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1.  Manic Symptoms in Youth With Bipolar Disorder: Factor Analysis by Age of Symptom Onset and Current Age 
Journal of affective disorders  2012;145(3):409-412.
Factor analysis has been used to identify potential clinical subtypes of mania in pediatric bipolar disorder. Results vary in the number of factors retained. The present study used a formal diagnostic instrument to examine how symptoms of mania in young people are expressed, depending on age of symptom onset and current age.
Trained clinicians completed the Schedule of Affective Disorders and Schizophrenia for School-Age Children (K-SADS) Mania Rating Scale (MRS) with parents of 163 children with child-onset of symptoms (before age 12), 94 adolescents with child-onset of symptoms, and 90 adolescents with adolescent-onset of symptoms (after age 12). Factor analysis of symptom ratings during the most severe lifetime manic episode was performed for each age group.
Symptom factor structures were established for each age group. Two factors were evident for children with child-onset of symptoms (“activated/pleasure seeking” and “labile/disorganized”), one factor was present for adolescents with child-onset of symptoms (“activated/pleasure seeking/disorganized”) and two factors were evident for adolescents with adolescent-onset of symptoms (“activated/pleasure seeking” and “disorganized/psychotic”). The factor structures for children with child-onset and adolescents with adolescent-onset of symptoms were highly similar, with the latter factor structure including psychotic symptoms.
Limitations include reliance on retrospective parent report and potential issues with generalizability.
Findings suggest mania symptomatology is largely similar when examined by both age of onset and current age, with some notable differences. Specifically, psychotic symptoms begin emerging as a distinct factor in adolescents with adolescent-onset of symptoms.
PMCID: PMC3535567  PMID: 23021377
pediatric bipolar disorder; course; onset
2.  Temporal Sequence of Comorbid Alcohol Use Disorder and Anorexia Nervosa 
Addictive behaviors  2012;38(3):1704-1709.
Women with eating disorders have a significantly higher prevalence of substance use disorders than the general population. The goal of the current study was to assess the temporal pattern of comorbid anorexia nervosa (AN) and alcohol use disorder (AUD) and the impact this ordering has on symptomatology and associated features. Women were placed into one of three groups based on the presence or absence of comorbid AUD and the order of AN and AUD onset in those with both disorders: (1) AN Only, (2) AN First, and (3) AUD First. The groups were compared on psychological symptoms and personality characteristics often associated with AN, AUD, or both using general linear models. Twenty-one percent of women (n = 161) with AN reported a history of AUD with 115 reporting AN onset first and 35 reporting AUD onset first. Women with binge-eating and/or purging type AN were significantly more likely to have AUD. In general, differences were found only between women with AN Only and women with AN and AUD regardless of order of emergence. Women with AN and AUD had higher impulsivity scores and higher prevalence of depression and borderline personality disorder than women with AN Only. Women with AN First scored higher on traits commonly associated with AN, whereas women with comorbid AN and AUD displayed elevations in traits more commonly associated with AUD. Results do not indicate a distinct pattern of symptomatology in comorbid AN and AUD based on the temporal sequence of the disorders.
PMCID: PMC3558554  PMID: 23254222
anorexia nervosa; alcohol use disorder; comorbidity; age of onset
3.  Use of Mental Health Services in Transition Age Youth with Bipolar Disorder 
Journal of psychiatric practice  2013;19(6):10.1097/01.pra.0000438185.81983.8b.
There is concern that treatment of serious mental illness in the United States declines precipitously following legal emancipation at age 18 years and transition from specialty youth clinical settings. We examined age transition effects on treatment utilization in a sample of youth with bipolar disorder.
Youth with bipolar disorder (N = 413) 7–18 years of age were assessed approximately twice per year (mean interval 8.2 months) for at least 4 years. Annual use of any individual, group, and family therapy, psychopharmacology visits, and hospitalization at each year of age, and monthly use from ages 17 through 19 years, were examined. The effect of age transition to 18 years on monthly visit probability was tested in the subsample with observed transitions (n = 204). Putative sociodemographic moderators and the influence of clinical course were assessed.
Visit probabilities for the most common modalities—psychopharmacology, individual psychotherapy, and home-based care— generally fell from childhood to young adulthood. For example, the annual probability of at least one psychopharmacology visit was 97% at age 8, 75% at age 17, 60% at age 19, and 46% by age 22. Treatment probabilities fell in transition-age youth from age 17 through 19, but a specific transition effect at age 18 was not found. Declines did not vary based on sociodemographic characteristics and were not explained by changing severity of the bipolar illness or functioning.
Mental health treatment declined with age in this sample of youth with bipolar disorder, but reductions were not concentrated during or after the transition to age 18 years. Declines were unrelated to symptom severity or impairment.
