Garrett, A., Mitsunaga, M. M., Bararpour, L., Howe, M., Reiss, A. L., Gotlib, I. H. 2012; 14 (6): 585-596


    A range of prefrontal and subcortical volumetric abnormalities have been found in adults and adolescents with bipolar disorder. It is unclear, however, if these deficits are present early in the onset of mania or are a consequence of multiple mood episodes or prolonged exposure to medication. The goal of this study was to examine whether youth with bipolar I disorder who recently experienced their first episode of mania are characterized by brain volumetric abnormalities.Anatomical images from magnetic resonance imaging of 26 13- to 18-year-old adolescents with bipolar I disorder and 24 age-comparable healthy controls with no personal or family history of psychopathology were analyzed using whole-brain voxel-based morphometry (VBM).Compared with healthy controls, adolescents with bipolar I disorder had significantly less gray matter volume in the left subgenual cingulate cortex [p<0.05, family-wise error (FWE)-corrected].Adolescents with a recent single episode of mania have smaller subgenual cingulate cortex volume than do their healthy counterparts, suggesting that this anomaly occurs early in the onset of, or may predate the disorder. Longitudinal studies are needed to examine the impact of this volumetric reduction on the course and outcome of this disorder.

    View details for DOI 10.1111/j.1399-5618.2012.01043.x

    View details for Web of Science ID 000308286800002

    View details for PubMedID 22938166

  • Information processing in adolescents with bipolar I disorder JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY Whitney, J., Joormann, J., Gotlib, I. H., Kelley, R. G., Acquaye, T., Howe, M., Chang, K. D., Singh, M. K. 2012; 53 (9): 937-945


    Cognitive models of bipolar I disorder (BD) may aid in identification of children who are especially vulnerable to chronic mood dysregulation. Information-processing biases related to memory and attention likely play a role in the development and persistence of BD among adolescents; however, these biases have not been extensively studied in youth with BD.We administered the self-referent encoding task and the dot-probe task to adolescents with bipolar I disorder (BD, n = 35) and a demographically similar healthy comparison group (HC, n = 25) at baseline, and at a 1-year follow-up in a subset of this cohort (n = 22 per group).At both baseline and 1-year follow-up, there were significant interactions of group (BD, HC) and valence of stimulus (positive, negative adjective) on endorsement and recall of self-referent adjectives. HC adolescents endorsed and recalled more positive self-referent adjectives at baseline and follow-up while adolescents with BD endorsed and recalled more negative self-referent adjectives at baseline but not follow-up. Over time, depression symptomatology was associated with impaired memory for positive self-referent adjectives. There were no group differences in attentional bias at either time points.Adolescents with BD exhibit bias away from endorsement and recall of positive adjectives, which remained stable over time and independent of mood state.

    View details for DOI 10.1111/j.1469-7610.2012.02543.x

    View details for Web of Science ID 000307954500006

    View details for PubMedID 22390273

  • Abnormal Amygdala and Prefrontal Cortex Activation to Facial Expressions in Pediatric Bipolar Disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Garrett, A. S., Reiss, A. L., Howe, M. E., Kelley, R. G., Singh, M. K., Adleman, N. E., Karchemskiy, A., Chang, K. D. 2012; 51 (8): 821-831


    Previous functional magnetic resonance imaging (fMRI) studies in pediatric bipolar disorder (BD) have reported greater amygdala and less dorsolateral prefrontal cortex (DLPFC) activation to facial expressions compared to healthy controls. The current study investigates whether these differences are associated with the early or late phase of activation, suggesting different temporal characteristics of brain responses.A total of 20 euthymic adolescents with familial BD (14 male) and 21 healthy control subjects (13 male) underwent fMRI scanning during presentation of happy, sad, and neutral facial expressions. Whole-brain voxelwise analyses were conducted in SPM5, using a three-way analysis of variance (ANOVA) with factors group (BD and healthy control [HC]), facial expression (happy, sad, and neutral versus scrambled), and phase (early and late, corresponding to the first and second half of each block of faces).There were no significant group differences in task performance, age, gender, or IQ. Significant activation from the main effect of group included greater DLPFC activation in the HC group, and greater amygdala/hippocampal activation in the BD group. The interaction of Group × Phase identified clusters in the superior temporal sulcus/insula and visual cortex, where activation increased from the early to late phase of the block for the BD but not the HC group.These findings are consistent with previous studies that suggest deficient prefrontal cortex regulation of heightened amygdala response to emotional stimuli in pediatric BD. Increasing activation over time in superior temporal and visual cortices suggests difficulty processing or disengaging attention from emotional faces in BD.

    View details for DOI 10.1016/j.jaac.2012.06.005

    View details for Web of Science ID 000307128300010

    View details for PubMedID 22840553

  • Neurometabolite Effects of Response to Quetiapine and Placebo in Adolescents with Bipolar Depression JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Chang, K., DelBello, M., Chu, W., Garrett, A., Kelley, R., Mills, N., Howe, M., Bryan, H., Adler, C., Eliassen, J., Spielman, D., Strakowski, S. M. 2012; 22 (4): 261-268


    Mood stabilizers have been reported to affect brain concentrations of myo-inositol (mI) and N-acetylaspartate (NAA). We examined the effects of quetiapine (QUET), an atypical antipsychotic, on these neurochemicals, and potential predictors of response to QUET in adolescents with bipolar depression.Twenty-six adolescents with bipolar depression participated in an 8-week placebo-controlled trial of QUET monotherapy. Subjects were scanned at baseline and after 8 weeks with proton magnetic resonance spectroscopy (1H-MRS) at 3T and 4T at two sites, with 8?cm(3) voxels placed in the right and left dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). LCModel was used to calculate absolute concentrations of NAA and mI.Twenty-six subjects had pre- and posttreatment scans (mean age=15.6 years, 9 boys). Of these subjects, 5 out of 16 subjects receiving QUET and 5 out of 10 receiving placebo (PBO) were responders (50% decrease in Children's Depression Rating Scale [CDRS] score). Although baseline ACC mI did not predict responder status, responders had significantly lower posttreatment ACC mI values than did nonresponders (3.27±.71 vs. 4.23±.70; p=0.004). There were no significant differences in the changes in ACC and DLPFC NAA levels in the QUET group compared with the PBO group (ACC: -0.55±1.3 vs.+0.25±1.5, p=0.23; right-DLPFC: -0.55±1.3 vs. 0.33±0.89, p=0.13; left-DLPFC: -0.04±0.91 vs.+0.29±0.61, p=0.41).We found that posttreatment, not baseline, ACC mI levels were associated with response to QUET in adolescents with bipolar depression. There were no differences in NAA concentration changes between the QUET and PBO groups. Larger studies including different brain regions would help to clarify the effects of QUET on neurochemistry in patients with bipolar disorder.

    View details for DOI 10.1089/cap.2011.0153

    View details for Web of Science ID 000307933800002

    View details for PubMedID 22849427

  • The functional neuroanatomy of bipolar disorder: a consensus model BIPOLAR DISORDERS Strakowski, S. M., Adler, C. M., Almeida, J., Altshuler, L. L., Blumberg, H. P., Chang, K. D., DelBello, M. P., Frangou, S., McIntosh, A., Phillips, M. L., Sussman, J. E., Townsend, J. D. 2012; 14 (4): 313-325


    Functional neuroimaging methods have proliferated in recent years, such that functional magnetic resonance imaging, in particular, is now widely used to study bipolar disorder. However, discrepant findings are common. A workgroup was organized by the Department of Psychiatry, University of Cincinnati (Cincinnati, OH, USA) to develop a consensus functional neuroanatomic model of bipolar I disorder based upon the participants' work as well as that of others.Representatives from several leading bipolar disorder neuroimaging groups were organized to present an overview of their areas of expertise as well as focused reviews of existing data. The workgroup then developed a consensus model of the functional neuroanatomy of bipolar disorder based upon these data.Among the participants, a general consensus emerged that bipolar I disorder arises from abnormalities in the structure and function of key emotional control networks in the human brain. Namely, disruption in early development (e.g., white matter connectivity and prefrontal pruning) within brain networks that modulate emotional behavior leads to decreased connectivity among ventral prefrontal networks and limbic brain regions, especially the amygdala. This developmental failure to establish healthy ventral prefrontal-limbic modulation underlies the onset of mania and ultimately, with progressive changes throughout these networks over time and with affective episodes, a bipolar course of illness.This model provides a potential substrate to guide future investigations and areas needing additional focus are identified.

    View details for DOI 10.1111/j.1399-5618.2012.01022.x

    View details for Web of Science ID 000304441200001

    View details for PubMedID 22631617

  • Effects of medication on neuroimaging findings in bipolar disorder: an updated review BIPOLAR DISORDERS Hafeman, D. M., Chang, K. D., Garrett, A. S., Sanders, E. M., Phillips, M. L. 2012; 14 (4): 375-410


    Neuroimaging is an important tool for better understanding the neurobiological underpinnings of bipolar disorder (BD). However, potential study participants are often receiving psychotropic medications which can possibly confound imaging data. To better interpret the results of neuroimaging studies in BD, it is important to understand the impact of medications on structural magnetic resonance imaging (sMRI), functional MRI (fMRI), and diffusion tensor imaging (DTI).To better understand the impact of medications on imaging data, we conducted a literature review and searched MEDLINE for papers that included the key words bipolar disorder and fMRI, sMRI, or DTI. The search was limited to papers that assessed medication effects and had not been included in a previous review by Phillips et al. (Medication effects in neuroimaging studies of bipolar disorder. Am J Psychiatry 2008; 165: 313-320). This search yielded 74 sMRI studies, 46 fMRI studies, and 15 DTI studies.Medication appeared to influence many sMRI studies, but had limited impact on fMRI and DTI findings. From the structural studies, the most robust finding (20/45 studies) was that lithium was associated with increased volumes in areas important for mood regulation, while antipsychotic agents and anticonvulsants were generally not. Regarding secondary analysis of the medication effects of fMRI and DTI studies, few showed significant effects of medication, although rigorous analyses were typically not possible when the majority of subjects were medicated. Medication effects were more frequently observed in longitudinal studies designed to assess the impact of particular medications on the blood oxygen level-dependent (BOLD) signal. With a few exceptions, the observed effects were normalizing, meaning that the medicated individuals with BD were more similar than their unmedicated counterparts to healthy subjects.The effects of psychotropic medications, when present, are predominantly normalizing and thus do not seem to provide an alternative explanation for differences in volume, white matter tracts, or BOLD signal between BD participants and healthy subjects. However, the normalizing effects of medication could obfuscate differences between BD and healthy subjects, and thus might lead to type II errors.

