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1.  Behavioral and Psychophysiological Responsiveness During Child Feeding in Mothers with Histories of Eating Disorders: A Pilot Study 
The aim of this pilot project was to describe maternal responsiveness during child feeding in mothers with eating disorder histories through the combined use of observational, self-report, and physiologic methods. For this non-randomized cohort pilot study, 25 mothers with histories of eating disorders and 25 mothers with no history of an eating disorder with children ages 6–36 months were selected such that the groups were similar based on child age group (within 6 months) and child sex. Maternal behavioral responsiveness to child cues was assessed by video-recording and behavioral coding of both a free-play and feeding episode. Physiologic engagement was assessed through measurement of respiratory sinus arrhythmia (RSA) reactivity during free-play and feeding episodes. No differences were detected in observed behavioral responsiveness during feeding or free-play in mothers with eating disorder histories compared with controls. Mothers with eating disorder histories did report more parenting stress, increased anxiety, and exhibited a blunted physiologic stress response (less RSA reactivity) during both feeding and free-play interactions with their children. These results support future larger-scale investigations of RSA reactivity in mothers with eating disorders.
doi:10.1007/s10862-013-9357-2
PMCID: PMC3913224  PMID: 24511180
eating disorders; mothers; feeding behavior; maternal responsiveness; RSA reactivity; infant feeding
2.  Effectiveness of Paliperidone Palmitate vs. Haloperidol Decanoate for Maintenance Treatment of Schizophrenia: A Randomized Clinical Trial 
Importance
Long-acting injectable (LAI) antipsychotics are used to reduce medication non-adherence and subsequent relapse in schizophrenia-spectrum disorders. The relative effectiveness of LAI versions of second-generation (atypical) and older antipsychotics has not been assessed.
Objective
To compare the effectiveness of the second-generation LAI antipsychotic paliperidone palmitate (PP) to the older LAI antipsychotic haloperidol decanoate (HD).
Design, Setting, and Participants
Multisite, double-blind, randomized clinical trial conducted at 22 clinical research sites in the U.S. The 311 randomized patients (PP=157, HD=154) were adults diagnosed with schizophrenia or schizoaffective disorder who were clinically assessed to be at risk of relapse and likely to benefit from a LAI antipsychotic.
Interventions
Intramuscular injections of HD 25–200 mg or PP 39–234 mg every month for up to 24 months.
Main Outcome Measures
Efficacy failure, which reflected inadequate control of psychopathology by the study medication, as determined by a blinded adjudication committee. Key secondary outcomes were common adverse effects of antipsychotic medications.
Results
There was no statistically significant difference in the rate of efficacy failure for PP compared to HD (adjusted hazard ratio 0.98, 95% confidence interval [CI] 0.65–1.47). On average, patients on PP gained and those on HD lost weight; after six months the least squares mean weight change on PP was +2.17 kg (1.25 to 3.09) and on HD was −0.96 kg (−1.88 to −0.04). Patients taking PP had significantly greater increases in serum prolactin (men 34.56 µg/L (29.75 to 39.37) vs. 15.41 (10.73 to 20.08), p<0.001; women 75.19 (63.03 to 87.36) vs. 26.84 (13.29 to 40.40), p<0.001). Patients taking HD had significantly larger increases in global ratings of akathisia (0.73 [0.59 to 0.87] vs. 0.45 [0.31 to 0.59], p=0.006).
Conclusions and Relevance
Among adults with schizophrenia or schizoaffective disorder, treatment with paliperidone palmitate compared with haloperidol decanoate did not result in a statistically significant difference in efficacy failure, but was associated with more weight gain and greater increases in serum prolactin, whereas haloperidol was associated with more akathisia. However, based on the 95% confidence limits, a clinically meaningful difference in efficacy failure between treatments cannot be ruled out.
Trial Registration
clinicaltrials.gov identifier NCT01136772
doi:10.1001/jama.2014.4310
PMCID: PMC4101890  PMID: 24846035
3.  Remission, continuation, and incidence of eating disorders during early pregnancy: A validation study on a population-based birth cohort 
Psychological medicine  2012;43(8):1723-1734.
Background
The objective of this study was to validate previously published rates of remission, continuation, and incidence of broadly defined eating disorders during pregnancy. The previous rate modeling was done by our group (Bulik et al. 2007) and yielded participants halfway into recruitment of the planned 100,000 pregnancies in the Norwegian Mother and Child (MoBa) Cohort at the Norwegian Institute of Public Health. This study aimed to internally validate the findings with the completed cohort.
Methods
77267 pregnant women enrolled at 17 weeks gestation between 2001 and 2009 were included. Participants were split into a “training” sample (n=41243) based on participants in the MoBa version 2 dataset of the original study and a “validation” sample (n=36024) comprising individuals in the MoBa version 5 dataset that were not in the original study (Bulik et al. 2007). Internal validation of all original rate models involved fitting a calibration model to compare model parameters between the “training” and “validation” samples as well as bootstrap estimates of bias in the entire version 5 dataset.