PMCID: PMC3885866  PMID: 24241500
bipolar disorder; longitudinal studies; treatment use; transition-age youth; children; adolescents
To examine childhood perfectionism in anorexia nervosa (AN) restricting (RAN), purging (PAN), and binge eating with or without purging (BAN) subtypes.
The EATATE, a retrospective assessment of childhood perfectionism, and the Eating Disorder Inventory (EDI-2) were administered to 728 AN participants.
EATATE responses revealed General Childhood Perfectionism, 22.3% of 333 with RAN, 29.2% of 220 with PAN, and 24.8% of 116 with BAN; School Work Perfectionism, 31.2% with RAN, 30.4% with PAN, and 24.8% with BAN; Childhood Order and Symmetry, 18.7% with RAN, 21.7% with PAN, and 17.8% with BAN; and Global Childhood Rigidity, 42.6% with RAN, 48.3% with PAN and 48.1% with BAN. Perfectionism preceded the onset of AN in all subtypes. Significant associations between EDI-2 Drive for Thinness and Body Dissatisfaction were present with four EATATE subscales.
Global Childhood Rigidity was the predominate feature that preceded all AN subtypes. This may be a risk factor for AN.
PMCID: PMC3418385  PMID: 22488115
5.  The Genetics of Anorexia Nervosa Collaborative Study: Methods and Sample Description 
Supported by National Institute of Mental Health (NIMH), this 12-site international collaboration seeks to identify genetic variants that affect risk for anorexia nervosa (AN).
Four hundred families will be ascertained with two or more individuals affected with AN. The assessment battery produces a rich set of phenotypes comprising eating disorder diagnoses and psychological and personality features known to be associated with vulnerability to eating disorders.
We report attributes of the first 200 families, comprising 200 probands and 232 affected relatives.
These results provide context for the genotyping of the first 200 families by the Center for Inherited Disease Research. We will analyze our first 200 families for linkage, complete recruitment of roughly 400 families, and then perform final linkage analyses on the complete cohort. DNA, genotypes, and phenotypes will form a national eating disorder repository maintained by NIMH and available to qualified investigators.
PMCID: PMC3755506  PMID: 18236451
anorexia nervosa; eating disorders; bulimia nervosa; psychiatric disorders; genetics; linkage analysis; genomics
6.  Irritability and Elation in a Large Bipolar Youth Sample: Relative Symptom Severity and Clinical Outcomes Over 4 Years 
The Journal of clinical psychiatry  2013;74(1):e110-e117.
To assess whether relative severity of irritability symptoms versus elation symptoms in mania is stable and predicts subsequent illness course in youth with DSM-IV bipolar I or II disorder or operationally defined bipolar disorder not otherwise specified.
Investigators used the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children to assess the most severe lifetime manic episode in bipolar youth aged 7–17 years who were recruited from 2000 to 2006 as part of the Course and Outcomes of Bipolar Youth prospective cohort study (N = 361), conducted at university-affiliated mental health clinics. Subjects with at least 4 years of follow-up (N = 309) were categorized as irritable-only (n = 30), elated-only (n = 42), or both irritable and elated (n = 237) at baseline. Stability of this categorization over follow-up was the primary outcome. The course of mood symptoms and episodes, risk of suicide attempt, and functioning over follow-up were also compared between baseline groups.
Most subjects experienced both irritability and elation during follow-up, and agreement between baseline and follow-up group assignment did not exceed that expected by chance (κ = 0.03; 95% CI, −0.06 to 0.12). Elated-only subjects were most likely to report the absence of both irritability and elation symptoms at every follow-up assessment (35.7%, versus 26.7% of irritable-only subjects and 16.9% of those with both irritability and elation; P = .01). Baseline groups experienced mania or hypomania for a similar proportion of the follow-up period, but irritable-only subjects experienced depression for a greater proportion of the follow-up period than did subjects who were both irritable and elated (53.9% versus 39.7%, respectively; P = .01). The groups did not otherwise differ by course of mood episode duration, polarity, bipolar diagnostic type, suicide attempt risk, or functional impairment.
Most bipolar youth eventually experienced both irritability and elation irrespective of history. Irritable-only youth were at similar risk for mania but at greater risk for depression compared with elated-only youth and youth who had both irritability and elation symptoms.
PMCID: PMC3600607  PMID: 23419232
7.  History of suicide attempts in pediatric bipolar disorder: factors associated with increased risk 
Bipolar disorders  2005;7(6):525-535.
Despite evidence indicating high morbidity associated with pediatric bipolar disorder (BP), little is known about the prevalence and clinical correlates of suicidal behavior among this population.
To investigate the prevalence of suicidal behavior among children and adolescents with BP, and to compare subjects with a history of suicide attempt to those without on demographic, clinical, and familial risk factors.