    View details for DOI 10.1111/j.1399-5618.2012.01023.x

    View details for Web of Science ID 000304441200005

    View details for PubMedID 22631621

  • Biological Evidence for a Neurodevelopmental Model of Pediatric Bipolar Disorder ISRAEL JOURNAL OF PSYCHIATRY AND RELATED SCIENCES Roybal, D. J., Singh, M. K., Cosgrove, V. E., Howe, M., Kelley, R., Barnea-Goraly, N., Chang, K. D. 2012; 49 (1): 28-43
  • Amygdalar, hippocampal, and thalamic volumes in youth at high risk for development of bipolar disorder PSYCHIATRY RESEARCH-NEUROIMAGING Karchemskiy, A., Garrett, A., Howe, M., Adleman, N., Simeonova, D. I., Alegria, D., Reiss, A., Chang, K. 2011; 194 (3): 319-325


    Children of parents with bipolar disorder (BD), especially those with attention deficit hyperactivity disorder (ADHD) and symptoms of depression or mania, are at significantly high risk for developing BD. As we have previously shown amygdalar reductions in pediatric BD, the current study examined amygdalar volumes in offspring of parents (BD offspring) who have not yet developed a full manic episode. Youth participating in the study included 22 BD offspring and 22 healthy controls of comparable age, gender, handedness, and IQ. Subjects had no history of a manic episode, but met criteria for ADHD and moderate mood symptoms. MRI was performed on a 3T GE scanner, using a 3D volumetric spoiled gradient echo series. Amygdalae were manually traced using BrainImage Java software on positionally normalized brain stacks. Bipolar offspring had similar amygdalar volumes compared to the control group. Exploratory analyses yielded no differences in hippocampal or thalamic volumes. Bipolar offspring do not show decreased amygdalar volume, possibly because these abnormalities occur after more prolonged illness rather than as a preexisting risk factor. Longitudinal studies are needed to determine whether amygdalar volumes change during and after the development of BD.

    View details for DOI 10.1016/j.pscychresns.2011.03.006

    View details for Web of Science ID 000298522600016

    View details for PubMedID 22041532

  • Characterization and Factors Associated with Sleep Quality in Adolescents with Bipolar I Disorder CHILD PSYCHIATRY & HUMAN DEVELOPMENT Roybal, D. J., Chang, K. D., Chen, M. C., Howe, M. E., Gotlib, I. H., Singh, M. K. 2011; 42 (6): 724-740


    Sleep disturbance is an early marker for bipolar disorder (BD) onset in youth. We characterized sleep quality in adolescents experiencing mania within the last 6-12 months. We examined the association between mood and sleep in 27 adolescents with BD and 24 matched healthy controls (HC). Subjects were assessed by parent and teen report of sleep, a semi-structured clinical interview, the Young Mania Rating Scale (YMRS), and the Childhood Depression Rating Scale (CDRS-R). Average BD youth YMRS (mean 20.3 ± 7.3) and CDRS-R (mean 42.4 ± 14.1) scores indicated they were still ill at time of assessment. Compared to HCs, adolescents with BD have distinct patterns of prolonged sleep onset latency, frequent nighttime awakenings, and increased total time awake. Mood symptoms, specifically excessive guilt, self-injurious behavior, and worsening evening mood, interfered with sleep. Further studies are needed to determine whether early regulation of sleep would improve long-term outcome in BD youth.

    View details for DOI 10.1007/s10578-011-0239-0

    View details for Web of Science ID 000296879200008

    View details for PubMedID 21701911

  • Striatal volumes in pediatric bipolar patients with and without comorbid ADHD PSYCHIATRY RESEARCH-NEUROIMAGING Liu, I. Y., Howe, M., Garrett, A., Karchemskiy, A., Kelley, R., Alegria, D., Reiss, A., Chang, K. 2011; 194 (1): 14-20


    The most prevalent comorbid disorder in pediatric bipolar disorder (BD) is attention-deficit/hyperactivity disorder (ADHD). As caudate volume abnormalities have been demonstrated in both BD and ADHD, this study sought to determine whether these findings could be attributed to separable effects from either diagnosis. High resolution anatomical magnetic resonance (MRI) images were obtained from youth in 4 groups: BD with comorbid ADHD (n=17), BD without comorbid ADHD (n=12), youth with ADHD alone (n=11), and healthy control subjects (n=24). Caudate, putamen, and globus pallidus volumes were manually traced for each subject using BrainImageJava software by a reliable rater blinded to diagnosis. There was a significant effect of diagnosis on striatal volumes, with ADHD associated with decreased caudate and putamen volumes, and BD associated with increased caudate, putamen, and globus pallidus volumes. Thus, the presence or absence of comorbid ADHD in patients with BD was associated with distinct alterations in caudate volumes, suggesting that these groups have different, but related, mechanisms of neuropathology.

    View details for DOI 10.1016/j.pscychresns.2011.06.008

    View details for Web of Science ID 000296544300003

    View details for PubMedID 21875781

  • Increased Subgenual Cingulate Cortex Volume in Pediatric Bipolar Disorder Associated with Mood Stabilizer Exposure JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Mitsunaga, M. M., Garrett, A., Howe, M., Karchemskiy, A., Reiss, A., Chang, K. 2011; 21 (2): 149-155


    The subgenual cingulate (SGC) cortex has been implicated in the pathophysiology of mood disorders. We sought to study morphometric characteristics of the SGC in pediatric subjects with familial bipolar disorder (BD) compared with healthy controls.Twenty children and adolescents with BD (mean age?=?14.6 years, 4 females) and 20 healthy age-, gender-, and intelligence quotient-matched controls underwent high-resolution anatomical magnetic resonance imaging. Patients were primarily euthymic and most were taking medications. SGC cortex volumes were determined by manual tracings from a reliable rater, blinded to diagnosis. Analyses of covariance were performed with total cerebral gray matter and age as covariates.No differences were found in SGC volumes between BD subjects and healthy controls. Further analysis revealed that BD subjects with past mood stabilizer exposure had significantly increased SGC volumes compared with BD subjects without mood stabilizer exposure, and compared with controls. The increase was driven by larger bilateral posterior SGC volumes.Youth with familial BD do not appear to have abnormalities in SGC volume. Mood stabilizer exposure, however, may be correlated with increases in SGC volume.

    View details for DOI 10.1089/cap.2010.0094

    View details for Web of Science ID 000289678800006

    View details for PubMedID 21486168

  • Neurochemical deficits in the cerebellar vermis in child offspring of parents with bipolar disorder BIPOLAR DISORDERS Singh, M. K., Spielman, D., Libby, A., Adams, E., Acquaye, T., Howe, M., Kelley, R., Reiss, A., Chang, K. D. 2011; 13 (2): 189-197


    We aimed to compare concentrations of N-acetyl aspartate, myo-inositol, and other neurometabolites in the cerebellar vermis of offspring at risk for bipolar disorder (BD) and healthy controls to examine whether changes in these neuronal metabolite concentrations occur in at-risk offspring prior to the onset of mania.A total of 22 children and adolescents aged 9-17 years with a familial risk for bipolar I or II disorder [at-risk offspring with non-bipolar I disorder mood symptoms (AR)], and 25 healthy controls (HC) were examined using proton magnetic resonance spectroscopy at 3T to study metabolite concentrations in an 8-cc voxel in the cerebellar vermis.Decreased myo-inositol and choline concentrations in the vermis were seen in the AR group compared to HC (p<0.01).Decreased cellular metabolism and interference with second messenger pathways may be present in the cerebellar vermis in youth at risk for BD as evident by decreased myo-inositol and choline concentrations in this region. These results may be limited by a cross-sectional design, co-occurring diagnoses, and medication exposure. Longitudinal studies are necessary to determine whether early neurochemical changes can predict the development of mania. Improved methods for identifying children with certain neurochemical vulnerabilities may inform preventive and early intervention strategies prior to the onset of mania.

    View details for DOI 10.1111/j.1399-5618.2011.00902.x

    View details for Web of Science ID 000288863500008

    View details for PubMedID 21443573

  • Early psychosocial intervention for youth at risk for bipolar I or II disorder: a one-year treatment development trial BIPOLAR DISORDERS Miklowitz, D. J., Chang, K. D., Taylor, D. O., George, E. L., Singh, M. K., Schneck, C. D., Dickinson, L. M., Howe, M. E., Garber, J. 2011; 13 (1): 67-75


    Previous studies have identified behavioral phenotypes that predispose genetically vulnerable youth to a later onset of bipolar I or II disorder, but few studies have examined whether early psychosocial intervention can reduce risk of syndromal conversion. In a one-year open trial, we tested a version of family-focused treatment adapted for youth at high risk for bipolar disorder (FFT-HR).A referred sample of 13 children (mean 13.4±2.69 years; 4 boys, 9 girls) who had a parent with bipolar I or II disorder participated at one of two outpatient specialty clinics. Youth met DSM-IV criteria for major depressive disorder (n=8), cyclothymic disorder (n=1), or bipolar disorder not otherwise specified (n=4), with active mood symptoms in the past month. Participants were offered FFT-HR (12 sessions in four months) with their parents, plus psychotropic medications as needed. Independent evaluators assessed depressive symptoms, hypomanic symptoms, and global functioning at baseline and then every four months for one year, with retrospective severity and impairment ratings made for each week of the follow-up interval.Families were mostly adherent to the treatment protocol (85% retention), and therapists administered the FFT-HR manual with high levels of fidelity. Youth showed significant improvements in depression, hypomania, and psychosocial functioning scores on the Adolescent Longitudinal Interval Follow-up Evaluation. They also showed significant improvements in Young Mania Rating Scale and Children's Depression Rating Scale scores.FFT-HR is a promising intervention for youth at high risk for BD. Larger-scale randomized trials that follow youth into young adulthood will be necessary to determine whether early psychosocial intervention can reduce the probability of developing bipolar I or II disorder among genetically vulnerable youth.

    View details for DOI 10.1111/j.1399-5618.2011.00890.x

    View details for Web of Science ID 000287311200007

    View details for PubMedID 21320254

  • Antidepressants and Psychostimulants in Pediatric Populations Is there an Association with Mania? PEDIATRIC DRUGS Goldsmith, M., Singh, M., Chang, K. 2011; 13 (4): 225-243


    This article reviews the literature that examines whether exposure to psychostimulants or antidepressants precipitates or exacerbates manic symptoms, or decreases the age at onset of mania in pediatric populations. A PubMed search using relevant key words identified studies targeting five distinct clinical groups: (i) youth without a diagnosis of bipolar disorder (BD) at the time of exposure to psychostimulants; (ii) youth with a diagnosis of BD at the time of exposure to psychostimulants; (iii) youth without a diagnosis of BD at the time of exposure to antidepressants; (iv) youth with a diagnosis of BD at the time of exposure to antidepressants; and (v) youth who develop BD after exposure to these medications. In patients with attention-deficit hyperactivity disorder (ADHD), the risk for mania was found to be relatively low with the use of psychostimulants. For patients with BD and ADHD, effective mood stabilization is important prior to adding a stimulant. For children with depression and/or anxiety, the risk of antidepressant-induced mania (AIM) was generally low (<2%), but the risk of general 'activation' secondary to a selective serotonin reuptake inhibitor (SSRI) may be greater (2-10%). However, rates of AIM in specialty clinics appear to be much higher. SSRIs may be particularly problematic in specific populations, such as those with some symptoms of mania or a family history of BD, but the precise risk is unknown. There is no clear evidence that stimulants or SSRIs accelerate the natural course of BD development in overall samples, but in individual cases prescribers should proceed cautiously when using these agents in youth already at risk for developing BD, such as those with ADHD and mood dysregulation, a history of prior AIM, a history of psychosis, or a family history of BD.

