Faculty Bibliography

OBJECTIVE:Most studies of pediatric bipolar disorder (BP) combine youth who have manic symptoms, but do not meet criteria for BP I/II, into one "not otherwise specified" (NOS) group. Consequently, little is known about how youth with cyclothymic disorder (CycD) differ from youth with BP NOS. The objective of this study was to determine whether youth with a research diagnosis of CycD (RDCyc) differ from youth with operationalized BP NOS. METHOD:Participants from the Course and Outcome of Bipolar Youth study were evaluated to determine whether they met RDCyc criteria. Characteristics of RDCyc youth and BP NOS youth were compared at baseline, and over eight-years follow-up. RESULTS:Of 154 youth (average age 11.96 (3.3), 42% female), 29 met RDCyc criteria. RDCyc youth were younger (p = .04) at baseline. Over follow-up, RDCyc youth were more likely to have a disruptive behavior disorder (p = .01), and were more likely to experience irritability (p = .03), mood reactivity (p = .02), and rejection sensitivity (p = .03). BP NOS youth were more likely to develop hypomania (p = .02), or depression (p = .02), and tended to have mood episodes earlier in the eight-year follow-up period. LIMITATIONS:RDCyc diagnoses were made retrospectively and followed stringent criteria, which may highlight differences that, under typical clinical conditions and more vague criteria, would not be evident. CONCLUSION:There were few differences between RDCyc and BP NOS youth. However, the ways in which the groups diverged could have implications; chronic subsyndromal mood symptoms may portend a severe, but ultimately non-bipolar, course. Longer follow-up is necessary to determine the trajectory and outcomes of CycD symptoms.

BACKGROUND:There is substantial evidence that bipolar disorder (BD) manifests on a spectrum rather than as a categorical condition. Detection of people with subthreshold manifestations of BD is therefore important. The Hypomania Checklist-32 (HCL-32) was developed as a tool to identify such people. PURPOSE:The aims of this paper were to: (1) investigate the factor structure of HCL-32; (2) determine whether the HCL-32 can discriminate between mood disorder subtypes; and (3) assess the familial aggregation and cross-aggregation of hypomanic symptoms assessed on the HCL with BD. PROCEDURES:Ninety-six probands recruited from the community and 154 of their adult first-degree relatives completed the HCL-32. Diagnosis was based on semi-structured interviews and family history reports. Explanatory factor analysis and mixed effects linear regression models were used. FINDINGS:A four-factor ("Activity/Increased energy," "Distractibility/Irritability", "Novelty seeking/Disinhibition, "Substance use") solution fit the HCL-32, explaining 11.1% of the total variance. The Distractibility/Irritability score was elevated among those with BP-I and BP-II, compared to those with depression and no mood disorders. Higher HCL-32 scores were associated with increased risk of BD-I (OR = 1.22, 95%CI 1.14-1.30). The "Distractibility/Irritability" score was transmitted within families (β = 0.15, p = 0.040). However, there was no familial cross-aggregation between mood disorders and the 4 HCL factors. CONCLUSIONS:Our findings suggest that the HCL-32 discriminates the mood disorder subtypes, is familial and may provide a dimensional index of propensity to BD. Future studies should explore the heritability of symptoms, rather than focusing on diagnoses.

Shifting definitions and differences in the conceptualization of bipolar disorders have contributed to long diagnostic delays, poor reliability, and inconsistent findings. Rating scales are independent of clinical judgment and offer a reliable way to assess manic symptoms, making them good tools to improve both clinical and research diagnoses of bipolar disorder. However, there are dozens of candidates, with few obvious distinguishing characteristics, making it difficult to select one. Our goal was to metaanalyze the diagnostic accuracy of rating scales designed to identify [hypo]manic symptoms. Additionally, we explored potential moderator variables including global region, translation into a different language, and sample composition. Nearly 4000 articles were identified with searches in PubMed and PsycINFO, yielding 127 effect sizes from 103 studies that met the following inclusion criteria: (a) statistics reported by which a standardized effect size could be calculated, (b) participants age 18 + years, (c) reference diagnoses made by semistructured/structured diagnostic interview, (d) results published in English. Multivariate mixed regression models accounted for multiple effect sizes nested within sample. One hundred twenty-seven effect sizes across 14 rating scales were evaluated. There was significant heterogeneity across effect sizes; Cochran's Q(126 df) = 1622.08, p < .00005, and substantial variance components both within (σ2 = .057) and between samples (σ2 = .253). Four measures performed similarly well and significantly better than some competitors after controlling for design and reporting features. The best rating scales offer an inexpensive, efficient way to improve research and clinical diagnostic processes across diverse populations, and could also complement formal diagnoses for examining secular and cultural trends. (PsycINFO Database Record