Subjects were 405 children and adolescents aged 7–17 years, who fulfilled DSM-IV criteria for BPI (n = 236) or BPII (n = 29), or operationalized criteria for BP not otherwise specified (BP NOS; n = 140) via the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. As part of a multi-site longitudinal study of pediatric BP (Course and Outcome of Bipolar Youth), demographic, clinical, and family history variables were measured at intake via clinical interview with the subject and a parent/guardian.
Nearly one-third of BP patients had a lifetime history of suicide attempt. Attempters, compared with non-attempters, were older, and more likely to have a lifetime history of mixed episodes, psychotic features, and BPI. Attempters were more likely to have a lifetime history of comorbid substance use disorder, panic disorder, non-suicidal self-injurious behavior, family history of suicide attempt, history of hospitalization, and history of physical and/or sexual abuse. Multivariate analysis found that the following were the most robust set of predictors for suicide attempt: mixed episodes, psychosis, hospitalization, self-injurious behavior, panic disorder, and substance use disorder.
These findings indicate that children and adolescents with BP exhibit high rates of suicidal behavior, with more severe features of BP illness and comorbidity increasing the risk for suicide attempt. Multiple clinical factors emerged distinguishing suicide attempters from non-attempters. These clinical factors should be considered in both assessment and treatment of pediatric BP.
PMCID: PMC3679347  PMID: 16403178
pediatric bipolar disorder; risk factors; suicide; suicide attempt
8.  Incremental Cost-effectiveness of Combined Therapy vs Medication Only for Youth With Selective Serotonin Reuptake Inhibitor–Resistant Depression 
Archives of general psychiatry  2011;68(3):253-262.
Many youth with depression do not respond to initial treatment with selective serotonin reuptake inhibitors (SSRIs), and this is associated with higher costs. More effective treatment for these youth may be cost-effective.
To evaluate the incremental cost-effectiveness over 24 weeks of combined cognitive behavior therapy plus switch to a different antidepressant medication vs medication switch only in adolescents who continued to have depression despite adequate initial treatment with an SSRI.
Randomized controlled trial.
Six US academic and community clinics.
Three hundred thirty-four patients aged 12 to 18 years with SSRI-resistant depression.
Participants were randomly assigned to (1) switch to a different medication only or (2) switch to a different medication plus cognitive behavior therapy.
Main Outcome Measures
Clinical outcomes were depression-free days (DFDs), depression-improvement days (DIDs), and quality-adjusted life-years based on DFDs (DFD-QALYs). Costs of intervention, nonprotocol services, and families were included.
Combined treatment achieved 8.3 additional DFDs (P=.03), 0.020 more DFD-QALYs (P=.03), and 11.0 more DIDs (P=.04). Combined therapy cost $1633 more (P=.01). Cost per DFD was $188 (incremental cost-effectiveness ratio [ICER]=$188; 95% confidence interval [CI], −$22 to $1613), $142 per DID (ICER=$142; 95% CI, −$14 to $2529), and $78 948 per DFD-QALY (ICER=$78 948; 95% CI, −$9261 to $677 448). Cost-effectiveness acceptability curve analyses suggest a 61% probability that combined treatment is more cost-effective at a willingness to pay $100 000 per QALY. Combined treatment had a higher net benefit for subgroups of youth without a history of abuse, with lower levels of hopelessness, and with comorbid conditions.
For youth with SSRI-resistant depression, combined treatment decreases the number of days with depression and is more costly. Depending on a decision maker’s willingness to pay, combined therapy may be cost-effective, particularly for some subgroups.
PMCID: PMC3679348  PMID: 21383263
9.  The Significance of Repetitive Hair-Pulling Behaviors in Eating Disorders 
Journal of clinical psychology  2011;67(4):391-403.
We studied the relation between intrusive and repetitive hair-pulling, the defining feature of trichotillomania, and compulsive and impulsive features in 1453 individuals with anorexia nervosa and bulimia nervosa. We conducted a series of regression models examining the relative influence of compulsive features associated with obsessive compulsive disorder; compulsive features associated with eating disorders; trait features related to harm avoidance, perfectionism and novelty seeking; and self harm. A final model with a reduced sample (n=928) examined the additional contribution of impulsive attributes. One out of 20 individuals endorsed hair-pulling. Evidence of a positive association with endorsement of compulsive behavior of the obsessive compulsive spectrum emerged. Hair-pulling may be more consonant with ritualistic compulsions than impulsive urges in those with eating disorders.
PMCID: PMC3664303  PMID: 21365638
eating disorders; trichotillomania; hair-pulling; anorexia nervosa; bulimia nervosa; impulsivity; compulsivity
10.  Understanding the Association of Impulsivity, Obsessions, and Compulsions with Binge Eating and Purging Behaviors in Anorexia Nervosa 
To further refine our understanding of impulsivity, obsessions, and compulsions in anorexia nervosa (AN) by isolating which behaviors—binge eating, purging, or both—are associated with these features.