    View details for Web of Science ID 000292996000004

    View details for PubMedID 21692547

  • Brain glutamatergic characteristics of pediatric offspring of parents with bipolar disorder PSYCHIATRY RESEARCH-NEUROIMAGING Singh, M., Spielman, D., Adleman, N., Alegria, D., Howe, M., Reiss, A., Chang, K. 2010; 182 (2): 165-171


    We wished to determine whether decreases in prefrontal glutamate concentrations occur in offspring of parents with bipolar disorder with and at high risk for mania. Sixty children and adolescents, 9-18 years old, of parents with bipolar I or II disorder (20 offspring with established history of mania, "BD", 20 offspring with symptoms subsyndromal to mania, "SS", and 20 healthy controls "HC") were examined using proton magnetic resonance spectroscopy at 3T to study glutamatergic metabolite concentrations in the anterior cingulate cortex (ACC). A signal for reductions in absolute glutamate concentrations in the ACC was seen in the BD compared with HC and SS groups. No other statistically significant differences among groups were found. Offspring of parents with BD with prior histories of mania may have disruptions in glutamatergic function compared with HC or children at risk for BD who have not yet developed mania. Longitudinal studies are necessary to confirm whether prefrontal glutamate decreases only after the onset of full mania.

    View details for DOI 10.1016/j.pscychresns.2010.01.003

    View details for Web of Science ID 000278701500013

    View details for PubMedID 20413280

  • Course and impact of bipolar disorder in young patients. journal of clinical psychiatry Chang, K. D. 2010; 71 (2)


    The presentation of bipolar disorder in children and adolescents may vary from its presentation in adults. Rage, irritability, and long episodes are common manifestations of mania in young people with bipolar disorder. Frequent comorbid disorders in young patients include ADHD and anxiety disorders. Prodromal and subsyndromal states of bipolar disorder, such as bipolar disorder NOS, present opportunities for early intervention and prevention. Early recognition and intervention are crucial, because untreated pediatric bipolar disorder becomes chronic, has a high incidence of relapse, and has a poor prognosis.

    View details for DOI 10.4088/JCP.8125tx7c

    View details for PubMedID 20193644

  • Neural Correlates of Response Inhibition in Pediatric Bipolar Disorder JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Singh, M. K., Chang, K. D., Mazaika, P., Garrett, A., Adleman, N., Kelley, R., Howe, M., Reiss, A. 2010; 20 (1): 15-24


    Pediatric bipolar disorder is characterized by core deficits in mood and executive function and commonly co-occurs with attention-deficit/hyperactivity disorder (ADHD). We aimed to examine response inhibition in this population, as an element of executive function, which, if aberrant, may interfere with learning and information processing.Children (9-18 years) with bipolar I or II disorder (BD, n = 26) and age, gender, and intelligence quotient (IQ) comparable healthy children (HC, n = 22) without any psychopathology were given a standardized Go/NoGo computerized task measuring response inhibition. A whole-brain functional magnetic resonance imaging (MRI) group analysis was performed using statistical parametric mapping software (SPM2) for comparing NoGo to Go epochs.There were no statistically significant group differences between groups in age, gender, or ethnicity. The BD group had high rates of co-morbid disorders, including 81% with ADHD, 62% with oppositional defiant disorder (ODD), and 46% with anxiety disorders. This BD group had fewer correct responses on Go (84% vs. 96%, T[46] = 3.35, p = 0.002) and overall (85% vs. 94%, T[46] = 4.12, p = 0.0002) trials as compared to the HC group. However, there were no statistically significant group differences in response inhibition on NoGo trials (p = 0.11). In the NoGo-Go contrast, the BD group showed increased neural activation in the right dorsolateral prefrontal cortex (DLPFC) compared to HC (T[46] = 4.21, p < 0.001).During accurate NoGo but impaired Go trial performance, children with BD showed increased right DLPFC activation versus controls, suggesting increased recruitment of executive control regions for accurate response inhibition. Studies relating these results to mood regulation in pediatric BD are warranted.

    View details for DOI 10.1089/cap.2009.0004

    View details for Web of Science ID 000274636300003

    View details for PubMedID 20166792

  • Psychotropic Medication Exposure and Age at Onset of Bipolar Disorder in Offspring of Parents with Bipolar Disorder JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Chang, K. D., Saxena, K., Howe, M., Simeonova, D. 2010; 20 (1): 25-32


    Exposure to psychotropic medications before the onset of bipolar disorder (BD) in children may have profound effects on the course of illness. Both antidepressant and stimulant exposure have been proposed to hasten the course of BD development, whereas mood stabilizers have been proposed as protective. We sought to describe psychotropic medication exposure in a cohort of children at risk for BD and retrospectively determine the effect of medication exposure on age at onset (AAO) of BD.Subjects were 106 children and adolescents who had at least 1 parent with BD. Of these, 63 had BD I or BD II and 43 had subsyndromal symptoms of BD. AAO was determined as nearest month of first manic or hypomanic episode. Past psychotropic medication exposure prior to AAO was determined through interview and chart review.Both groups had high rates of exposure to psychotropic medications. Antidepressant or stimulant exposure was not correlated with an earlier AAO of BD. However, mood stabilizer exposure was associated with a later AAO.Children with full or subsyndromal BD are frequently exposed to a variety of psychotropic medications before their first manic episode. Our findings do not support that early stimulant or antidepressant exposure leads to an earlier AAO of BD. However, early mood stabilizer exposure may be associated with delayed AAO. Longitudinal studies are needed to clarify these results.

    View details for DOI 10.1089/cap.2009.0036

    View details for Web of Science ID 000274636300004

    View details for PubMedID 20166793

  • Atypical Antipsychotics for Acute Manic and Mixed Episodes in Children and Adolescents with Bipolar Disorder Efficacy and Tolerability DRUGS Singh, M. K., Ketter, T. A., Chang, K. D. 2010; 70 (4): 433-442


    The diagnosis of bipolar disorder (BD) in children is increasing, and often requires a comprehensive treatment plan to address a complex array of symptoms and associated morbidities. Pharmacotherapy, in combination with psychotherapeutic interventions, is essential for the treatment and stabilization of disrupted mood. Current evidence collectively demonstrates, by randomized controlled design, that atypical antipsychotics have efficacy for the treatment of acute manic or mixed symptoms in children and adolescents with BD. Additional longitudinal and biological studies are warranted to characterize the effects of atypical antipsychotics on all phases and stages of bipolar illness development in children and adolescents.

    View details for Web of Science ID 000276278400004

    View details for PubMedID 20205485

  • Diagnosing bipolar disorder in children and adolescents. journal of clinical psychiatry Chang, K. D. 2009; 70 (11)


    Pediatric-onset bipolar disorder is common but often difficult to diagnose in younger patients. Clinicians should be sure to establish the presence of a full manic episode to make the diagnosis of bipolar I disorder. Because adult criteria are used for children and adolescents, clinicians also should be aware of developmental norms that can help to make an accurate diagnosis. Bipolar disorder NOS and other disorders in children and adolescents may be prodromal states for bipolar disorder, especially in the presence of a positive family history.

    View details for DOI 10.4088/JCP.8125tx6c

    View details for PubMedID 20031089

  • Atomoxetine as an Adjunct Therapy in the Treatment of Co-Morbid Attention-Deficit/Hyperactivity Disorder in Children and Adolescents with Bipolar I or II Disorder JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Chang, K., Nayar, D., Howe, M., Rana, M. 2009; 19 (5): 547-551


    Atomoxetine has been proposed to be effective for treating co-morbid attention-deficit/hyperactivity disorder (ADHD) in children with bipolar disorder (BPD) without destabilizing mood. We conducted an 8-week, open label study to study the efficacy and tolerability of adjunct atomoxetine in euthymic children and adolescents with BPD and ADHD.We evaluated 12 youth aged 6-17 years (mean = 11.3 years; 7 males) with a diagnosis of BPD I or II and ADHD. Subjects were euthymic at baseline and taking at least one mood stabilizer or antipsychotic. Primary outcome measure was the ADHD Rating Scale-IV (ADHD-RS-IV) (response = 25% decrease; remission = 40% decrease). Secondary outcome measures were change in Young Mania Rating Scale (YMRS) and Children's Depression Rating Scale (CDRS).In primary outcome criteria, 8 (67%) were responders and 6 (50%) were remitters by ADHD-RS criteria. There was a significant decrease in ADHD-RS scores over the study (p < 0.0001; Cohen d = 2.18, effect size = 0.73). YMRS and CDRS scores did not change significantly from baseline to week 8. No subjects experienced a manic or mixed episode during the study, but 2 subjects were discontinued early due to worsening of mood symptoms.We found atomoxetine to be efficacious in treating symptoms of ADHD in children and adolescents with BPD taking mood stabilizers or antipsychotics. It is unclear whether symptomatic worsening of 2 subjects was due to atomoxetine or the natural course of illness. Placebo-controlled studies are needed to clarify the role of atomoxetine in this population.

    View details for DOI 10.1089/cap.2009.0030

    View details for Web of Science ID 000271392100009

    View details for PubMedID 19877979

  • Subcortical volumetric correlates of anxiety in familial pediatric bipolar disorder: A preliminary investigation PSYCHIATRY RESEARCH-NEUROIMAGING Simeonova, D. I., Jackson, V., Attalla, A., Karchemskiy, A., Howe, M., Adlernan, N., Chang, K. 2009; 173 (2): 113-120


    Anxiety is a common comorbid condition in pediatric bipolar disorder (BD). However, there is little known about the effects of comorbidity on brain morphometry in this population. The aim of the present study was to examine subcortical correlates of anxiety in familial pediatric BD. The subject group comprised 120 children (mean age=12+/-3.3 years) with at least one parent diagnosed with BD. Bipolar offspring with BD were compared with bipolar offspring without BD on a measure of overall lifetime anxiety. A sub-sample of 20 bipolar offspring with BD (mean age=14.6+/-2.8 years) underwent magnetic resonance imaging (MRI) with a 3-T scanner. Correlational analyses were conducted between hippocampal and amygdalar volumes, and anxiety scores. The results showed significantly higher anxiety in bipolar offspring with BD compared to bipolar offspring without BD. There was a significant negative association between total hippocampal volume and anxiety scores. No significant association was found between total amygdalar volume and anxiety scores. Clinically, these findings suggest that anxiety comorbidity needs to be properly assessed and treated in the management of pediatric BD. This is the first study to show a negative association between hippocampal volume and anxiety in this population. The overlap between anxiety and familial pediatric BD suggests that anxiety may be one important area of future research in parsing out the heterogeneous nature and complex etiology of early-onset BD.

    View details for DOI 10.1016/j.pscychresns.2009.01.004

    View details for Web of Science ID 000269113000006

    View details for PubMedID 19559573

  • Limbic and Corpus Callosum Aberrations in Adolescents with Bipolar Disorder: A Tract-Based Spatial Statistics Analysis BIOLOGICAL PSYCHIATRY Barnea-Goraly, N., Chang, K. D., Karchemskiy, A., Howe, M. E., Reiss, A. L. 2009; 66 (3): 238-244


    Bipolar disorder (BD) is a common and debilitating condition, often beginning in adolescence. Converging evidence from genetic and neuroimaging studies indicates that white matter abnormalities may be involved in BD. In this study, we investigated white matter structure in adolescents with familial bipolar disorder using diffusion tensor imaging (DTI) and a whole brain analysis.We analyzed DTI images using tract-based spatial statistics (TBSS), a whole-brain voxel-by-voxel analysis, to investigate white matter structure in 21 adolescents with BD, who also were offspring of at least one parent with BD, and 18 age- and IQ-matched control subjects. Fractional anisotropy (FA; a measure of diffusion anisotropy), trace values (average diffusivity), and apparent diffusion coefficient (ADC; a measure of overall diffusivity) were used as variables in this analysis. In a post hoc analysis, we correlated between FA values, behavioral measures, and medication exposure.Adolescents with BD had lower FA values than control subjects in the fornix, the left mid-posterior cingulate gyrus, throughout the corpus callosum, in fibers extending from the fornix to the thalamus, and in parietal and occipital corona radiata bilaterally. There were no significant between-group differences in trace or ADC values and no significant correlation between behavioral measures, medication exposure, and FA values.Significant white matter tract alterations in adolescents with BD were observed in regions involved in emotional, behavioral, and cognitive regulation. These results suggest that alterations in white matter are present early in the course of disease in familial BD.