Results
Remission, continuation, and incidence estimates from the “training” sample remained stable when evaluated via a split sample validation procedure. Pre-pregnancy prevalence estimates in the “validation” sample were 0.1% for anorexia nervosa, 1.0% for bulimia nervosa (BN), 3.3% for binge eating disorder (BED), and 0.1% for purging disorder (EDNOS-P). In early pregnancy, estimates were 0.2% for BN, 4.8% for BED, and <0.01% for EDNOS-P. Consistent with the original study, incident BN and EDNOS-P during pregnancy were rare. For BED, the adjusted incidence rate in the “validation” sample was 1.17 per 1000 person-weeks. The highest rates were for full or partial remission for BN and EDNOS-P, and continuation for BED.
Conclusions
This study provides evidence of validity of previously estimated rates of remission, continuation, and incidence of eating disorders during pregnancy. Eating disorders during pregnancy were relatively common, occurring in nearly 1 in every 20 women, although almost all were cases of BED. Pregnancy was a window of remission from BN but a window of vulnerability for onset and continuation of BED. Training to detect the signs and symptoms of eating disorders by obstetricians/gynecologists and interventions to enhance pregnancy and neonatal outcomes warrant attention.
doi:10.1017/S0033291712002516
PMCID: PMC4206832  PMID: 23164164
Eating disorders; epidemiology; incidence; pregnancy; prospective; remission; The Norwegian Mother and Child Cohort Study
4.  Metformin for Weight Loss and Metabolic Control in Overweight Outpatients With Schizophrenia and Schizoaffective Disorder 
The American journal of psychiatry  2013;170(9):10.1176/appi.ajp.2013.12010127.
Objective
The purpose of this study was to determine whether metformin promotes weight loss in overweight out-patients with chronic schizophrenia or schizoaffective disorder.
Method
In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16.
Results
Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was −3.0 kg (95% CI=−4.0 to −2.0) for the metformin group and −1.0 kg (95% CI= −2.0 to 0.0) for the placebo group, with a between-group difference of −2.0 kg (95% CI=−3.4 to −0.6). Metformin also demonstrated a significant between-group advantage for BMI (−0.7; 95% CI=−1.1 to −0.2), triglyceride level (−20.2 mg/dL; 95% CI=−39.2 to −1.3), and hemoglobin A1c level (−0.07%; 95% CI=−0.14 to −0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation.
Conclusions
Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia.
doi:10.1176/appi.ajp.2013.12010127
PMCID: PMC3874085  PMID: 23846733
5.  NURTURE: Development and Pilot Testing of a Novel Parenting Intervention for Mothers with Histories of an Eating Disorder 
Objective
To describe the treatment development and pilot testing of a group parenting intervention, NURTURE (Networking, Uniting, and Reaching out To Upgrade Relationships and Eating), for mothers with histories of eating disorders.
Method
Based on focus group findings, extant research, and expert opinion, NURTURE was designed to be delivered weekly over 16 (1.5 hour) sessions via an interactive web conferencing forum. It comprises four modules: 1) laying the foundation, 2) general parenting skills, 3) eating and feeding, and 4) breaking the cycle of risk. Pilot testing was conducted with three groups of 3–6 mothers (N = 13) who had children ages 0–3 years to determine feasibility (e.g., retention), acceptability (e.g., feedback questionnaire responses), and preliminary efficacy. Maternal satisfaction with NURTURE and changes in mother-child feeding relationship measures, maternal feeding style, maternal self-efficacy, and maternal psychopathology (eating disorder, depression, and anxiety symptoms) across three time points (baseline, post-treatment, 6-month follow-up) were examined. All outcomes were exploratory.
Results
The intervention was well tolerated with a 100% retention rate. Feedback from mothers was generally positive and indicated that the groups provided an engaging, supportive experience to participants. We observed changes suggestive of improvement in self-reported maternal self-efficacy and competence with parenting. There were no notable changes in measures of maternal feeding style or psychopathology.
Discussion
NURTURE is a feasible, acceptable, and potentially valuable intervention for mothers with eating disorder histories. Results of this pilot will inform a larger randomized-controlled intervention to determine efficacy and impact on child outcomes.
doi:10.1002/eat.22178
PMCID: PMC4009482  PMID: 23983082
6.  Effects of switching from olanzapine, quetiapine, and risperidone to aripiprazole on 10-year coronary heart disease risk and metabolic syndrome status: Results from a randomized controlled trial 
Schizophrenia research  2013;146(0):190-195.
Purpose
This study examined the clinical significance of switching from olanzapine, quetiapine, or risperidone to aripiprazole by examining changes in predicted risk of cardiovascular disease (CVD) according to the Framingham Risk Score (FRS) and metabolic syndrome status. FRS estimates 10-year risk of “hard” coronary heart disease (CHD) outcomes (myocardial infarction and coronary death) while metabolic syndrome is associated with increased risk of CVD, stroke, and diabetes mellitus.