We conducted regression analyses with binge eating, purging, and the interaction of binge eating with purging as individual predictors of scores for impulsivity, obsessions, and compulsions in two samples of women with AN (n = 1373).
Purging, but not binge eating, was associated with higher scores of impulsivity, obsessions and compulsions. Purging was also associated with worst eating rituals and with worst eating preoccupations.
Our results suggest that purging, compared with binge eating, may be a stronger correlate of impulsivity, obsessions, and compulsions in AN.
PMCID: PMC3443865  PMID: 22351620
anorexia nervosa; impulsivity; compulsivity; binge eating; purging
11.  Antidepressant Exposure as a Predictor of Clinical Outcomes in the Treatment of Resistant Depression in Adolescents (TORDIA) Study 
This paper examines the relationship between plasma concentration of antidepressant and both clinical response and adverse effects in treatment-resistant depressed adolescents. Adolescents (n = 334) with major depression who had not responded to a selective serotonin reuptake inhibitor (SSRI) were randomized to 1 of 4 treatments: switch to another SSRI (fluoxetine, citalopram, or paroxetine), switch to venlafaxine, switch to SSRI plus cognitive behavior therapy, or switch to venlafaxine plus cognitive behavior therapy. Adolescents who did not improve by 6 weeks had their dose increased. Plasma concentrations of medication and metabolites were measured at 6 weeks in 244 participants and at 12 weeks in 204 participants. Adolescents treated with citalopram whose plasma concentration was equal to or greater than the geometric mean (GM) showed a higher response rate compared to those with less than the GM, with parallel but nonsignificant findings for fluoxetine. A dose increase of citalopram or fluoxetine at week 6 was most likely to result in response when it led to a change in concentration from less than the GM at 6 weeks to the GM or greater at week 12. Plasma levels of paroxetine, venlafaxine, or O-desmethylvenlafaxine were not related to clinical response. Exposure was associated with more cardiovascular and dermatologic side effects in those receiving venlafaxine. Antidepressant concentration may be useful in optimizing treatment for depressed adolescents receiving fluoxetine or citalopram.
PMCID: PMC3603695  PMID: 21192150
major depressive disorder; adolescents; plasma concentration; drug exposure; optimization
12.  Factors associated with mental health service utilization among bipolar youth 
Bipolar disorders  2007;9(8):839-850.
This study aims to characterize patterns of mental health service utilization within a sample of bipolar youth. Demographic variables, youth bipolar characteristics, youth comorbid conditions, and parental psychopathology were examined as predictors of treatment utilization across different levels of care.
A total of 293 bipolar youth (aged 7–17 years) and their parents completed a diagnostic interview, family psychiatric history measures, and an assessment of mental health service utilization. Demographic and clinical variables were measured at baseline and mental health service use was measured at the six-month follow-up.
Approximately 80% of bipolar youth attended psychosocial treatment services over the span of 6 months. Of those who attended treatment, 67% attended only outpatient services, 22% received inpatient/partial hospitalization, and 12% received residential/therapeutic school-based services. Using multinomial logistic regression, older age, female gender, and bipolar characteristics, including greater symptom severity and rapid cycling, were found to predict higher levels of care. Youth suicidal and non-suicidal self-injurious behavior, comorbid conduct disorder, and parental substance use disorders also predicted use of more restrictive treatment settings.
Results underscore the importance of assessing for and addressing suicidality, comorbid conduct disorder, and parental substance use disorders early in the treatment of bipolar youth to potentially reduce the need for more restrictive levels of care.
PMCID: PMC3600857  PMID: 18076533
adolescence; bipolar disorder; childhood; service utilization
13.  Factors Associated With the Persistence and Onset of New Anxiety Disorders in Youth With Bipolar Spectrum Disorders 
Anxiety disorders are among the most common comorbid conditions in youth with bipolar disorder, but, to our knowledge, no studies examined the course of anxiety disorders in youth and adults with bipolar disorder.
As part of the Course and Outcome of Bipolar Youth study, 413 youth, ages 7 to 17 years who met criteria for Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) bipolar I disorder (n = 244), bipolar II disorder (n = 28), and operationally defined bipolar disorder not otherwise specified (n = 141) were recruited primarily from outpatient clinics. Subjects were followed on average for 5 years using the Longitudinal Interval Follow-Up Evaluation. We examined factors associated with the persistence (> 50% of the follow-up time) and onset of new anxiety disorders in youth with bipolar disorder.