    View details for DOI 10.1016/j.biopsych.2009.02.025

    View details for Web of Science ID 000267961600007

    View details for PubMedID 19389661

  • A Double-Blind, Randomized, Placebo-Controlled Trial of Divalproex Extended-Release in the Treatment of Bipolar Disorder in Children and Adolescents JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Wagner, K. D., Redden, L., Kowatch, R. A., Wilens, T. E., Segal, S., Chang, K., Wozniak, P., Vigna, N. V., Abi-Saab, W., Saltarelli, M. 2009; 48 (5): 519-532


    To compare the efficacy and safety of divalproex extended-release (ER) to placebo in a 28-day double-blind study of bipolar disorder in children and adolescents and evaluate the safety of divalproex ER in a 6-month open-label extension study.In the double-blind study, 150 patients (manic or mixed episode, aged 10-17 years) with baseline Young Mania Rating Scale (YMRS) score of 20 or higher were randomized to once-daily placebo or divalproex ER, which was titrated to clinical response or serum valproate concentration of 80 to 125 microg/mL. Sixty-six patients enrolled in the extension study.In the double-blind study, a treatment effect was not observed with divalproex ER based on change in mean YMRS score (divalproex ER -8.8 [n = 74]; placebo -7.9 [n = 70]) or secondary measures. Divalproex was similar to placebo based on incidence of adverse events. Four subjects treated with divalproex ER and three treated with placebo discontinued because of adverse events. Mean ammonia levels increased in the divalproex ER group, but only one patient was symptomatic. In the long-term study, YMRS scores decreased modestly (2.2 points from baseline). The most common adverse events were headache and vomiting.The results of the study do not provide support for the use of divalproex ER in the treatment of youths with bipolar I disorder, mixed or manic state. Further controlled trials are required to confirm or refute the findings from this study.

    View details for DOI 10.1097/CHI.0b013e31819c55ec

    View details for Web of Science ID 000265461000009

    View details for PubMedID 19325497

  • Effect of Divalproex on Brain Morphometry, Chemistry, and Function in Youth at High-Risk for Bipolar Disorder: A Pilot Study JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Chang, K., Karchemskiy, A., Kelley, R., Howe, M., Garrett, A., Adleman, N., Reiss, A. 2009; 19 (1): 51-59


    Divalproex has been found efficacious in treating adolescents with and at high risk for bipolar disorder (BD), but little is known about the effects of mood stabilizers on the brain itself. We sought to examine the effects of divalproex on the structure, chemistry, and function of specific brain regions in children at high-risk for BD.A total of 24 children with mood dysregulation but not full BD, all offspring of a parent with BD, were treated with divalproex monotherapy for 12 weeks. A subset of 11 subjects and 6 healthy controls were scanned with magnetic resonance imaging (MRI, magnetic resonance spectroscopy [MRS], and functional MRI [fMRI]) at baseline and after 12 weeks.There were no significant changes in amygdalar or cortical volume found over 12 weeks. Furthermore, no changes in neurometabolite ratios were found. However, we found the degree of decrease in prefrontal brain activation to correlate with degree of decrease in depressive symptom severity.Bipolar offspring at high risk for BD did not show gross morphometric, neurometabolite, or functional changes after 12 weeks of treatment with divalproex. Potential reasons include small sample size, short exposure to medications, or lack of significant neurobiological impact of divalproex in this particular population.

    View details for DOI 10.1089/cap.2008.060

    View details for Web of Science ID 000263913500007

    View details for PubMedID 19232023

  • Challenges in the diagnosis and treatment of pediatric bipolar depression. Dialogues in clinical neuroscience Chang, K. 2009; 11 (1): 73-80


    There has been great public and academic interest in the diagnosis and treatment of bipolar disorders (BD) in children and adolescents over the past decade, originally in the US, but now extending internationally. Much of the interest in pediatric BD has focused on the unique manifestation of mania in younger populations. Depression is often overlooked, both as a topic, and as a clinical reality, in these children. While it is becoming clear that adults with BD spend the majority of their symptomatic time in depressive rather than manic episodes, less is known about the pediatric experience of bipolar depression. However, children and adolescents with BD clearly do experience significant depressive symptoms as well as depressive episodes, and therefore early recognition and treatment is necessary. This review addresses what is known about the prevalence, presentation, and treatment of depressive symptoms and episodes in youth with BD, and includes a discussion about the recognition and treatment of bipolar depressive episodes that occur before the first manic episode.

    View details for PubMedID 19432389

  • The role of the amygdala in bipolar disorder development DEVELOPMENT AND PSYCHOPATHOLOGY Garrett, A., Chang, K. 2008; 20 (4): 1285-1296


    The amygdala has received great interest as a possible neurophysiological substrate of bipolar disorder (BD). This review summarizes information about the structure and function of the amygdala with attention to its role in experienced emotion and mood. We review the evidence for amygdala pathology in psychiatric conditions and discuss the role of the amygdala in BD during development. There appear to be consistent findings in the neuroimaging literature that suggest an etiological model for BD that involves abnormalities in the structure and function of the amygdala, but also depends on the failure of prefrontal cortical regions to modulate amygdala activity. In addition, evidence is accumulating to suggest that this model has flexible outcomes, depending on factors intrinsic and extrinsic to BD, and may follow several possible paths across the course of maturational development.

    View details for DOI 10.1017/S0954579408000618

    View details for Web of Science ID 000260993800014

    View details for PubMedID 18838042

  • Prevention of bipolar disorder in at-risk children: Theoretical assumptions and empirical foundations DEVELOPMENT AND PSYCHOPATHOLOGY Miklowitz, D. J., Chang, K. D. 2008; 20 (3): 881-897


    This article examines how bipolar symptoms emerge during development, and the potential role of psychosocial and pharmacological interventions in the prevention of the onset of the disorder. Early signs of bipolarity can be observed among children of bipolar parents and often take the form of subsyndromal presentations (e.g., mood lability, episodic elation or irritability, depression, inattention, and psychosocial impairment). However, many of these early presentations are diagnostically nonspecific. The few studies that have followed at-risk youth into adulthood find developmental discontinuities from childhood to adulthood. Biological markers (e.g., amygdalar volume) may ultimately increase our accuracy in identifying children who later develop bipolar I disorder, but few such markers have been identified. Stress, in the form of childhood adversity or highly conflictual families, is not a diagnostically specific causal agent but does place genetically and biologically vulnerable individuals at risk for a more pernicious course of illness. A preventative family-focused treatment for children with (a) at least one first-degree relative with bipolar disorder and (b) subsyndromal signs of bipolar disorder is described. This model attempts to address the multiple interactions of psychosocial and biological risk factors in the onset and course of bipolar disorder.

    View details for DOI 10.1017/S0954579408000424

    View details for Web of Science ID 000257736100008

    View details for PubMedID 18606036

  • A preliminary functional magnetic resonance imaging study of prefrontal-amygdalar activation changes in adolescents with bipolar depression treated with lamotrigine BIPOLAR DISORDERS Chang, K. D., Wagner, C., Garrett, A., Howe, M., Reiss, A. 2008; 10 (3): 426-431


    Hypotheses regarding mood dysregulation in bipolar disorder (BD) have centered on limbic overactivity with relative prefrontal underactivity during mood episodes. Therefore, we hypothesized that adolescents with bipolar depression successfully treated with lamotrigine would show decreases in amygdalar activation, and increases in prefrontal activation.Eight adolescents with BD underwent functional magnetic resonance imaging (fMRI) at baseline and after eight weeks of lamotrigine treatment. Blocks of negatively and neutrally valenced emotional pictures were presented during scanning, and subjects were asked to rate how each picture made them feel. Activation in bilateral amygdalae and dorsolateral prefrontal cortices (DLPFC) for negative minus neutral pictures was correlated with Children's Depression Rating Scale (CDRS) scores.Mean (SD) CDRS scores decreased significantly, from 53.0 (10.6) at baseline to 26.3 (5.3) at Week 8. This clinical improvement was correlated with decreased right amygdalar activation (r = 0.91, p = 0.002). At Week 8, but not baseline, CDRS score was positively correlated with bilateral amygdalar activation (r = 0.85, p = 0.007). DLPFC activation was not correlated with change in CDRS score.These preliminary results indicate that adolescents with BD treated with lamotrigine demonstrated less amygdalar activation when viewing negative stimuli as depressive symptoms improved. Larger controlled studies are needed to confirm these findings.

    View details for Web of Science ID 000254807600008

    View details for PubMedID 18402630

  • The bipolar spectrum in children and adolescents: developmental issues. journal of clinical psychiatry Chang, K. D. 2008; 69 (3)


    Bipolar disorders are common, chronic illnesses that can develop in children and adolescents at early ages. However, diagnosing bipolar disorders in youths can be difficult because currently defined gradations of the disorder, including bipolar I and bipolar II disorders and bipolar disorder not otherwise specified, were not created with the developmental differences of children in mind. Children with major depression or attention-deficit/hyperactivity disorder plus a family history of bipolar disorder may be presenting with prodromal signs and symptoms of a bipolar disorder, although longitudinal studies are needed to clarify risk factors for developing bipolar disorders. Neuropsychological and biological markers may eventually aid clinicians in distinguishing bipolar spectrum disorders and offering early intervention for at-risk children and adolescents.

    View details for PubMedID 18402496

  • The use of atypical antipsychotics in pediatric bipolar disorder JOURNAL OF CLINICAL PSYCHIATRY Chang, K. D. 2008; 69: 4-8


    Diagnosis of bipolar disorder in children and adolescents is increasing, and the early-onset form of bipolar disorder usually carries more morbidity than later-onset forms. Patient education and psychotherapeutic and psychosocial interventions should be used in conjunction with carefully planned medication regimens. Recent data support the use of atypical antipsychotics for manic or mixed states in children and adolescents. However, more information is needed about long-term treatment of mania, treatment of bipolar depression, and treatment of comorbid psychiatric conditions.

    View details for Web of Science ID 000256559100001

    View details for PubMedID 18533762

  • Divalproex sodium for the treatment of PTSD and conduct disordered youth: A pilot randomized controlled clinical trial CHILD PSYCHIATRY & HUMAN DEVELOPMENT Steiner, H., Saxena, K. S., Carrion, V., Khanzode, L. A., Silverman, M., Chang, K. 2007; 38 (3): 183-193


    We examined the efficacy of divalproex sodium (DVP) for the treatment of PTSD in conduct disorder, utilizing a previous study in which 71 youth were enrolled in a randomized controlled clinical trial. Twelve had PTSD. Subjects (all males, mean age 16, SD 1.0) were randomized into high and low dose conditions. Clinical Global Impression (CGI) ratings for core PTSD symptoms (Intrusion, avoidance and hyper arousal) were primary outcome measures, weekly slopes of impulsivity secondary ones. Intent-to-treat analyses showed significant positive associations between receiving high dose of DVP CGI's. Parallel analyses comparing outcome by drug level achieved strengthened the results.

