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1.  Effects of Comorbid Anxiety Disorders on the Longitudinal Course of Pediatric Bipolar Disorders 
OBJECTIVE
To examine the longitudinal effects of comorbid anxiety disorders in youth with bipolar spectrum disorder (BP).
METHOD
As part of the Course and Outcome of Bipolar Youth study, 413 youth, ages 7 to 17 years who met criteria for DSM-IV BP-I (n=244), BP-II (n=28), and operationally defined bipolar disorder not otherwise specified (BP-NOS) (n=141) were included. Subjects were followed on average 5 years using the Longitudinal Interval Follow-up Evaluation. Effects of anxiety on the time to mood recovery and recurrence and percentage of time with syndromal and subsyndromal mood symptomatology during the follow-up period were analyzed.
RESULTS
At intake and during the follow-up, 62% of youth with BP met criteria for at least one anxiety disorder. About 50% of the BP youth with anxiety had ≥ 2 anxiety disorders. Compared to BP youth without anxiety, those with anxiety had significantly more depressive recurrences and significantly longer median time to recovery. The effects of anxiety on recovery disappeared when the severity of depression at intake was taken into account. After adjusting for confounding factors, BP youth with anxiety, particularly those with ≥ 2 anxiety disorders, spent significantly less follow-up time asymptomatic and more time with syndromal mixed/cycling and subsyndromal depressive symptomatology compared to those without anxiety.
CONCLUSIONS
Anxiety disorders are common and adversely affect the course of BP in youth, as characterized by more mood recurrences, longer time to recovery, less time euthymic, more time in mixed/cycling and depressive episodes. Prompt recognition and the development of treatments for BP youth with anxiety are warranted.
doi:10.1016/j.jaac.2013.09.020
PMCID: PMC3868011  PMID: 24342387
anxiety disorders; bipolar disorders; longitudinal study
2.  Primary Amenorrhea in Anorexia Nervosa: Impact on Characteristic Masculine and Feminine Traits 
Animal studies indicate gonadal hormones at puberty have an effect on the development of masculine and feminine traits. However, it is unknown whether similar processes occur in humans. We examined whether women with anorexia nervosa (AN), who often experience primary amenorrhea, exhibit attenuated feminization in their psychological characteristics in adulthood due to the decrease/absence of gonadal hormones at puberty. Women with AN were compared on a number of psychological characteristics using General Linear Models based on the presence/absence of primary amenorrhea. Although women with primary amenorrhea exhibited lower anxiety scores than those without primary amenorrhea, in general, results did not provide evidence of attenuated feminization in women with AN with primary amenorrhea. Future research should utilize novel techniques and direct hormone measurement to explore the effects of pubertal gonadal hormones on masculine and feminine traits.
doi:10.1002/erv.2263
PMCID: PMC4266542  PMID: 24123541
Organizational effects; sex differences; amenorrhea; pubertal timing; anorexia nervosa
3.  Predictors of First-Onset Substance Use Disorders During the Prospective Course of Bipolar Spectrum Disorders in Adolescents 
Objective
Substance use disorders (SUD) are common and problematic in bipolar disorder (BP). We prospectively examined predictors of first-onset SUD among adolescents with BP.
Method
Adolescents (12–17 years old; N=167) in the Course and Outcome of Bipolar Youth (COBY) study fulfilling criteria for BP-I, BP-II, or operationalized BP not otherwise specified, without SUD at intake, were included. Baseline demographic, clinical, and family history variables, and clinical variables assessed during follow-up, were examined in relation to first-onset SUD. Participants were prospectively interviewed every 38.5±22.2 weeks for an average of 4.25±2.11 years.
Results
First-onset SUD developed among 32% of subjects, after a mean of 2.7±2.0 years from intake. Lifetime alcohol experimentation at intake most robustly predicted first-onset SUD. Lifetime oppositional defiant disorder and panic disorder, family history of SUD, low family cohesiveness, and absence of antidepressant treatment at intake were also associated with increased risk of SUD, whereas BP subtype was not. Risk of SUD increased with increasing number of these six predictors: 54.7% of subjects with ≥3 predictors developed SUD vs. 14.1% of those with <3 predictors (Hazard Ratio 5.41 95% CI 2.7–11.0 p<0.0001). Greater hypo/manic symptom severity in the preceding 12 weeks predicted greater likelihood of SUD onset. Lithium exposure in the preceding 12 weeks predicted lower likelihood of SUD.
Conclusions
This study identifies several predictors of first-onset SUD in the COBY sample which, if replicated, may suggest targets of preventive interventions for SUD among youth with BP. Treatment-related findings are inconclusive and must be interpreted tentatively given the limitations of observational naturalistic treatment data. There is a substantial window of opportunity between BP and SUD onset during which preventive strategies may be employed.
doi:10.1016/j.jaac.2013.07.009
PMCID: PMC3787940  PMID: 24074469
bipolar; predictors; prevention; prospective; substance use disorder
4.  Longitudinal Trajectories and Associated Baseline Predictors in Youths With Bipolar Spectrum Disorders 
The American journal of psychiatry  2014;171(9):990-999.