Method
Changes in FRS and metabolic syndrome status were compared between patients with BMI ≥ 27 and non-HDL-C ≥ 130 mg/dL randomly assigned to stay on stable current treatment (olanzapine, quetiapine, or risperidone) or switch to treatment with aripiprazole with 24 weeks of follow-up. All study participants were enrolled in a behavioral program that promoted healthy diet and exercise.
Results
The pre-specified analyses included 89 switchers and 98 stayers who had post-baseline measurements needed to assess changes. Least squares mean estimates of 10-year CHD risk decreased more for the switch (from 7.0% to 5.2%) than the stay group (from 7.4% to 6.4%) (p=0.0429). The odds ratio for having metabolic syndrome (stay vs. switch) at the last observation was 1.748 (95% CI 0.919, 3.324, p=0.0885).
Conclusion
Switching from olanzapine, quetiapine, or risperidone to aripiprazole was associated with larger reductions in predicted 10-year risk of CHD than the behavioral program alone. The advantage of switching on metabolic syndrome was not statistically significant. The benefits of switching must be balanced against its risks, which in this study included more discontinuations of the study treatment but no significant increase in symptoms or hospitalizations.
doi:10.1016/j.schres.2013.01.013
PMCID: PMC3622801  PMID: 23434503
Antipsychotics; Metabolic side effects; Randomized clinical trial
7.  Promoviendo una Alimentación Saludable (PAS) Design and Methods: Engaging Latino Families in Eating Disorder Treatment 
Contemporary clinical trials  2013;35(1):52-61.
The use of culturally sensitive intervention could improve mental health care for the eating disorders treatment in the Latino population. The aim of this report is to describe the rationale, design, and methods of the ongoing study entitled “Engaging Latino families in eating disorders treatment.” The primary aim of the study is to compare (a) the combined effect of individual cognitive behavioral therapy for bulimia nervosa (CBT-BN) that has been previously adapted for the Latino population plus Family Enhanced (FE) modules, with (b) the standard adapted individual CBT-BN in a proof-of-principle study with 40 Latina adults with eating disorders and one relative or significant other per patient. We hypothesize that 1) the feasibility, acceptability, and adherence of participants in CBT-BN+ FE will be superior to individual CBT-BN only; 2) relatives in CBT-BN+ FE will report greater treatment satisfaction, greater reduction in family conflict, and greater decreases in caregiver burden than relatives in the individual CBT-BN only condition; and 3) patients who participate in CBT-BN+ FE will show trends towards greater decreases in ED symptoms compared with patients in CBT-BN only; although power will be limited to detect this difference. However, we predict that they will show greater retention in treatment, greater treatment satisfaction, and greater decreases in family conflict than patients in CBT-BN only. The completion of this investigation will yield important information regarding the acceptability and feasibility of a culturally sensitive evidence-based treatment model for Latinos with eating disorders. (Word Count=240)
doi:10.1016/j.cct.2013.01.005
PMCID: PMC3640683  PMID: 23376815
Latinas; Eating disorders; Cultural adaptation; Family intervention; Clinical trial; Cognitive-behavioral therapy
8.  A prospective study of perinatal depression and trauma history in pregnant minority adolescents 
OBJECTIVE
Adolescent pregnancy is common and minority adolescents are at high risk. We sought the following: (1) to prospectively assess prevalence of antenatal depression (AND) and postpartum depression (PPD) in minority adolescents and (2) to examine the association of social support and adjustment, trauma, and stress on depression status.
STUDY DESIGN
A total of 212 pregnant adolescents were recruited from public prenatal clinics and administered a prospective research survey during pregnancy and 6 weeks postpartum. Depression was measured using the Edinburgh Postnatal Depression Scale. Univariate, bivariate, and multivariable analyses were performed using logistic regression to assess predictors of AND and PPD.
RESULTS
In our cohort, 20% screened positive for AND and 10% for PPD. The strongest predictor of PPD was AND (odds ratio [OR], 4.89; P < .001). Among adolescents with trauma history, there was a 5-fold increase (OR, 5.01) in the odds of AND and a 4-fold increase (OR, 3.76) in the odds of PPD. AND was associated with the adolescent’s poor social adjustment (P < .001), perceived maternal stress (P < .001), less social support (P < .001), and a less positive view of pregnancy (P < .001). PPD was significantly associated with primiparity (P = .002), poor social adjustment (P < .001), less social support and involvement of the baby’s father (P < .001), and less positive view of pregnancy (P < .001).