    View details for DOI 10.1007/s10578-007-0055-8

    View details for Web of Science ID 000248055300002

    View details for PubMedID 17570057

  • Adult bipolar disorder is continuous with pediatric bipolar disorder CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE Chang, K. 2007; 52 (7): 418-425


    Considerable debate exists regarding the continuity of bipolar disorder (BD) in children and adolescents. Do affected children continue to have BD as adults? Are pediatric forms of BD distinct from adult forms of the disorder? Here, I argue that, in fact, strictly defined BD I and II in children and adolescents is continuous with adult BD. First, if we take developmental differences into account, children and adults share similar symptoms, since they are both diagnosed according to DSM-IV criteria. Next, retrospective studies indicate that 50% to 66% of adults with BD had onset of their disorder before age 19 years. Early prospective data indicate that adolescents with BD progress to become young adults with BD. Further, family studies of pediatric BD probands find high rates of BD in adult relatives, and pediatric offspring of parents with BD have elevated rates of BD, compared with control subjects. Finally, biological characteristics of pediatric BD (such as treatment response, neurobiology, and genetics) are either shared with adults having BD or fit logically into developmental models of BD. Thus, while not conclusive, a preponderance of data support the hypothesis that pediatric BD is continuous with adult BD. Prospective studies incorporating phenomenological and biological assessment are needed to decisively address this issue.

    View details for Web of Science ID 000248207500003

    View details for PubMedID 17688005

  • A pilot study of antidepressant-induced mania in pediatric bipolar disorder: Characteristics, risk factors, and the serotonin transporter gene BIOLOGICAL PSYCHIATRY Baumer, F. M., Howe, M., Gallelli, K., Simeonova, D. L., Hallmayer, J., Chang, K. D. 2006; 60 (9): 1005-1012


    Antidepressant-induced mania (AIM) has been described in bipolar disorder (BD) and has been associated with the short-allele of the serotonin transporter gene (5-HTT). We wished to investigate the frequency of and risk factors for AIM in pediatric patients with or at high risk for BD.Fifty-two children and adolescents (30 with BD and 22 with subthreshold manic symptoms, 15.1 +/- 3.4 years old), all with a parent with BD, were interviewed with their parents for manic/depressive symptoms occurring before and after past antidepressant treatment. The 47 subjects with serotonin reuptake inhibitor (SSRI) exposure were genotyped for the 5-HTT polymorphism.Fifty percent of subjects were AIM+ and 25.5% had new onset of suicidal ideation. The AIM+ and AIM- groups did not differ significantly in relation to allele (p = .36) or genotype (p = .53) frequencies of the 5-HTT polymorphism. The AIM+ subjects were more likely to have more comorbidities (3.2 vs. 2.4; p = .02) and be BD type I (p = .04) than AIM- subjects.Youth with or at high risk for BD may be particularly vulnerable to SSRI AIM and thus should be monitored if given SSRIs. In this preliminary study, we did not find that the 5-HTT polymorphism significantly influenced vulnerability to AIM.

    View details for DOI 10.1016/j.biopsych.2006.06.010

    View details for Web of Science ID 000241691600015

    View details for PubMedID 16945343

  • Will neuroimaging ever be used to diagnose pediatric bipolar disorder? DEVELOPMENT AND PSYCHOPATHOLOGY Chang, K., Adleman, N., Wagner, C., Barnea-Goraly, N., Garrett, A. 2006; 18 (4): 1133-1146


    There is a great need for discovery of biological markers that could be used diagnostically for pediatric onset disorders, particularly those with potentially confusing phenomenology such as pediatric-onset bipolar disorder (BD). Obtaining these markers would help overcome current subjective diagnostic techniques of relying on parent and child interview and symptomatic history. Brain imaging may be the most logical choice for a diagnostic tool, and certain neurobiological abnormalities have already been found in pediatric BD. However, much work remains to be done before neuroimaging can be used reliably to diagnose this disorder, and because of the nature of BD and the limitations of imaging technology and technique, neuroimaging will likely at most be only a diagnostic aide in the near future. In this paper we discuss the characteristics of pediatric BD that complicate the use of biological markers as diagnostic tools, how neuroimaging techniques have been used to study pediatric BD so far, and the limitations and potential of such techniques for future diagnostic use.

    View details for DOI 10.1017/S0954579406060548

    View details for Web of Science ID 000241933300009

    View details for PubMedID 17064431

  • Efficacy profiles of psychopharmacology: Divalproex sodium in conduct disorder CHILD PSYCHIATRY & HUMAN DEVELOPMENT Khanzode, L. A., Saxena, K., Kraemer, H., Chang, K., Steiner, H. 2006; 37 (1): 55-64


    Little is known about how deeply medication treatment penetrates different levels of the mind/brain system. Psychopathology consists of relatively simple constructs (e.g., anger, irritability), or complex ones (e.g., responsibility). This study examines the efficacy of a specific compound, divalproex sodium (DVPX), on the various levels of psychopathology, utilizing a previous study in which 71 youth with conduct disorder were enrolled in a randomized controlled 7-week clinical trial. We examined weekly slopes of "emotional cognitions" of varying degrees of complexity obtained by Weinberger Adjustment Inventory (WAI), measuring more basic states, such as anger, depression, happiness and anxiety, and complex states, such as impulse control, consideration of others, responsibility and self-esteem. Intent-to-treat analyses showed significant associations between assignment to the active treatment and improvement in depression and impulse control. This is a rare clinical trial, which provides preliminary evidence for the different profiles of efficacy of medication treatment.

    View details for DOI 10.1007/s10578-006-0019-4

    View details for Web of Science ID 000240472800005

    View details for PubMedID 16927177

  • Treatment of aggression with risperidone in children and adolescents with bipolar disorder: a case series BIPOLAR DISORDERS Saxena, K., Chang, K., Steiner, H. 2006; 8 (4): 405-410


    To evaluate the effectiveness and safety of risperidone in children and adolescents with bipolar disorder characterized by aggression and mania, despite treatment with mood stabilizers.A retrospective chart review of patients seen in an outpatient pediatric mood disorders clinic over an 18-month period was performed. Data were extracted from charts of patients who had a diagnosis of bipolar disorder with aggression that was uncontrolled on a mood stabilizer; as a result, these patients had risperidone added to their regimen.Four boys (aged 7-15 years) and two girls (aged 8 and 14 years) were treated with risperidone (mean dosage, 0.85 mg/day) for 3-16 months. Aggressive behavior improved in all patients after risperidone was started and remained improved for the duration of follow-up. Other symptoms of mania also improved. Risperidone was generally well tolerated. Sedation and akathisia were reported in one patient.The addition of risperidone to a mood stabilizer may improve aggression and other symptoms of mania in pediatric patients with bipolar disorder who do not respond adequately to a mood stabilizer alone. The long-term efficacy and safety of this regimen should be evaluated in a controlled clinical trial.

    View details for Web of Science ID 000239111900010

    View details for PubMedID 16879141

  • Divalproex sodium reduces overall aggression in youth at high risk for bipolar disorder JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Saxena, K., Howe, M., Simeonova, D., Steiner, H., Chang, K. 2006; 16 (3): 252-259


    The psychopharmacology of aggression in youth is relatively unexplored, even though such maladaptive aggression manifests across many different diagnoses.This study was a 12-week, open-label trial with divalproex sodium (DVPX) in 24 bipolar offspring 6-18 years of age (mean age = 11.3 years; 17 boys) with mixed diagnoses of major depression, cyclothymia, attention-deficit/hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD). The Overt Aggression Scale (OAS) was used to measure aggression in 4-week intervals. We measured serum gamma-butyric acid (GABA) and glutamate levels at baseline and week 12.Seventy-one percent of evaluable subjects were considered responders to DVPX treatment by the OAS. There was a significant correlation between the Young Mania Rating Scale (YMRS) and OAS scores at week 0 (p = 0.036) and week 12 (p = 0.025). Serum DVPX level did not correlate with treatment response.These youths who are at high risk for bipolar disorder experienced an overall decrease in aggressive behavior in response to DVPX. Age or gender did not predict a positive response to DVPX. This study is the first report of treatment efficacy of a mood stabilizer for aggression in youth at high risk for bipolar disorder.

    View details for Web of Science ID 000238459000004

    View details for PubMedID 16768633

  • An open-label study of lamotrigine adjunct or monotherapy for the treatment of adolescents with bipolar depression JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Chang, K., Saxena, K., Howe, M. 2006; 45 (3): 298-304


    The treatment of pediatric bipolar depression has not been well studied. The authors wished to prospectively study the efficacy of lamotrigine as adjunctive or monotherapy in adolescents with bipolar disorder who were experiencing a depressive episode.This was an 8-week open-label trial of lamotrigine with 20 adolescents ages 12-17 years (mean age 15.8; 7 boys, 13 girls) with diagnoses of bipolar disorder I, II, or not otherwise specified, who were experiencing a depressive episode. Lamotrigine was begun at 12.5 to 25 mg/day. Primary response criteria was a 1 or a 2 on the Clinical Global Impression-Improvement at week 8. A secondary criterion was at least a 50% decrease in Children's Depression Rating Scale-Revised scores.Nineteen subjects completed the trial. The mean final dose was 131.6 mg/day. Seven subjects were taking other psychotropic medications. Sixteen subjects (84%) responded by primary criteria, and 12 (63%) responded to our secondary criteria. Eleven subjects (58%) were considered in remission at week 8. Young Mania Rating Scale and Overt Aggression Scale-Modified scores also decreased significantly during the trial. There was no significant weight change, rash, or other adverse effects during the trial.Adolescents with bipolar depression appeared to respond to lamotrigine treatment, whether as adjunctive therapy or monotherapy, with decreases in depression, mania, and aggression. Larger, placebo-controlled studies of lamotrigine are needed in this population.

    View details for DOI 10.1097/01.chi.0000194566.86160.a3

    View details for Web of Science ID 000235722700005

    View details for PubMedID 16540814

  • Prevention of pediatric bipolar disorder - Integration of neurobiological and psychosocial processes RESILIENCE IN CHILDREN Chang, K., Howe, M., Gallelli, K., Miklowitz, D. 2006; 1094: 235-247


    Bipolar disorder (BD) is a prevalent condition in the United States that typically begins before the age of 18 years and is being increasingly recognized in children and adolescents. Despite great efforts in discovering more effective treatments for BD, it remains a difficult-to-treat condition with high morbidity and mortality. Therefore, it appears prudent to focus energies into developing interventions designed to prevent individuals from ever fully developing BD. Such interventions early in the development of the illness might prevent inappropriate interventions that may worsen or hasten development of BD, delay the onset of first manic episode, and/or prevent development of full BD. Studies of populations at high-risk for BD development have indicated that children with strong family histories of BD, who are themselves experiencing symptoms of attention-deficit/hyperactive disorder (ADHD) and/or depression or have early mood dysregulation, may be experiencing prodromal states of BD. Understanding the neurobiological and genetic underpinnings that create risk for BD development would help with more accurate identification of this prodromal population, which could then lead to suitable preventative interventions. Such interventions could be pharmacologic or psychosocial in nature. Reductions in stress and increases in coping abilities through psychosocial interventions could decrease the chance of a future manic episode. Similarly, psychotropic medications may decrease negative sequelae of stress and have potential for neuroprotective and neurogenic effects that may contribute to prevention of fully expressed BD. Further research into the biologic and environmental mechanisms of BD development as well as controlled early intervention studies are needed to ameliorate this significant public health problem.