Objective
The authors sought to identify and evaluate longitudinal mood trajectories and associated baseline predictors in youths with bipolar disorder.
Method
A total of 367 outpatient youths (mean age, 12.6 years) with bipolar disorder with at least 4 years of follow-up were included. After intake, participants were interviewed on average 10 times (SD=3.2) over a mean of 93 months (SD=8.3). Youths and parents were interviewed for psychopathology, functioning, treatment, and familial psychopathology and functioning.
Results
Latent class growth analysis showed four different longitudinal mood trajectories: “predominantly euthymic” (24.0%), “moderately euthymic” (34.6%), “ill with improving course” (19.1%), and “predominantly ill” (22.3%). Within each class, youths were euthymic on average 84.4%, 47.3%, 42.8%, and 11.5% of the follow-up time, respectively. Multivariate analyses showed that better course was associated with higher age at onset of mood symptoms, less lifetime family history of bipolar disorder and substance abuse, and less history at baseline of severe depression, manic symptoms, suicidality, subsyndromal mood episodes, and sexual abuse. Most of these factors were more noticeable in the “predominantly euthymic” class. The effects of age at onset were attenuated in youths with lower socioeconomic status, and the effects of depression severity were absent in those with the highest socioeconomic status.
Conclusions
A substantial proportion of youths with bipolar disorder, especially those with adolescent onset and the above-noted factors, appear to be euthymic over extended periods. Nonetheless, continued syndromal and subsyndromal mood symptoms in all four classes underscore the need to optimize treatment.
doi:10.1176/appi.ajp.2014.13121577
PMCID: PMC4164021  PMID: 24874203
5.  Factors Associated With Recovery from Anorexia Nervosa 
Journal of psychiatric research  2013;47(7):972-979.
Previous studies of prognostic factors of anorexia nervosa (AN) course and recovery have followed clinical populations after treatment discharge. This retrospective study examined the association between prognostic factors—eating disorder features, personality traits, and psychiatric comorbidity—and likelihood of recovery in a large sample of women with AN participating in a multi-site genetic study. The study included 680 women with AN. Recovery was defined as the offset of AN symptoms if the participant experienced at least one year without any eating disorder symptoms of low weight, dieting, binge eating, and inappropriate compensatory behaviors. Participants completed a structured interview about eating disorders features, psychiatric comorbidity, and self-report measures of personality. Survival analysis was applied to model time to recovery from AN. Cox regression models were used to fit associations between predictors and the probability of recovery. In the final model, likelihood of recovery was significantly predicted by the following prognostic factors: vomiting, impulsivity, and trait anxiety. Self-induced vomiting and greater trait anxiety were negative prognostic factors and predicted lower likelihood of recovery. Greater impulsivity was a positive prognostic factor and predicted greater likelihood of recovery. There was a significant interaction between impulsivity and time; the association between impulsivity and likelihood of recovery decreased as duration of AN increased. The anxiolytic function of some AN behaviors may impede recovery for individuals with greater trait anxiety.
doi:10.1016/j.jpsychires.2013.02.011
PMCID: PMC3682792  PMID: 23535032
Eating disorders; anorexia nervosa; recovery; prognostic factors; personality; comorbidity
6.  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.
Background
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.
Methods
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.
Results
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
Limitations include reliance on retrospective parent report and potential issues with generalizability.
Conclusions
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.
doi:10.1016/j.jad.2012.06.024
PMCID: PMC3535567  PMID: 23021377
pediatric bipolar disorder; course; onset
7.  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.
doi:10.1016/j.addbeh.2012.10.005
PMCID: PMC3558554  PMID: 23254222
anorexia nervosa; alcohol use disorder; comorbidity; age of onset
8.  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.
Objectives
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/01.pra.0000438185.81983.8b
PMCID: PMC3885866  PMID: 24241500
bipolar disorder; longitudinal studies; treatment use; transition-age youth; children; adolescents
9.  EARLY CHILDHOOD PEREFCTIONISM 
Objective
To examine childhood perfectionism in anorexia nervosa (AN) restricting (RAN), purging (PAN), and binge eating with or without purging (BAN) subtypes.
Method
The EATATE, a retrospective assessment of childhood perfectionism, and the Eating Disorder Inventory (EDI-2) were administered to 728 AN participants.
Results
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.
Discussion
Global Childhood Rigidity was the predominate feature that preceded all AN subtypes. This may be a risk factor for AN.
doi:10.1002/eat.22019
PMCID: PMC3418385  PMID: 22488115
10.  The Genetics of Anorexia Nervosa Collaborative Study: Methods and Sample Description 
Objective
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).