This study investigated the clinical utility of the Achenbach System of Empirically Based Assessment (ASEBA) for identifying youth at risk for suicide. Specifically, we investigated how well the Total Problems scores and the sum of two suicide-related items (#18 "Deliberately harms self or attempts suicide" and #91 "Talks about killing self") were able to distinguish youth with a history of suicidal behavior. Youth (N = 1117) aged 5-18 were recruited for two studies of mental illness. History of suicidal behavior was assessed by semi-structured interviews (K-SADS) with youth and caregivers. Youth, caregivers, and a primary teacher each completed the appropriate form (YSR, CBCL, and TRF, respectively) of the ASEBA. Areas under the curve (AUCs) from ROC analyses and diagnostic likelihood ratios (DLRs) were used to measure the ability of both Total Problems T scores, as well as the summed score of two suicide-related items, to identify youth with a history of suicidal behavior. The Suicide Items from the CBCL and YSR performed well (AUCs = 0.85 and 0.70, respectively). The TRF Suicide Items did not perform better than chance, AUC = 0.45. The AUCs for the Total Problems scores were poor-to-fair (0.33-0.65). The CBCL Suicide Items outperformed all other scores (ps = 0.04 to <0.0005). Combining the CBCL and YSR items did not lead to incremental improvement in prediction over the CBCL alone. The sum of two questions from a commonly used assessment tool can offer important information about a youth's risk for suicidal behavior. The low burden of this approach could facilitate wide-spread screening for suicide in an increasingly at-risk population.

This study investigated the diagnostic and clinical utility of the parent-rated Screen for Child Anxiety Related Emotional Disorders (SCARED-P) for detecting youth anxiety disorders. Youth ages 6 to 12 years, 11 months were recruited from 9 outpatient mental health clinics (N = 707). Consensus diagnoses were based on semistructured interviews (Schedule for Affective Disorders and Schizophrenia for School-Age Children) with youth and caregivers; 31% were diagnosed with at least one anxiety disorder. Caregivers completed the SCARED-P to describe youth anxiety levels. SCARED-P scores were not considered during the consensus diagnoses. Areas under the curve (AUCs) from receiver operating characteristic analyses and diagnostic likelihood ratios (DLRs) quantified performance of the SCARED-P total score and subscale scores (generalized anxiety disorder and separation anxiety disorder). SCARED-P total scores had variable efficiency (AUCs = .69-.88), and Generalized Anxiety Disorder and Separation Anxiety subscale scores were excellent (AUCs = .86-.89) for identifying specific anxiety disorders. Optimal subscale cutoff scores were computed to help rule in (DLRs = 2.7-5.4) or rule out (DLRs < 1.0) anxiety disorders among youth. Results suggest that the Generalized Anxiety Disorder and Separation Anxiety SCARED-P subscales accurately identify their respective matched diagnoses. DLRs may aid clinicians in screening for youth anxiety disorders and improve accuracy of diagnosis.

OBJECTIVE:To test whether rates of bipolar disorder (BD) have changed over time or vary across geographic regions after adjusting for design features meta-analyzing epidemiologic studies reporting BD prevalence in adults worldwide. DATA SOURCES:Searches in PubMed and PsycINFO using the terms (epidemiology OR community OR prevalence) AND (mania OR "bipolar disorder" OR cyclothymi*) AND adult and backward searches from published reviews were conducted. STUDY SELECTION:Eighty-five epidemiologic studies published in English from 1980 onward that reported prevalence rates for BD or mania for subjects ≥ 18 years old were included. DATA EXTRACTION:We coded BD prevalence, method of data collection, diagnostic criteria, year of study, country, and quality of study design and data reporting. Meta-regression tested whether sample characteristics influenced prevalence rates using the metafor package in R. RESULTS:Eighty-five effect sizes, from 44 countries, from studies spanning the years 1980-2012, included 67,373 people with BD. Lifetime prevalence for BD spectrum was 1.02% (95% CI, 0.81%-1.29%). Prevalence was moderated by the inclusion of BD not otherwise specified (P = .009) and by geographic region; rates from Africa and Asia were less than half of those from North and South America. Rates did not change significantly over 3 decades after controlling for design features. CONCLUSIONS:The overall prevalence rate is consistent with historical estimates, but rates vary significantly across studies. Differences in methodology contribute to the perception that rates of BD have increased over time. Rates varied markedly by geographic region, even after controlling for all other predictors. Research using consistent definitions and methods may expose specific factors that confer risk for BD.

OBJECTIVES:Over the past two decades, there has been tremendous growth in research regarding bipolar disorder (BD) among children and adolescents (ie, pediatric BD [PBD]). The primary purpose of this article is to distill the extant literature, dispel myths or exaggerated assertions in the field, and disseminate clinically relevant findings. METHODS:An international group of experts completed a selective review of the literature, emphasizing areas of consensus, identifying limitations and gaps in the literature, and highlighting future directions to mitigate these gaps. RESULTS:Substantial, and increasingly international, research has accumulated regarding the phenomenology, differential diagnosis, course, treatment, and neurobiology of PBD. Prior division around the role of irritability and of screening tools in diagnosis has largely abated. Gold-standard pharmacologic trials inform treatment of manic/mixed episodes, whereas fewer data address bipolar depression and maintenance/continuation treatment. Adjunctive psychosocial treatment provides a forum for psychoeducation and targets primarily depressive symptoms. Numerous neurocognitive and neuroimaging studies, and increasing peripheral biomarker studies, largely converge with prior findings from adults with BD. CONCLUSIONS:As data have accumulated and controversy has dissipated, the field has moved past existential questions about PBD toward defining and pursuing pressing clinical and scientific priorities that remain. The overall body of evidence supports the position that perceptions about marked international (US vs elsewhere) and developmental (pediatric vs adult) differences have been overstated, although additional research on these topics is warranted. Traction toward improved outcomes will be supported by continued emphasis on pathophysiology and novel therapeutics.