    View details for DOI 10.1196/annals.1376.026

    View details for Web of Science ID 000245807000019

    View details for PubMedID 17347355

  • Bipolar disorder in children and adolescents: international perspective on epidemiology and phenomenology BIPOLAR DISORDERS Soutullo, C. A., Chang, K. D., Diez-Suarez, A., Figueroa-Quintana, A., Escamilla-Canales, I., Rapado-Castro, M., Ortuno, F. 2005; 7 (6): 497-506


    There is considerable skepticism outside the US over the prevalence of pediatric bipolar disorder (BD). We wished to evaluate the epidemiology of BD in children and adolescents in non-US samples.We reviewed studies on the prevalence of BD in children and adolescents in international samples. We also describe our sample of 27 children with BD at the University of Navarra.There are important and frequently overlooked differences in the definition of BD between the International Classification of Diseases 10th edition (ICD-10) and DSM-IV and methodological differences in epidemiological studies that may partially explain international differences in prevalence of pediatric BD. The prevalence of bipolar spectrum disorder in young adults in Switzerland is 11%. In Holland the 6-month prevalence of mania in adolescents was 1.9% and of hypomania 0.9%. Only 1.2% of hospitalized youth (<15 years) in Denmark and 1.7% of adolescents in Finland had BD. In our clinic, the prevalence of DSM-IV BD in children 5-18 years old is 4%, and of any mood disorders 27%. There are also data from Brazil, India and Turkey with varying results.Relative lack of data, ICD-10 and DSM-IV differences in diagnostic criteria, different levels of recognition of Child and Adolescent Psychiatry as a true specialty in Europe, clinician bias against BD, an overdiagnosis of the disorder in USA and/or a true higher prevalence of pediatric BD in USA may explain these results. US-International differences may be a methodological artifact and research is needed in this field.

    View details for Web of Science ID 000233818300003

    View details for PubMedID 16403175

  • N-acetylaspartate levels in bipolar offspring with and at high-risk for bipolar disorder BIPOLAR DISORDERS Gallelli, K. A., Wagner, C. M., Karchemskiy, A., Howe, M., Spielman, D., Reiss, A., Chang, K. D. 2005; 7 (6): 589-597


    Studies have reported decreased N-acetylaspartate (NAA) in dorsolateral prefrontal cortex (DLPFC) of adults and children with bipolar disorder (BD), suggesting decreased neuronal density in this area. However, it is unclear if this finding represents neurodegeneration after or a trait marker present before BD onset. To address this question, we used proton magnetic resonance spectroscopy ((1)H-MRS) to compare DLPFC levels of NAA among bipolar offspring with early-onset BD, bipolar offspring with subsyndromal symptoms of BD and healthy children.Participants were 9-18 years old, and included 60 offspring of parents with bipolar I or II disorder (32 with BD and 28 with subsyndromal symptoms of BD), and 26 healthy controls. (1)H-MRS at 3 T was used to study 8-cm(3) voxels placed in left and right DLPFC.There were no significant group differences in mean right or left DLPFC NAA/Cr ratios. Exploratory analyses of additional metabolites (myoinositol, choline) also yielded no significant group differences. NAA/Cr ratios were not correlated with age, duration of illness, or exposure to lithium or valproate.Our findings suggest that DLPFC NAA/Cr ratios cannot be used as a trait marker for BD. Although we did not find decreased DLPFC NAA/Cr ratios in children and adolescents with BD, it is still possible that such levels begin to decrease after longer durations of illness into adulthood. Longitudinal neuroimaging studies of patients with BD accounting for developmental and treatment factors are needed to further clarify the neurodegenerative aspects of BD.

    View details for Web of Science ID 000233818300012

    View details for PubMedID 16403184

  • Baseline predictors of response to divalproex in conduct disorder JOURNAL OF CLINICAL PSYCHIATRY Saxena, K., Silverman, M. A., Chang, K., Khanzode, L., Steiner, H. 2005; 66 (12): 1541-1548


    Successful treatment of conduct disorder remains difficult. On the basis of a positive response to divalproex among adolescent boys with conduct disorder, we conducted an analysis of the impact of baseline comorbid diagnoses and personality factors on the likelihood of treatment response to divalproex.Seventy-one adolescent boys with conduct disorder (DSM-IV) and a history of at least 1 offense against persons were randomly assigned to receive high- or low-dose divalproex for 7 weeks. Evaluations included best estimate diagnoses, the Clinical Global Impressions-Severity of Illness scale (CGI-S) and CGI-Improvement scale (CGI-I), the 62-item Weinberger Adjustment Inventory (WAI-62) assessment of distress and restraint, the Response Evaluation Measure assessment of immature and mature defenses, and the Achenbach Youth Self-Report assessment of overall psychopathology. All were conducted at study entry and exit, and the WAI-62 was conducted weekly throughout the 7-week study period. Treatment response was defined as a rating of much improved or very much improved on the CGI-I. Data were collected from June 1997 to April 1998.Fifty-eight subjects completed the study and were eligible for inclusion in the analysis. Plasma divalproex level (p = .003) and immature defenses (p = .004) were significant positive predictors of treatment response, while restraint (p = .01) and level and range of psychopathology (p = .04) were significant predictors of nonresponse. Comorbidities or distress (p = .06) were not significantly associated with treatment outcome.Predictors of response to divalproex treatment for conduct disorder were identified, despite the small sample size in this study. The pattern of positive and negative predictors of response to divalproex, an antikindling agent, tends to support a model of kindling-reinforced reactive/affective/defensive/impulsive aggression among adolescent boys with conduct disorder. Additional studies are needed to identify more subtle predictors of treatment response and to clarify the mechanisms contributing to the development of conduct disorder.

    View details for Web of Science ID 000234415900007

    View details for PubMedID 16401155

  • Atomoxetine for the treatment of attention-deficit/hyperactivity disorder in children and adolescents with bipolar disorders JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Hah, M., Chang, K. K. 2005; 15 (6): 996-1004


    Children and adolescents with bipolar disorder (BD) have a high incidence of comorbid attention-deficit/hyperactivity disorder (ADHD). In this paper, we report a consecutive case series on 7 patients with pediatric BD and ADHD who were treated with atomoxetine-and all but one were also treated in conjunction with mood stabilizers. All patients were outpatients at the Stanford Pediatric Bipolar Disorders Clinic. Information on patients was collected in a retrospective chart review. All but 1 patient demonstrated significant improvement in symptoms of ADHD. No patients had episodes of hypomania or mania during the treatment period. Adverse effects of atomoxetine treatment included sedation, nausea, and decreased appetite. These cases suggest that atomoxetine may be a safe and effective treatment for ADHD in conjunction with mood stabilizers in children with BD.

    View details for Web of Science ID 000234442700050

    View details for PubMedID 16379520

  • Creativity in familial bipolar disorder JOURNAL OF PSYCHIATRIC RESEARCH Simeonova, D. I., Chang, K. D., Strong, C., Ketter, T. A. 2005; 39 (6): 623-631


    Studies have demonstrated relationships between creativity and bipolar disorder (BD) in individuals, and suggested familial transmission of both creativity and BD. However, to date, there have been no studies specifically examining creativity in offspring of bipolar parents and clarifying mechanisms of intergenerational transmission of creativity. We compared creativity in bipolar parents and their offspring with BD and bipolar offspring with attention-deficit/hyperactivity disorder (ADHD) with healthy control adults and their children. 40 adults with BD, 20 bipolar offspring with BD, 20 bipolar offspring with ADHD, and 18 healthy control parents and their healthy control children completed the Barron-Welsh Art Scale (BWAS), an objective measure of creativity. Adults with BD compared to controls scored significantly (120%) higher on the BWAS Dislike subscale, and non-significantly (32%) higher on the BWAS Total scale. Mean BWAS Dislike subscale scores were also significantly higher in offspring with BD (107% higher) and offspring with ADHD (91% higher) than in healthy control children. Compared to healthy control children, offspring with BD had 67% higher and offspring with ADHD had 40% higher BWAS Total scores, but these differences failed to reach statistical significance when adjusted for age. In the bipolar offspring with BD, BWAS Total scores were negatively correlated with duration of illness. The results of this study support an association between BD and creativity and contribute to a better understanding of possible mechanisms of transmission of creativity in families with genetic susceptibility for BD. This is the first study to show that children with and at high risk for BD have higher creativity than healthy control children. The finding in children and in adults was related to an enhanced ability to experience and express dislike of simple and symmetric images. This could reflect increased access to negative affect, which could yield both benefits with respect to providing affective energy for creative achievement, but also yield liabilities with respect to quality of interpersonal relationships or susceptibility to depression.

    View details for DOI 10.1016/j.jpsychires.2005.01.005

    View details for Web of Science ID 000232409200009

    View details for PubMedID 16157163

  • Cortical magnetic resonance imaging findings in familial pediatric bipolar disorder BIOLOGICAL PSYCHIATRY Chang, K., Barnea-Goraly, N., Karchemskiy, A., Simeonova, D. I., Barnes, P., Ketter, T., Reiss, A. L. 2005; 58 (3): 197-203


    Morphometric magnetic resonance imaging (MRI) studies of pediatric bipolar disorder (BD) have not reported on gray matter volumes but have reported increased lateral ventricular size and presence of white matter hyperintensities (WMH). We studied gray matter volume, ventricular-to-brain ratios (VBR), and number of WMH in patients with familial, pediatric BD compared with control subjects.Twenty subjects with BD (aged 14.6 +/- 2.8 years; 4 female) according to the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia, each with a parent with BD, and 20 age-, gender-, and intelligence quotient-matched healthy control subjects (aged 14.1 +/- 2.8 years; 4 female) were scanned at 3 T. Most subjects were taking psychotropic medications. A high-resolution T1-weighted spoiled gradient echo three-dimensional MRI sequence was analyzed by BrainImage for volumetric measurements, and T2-weighted images were read by a neuroradiologist to determine presence of WMH.After covarying for age and total brain volume, there were no significant differences between subjects with BD and control subjects in volume of cerebral (p = .09) or prefrontal gray matter (p = .34). Subjects with BD did not have elevated numbers of WMH or greater VBR when compared with control subjects.Children and adolescents with familial BD do not seem to have decreased cerebral grey matter or increased numbers of WMH, dissimilar to findings in adults with BD. Gray matter decreases and development of WMH might be later sequelae of BD or unique to adult-onset BD.

    View details for DOI 10.1016/j.biopsych.2005.03.039

    View details for Web of Science ID 000231057100003

    View details for PubMedID 16084840

  • Reduced amygdalar gray matter volume in familial pediatric bipolar disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Chang, K., Karchemskiy, A., Barnea-Goraly, N., Garrett, A., Simeonova, D. I., Reiss, A. 2005; 44 (6): 565-573


    Subcortical limbic structures have been proposed to be involved in the pathophysiology of adult and pediatric bipolar disorder (BD). We sought to study morphometric characteristics of these structures in pediatric subjects with familial BD compared with healthy controls.Twenty children and adolescents with BD I (mean age = 14.6 years, four females) and 20 healthy age, gender, and IQ-matched controls underwent high-resolution magnetic resonance imaging at 3 T. Patients were mostly euthymic and most were taking medications. Amygdala, hippocampus, thalamus, and caudate volumes were determined by manual tracings from researchers blinded to diagnosis. Analyses of covariance were performed, with total brain volume, age, and gender as covariates.No differences were found in the volumes of hippocampus, caudate, and thalamus between subjects with BD and controls. Subjects with BD had smaller volumes in the left and right amygdala, driven by reductions in gray matter volume. Exploratory analyses revealed that subjects with BD with past lithium or valproate exposure tended to have greater amygdalar gray matter volume than subjects with BD without such exposure.Children and adolescents with early-onset BD may have reduced amygdalar volumes, consistent with other studies in this population. Prolonged medication exposure to lithium or valproate may account for findings in adults with BD of increased amygdalar volume relative to controls.