CONCLUSION
Significant independent risk factors for PPD include AND, view of pregnancy, and social support. Trauma history was highly prevalent and strongly predicted AND and PPD. Point prevalence decreased postpartum, and this may be due to transient increased social support following the birth, warranting longer follow-up and development of appropriate interventions in future work.
doi:10.1016/j.ajog.2012.12.020
PMCID: PMC3762981  PMID: 23246315
adolescents; perinatal depression; postpartum depression; pregnancy; trauma
9.  Longitudinal Development of Cortical and Subcortical Gray Matter from Birth to 2 Years 
Cerebral Cortex (New York, NY)  2011;22(11):2478-2485.
Very little is known about cortical development in the first years of life, a time of rapid cognitive development and risk for neurodevelopmental disorders. We studied regional cortical and subcortical gray matter volume growth in a group of 72 children who underwent magnetic resonance scanning after birth and at ages 1 and 2 years using a novel longitudinal registration/parcellation approach. Overall, cortical gray matter volumes increased substantially (106%) in the first year of life and less so in the second year (18%). We found marked regional differences in developmental rates, with primary motor and sensory cortices growing slower in the first year of life with association cortices growing more rapidly. In the second year of life, primary sensory regions continued to grow more slowly, while frontal and parietal regions developed relatively more quickly. The hippocampus grew less than other subcortical structures such as the amygdala and thalamus in the first year of life. It is likely that these patterns of regional gray matter growth reflect maturation and development of underlying function, as they are consistent with cognitive and functional development in the first years of life.
doi:10.1093/cercor/bhr327
PMCID: PMC3464410  PMID: 22109543
amygdala; cerebral cortex; hippocampus; lateral ventricle; magnetic resonace imaging
10.  CBT4BN versus CBTF2F: Comparison of Online versus Face-To-FaceTreatment for Bulimia Nervosa 
Contemporary clinical trials  2012;33(5):1056-1064.
Cognitive-behavioral therapy (CBT) is currently the “gold standard” for treatment of bulimia nervosa (BN), and is effective for approximately 40–60% of individuals receiving treatment; however, the majority of individuals in need of care do not have access to CBT. New strategies for service delivery of CBT and for maximizing maintenance of treatment benefits are critical for improving our ability to treat BN. This clinical trial is comparing an Internet-based version of CBT (CBT4BN) in which group intervention is conducted via therapeutic chat group with traditional group CBT (CBTF2F) for BN conducted via face-to-face therapy group. The purpose of the trial is to determine whether manualized CBT delivered via the Internet is not inferior to the gold standard of manualized group CBT. In this two-site randomized controlled trial, powered for non-inferiority analyses, 180 individuals with BN are being randomized to either CBT4BN or CBTF2F. We hypothesize that CBT4BN will not be inferior to CBTF2F and that participants will value the convenience of an online intervention. If not inferior, CBT4BN may be a cost-effective approach to service delivery for individuals requiring treatment for BN.
doi:10.1016/j.cct.2012.05.008
PMCID: PMC3408767  PMID: 22659072
11.  Feasibility and Pilot Efficacy Results from the Multi-site Cognitive Remediation in the Schizophrenia Trials Network (CRSTN) Study 
The Journal of clinical psychiatry  2012;73(7):1016-1022.
Background
The true benefit of pharmacological intervention to improve cognition in schizophrenia may not be evident without regular cognitive enrichment. Clinical trials assessing the neurocognitive effects of new medications may require engagement in cognitive remediation exercises to stimulate the benefit potential. However, the feasibility of large-scale multi-site studies using cognitive remediation at clinical trials sites has not been established.
Methods
Patients with DSM-IV schizophrenia from nine sites were randomized to a cognitive remediation condition that included the Posit Science Brain Fitness auditory training program with weekly NEAR ‘bridging groups,’ or a control condition of computer games and weekly healthy lifestyles groups. Patients were expected to complete 3–5 one-hour sessions weekly for 40 sessions or 12 weeks, whichever came first.
Results
The primary outcomes were feasibility results as measured by rate of enrollment, retention, and completion rate of primary outcome measures. Within the 3-month enrollment period, 53 of a projected 54 patients were enrolled and 47 completed the study. Thirty-one patients completed all 40 sessions and all patients completed all primary outcome measures. Preliminary efficacy results indicated that after 20 sessions, patients in the cognitive remediation condition demonstrated mean MCCB composite score improvements that were 3.7 (95% CI: 7.34, 0.05) T-score points greater than in patients in the computer games control group (F=4.16, df=1,46, p=0.047). At the end of treatment, a trend favoring cognitive remediation was not statistically significant (F=2.26, df=1,47, p=0.14).
Discussion
Multi-site clinical trials of cognitive remediation using the Posit Science auditory training program with the NEAR method of weekly bridging groups in traditional clinical sites appear feasible.
doi:10.4088/JCP.11m07100
PMCID: PMC3746329  PMID: 22687548
12.  Improving metabolic parameters of antipsychotic child treatment (IMPACT) study: rationale, design, and methods 
Background
Youth with serious mental illness may experience improved psychiatric stability with second generation antipsychotic (SGA) medication treatment, but unfortunately may also experience unhealthy weight gain adverse events. Research on weight loss strategies for youth who require ongoing antipsychotic treatment is quite limited. The purpose of this paper is to present the design, methods, and rationale of the Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) study, a federally funded, randomized trial comparing two pharmacologic strategies against a control condition to manage SGA-related weight gain.