Of the 170 youth who had anxiety at intake, 80.6% had an anxiety disorder at any time during the follow-up. Most of the anxiety disorders during the follow-up were of the same type as those present at intake. About 50% of the youth had persistent anxiety, particularly generalized anxiety disorder (GAD). Persistence was associated with multiple anxiety disorders, less follow-up time in euthymia, less conduct disorder, and less treatment with antimanic and antidepressant medications (all P values ≤ .05). Twenty-five percent of the sample who did not have an anxiety disorder at intake developed new anxiety disorders during follow-up, most commonly GAD. The onset of new anxiety disorders was significantly associated with being female, lower socioeconomic status, presence of attention-deficit/hyperactivity disorder and substance use disorder, and more follow-up time with manic or hypomanic symptoms (all P values ≤ .05)
Anxiety disorders in youth with bipolar disorder tend to persist, and new-onset anxiety disorders developed in a substantial proportion of the sample. Early identification of factors associated with the persistence and onset of new anxiety disorders may enable the development of strategies for treatment and prevention.
PMCID: PMC3600866  PMID: 22226375
14.  Predictors of Prospectively Examined Suicide Attempts Among Youth With Bipolar Disorder 
Archives of general psychiatry  2012;69(11):1113-1122.
Individuals with early onset of bipolar disorder are at high risk for suicide. Yet, no study to date has examined factors associated with prospective risk for suicide attempts among youth with bipolar disorder.
To examine past, intake, and follow-up predictors of prospectively observed suicide attempts among youth with bipolar disorder.
We interviewed subjects, on average, every 9 months over a mean of 5 years using the Longitudinal Interval Follow-up Evaluation.
Outpatient and inpatient units at 3 university centers.
A total of 413 youths (mean [SD] age, 12.6 [3.3] years) who received a diagnosis of bipolar I disorder (n=244), bipolar II disorder (n=28), or bipolar disorder not otherwise specified (n=141).
Main Outcome Measures
Suicide attempt over prospective follow-up and past, intake, and follow-up predictors of suicide attempts.
Of the 413 youths with bipolar disorder, 76 (18%) made at least 1 suicide attempt within 5 years of study intake; of these, 31 (8% of the entire sample and 41% of attempters) made multiple attempts. Girls had higher rates of attempts than did boys, but rates were similar for bipolar subtypes. The most potent past and intake predictors of prospectively examined suicide attempts included severity of depressive episode at study intake and family history of depression. Follow-up data were aggregated over 8-week intervals; greater number of weeks spent with threshold depression, substance use disorder, and mixed mood symptoms and greater number of weeks spent receiving outpatient psychosocial services in the preceding 8-week period predicted greater likelihood of a suicide attempt.
Early-onset bipolar disorder is associated with high rates of suicide attempts. Factors such as intake depressive severity and family history of depression should be considered in the assessment of suicide risk among youth with bipolar disorder. Persistent depression, mixed presentations, and active substance use disorder signal imminent risk for suicidal behavior in this population.
PMCID: PMC3600896  PMID: 22752079
15.  Predictors of Spontaneous and Systematically Assessed Suicidal Adverse Events in the Treatment of SSRI Resistant Depression in Adolescents (TORDIA) Study 
The American journal of psychiatry  2009;166(4):418-426.
The authors sought to identify predictors of self-harm adverse events in treatment-resistant, depressed adolescents during the first 12 weeks of treatment.
Depressed adolescents (N=334) who had not responded to a previous trial with an SSRI antidepressant were randomized to a switch to either another SSRI or venlafaxine, with or without cognitive behavior therapy. Self-harm events, i.e., suicidal and non-suicidal self-injury adverse events were assessed by spontaneous report for the first 181 participants, and by systematic weekly assessment for the last 153 participants.
Higher rates of suicidal (20.8% vs. 8.8%) and nonsuicidal self-injury (17.6% vs. 2.2%), but not serious adverse events (8.4% vs. 7.3%) were detected with systematic monitoring. Median time to a suicidal event was 3 weeks, predicted by high baseline suicidal ideation, family conflict, and drug and alcohol use. Median time to nonsuicidal self-injury was 2 weeks, predicted by previous history of nonsuicidal self-injury. While there were no main effects of treatment, venlafaxine treatment was associated with a higher rate of self-harm adverse events in those with higher suicidal ideation. Adjunctive use of benzodiazepines, while in a small number of participants (N=10) was associated with higher rate of both suicidal and nonsuicidal self-injury adverse events.
Since predictors of suicidal adverse events also predict poor response to treatment, and many of these events occurred early in treatment, improving the speed of response to depression, by targeting of family conflict, suicidal ideation, and drug use may help to reduce their incidence. The relationship of venlafaxine and of benzodiazepines to selfharm events requires further study and clinical caution.
PMCID: PMC3593721  PMID: 19223438
16.  Retrospective Maternal Report of Early Eating Behaviors in Anorexia Nervosa 
European Eating Disorders Review  2011;20(2):111-115.