    View details for DOI 10.1097/01.chi.0000159948.75136.0d

    View details for Web of Science ID 000229245600011

    View details for PubMedID 15908839

  • Divalproex sodium in the treatment of pediatric psychiatric disorders. Expert review of neurotherapeutics Rana, M., Khanzode, L., Karnik, N., Saxena, K., Chang, K., Steiner, H. 2005; 5 (2): 165-176


    Divalproex sodium is an anticonvulsant that is used extensively in adults with indications for epilepsy, acute mania and migraine prophylaxis. It has been used in children and adolescents as a first-line agent for mania in bipolar disorder. Its efficacy as a mood stabilizer has been established, and there have been studies outlining its efficacy as an agent effective in the treatment of conduct disorder, disruptive behavior disorders, aggression and explosive disorder. Longer-acting formulations are now available that cause less gastrointestinal side effects and can also be taken once a day, thus potentially increasing adherence, an important factor in this patient population. Future directions would include developing a more potent valproic acid formulation with fewer side effects, completing randomized controlled trials to establish the efficacy of divalproex sodium in various other pediatric psychiatric disorders, establishing the relative efficacy of the compound in head-to-head comparisons with other mood stabilizers, examining systematically the value of the compound in multimodal pediatric psychiatric treatment packages, and complete effectiveness trials that demonstrate the short- and long-term effectiveness of the compound in the real world of clinicians. In this drug profile, divalproex sodium and its uses in the pediatric population for psychiatric conditions are reviewed.

    View details for PubMedID 15853487

  • Attention and memory biases in the offspring of parents with bipolar disorder: indications from a pilot study JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY Gotlib, I. H., Traill, S. K., Montoya, R. L., Joormann, J., Chang, K. 2005; 46 (1): 84-93


    Although children of bipolar parents are at heightened risk for developing emotional disorders, the processes underlying this vulnerability are not well understood. This study examined biases in the processing of emotional stimuli as a potential vulnerability marker of bipolar disorder.Sixteen children of bipolar parents who did not show any indication of having an emotional disorder at the time of testing and ten children of never-disordered control parents underwent a negative mood induction designed to activate cognitive schemas and were then administered an emotion Stroop task and a self-referent encoding task.Children of bipolar parents were found to exhibit an attentional bias towards social-threat and manic-irritable words. Furthermore, although high- and low-risk children did not differ in their endorsement of positive and negative words as self-descriptive, the high-risk children demonstrated better recall of negative words than did the low-risk children.Thus, children without a mood disorder who are at high risk for developing a mood disorder were found to exhibit biases in attention and memory that are similar to those found for bipolar and unipolar depressed adults, suggesting that children at increased risk for affective disorder are characterized by potentially pathogenic cognitive structures that can be activated by sad mood. These findings offer insights into mechanisms of cognitive vulnerability for bipolar disorders.

    View details for Web of Science ID 000226637500008

    View details for PubMedID 15660646

  • Practical Clues to Early Recognition of Bipolar Disorder: A Primary Care Approach. Primary care companion to the Journal of clinical psychiatry Swann, A. C., Geller, B., Post, R. M., Altshuler, L., Chang, K. D., Delbello, M. P., Reist, C., Juster, I. A. 2005; 7 (1): 15-21


    Early treatment can favorably impact the course of bipolar disorder, a lifelong illness. Because bipolar disorder can masquerade as various mental and physical illnesses-primarily major depressive disorder-patients with this condition frequently go unrecognized for years. During this recognition lag, such patients may present to their primary care physician on multiple occasions. Accordingly, primary care physicians would benefit from knowing the "clues" to early recognition of the disorder, because early recognition and management can reduce disability, improve social and employment stability, and result in improved functional outcomes. This review describes 3 pathways to the diagnosis of bipolar disorder relevant to the primary care setting: detection of mania or hypomania, differential diagnosis of recurrent depressive episodes, and identification of interepisode disorder and its comorbidities. We summarize these pathways in terms of a practical tool that a primary care physician can use to trigger further evaluation or referral.

    View details for PubMedID 15841189

  • Anomalous prefrontal-subcortical activation in familial pediatric bipolar disorder - A functional magnetic resonance imaging investigation ARCHIVES OF GENERAL PSYCHIATRY Chang, K., Adleman, N. E., Dienes, K., Simeonova, D. I., Menon, V., Reiss, A. 2004; 61 (8): 781-792


    The neurobiological features of pediatric bipolar disorder (BD) are largely unknown. Children and adolescents with BD may be important to study with functional neuroimaging techniques because of their unique status of early-onset BD and high familial loading for the disorder. Neuroimaging studies of adults with BD have implicated the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in the development of this disorder.To study children and adolescents with BD via functional magnetic resonance imaging using cognitive and affective tasks and to examine possible abnormalities in the DLPFC and ACC, as well as selected subcortical areas, in pediatric familial BD.We evaluated 12 male subjects aged 9 to 18 years with BD who had at least 1 parent with BD as well as 10 age- and IQ-matched healthy male controls. Stimulants were discontinued for at least 24 hours; other medications were continued. Subjects underwent functional magnetic resonance imaging at 3 T while performing a 2-back visuospatial working memory task and an affective task involving the visualization of positively, neutrally, or negatively valenced pictures.An academic referral setting, drawing from the Bay Area of San Francisco, Calif.Compared with controls, for the visuospatial working memory task, subjects with BD had greater activation in several areas including the bilateral ACC, left putamen, left thalamus, left DLPFC, and right inferior frontal gyrus. Controls had greater activation in the cerebellar vermis. In viewing negatively valenced pictures, subjects with BD had greater activation in the bilateral DLPFC, inferior frontal gyrus, and right insula. Controls had greater activation in the right posterior cingulate gyrus. For positively valenced pictures, subjects with BD had greater activation in the bilateral caudate and thalamus, left middle/superior frontal gyrus, and left ACC, whereas controls had no areas of greater activation.Children and adolescents with BD may have underlying abnormalities in the regulation of prefrontal-subcortical circuits. Further functional magnetic resonance imaging studies of attention and mood with greater sample sizes are needed.

    View details for Web of Science ID 000223140400004

    View details for PubMedID 15289277

  • Review of magnetic resonance imaging and spectroscopy studies in children with bipolar disorder. Expert review of neurotherapeutics Adleman, N. E., Barnea-Goraly, N., Chang, K. D. 2004; 4 (1): 69-77


    Pediatric bipolar disorder is a serious condition that affects a child's ability to function normally during important developmental stages. Pediatric bipolar disorder often presents with a different symptom complex than adult-onset bipolar disorder, including higher rates of irritability and rapid cycling. Due to these differences, it is important to understand the neural substrates of the disease as it presents in children, especially when compared with adults. Understanding the brain abnormalities associated with pediatric bipolar disorder may provide much needed markers useful in diagnosing childhood-onset bipolar disorder, give insight into the neurobiological etiology of the disorder and lead to more effective treatments. Currently, there has been little neuroimaging research into pediatric bipolar disorder, specifically with regards to brain function. This review summarizes the neurobiological research that has been conducted on childhood- and adolescent-onset bipolar disorder using magnetic resonance technology. Future directions of research needed in this area also are discussed in the context of the existing literature.

    View details for PubMedID 15853617

  • Studies of offspring of parents with bipolar disorder AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS Chang, K., Steiner, H., Ketter, T. 2003; 123C (1): 26-35


    Children and adolescents who are the biological offspring of individuals with bipolar disorder (BD) (bipolar offspring) represent a population rich in potential for revealing important aspects in the development of BD. Multiple cross-sectional assessments of psychopathology in bipolar offspring have confirmed high incidences of BD, as well as mood and behavioral disorders, and other psychopathology in this population. Longitudinal studies of offspring have begun to shed light on precursors of BD development. Other assessments of bipolar offspring have included dimensional reports of psychiatric and psychosocial functioning, temperament assessments, and descriptions of family environments and parenting styles. Neurobiological studies in bipolar offspring are just beginning to yield findings that may be related to the underlying neuropathophysiology of BD. The future holds promise for longitudinal studies of bipolar offspring incorporating all of these facets, including genetic analyses, to further elucidate the factors involved in the evolution of BD.

    View details for DOI 10.1002/ajmg.c.20011

    View details for Web of Science ID 000186309000004

    View details for PubMedID 14601034

  • Temperament characteristics of child and adolescent bipolar offspring JOURNAL OF AFFECTIVE DISORDERS Chang, K. D., Blasey, C. M., Ketter, T. A., Steiner, H. 2003; 77 (1): 11-19


    We wished to characterize temperament of children at high risk for bipolar disorder (BD).We collected data from the Dimensions of Temperament-Revised (DOTS-R) from 53 biological offspring of at least one parent with BD.Overall, our cohort differed from population means for the DOTS-R, having decreased Activity Level-General scores, and increased Approach, and Rhythmicity-Sleep scores. Offspring with psychiatric disorders differed from those without in having decreased Flexibility, Mood, and Task Orientation scores. Temperament profiles for diagnostic categories of BD and attention-deficit/hyperactivity disorder were performed in a descriptive manner.Self- or parent-report of temperament was used rather than clinical observation. Temperament characterization was cross-sectional and retrospective rather than prospective and may overlap with clinical diagnoses.Assessment of temperament may be useful in characterizing bipolar offspring. Decreased flexibility and task orientation, and presence of negative moods may be correlated with development of psychopathology.

    View details for DOI 10.1016/S0165-0327(02)00105-2

    View details for Web of Science ID 000186218700002

    View details for PubMedID 14550931

  • Divalproex monotherapy in the treatment of bipolar offspring with mood and behavioral disorders and at least mild affective symptoms JOURNAL OF CLINICAL PSYCHIATRY Chang, K. D., Dienes, K., Blasey, C., Adleman, N., Ketter, T., Steiner, H. 2003; 64 (8): 936-942


    Offspring of parents with bipolar disorder, by virtue of their high-risk status for developing bipolar disorder, merit an investigation of the efficacy of treatment with mood stabilizers. Behavioral and mood difficulties in this population may represent prodromal forms of bipolar disorder. We studied the efficacy of divalproex in treating child and adolescent bipolar offspring with mood or behavioral disorders who did not yet meet criteria for bipolar I or II disorder.We studied 24 children aged 6-18 years (mean = 11.3 years; 17 boys/7 girls) with at least 1 biological parent with bipolar disorder. Participants were diagnosed by the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia with at least 1 of the following DSM-IV disorders: major depressive disorder, dysthymic disorder, cyclothymic disorder, or attention-deficit/hyperactivity disorder. Subjects all had at least moderate affective symptoms (28-item Hamilton Rating Scale for Depression or Young Mania Rating Scale score > 12). After a 2-week washout period, subjects were treated with divalproex for 12 weeks, titrated to achieve serum levels of 50-120 micro g/mL (mean final dose = 821 mg/day; mean final serum level = 79.0 micro g/mL).One subject discontinued after 2 weeks due to continuation of symptoms. Of the remaining 23 subjects, 18 (78%) were considered responders by primary outcome criteria ("very much improved" or "much improved" on the Clinical Global Impressions-Improvement scale). Divalproex was well tolerated with no discontinuations due to adverse effects.Bipolar offspring with mood or behavioral disorders and at least mild affective symptoms may respond to divalproex treatment. Our study was limited by the open treatment, lack of a placebo group, and the heterogeneous nature of the sample. Controlled studies are warranted in the use of divalproex in symptomatic bipolar offspring.