Method
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.
Results
We report attributes of the first 200 families, comprising 200 probands and 232 affected relatives.
Conclusion
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.
doi:10.1002/eat.20509
PMCID: PMC3755506  PMID: 18236451
anorexia nervosa; eating disorders; bulimia nervosa; psychiatric disorders; genetics; linkage analysis; genomics
11.  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.
Objective
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.
Method
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.
Results
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.
Conclusions
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.
doi:10.4088/JCP.12m07874
PMCID: PMC3600607  PMID: 23419232
12.  History of suicide attempts in pediatric bipolar disorder: factors associated with increased risk 
Bipolar disorders  2005;7(6):525-535.
Background
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.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1399-5618.2005.00263.x
PMCID: PMC3679347  PMID: 16403178
pediatric bipolar disorder; risk factors; suicide; suicide attempt
13.  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.
Context
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.
Objective
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.
Design
Randomized controlled trial.
Setting
Six US academic and community clinics.
Patients
Three hundred thirty-four patients aged 12 to 18 years with SSRI-resistant depression.
Intervention
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.
Results
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.
Conclusions
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.
doi:10.1001/archgenpsychiatry.2011.9
PMCID: PMC3679348  PMID: 21383263
14.  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.
doi:10.1002/jclp.20770
PMCID: PMC3664303  PMID: 21365638
eating disorders; trichotillomania; hair-pulling; anorexia nervosa; bulimia nervosa; impulsivity; compulsivity
15.  Understanding the Association of Impulsivity, Obsessions, and Compulsions with Binge Eating and Purging Behaviors in Anorexia Nervosa 
Objective
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.
Methods
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).
Results
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.
Conclusion
Our results suggest that purging, compared with binge eating, may be a stronger correlate of impulsivity, obsessions, and compulsions in AN.
doi:10.1002/erv.2161
PMCID: PMC3443865  PMID: 22351620
anorexia nervosa; impulsivity; compulsivity; binge eating; purging
16.  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.
doi:10.1097/JCP.0b013e318204b117
PMCID: PMC3603695  PMID: 21192150
major depressive disorder; adolescents; plasma concentration; drug exposure; optimization
17.  Factors associated with mental health service utilization among bipolar youth 
Bipolar disorders  2007;9(8):839-850.
Objectives
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1399-5618.2007.00439.x
PMCID: PMC3600857  PMID: 18076533
adolescence; bipolar disorder; childhood; service utilization
18.  Factors Associated With the Persistence and Onset of New Anxiety Disorders in Youth With Bipolar Spectrum Disorders 
Objective
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.
Method
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.
Results
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)
Conclusions
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.
doi:10.4088/JCP.10m06720
PMCID: PMC3600866  PMID: 22226375
19.  Predictors of Prospectively Examined Suicide Attempts Among Youth With Bipolar Disorder 
Archives of general psychiatry  2012;69(11):1113-1122.
Context
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.
Objective
To examine past, intake, and follow-up predictors of prospectively observed suicide attempts among youth with bipolar disorder.
Design
We interviewed subjects, on average, every 9 months over a mean of 5 years using the Longitudinal Interval Follow-up Evaluation.
Setting
Outpatient and inpatient units at 3 university centers.
Participants
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.
Results
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.
Conclusions
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.
doi:10.1001/archgenpsychiatry.2012.650
PMCID: PMC3600896  PMID: 22752079
20.  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.
Objective
The authors sought to identify predictors of self-harm adverse events in treatment-resistant, depressed adolescents during the first 12 weeks of treatment.
Method
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.
Results
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.
Conclusions
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.
doi:10.1176/appi.ajp.2008.08070976
PMCID: PMC3593721  PMID: 19223438
21.  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.
doi:10.1002/erv.1153
PMCID: PMC3391535  PMID: 21830261
Anorexia Nervosa; Anorexia Nervosa Subtype; Feeding; Maternal Report; Infancy
22.  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.
doi:10.1038/npp.2011.108
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
23.  Course of Subthreshold Bipolar Disorder in Youth: Diagnostic Progression From Bipolar Disorder Not Otherwise Specified 
Objective
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.
Method
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jaac.2011.07.005
PMCID: PMC3185249  PMID: 21961775
Mood Disorders - Bipolar; Child Psychiatry; Adolescents; Diagnosis; Classification
24.  Post traumatic stress disorder in anorexia nervosa 
Psychosomatic medicine  2011;73(6):491-497.
Objective
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.
Methods
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.
Results
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%).
Conclusions
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.
doi:10.1097/PSY.0b013e31822232bb
PMCID: PMC3132652  PMID: 21715295
PTSD; anorexia nervosa; trauma; prevalence; comorbid; epigenetic
25.  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.
doi:10.1002/erv.1138
PMCID: PMC3261131  PMID: 21780254
covariates; eating disorders; association studies; personality; genetic

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