Methods
The design and methodology considerations of the IMPACT trial are described and embedded in a description of health risks associated with antipsychotic-related weight gain and the limitations of currently available research.
Results
The IMPACT study is a 4-site, six month, randomized, open-label, clinical trial of overweight/obese youth ages 8–19 years with pediatric schizophrenia-spectrum and bipolar-spectrum disorders, psychotic or non-psychotic major depressive disorder, or irritability associated with autistic disorder. Youth who have experienced clinically significant weight gain during antipsychotic treatment in the past 3 years are randomized to either (1) switch antipsychotic plus healthy lifestyle education (HLE); (2) add metformin plus HLE; or (3) HLE with no medication change. The primary aim is to compare weight change (body mass index z-scores) for each pharmacologic intervention with the control condition. Key secondary assessments include percentage body fat, insulin resistance, lipid profile, psychiatric symptom stability (monitored independently by the pharmacotherapist and a blinded evaluator), and all-cause and specific cause discontinuation. This study is ongoing, and the targeted sample size is 132 youth.
Conclusion
Antipsychotic-related weight gain is an important public health issue for youth requiring ongoing antipsychotic treatment to maintain psychiatric stability. The IMPACT study provides a model for pediatric research on adverse event management using state-of-the art methods. The results of this study will provide needed data on risks and benefits of two pharmacologic interventions that are already being used in pediatric clinical settings but that have not yet been compared directly in randomized trials.
Trial registration
Clinical Trials.gov NCT00806234
doi:10.1186/1753-2000-7-31
PMCID: PMC3846140  PMID: 23947389
13.  Plasma, Salivary, and Urinary Oxytocin in Anorexia Nervosa: A Pilot Study 
Eating Behaviors  2012;13(3):256-259.
While oxytocin (OT) has the potential to be an informative biomarker of social functioning in patients with eating disorders, the burden of invasive blood draws or lumbar punctures limits OT study. Salivary and urinary OT measurements may be advantageous, as they require less invasive sampling techniques which could be conducted in a wider variety of settings. Yet, the degree to which the concentration of OT in these fluids is correlated with blood levels is uncertain, as is the impact of vomiting on salivary secretion of OT. Therefore, we compared contemporaneously sampled OT concentration in blood, saliva, and urine from twenty women acutely ill with anorexia nervosa. Salivary OT was positively correlated with plasma OT in patients with no history of self-induced vomiting(r=0.89), but correlation was lower in those with recent history of self-induced vomiting(r=0.42). Urinary and plasma OT were not well-correlated(r=0.13), suggesting preliminarily that collection of plasma OT remains the method of choice. Self-induced vomiting in eating disorders may limit the applicability of salivary sampling for OT.
doi:10.1016/j.eatbeh.2012.02.004
PMCID: PMC3368224  PMID: 22664406
oxytocin; plasma; saliva; urine; eating disorder; self-induced vomiting
14.  Prenatal Isolated Mild Ventriculomegaly is Associated with Persistent Ventricle Enlargement at Ages 1 and 2 
Early Human Development  2012;88(8):691-698.
Background
Enlargement of the lateral ventricles is thought to originate from abnormal prenatal brain development and is associated with neurodevelopmental disorders. Fetal isolated mild ventriculomegaly (MVM) is associated with enlargement of lateral ventricle volumes in the neonatal period and developmental delays in early childhood. However, little is known about postnatal brain development in these children.
Methods
Twenty-eight children with fetal isolated MVM and 56 matched controls were followed at ages 1 and 2 years with structural imaging on a 3T Siemens scanner and assessment of cognitive development with the Mullen Scales of Early Learning. Lateral ventricle, total gray and white matter volumes, and Mullen cognitive composite scores and subscale scores were compared between groups.
Results
Compared to controls, children with prenatal isolated MVM had significantly larger lateral ventricle volumes at ages 1 and 2 years. Lateral ventricle volume at 1 and 2 years of age was significantly correlated with prenatal ventricle size. Enlargement of the lateral ventricles was associated with increased intracranial volumes and increased gray and white matter volumes. Children with MVM had Mullen composite scores similar to controls, although there was evidence of delay in fine motor and expressive language skills.