Research on positive emotion disturbance has gained increasing attention, yet it is not clear which specific positive emotions are affected by mood symptoms, particularly during the critical period of adolescence. This is especially pertinent for identifying potential endophenotypic markers associated with mood disorder onset and course. The present study examined self-reported discrete positive and negative emotions in association with clinician-rated manic and depressive mood symptoms in a clinically and demographically diverse group of 401 outpatient adolescents between 11-18 years of age. Results indicated that higher self reported joy and contempt were associated with increased symptoms of mania, after controlling for symptoms of depression. Low levels of joy and high sadness uniquely predicted symptoms of depression, after controlling for symptoms of mania. Results were independent of age, ethnicity, gender and bipolar diagnosis. These findings extend work on specific emotions implicated in mood pathology in adulthood, and provide insights into associations between emotions associated with goal driven behavior with manic and depressive mood symptom severity in adolescence. In particular, joy was the only emotion associated with both depressive and manic symptoms across adolescent psychopathology, highlighting the importance of understanding positive emotion disturbance during adolescent development.

OBJECTIVES:Epidemiological studies suggest that cyclothymic disorder is the most prevalent subtype of bipolar disorder (BD). However, it is rarely diagnosed, especially in youth. This may be because it can be difficult to ascertain whether a youth meets diagnostic criteria. Clearer, easy-to-apply criteria could reduce misdiagnosis. The objective oftable this study was to determine whether proposed research diagnostic criteria for cyclothymic disorder (RDCyc), based on DSM-5 criteria, could be quantified and validated in youth. METHODS:Participants from the Longitudinal Assessment of Manic Symptoms (LAMS) study were recruited based on symptoms of mania and followed prospectively. RDCyc criteria were: 1) At least one core symptom each of mania and depression; 2) one additional symptom of mania and of depression; 3) persistence over two consecutive six-month periods, and 4) impairment. Exclusionary criteria were having a [hypo]manic or depressive episode. Outcomes at the two-year follow-up were compared between RDCyc youth and other diagnostic groups (BD I/II, BD NOS/non-RDCyc cyclothymic disorder, disruptive behavior disorders [DBD], depression). RESULTS:Thirty-seven youth met RDCyc criteria. There were no consistent differences between the RDCyc youth and youth with other BD subtypes (ps=0.001-0.960, with all-but-one p value >0.02). RDCyc youth had higher depression (p<0.0005) and mania scores (p=0.001), lower functioning (p=0.012), and higher suicide risk than DBD youth (p=0.001). They had higher mania scores than depressed youth (p.018). LIMITATIONS:The majority of youth in the sample were recruited due to elevated symptoms of mania, which may limit the generalizability of the results. Youth were followed for two years, which may not be long enough to determine whether or not they will eventually develop a manic or depressive episode. CONCLUSIONS:Applying RDCyc criteria identified youth who were similar to others with BD and were more impaired than those with DBD. Using these criteria could reduce misdiagnosis and increase our understanding of this prevalent, but largely ignored, diagnosis.

OBJECTIVE:Depression and bipolar disorder (negative mood disorders, NMD) are associated with dysregulated hypothalamic-pituitary-adrenal (HPA)-axis function and disrupted emotion processing. The neural networks involved in attenuation of HPA-axis reactivity overlap with the circuitry involved in perception and modulation of emotion; however, direct links between these systems are understudied. This study investigated whether cortisol activity prior to undergoing fMRI was related to neural processing of emotional information in participants with NMD. METHODS:=36.43, SD=17.33) provided salivary cortisol samples prior to completing a facial emotion perception test during 3-Tesla fMRI. RESULTS:Overall, pre-scan cortisol level was positively associated with greater engagement of the dorsal anterior cingulate (dACC), inferior parietal lobule, insula, putamen, precuneus, middle and medial frontal and postcentral gyri, posterior cingulate, and inferior temporal gyrus during emotion processing of all faces. NMD status moderated this effect; in NMD participants' pre-scan cortisol was associated with attenuated activation of the insula, postcentral gyrus, precuneus, and putamen for fearful faces and the medial frontal gyrus for angry faces relative to HCs. Cortisol-related attenuation of activation among NMD participants was also observed for facial identification in the dACC, putamen, middle temporal gyrus, precuneus, and caudate. CONCLUSIONS:Across all participants, cortisol was associated with greater activation in several regions involved in the perception and control of emotion. However, cortisol responsivity was associated with hypoactivation of several of these regions in the NMD group, suggesting that HPA-axis activity may selectively interfere with the potentially adaptive recruitment of circuits supporting emotion perception, processing and/or regulation in mood disorders.