This exploratory study assessed whether maternal recall of childhood feeding and eating practices differed across anorexia nervosa (AN) subtypes. Participants were 325 women from the Genetics of Anorexia Nervosa study whose mothers completed a childhood feeding and eating questionnaire. Multinomial logistic regression analyses were used to predict AN subtype from measures related to childhood eating: (a) infant feeding (breastfed, feeding schedule, age of solid food introduction), (b) childhood picky eating (picky eating before age one and between ages one and five), and (c) infant gastrointestinal problems (vomiting and colic). Results revealed no significant differences in retrospective maternal report of childhood feeding and eating practices among AN subtypes.
PMCID: PMC3391535  PMID: 21830261
Anorexia Nervosa; Anorexia Nervosa Subtype; Feeding; Maternal Report; Infancy
17.  Genetic Association of Recovery from Eating Disorders: The Role of GABA Receptor SNPs 
Neuropsychopharmacology  2011;36(11):2222-2232.
Follow-up studies of eating disorders (EDs) suggest outcomes ranging from recovery to chronic illness or death, but predictors of outcome have not been consistently identified. We tested 5151 single-nucleotide polymorphisms (SNPs) in approximately 350 candidate genes for association with recovery from ED in 1878 women. Initial analyses focused on a strictly defined discovery cohort of women who were over age 25 years, carried a lifetime diagnosis of an ED, and for whom data were available regarding the presence (n=361 ongoing symptoms in the past year, ie, ‘ill') or absence (n=115 no symptoms in the past year, ie, ‘recovered') of ED symptoms. An intronic SNP (rs17536211) in GABRG1 showed the strongest statistical evidence of association (p=4.63 × 10−6, false discovery rate (FDR)=0.021, odds ratio (OR)=0.46). We replicated these findings in a more liberally defined cohort of women age 25 years or younger (n=464 ill, n=107 recovered; p=0.0336, OR=0.68; combined sample p=4.57 × 10−6, FDR=0.0049, OR=0.55). Enrichment analyses revealed that GABA (γ-aminobutyric acid) SNPs were over-represented among SNPs associated at p<0.05 in both the discovery (Z=3.64, p=0.0003) and combined cohorts (Z=2.07, p=0.0388). In follow-up phenomic association analyses with a third independent cohort (n=154 ED cases, n=677 controls), rs17536211 was associated with trait anxiety (p=0.049), suggesting a possible mechanism through which this variant may influence ED outcome. These findings could provide new insights into the development of more effective interventions for the most treatment-resistant patients.
PMCID: PMC3176559  PMID: 21750581
GABA; anorexia nervosa; recovery from eating disorders; genetic association; single nucleotide polymorphisms; eating/metabolic disorders; GABA; eating/metabolic disorders; neurogenetics; biological psychiatry; genetic association; anorexia nervosa; recovery from eating disorders; single-nucleotide polymorphisms; phenomic association
18.  Course of Subthreshold Bipolar Disorder in Youth: Diagnostic Progression From Bipolar Disorder Not Otherwise Specified 
To determine the rate of diagnostic conversion from an operationalized diagnosis of Bipolar Disorder Not Otherwise Specified (BP-NOS) to Bipolar I or Bipolar II Disorders (BP-I/II) in youth over prospective follow-up and to identify factors associated with conversion.
Subjects were 140 children and adolescents recruited from clinical referrals or advertisement who met operationalized criteria for BP-NOS at intake and participated in at least one follow-up evaluation (91% of initial cohort). Diagnoses were assessed at follow-up interviews using the Longitudinal Interval Follow-Up Evaluation. The mean duration of follow-up was 5 years and the mean interval between assessments was 8.2 months.
Diagnostic conversion to BP-I/II occurred in 63 subjects (45%): 32 (23%) to BP-I (9 of whom had initially converted to BP-II) and 31 to only BP-II (22%). Median time from intake to conversion was 58 weeks. First or second-degree family history of mania or hypomania was the strongest baseline predictor of diagnostic conversion (p=.006). Over follow-up, conversion was associated with greater intensity of hypomanic symptoms and with greater exposure to specialized, intensive outpatient psychosocial treatments. There was no association between conversion and exposure to treatment with particular medication classes.
Children and adolescents referred with mood symptoms that meet operationalized criteria for BP-NOS, particularly those with a family history of BP, frequently progress to BP-I or BP-II disorders. Efforts to identify these youth and effectively intervene may have the potential to curtail the progression of mood disorders in this high-risk population.
PMCID: PMC3185249  PMID: 21961775
Mood Disorders - Bipolar; Child Psychiatry; Adolescents; Diagnosis; Classification
19.  Post traumatic stress disorder in anorexia nervosa 
Psychosomatic medicine  2011;73(6):491-497.
Comorbidity among eating disorders, traumatic events, and post traumatic stress disorder (PTSD) has been reported in several studies. The main objectives of this study were to describe the nature of traumatic events experienced and to explore the relation between PTSD and anorexia nervosa (AN) in a sample of women.
Eight hundred twenty-four participants from the National Institutes of Health funded Genetics of Anorexia Nervosa Collaborative Study were assessed for eating disorders, PTSD, and personality characteristics.