Conclusions
Children with prenatal MVM have persistent enlargement of the lateral ventricles through the age of 2 years; this enlargement is associated with increased gray and white matter volumes and some evidence of delay in fine motor and expressive language development. Further study is needed to determine if enlarged lateral ventricles are associated with increased risk for neurodevelopmental disorders.
doi:10.1016/j.earlhumdev.2012.02.003
PMCID: PMC3386468  PMID: 22445211
magnetic resonance imaging; ultrasound; gray matter; white matter; cognitive development
15.  Neurocognitive Outcomes in the Treatment of Early-Onset Schizophrenia Spectrum Disorders Study 
Objective
To assess neurocognitive outcomes following antipsychotic intervention in youth enrolled in the National Institute of Mental Health (NIMH)-funded Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS).
Method
Neurocognitive functioning of youth (ages 8–19 years) with schizophrenia or schizoaffective disorder was evaluated in a four-site randomized, double-blind clinical trial comparing molindone, olanzapine or risperidone. The primary outcomes were overall group change from baseline in neurocognitive composite and six domain scores after 8 weeks and continued treatment up to 52 weeks. Age and sex were included as covariates in all analyses.
Results
Seventy-seven of 116 TEOSS participants (66%) had post-baseline neurocognitive data. No significant differences emerged in the neurocognitive outcomes of the three medication groups. Therefore, the three treatment groups were combined into one group to assess overall neurocognitive outcomes. Significant modest improvements were observed in the composite score and in three of six domain scores in the acute phase, and in four of six domain scores in the combined acute and maintenance phases. Partial correlation analyses revealed very few relationships among Positive and Negative Syndrome Scale (PANSS) baseline or change scores and neurocognition change scores.
Conclusions
Antipsychotic intervention in youth with early-onset schizophrenia spectrum disorders (EOSS) led to modest improvement in measures of neurocognitive function. The changes in cognition were largely unrelated to baseline symptoms or symptom change. Small treatment effect sizes, easily accounted for by practice effects, highlight the critical need for the development of more efficacious interventions for the enduring neurocognitive deficits seen in EOSS.
doi:10.1016/j.jaac.2012.02.001
PMCID: PMC3337647  PMID: 22525956
early-onset; schizophrenia; neurocognition; outcomes; antipsychotics
16.  Lateral ventricle morphology analysis via mean latitude axis 
Statistical shape analysis has emerged as an insightful method for evaluating brain structures in neuroimaging studies, however most shape frameworks are surface based and thus directly depend on the quality of surface alignment. In contrast, medial descriptions employ thickness information as alignment-independent shape metric. We propose a joint framework that computes local medial thickness information via a mean latitude axis from the well-known spherical harmonic (SPHARM-PDM) shape framework. In this work, we applied SPHARM derived medial representations to the morphological analysis of lateral ventricles in neonates. Mild ventriculomegaly (MVM) subjects are compared to healthy controls to highlight the potential of the methodology. Lateral ventricles were obtained from MRI scans of neonates (9–144 days of age) from 30 MVM subjects as well as age- and sex-matched normal controls (60 total). SPHARM-PDM shape analysis was extended to compute a mean latitude axis directly from the spherical parameterization. Local thickness and area was straightforwardly determined. MVM and healthy controls were compared using local MANOVA and compared with the traditional SPHARM-PDM analysis. Both surface and mean latitude axis findings differentiate successfully MVM and healthy lateral ventricle morphology. Lateral ventricles in MVM neonates show enlarged shapes in tail and head. Mean latitude axis is able to find significant differences all along the lateral ventricle shape, demonstrating that local thickness analysis provides significant insight over traditional SPHARM-PDM. This study is the first to precisely quantify 3D lateral ventricle morphology in MVM neonates using shape analysis.
doi:10.1117/12.2006846
PMCID: PMC3630372  PMID: 23606800
Statistical shape analysis; pediatric imaging; magnetic resonance image biomarkers; mild ventriculomegaly; lateral ventricles
17.  Patterns and Prevalence of Disordered Eating and Weight Control Behaviors in Women Ages 25–45 
Eating and weight disorders : EWD  2009;14(4):e190-e198.
Objective
The current study describes detailed eating behaviors, dieting behaviors, and attitudes about shape and weight in 4,023 women ages 25 to 45.
Method
The survey was delivered on-line and participants were identified using a national quota-sampling procedure.
Results
Disordered eating behaviors, extreme weight loss measures, and negative cognitions about shape and weight were widely endorsed by women in this age group and were not limited to White participants. Thirty-one percent of women without a history of anorexia or binge eating reported having purged to control weight, and 74.5% of women reported that their concerns about shape and weight interfered with their happiness.
Discussion
Unhealthy approaches to weight control and negative attitudes about shape and weight are pervasive even among women without eating disorders. The development of effective approaches to address the impact of these unhealthy behaviors and attitudes on the general well-being and functioning of women is required.
PMCID: PMC3612547  PMID: 20179405
Eating Disorders; Race; Ethnicity; Dieting
19.  Birth Outcomes in Women with Eating Disorders in the Norwegian Mother and Child Cohort Study (MoBa) 
Background
We explored the impact of eating disorders on birth outcomes in the Norwegian Mother and Child Cohort Study (MoBa).