    View details for Web of Science ID 000184920400012

    View details for PubMedID 12927009

  • Decreased N-acetylaspartate in children with familial bipolar disorder BIOLOGICAL PSYCHIATRY Chang, K., Adleman, N., Dienes, K., Barnea-Goraly, N., Reiss, A., Ketter, T. 2003; 53 (11): 1059-1065


    Relatively low levels of brain N-acetylaspartate, as measured by magnetic resonance spectroscopy, may indicate decreased neuronal density or viability. Dorsolateral prefrontal levels of N-acetylaspartate have been reported to be decreased in adults with bipolar disorder. We used proton magnetic resonance spectroscopy to investigate dorsolateral prefrontal N-acetylaspartate levels in children with familial bipolar disorder.Subjects were 15 children and adolescents with bipolar disorder, who each had at least one parent with bipolar disorder, and 11 healthy controls. Mean age was 12.6 years for subjects and controls. Subjects were allowed to continue current medications. Proton magnetic resonance spectroscopy at 3-Tesla was used to study 8 cm(3) voxels placed in left and right dorsolateral prefrontal cortex.Bipolar subjects had lower N-acetylaspartate/Creatine ratios only in the right dorsolateral prefrontal cortex (p <.02). No differences in myoinositol or choline levels were found.Children and adolescents with bipolar disorder may have decreased dorsolateral prefrontal N-acetylaspartate, similar to adults with BD, indicating a common neuropathophysiology. Longitudinal studies of at-risk children before the onset and during the early course of bipolar disorder are needed to determine the role of prefrontal N-acetylaspartate as a possible risk marker and/or indication of early bipolar illness progression.

    View details for DOI 10.1016/S0006-3223(02)01744-4

    View details for Web of Science ID 000183339900016

    View details for PubMedID 12788251

  • Bipolar offspring: A window into bipolar disorder evolution BIOLOGICAL PSYCHIATRY Chang, K., Steiner, H., Dienes, K., Adleman, N., Ketter, T. 2003; 53 (11): 945-951


    Children of parents with bipolar disorder (bipolar offspring) represent a rich cohort for study with potential for illumination of prodromal forms of bipolar disorder. Due to their high-risk nature, bipolar offspring may present phenomenological, temperamental, and biological clues to early presentations of bipolar disorder. This article reviews the evidence for establishing bipolar offspring as a high-risk cohort, the studies which point to possible prodromal states in bipolar offspring, biological findings in bipolar offspring which may be indicators of even higher risk for bipolar disorder, initial attempts at early intervention in prodromal pediatric bipolar disorder, and implications for future research.

    View details for DOI 10.1016/S0006-3223(03)00061-1

    View details for Web of Science ID 000183339900004

    View details for PubMedID 12788239

  • Psychopharmacologic strategies for the treatment of aggression in juveniles CNS SPECTRUMS Steiner, H., Saxena, K., Chang, K. 2003; 8 (4): 298-308


    Maladaptive aggression in youth is one of the most common and troublesome reasons for referrals to child psychiatrists. It has a complex relationship with psychopathology. There are several syndromes, which are primary disturbances of clustered maladaptive aggression, most notably oppositional defiant disorder and conduct disorder. However, problems with aggression also appear in a wide range of other disturbances, such as bipolar disorder, posttraumatic stress disorder, and mood disorders. Additionally, aggression is normative, serves an adaptive purpose and can be situationally induced. These complexities need to be carefully addressed before targeting maladaptive aggression psychopharmacologically. We summarize the literature on the psychopharmacology of maladaptive aggression in youth, focusing on disorders without cognitive impairment. We delineate the subtypes of aggression which are most likely to respond to medication (reactive-affective-defensive-impulsive in their acute and chronic form) and conclude with a discussion of specific medication strategies which are supported by controlled clinical trials and clinical experience.

    View details for Web of Science ID 000184683600013

    View details for PubMedID 12679744

  • Characterization of children of bipolar parents by parent report CBCL JOURNAL OF PSYCHIATRIC RESEARCH Dienes, K. A., Chang, K. D., Blasey, C. M., Adleman, N. E., Steiner, H. 2002; 36 (5): 337-345


    In past research the Child Behavior Checklist (CBCL) has differentiated among various diagnostic categories for children and adolescents. However, research has not been conducted on whether the CBCL differentiates among diagnostic categories for children at high risk for development of psychopathology. This study compares four diagnostic groups [bipolar disorder (BD), attention/deficit-hyperactivity disorder (ADHD), Depressed/Anxious and No Diagnosis] within a cohort of 58 children of bipolar parents to determine whether their CBCL scores will replicate the scores of children not at high risk for bipolar disorder. The cohort of children of bipolar parents received elevated scores on the CBCL scales in comparison with non-clinical populations. In addition, the CBCL distinguished between children of bipolar parents with and without clinical disorders. Finally the BD group differed from the ADHD group only on the Aggressive Behaviors, Withdrawn and Anxious/Depressed subscales of the CBCL. Therefore the CBCL did not discriminate between the BD and ADHD groups as it had in previous studies of children with BD and unspecified family history. It is possible that this discrepancy is due to a group of children of bipolar parents with ADHD who are currently prodromal for bipolar disorder and therefore received higher scores on the CBCL based on prodromal symptomatology. A longitudinal follow-up of this cohort is necessary to ascertain whether this is the case.

    View details for Web of Science ID 000178254700009

    View details for PubMedID 12127602

  • Special issues in the treatment of paediatric bipolar disorder. Expert opinion on pharmacotherapy Chang, K. D., Ketter, T. A. 2001; 2 (4): 613-622


    Paediatric bipolar disorder (PBD) is an increasingly diagnosed disorder affecting an estimated 1% of children and adolescents. Pharmacological treatment studies in PBD have lagged far behind those in adults. Children are currently treated with pharmacological agents, most of which have proven efficacy in adults. However, PBD is distinct from adult forms of bipolar disorder (BD) and may present unique treatment challenges. PBD often presents with rapid cycling and mixed manic states and a high co-morbidity with behavioural and attention disorders. Early onset depression may also be an early sign of PBD. Due to developmental considerations, the diagnosis of BD may be difficult to make in children without semi-structured interviews. This report discusses the special issues that should be considered when treating PBD and reviews the current literature regarding pharmacotherapy of this population. Mood stabilisers have been studied mostly in an open, uncontrolled fashion but there is growing evidence that lithium, divalproex and carbamazepine are effective in treating PBD. More recent treatment options include atypical antipsychotics and newer anticonvulsants. Other novel agents are currently being investigated in adult BD and may prove applicable to the paediatric form. Finally, based on the available data, a treatment algorithm for PBD is proposed.

    View details for PubMedID 11336611

  • Family environment of children and adolescents with bipolar parents BIPOLAR DISORDERS Chang, K. D., Blasey, C., Ketter, T. A., Steiner, H. 2001; 3 (2): 73-78


    The effect of family environment on the development of bipolar disorder (BD) in children is not known. We sought to characterize families with children at high risk for developing BD in order to better understand the contributions of family environment to the development of childhood BD.We collected demographic data and parental ratings on the Family Environment Scale (FES) for 56 children (aged 6-18 years) from 36 families with at least one biological parent with BD. The cohort had previously been psychiatrically diagnosed according to semistructured interviews.Statistical comparisons with normative data indicated that parents' ratings were significantly lower on the FES Cohesion and Organization scales and were significantly higher on the FES Conflict scale. Multivariate analyses of variance indicated that families with both parents having a mood disorder had no significantly different FES scores than families with only one parent with a mood disorder (BD). Diagnostic data indicated that while 54% of the children in the sample had an Axis I disorder and 14% had BD, FES scores did not differ significantly for subjects with or without an Axis I disorder, or with or without BD.Families with a bipolar parent differ from the average family in having less cohesion and organization, and more conflict. Despite this difference, it does not appear that the environment alone of families with a bipolar parent determines the outcome of psychopathology in the children, or that the psychopathology of the children determines the family environment.

    View details for Web of Science ID 000168120300005

    View details for PubMedID 11333066

  • Psychiatric phenomenology of child and adolescent bipolar offspring JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Chang, K. K., Steiner, H., Ketter, T. A. 2000; 39 (4): 453-460


    To establish prodromal signs of and risk factors for childhood bipolar disorder (BD) by characterizing youths at high risk for BD.Structured diagnostic interviews were performed on 60 biological offspring of at least one parent with BD. Demographics, family histories, and parental history of childhood disruptive behavioral disorders were also assessed.Fifty-one percent of bipolar offspring had a psychiatric disorder, most commonly attention-deficit/hyperactivity disorder (ADHD), major depression or dysthymia, and BD. BD in offspring tended to be associated with earlier parental symptom onset when compared with offspring without a psychiatric diagnosis. Bipolar parents with a history of childhood ADHD were more likely to have children with BD, but not ADHD. Offspring with bilineal risk had increased severity of depressed and irritable mood, lack of mood reactivity, and rejection sensitivity, while severity of grandiosity, euphoric mood, and decreased need for sleep were not preferentially associated with such offspring.Bipolar offspring have high levels of psychopathology. Parental history of early-onset BD and/or childhood ADHD may increase the risk that their offspring will develop BD. Prodromal symptoms of childhood BD may include more subtle presentations of mood regulation difficulties and less presence of classic manic symptoms.

    View details for Web of Science ID 000086190000014

    View details for PubMedID 10761347

  • Mood stabilizer augmentation with olanzapine in acutely manic children JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Chang, K. D., Ketter, T. A. 2000; 10 (1): 45-49


    We report on three cases of acutely manic prepubertal children diagnosed with bipolar disorder who were treated with olanzapine in addition to their existing mood stabilizer regimens. All three had marked improvement of their manic symptoms within 3-5 days of beginning olanzapine therapy as measured by clinician-rated instruments. Adverse effects included sedation and weight gain. These results suggest that olanzapine may have an antimanic or mood stabilizing effect in acutely manic children with bipolar disorder.

    View details for Web of Science ID 000085902900007

    View details for PubMedID 10755582

  • Differences in thyroid function between bipolar manic and mixed states BIOLOGICAL PSYCHIATRY Chang, K. D., Keck, P. E., Stanton, S. P., McElroy, S. L., Strakowski, S. M., Geracioti, T. D. 1998; 43 (10): 730-733


    High rates of thyroid axis abnormalities have been reported in most studies of patients with rapid-cycling bipolar disorder. Mixed states share similarities with rapid-cycling, including close temporal occurrence of manic and depressive symptoms, predominance in women, poor outcome, and less robust response to lithium compared with pure mania; however, thyroid axis abnormalities have not been well studied in mixed mania.To test the hypothesis that mixed states are associated with a higher prevalence of hypothyroidism than pure mania, immunoreactive triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) concentrations were determined from serum obtained at the time of admission in 37 consecutive patients with DSM-III-R bipolar disorder, manic or mixed.The mean TSH concentration was significantly higher, and the mean T4 concentration was significantly lower in patients with mixed mania compared with pure mania. There were no significant differences in T3 concentration or in previous lithium exposure.These findings suggest thyroid axis dysfunction is more common in bipolar mixed than in bipolar manic patients.

    View details for Web of Science ID 000073651200004

    View details for PubMedID 9606526

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