From a final sample of 753 women with AN, 13.7% (n=103) met DSM-IV criteria for PTSD. The sample mean age was 29.5 years (SD=11.1). In pairwise comparisons across AN subtypes, the odds of having a PTSD diagnosis were significantly lower in individuals with restricting AN (RAN) than individuals with purging AN without binge eating (PAN) (OR=0.49, 95% CI=0.30, 0.80). The majority of participants with PTSD reported the first traumatic event before the onset of AN (64.1%, n=66). The most common traumatic events reported by those with a PTSD diagnosis were sexual related traumas during childhood (40.8%) and during adulthood (35.0%).
AN and PTSD do co-occur and traumatic events tend to occur prior to the onset of AN. Clinically, these results underscore the importance of assessing trauma history and PTSD in individuals with AN and raise the question of whether specific modifications or augmentations to standard treatment for AN should be considered in a subgroup to address PTSD-related psychopathology.
PMCID: PMC3132652  PMID: 21715295
PTSD; anorexia nervosa; trauma; prevalence; comorbid; epigenetic
20.  Association of Candidate Genes with Phenotypic Traits Relevant to Anorexia Nervosa 
European Eating Disorders Review  2011;19(6):487-493.
This analysis is a follow-up to an earlier investigation of 182 genes selected as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN). As those initial case-control results revealed no statistically significant differences in single nucleotide polymorphisms, herein we investigate alternative phenotypes associated with AN. In 1762 females using regression analyses we examined: (1) lowest illness-related attained body mass index; (2) age at menarche; (3) drive for thinness; (4) body dissatisfaction; (5) trait anxiety; (6) concern over mistakes; and (7) the anticipatory worry and pessimism vs. uninhibited optimism subscale of the harm avoidance scale. After controlling for multiple comparisons, no statistically significant results emerged. Although results must be viewed in the context of limitations of statistical power, the approach illustrates a means of potentially identifying genetic variants conferring susceptibility to AN because less complex phenotypes associated with AN are more proximal to the genotype and may be influenced by fewer genes.
PMCID: PMC3261131  PMID: 21780254
covariates; eating disorders; association studies; personality; genetic
21.  Treatment of Resistant Depression in Adolescents (TORDIA): Week 24 Outcomes 
The American Journal of Psychiatry  2010;167(7):782-791.
The purpose of this study was to report on the outcome of participants in the Treatment of Resistant Depression in Adolescents (TORDIA) trial after 24 weeks of treatment, including remission and relapse rates and predictors of treatment outcome.
Adolescents (ages 12–18 years) with selective serotonin reuptake inhibitor (SSRI)-resistant depression were randomly assigned to either a medication switch alone (alternate SSRI or venlafaxine) or a medication switch plus cognitive-behavioral therapy (CBT). At week 12, responders could continue in their assigned treatment arm and nonresponders received open treatment (medication and/or CBT) for 12 more weeks (24 weeks total). The primary outcomes were remission and relapse, defined by the Adolescent Longitudinal Interval Follow-Up Evaluation as rated by an independent evaluator.
Of 334 adolescents enrolled in the study, 38.9% achieved remission by 24 weeks, and initial treatment assignment did not affect rates of remission. Likelihood of remission was much higher (61.6% versus 18.3% ) and time to remission was much faster among those who had already demonstrated clinical response by week 12. Remission was also higher among those with lower baseline depression, hopelessness, and self-reported anxiety. At week 12, lower depression, hopelessness, anxiety, suicidal ideation, family conflict, and absence of comorbid dysthymia, anxiety, and drug/alcohol use and impairment also predicted remission. Of those who responded by week 12, 19.6% had a relapse of depression by week 24.
Continued treatment for depression among treatment-resistant adolescents results in remission in approximately one-third of patients, similar to adults. Eventual remission is evident within the first 6 weeks in many, suggesting that earlier intervention among non-responders could be important.
PMCID: PMC3257891  PMID: 20478877
22.  Specific common variants of the obesity-associated FTO gene are not associated with psychological and behavioral eating disorder phenotypes 
Extensive population-based genome-wide association studies have identified an association between the FTO gene and BMI; however, the mechanism of action is still unknown. To determine whether FTO may influence weight regulation through psychological and behavioral factors, seven single nucleotide polymorphisms (SNPs) of the FTO gene were genotyped in 1085 individuals with anorexia nervosa (AN) and 677 healthy weight controls from the international Price Foundation Genetic Studies of Eating Disorders. Each SNP was tested in association with eating disorder phenotypes and measures that have previously been associated with eating behavior pathology: trait anxiety, harm-avoidance, novelty seeking, impulsivity, obsessionality, compulsivity, and concern over mistakes. After appropriate correction for multiple comparisons, no significant associations between individual FTO gene SNPs and eating disorder phenotypes or related eating behavior pathology were identified in cases or controls. Thus, this study found no evidence that FTO gene variants associated with weight regulation in the general population are associated with eating disorder phenotypes in AN participants or matched controls.