Method
35,929 pregnant women in the MoBa included women with broadly defined anorexia nervosa (AN; n=35), bulimia nervosa (BN; n=304), binge eating disorder (BED; n=1,812), and EDNOS-purging type (EDNOS-P; n=36) in the six months prior to or during pregnancy and the referent group--women who reported no eating disorders (no-ED; n=33,742).
Results
Pre-pregnancy BMI was significantly lower in mothers with AN and higher in mothers with BED than the referent. Mothers with AN, BN, and BED reported greater weight gain during pregnancy and more mothers with eating disorders reported smoking during pregnancy than the referent. Women with BED had higher birth weight babies, lower risk of small for gestational age babies, and higher risk for large for gestational age babies and cesarean section than the referent.
Conclusions
BED influences birth outcomes. The absence of differences in birth outcomes in women with AN and EDNOS-P may reflect small sample size and differential severity of illness in population versus clinical samples. The detection of eating disorders in pregnancy could help identify modifiable factors (e.g., binge eating, smoking) that could influence birth outcomes.
doi:10.1002/eat.20578
PMCID: PMC3586575  PMID: 18720472
20.  Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia 
The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n = 9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change = 10.38) compared with patients receiving placebo (mean change = 2.33), p = 0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (rs = 0.81, p = 0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs = 0.74, p = 0.046). In addition, baseline pregnenolone (rs = −0.76, p = 0.037), pregnenolone sulfate (rs = − 0.83, p = 0.015), and allopregnanolone levels (rs = −0.83, p = 0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs = 0.74, p <0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.
doi:10.1038/npp.2009.26
PMCID: PMC3427920  PMID: 19339966
schizophrenia; negative symptoms; cognitive symptoms; neurosteroid; pregnenolone; allopregnanolone
21.  2D:4D Ratios in the First 2 Years of Life: Stability and Relation to Testosterone Exposure and Sensitivity 
Hormones and behavior  2011;60(3):256-263.
The relative lengths of the 2nd and 4th digits (2D:4D) may provide an easily measurable and stable anthropometric index of prenatal androgen exposure, but no study has examined the development of 2D:4D in infancy and the potential impact of neonatal testosterone levels. We collected 2D:4D ratios from 364 children between 0 and 2 years of age. Saliva samples were collected from 236 of these children 3 months after birth and analyzed for testosterone. In addition, 259 children provided DNA samples which were genotyped for the CAG repeat polymorphism in the androgen receptor. There was substantial variability across age in 2D:4D. Sex differences were small compared to adults and did not consistently reach statistical significance. This suggests that 2D:4D may not function well as a proxy measure of prenatal testosterone exposure in infancy. In addition, the interaction of salivary T and CAG repeats predicted right hand digit ratio at 12 months and left hand digit ratio at 12 months and 24 months in males. The interaction of salivary testosterone and CAG repeat length also predicted change in left hand 2D:4D from 2 weeks to 12 months in males. This suggests that 2D:4D in adults may reflect, in part, neonatal testosterone exposure. No significant relationships were observed within females. No significant relationships were observed when salivary testosterone and CAG repeats were examined independent of each other. Results have important implications for the design and interpretation of studies which use 2D:4D as a proxy measure of prenatal testosterone exposure.
doi:10.1016/j.yhbeh.2011.05.009
PMCID: PMC3143220  PMID: 21664359
testosterone; androgen; 2D:4D; digit ratio
22.  Diet and Physical Activity in Women Recovered from Anorexia Nervosa: A Pilot Study 
The International journal of eating disorders  2010;44(4):10.1002/eat.20865.
Objective
After recovery, women with anorexia nervosa (AN) tend to maintain lower body mass indices (BMI) than women in the general population. Reasons for this are unknown as little is known about diet, food choices, physical activity levels (PAL), and reasons for exercise in women recovered from AN.
Method
Diet, reasons for food choice, PAL, and reasons for exercise were measured in an exploratory study of 15 women recovered from AN and 22 women with no eating disorder history.
Results
In these hypotheses generating analyses, mean BMI in recovered women was numerically lower than control women [21.4kg/m2 (2.0) and 23.6 kg/m2 (4.4); respectively (p<0.06)]. Recovered women were more likely to base food choice on health benefits (p <0.04) compared with control women.
Discussion
Pathological behaviors that are pathognomonic of AN may resolve into healthy food and activity choices that help maintain BMIs lower in the healthy range in recovered individuals.
doi:10.1002/eat.20865
PMCID: PMC3116942  PMID: 21472756
Anorexia nervosa; Recovery; Body mass index; Diet; Physical activity; Reasons for food choice
23.  Factors Associated with Binge Eating Disorder in Pregnancy 
Objective
To identify factors associated with incidence and course of broadly defined binge eating disorder (BED) in pregnancy.
Method
As a part of the Norwegian mother and child cohort study (MoBa), 45,644 women completed a questionnaire at approximately 18 weeks of gestation.
Results
Incidence of BED was significantly associated with lifetime sexual abuse, lifetime physical abuse, lifetime major depression, symptoms of anxiety and depression, low life satisfaction, low self-esteem, low partner relationship satisfaction, smoking, alcohol use, lack of social support, and several weight-related factors. Continuation was negatively associated with thoughts of being overweight before pregnancy. Remission was positively associated with thoughts of being overweight before pregnancy and negatively associated with overvaluation of weight.
Conclusion
Onset of BED in pregnancy was associated with psychological, social and weight-related factors, as well as health behaviors and adverse life events. In women with pre-pregnancy BED, thoughts of being overweight before pregnancy and overvaluation of weight were associated with course of BED during pregnancy.
doi:10.1002/eat.20797
PMCID: PMC2888703  PMID: 20127938
24.  Neurosteroids and Self-Reported Pain in Veterans Who Served in the U.S. Military After September 11, 2001 
Pain medicine (Malden, Mass.)  2010;11(10):1469-1476.
Objective
Nearly half of Operation Enduring Freedom / Operation Iraqi Freedom (OEF/OIF) veterans experience continued pain post-deployment. Several investigations report analgesic effects of allopregnanolone and other neurosteroids in animal models, but few data are currently available focusing on neurosteroids in clinical populations. Allopregnanolone positively modulates GABAA receptors and demonstrates pronounced analgesic and anxiolytic effects in rodents, yet studies examining the relationship between pain and allopregnanolone in humans are limited. We thus hypothesized that endogenous allopregnanolone and other neurosteroid levels may be negatively correlated with self-reported pain symptoms in humans.
Design
We determined serum neurosteroid levels by gas chromatography / mass spectrometry (allopregnanolone, pregnenolone) or radioimmunoassay (dehydroepiandrosterone [DHEA], progesterone, DHEA sulfate [DHEAS]) in 90 male veterans who served in the U.S. military after September 11, 2001. Self-reported pain symptoms were assessed in four areas (low back pain, chest pain, muscle soreness, headache). Stepwise linear regression analyses were conducted to investigate the relationship between pain assessments and neurosteroids, with the inclusion of smoking, alcohol use, age, and history of traumatic brain injury as covariates.
Setting
Durham VA Medical Center.
Results
Allopregnanolone levels were inversely associated with low back pain (p=0.044) and chest pain (p=0.013), and DHEA levels were inversely associated with muscle soreness (p=0.024). DHEAS levels were positively associated with chest pain (p=0.001). Additionally, there was a positive association between traumatic brain injury and muscle soreness (p=0.002).
Conclusions
Neurosteroids may be relevant to the pathophysiology of self-reported pain symptoms in this veteran cohort, and could represent future pharmacological targets for pain disorders.
doi:10.1111/j.1526-4637.2010.00927.x
PMCID: PMC2994993  PMID: 20735755
neuroactive steroid; allopregnanolone; pregnenolone; DHEA; nociception; pain; neurosteroid
25.  Prenatal and Neonatal Brain Structure and White Matter Maturation in Children at High Risk for Schizophrenia 
The American journal of psychiatry  2010;167(9):1083-1091.
Objective
Schizophrenia is a neurodevelopmental disorder associated with abnormalities of brain structure and white matter, although little is known about when these abnormalities arise. This study was conducted to identify structural brain abnormalities in the prenatal and neonatal periods associated with genetic risk for schizophrenia.
Method
Prenatal ultrasound scans and neonatal structural magnetic resonance imaging (MRI) and diffusion tensor imaging were prospectively obtained in the offspring of mothers with schizophrenia or schizoaffective disorder (N=26) and matched comparison mothers without psychiatric illness (N=26). Comparisons were made for prenatal lateral ventricle width and head circumference, for neonatal intracranial, CSF, gray matter, white matter, and lateral ventricle volumes, and for neonatal diffusion properties of the genu and splenium of the corpus callosum and corticospinal tracts.
Results
Relative to the matched comparison subjects, the offspring of mothers with schizophrenia did not differ in prenatal lateral ventricle width or head circumference. Overall, the high-risk neonates had nonsignificantly larger intracranial, CSF, and lateral ventricle volumes. Subgroup analysis revealed that male high-risk infants had significantly larger intracranial, CSF, total gray matter, and lateral ventricle volumes; the female high-risk neonates were similar to the female comparison subjects. There were no group differences in white matter diffusion tensor properties.
Conclusions
Male neonates at genetic risk for schizophrenia had several larger than normal brain volumes, while females did not. To the authors' knowledge, this study provides the first evidence, in the context of its limitations, that early neonatal brain development may be abnormal in males at genetic risk for schizophrenia.
doi:10.1176/appi.ajp.2010.09101492
PMCID: PMC3105376  PMID: 20516153

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