PMCID: PMC3249222  PMID: 21438147
The Journal of clinical psychiatry  2010;71(10):1344-1350.
Anxiety disorders are among the most common comorbid conditions in youth with bipolar disorder (BP). We aimed to examine the prevalence and correlates of comorbid anxiety disorders among youth with BP.
As part of the Course and Outcome of Bipolar Youth study (COBY), 446 youth ages 7 to 17, who met DSM-IV criteria for BP-I (n=260), BP-II (n=32) or operationalized criteria for BP not otherwise specified (BP-NOS; n=154) were included. Subjects were evaluated for current and lifetime Axis-I psychiatric disorders at intake using the Schedule for Affective Disorders and Schizophrenia for School-Aged Children–Present and Lifetime version (K-SADS-PL), and standardized instruments to assess functioning and family history.
Forty-four percent (n=194) of the sample met DSM-IV criteria for at least one lifetime anxiety disorder, most commonly Separation Anxiety (24%) and Generalized Anxiety Disorders (16%). Nearly 20% met criteria for two or more anxiety disorders. Overall, anxiety disorders predated the onset of BP. BP-II subjects were more likely than BP-I or BP-NOS subjects to have a comorbid anxiety disorder. After adjusting for confounding factors, BP youth with anxiety were more likely to have BP-II, longer duration of mood symptoms, more severe ratings of depression, and family history of depression, hopelessness and somatic complaints during their worst lifetime depressive episode than those without anxiety.
Comorbid anxiety disorders are common in youth with BP, and most often predate BP onset. BP-II, a family history of depression, and more severe lifetime depressive episodes distinguish BP youth with comorbid anxiety disorders from those without. Careful consideration should be given to the assessment of comorbid anxiety in BP youth.
PMCID: PMC2978760  PMID: 20868643
Youth; anxiety; bipolar disorder; prevalence; clinical correlates
24.  Clinical and psychosocial correlates of non-suicidal self-injury within a sample of children and adolescents with bipolar disorder 
Journal of affective disorders  2010;125(1-3):89-97.
The purpose of this study is to examine the prevalence and correlates of non-suicidal self-injury (NSSI) among children and adolescents diagnosed with bipolar disorder (BP).
Four hundred-thirty two youth with a diagnosis of BP and their parents, including 193 children and 239 adolescents, completed a diagnostic interview and instruments to assess youth clinical and illness history, youth comorbidity, parental mood disorder, and psychosocial functioning.
Approximately 22% of children and 22% of adolescents reported NSSI during the course of their most recent mood episode. In a multivariate model controlling for global impairment, among children, a BPI or BPII diagnosis (versus BPNOS), psychosis, separation anxiety disorder, and greater severity of depressive symptoms were found to be associated with NSSI. Among adolescents, a mixed episode, a suicide attempt, greater severity of depressive symptoms, and poor psychosocial functioning were found to be associated with NSSI. Neither the presence of a youth comorbid disruptive behavior disorder nor a parental mood disorder was associated with NSSI.
The primary limitations of this study include the use of a cross-sectional study design, lack of a control group, and limited generalizability of study results to non-clinical and ethnically diverse samples.
NSSI is not uncommon among youth with BP, particularly those who present with BPI or BPII, psychosis, a mixed episode, suicidal behavior, severe depressive symptoms, separation anxiety, and/or poor psychosocial functioning. However, the relative importance of these factors in relation to NSSI may vary with age. Treatments for BP that are developmentally sensitive, examine the function of NSSI for each youth, and teach adaptive skills to address emotional and social needs, may prove to be most successful.
PMCID: PMC2888943  PMID: 20089313
Bipolar Disorder; Self-Injury; Suicide; Comorbidity; Psychosocial
25.  Life Beyond the Eating Disorder: Education, Relationships, and Reproduction 
We investigated sociodemographic characteristics in women with and without lifetime eating disorders.
Participants were from a multi-site international study of eating disorders (N = 2096). Education level, relationship status, and reproductive status were examined across eating disorder subtypes and compared with a healthy control group.
Overall, women with eating disorders were less educated than controls, and duration of illness and age of onset were associated with educational attainment. Menstrual status was associated with both relationship and reproductive status, but eating disorder subtypes did not differ significantly from each other or from healthy controls on these dimensions.
Differences in educational attainment, relationships, and reproduction do exist in individuals with eating disorders and are differentially associated with various eating disorder symptoms and characteristics. These data could assist with educating patients and family members about long-term consequences of eating disorders.
PMCID: PMC2888627  PMID: 20143323
Children; relationship; education; anorexia nervosa; bulimia nervosa; amenorrhea

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