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Background: The goal of these secondary analyses of clinical trial data was to characterize clinical outcomes in patients with schizophrenia who met symptom severity or duration thresholds for two alternative definitions of remission, and to explore their relationships to improvement duration and quality of life outcomes. Methods: Definition 1 used threshold criteria for selected PANSS items sustained over at least 6-months Definition 2 used Brief Psychiatric Rating Scale (BPRS) % change, a threshold score for the Clinical Global Improvement-Severity (CGI-S) maintained for at least 8 weeks, and threshold scores for selected BPRS items. Positive and Negative Symptom Scale (PANSS) and Quality of Life scale (QLS) total scores were pooled from 6 clinical trials. The extent to which the alternative severity thresholds from these two definitions and duration of clinical improvement were associated with different clinical and QLS outcomes was explored. Regression analysis also assessed the relative contribution of each of the components of the two definition severity thresholds to improvements in QLS Total score. Results: Increases in QLS scores were greater for those patients who met either threshold criteria relative to those who met neither (p<.0001). Significantly greater improvements in QLS scores were observed for patients who met either threshold criteria at the 8-, 16- and 24-week visits relative to those who met criteria at weeks 16 and 24, or at week 24 only (p<0.001), as well as for the subset of patients who met threshold criteria at both 24 and 52 weeks relative to those who met criteria at only one of these 2 time points. Only 31% to 47% of patients meeting threshold criteria for either definition at the 8-, 16- or 24-week visits remained in remission at the 52-week visit. Among the severity threshold components analyzed, BPRS total % change from baseline was the strongest predictor of improvement in QLS scores. Conclusions: Quality of life improved most for patients who achieved severity thresholds associated with either remission criteria and who stayed improved for longer periods. Total BPRS change scores accounted for the greatest percentage of the QLS scores variance. Only a fraction of patients who meet severity criteria for either remission definition early in treatment will remain at that level of improvement within the subsequent 9-12 months. [ABSTRACT FROM AUTHOR]

Background: Available studies suggest comparable efficacy of olanzapine and risperidone for the treatment of schizophrenia over the short term.Method: This retrospective analysis of data from a 28-week, double-blind, schizophrenia trial compared the cumulative amount of time that patients met severity criteria for remission during olanzapine (10-20 mg/day) or risperidone (4-12 mg/day) treatment.Results: The percentage cumulative time spent in remission was 40% for olanzapine- and 31% for risperidone-treated patients (P = 0.03) using Definition 1 (PANSS items P1, P2, P3, N1, N4, N6, G5, G9 < or = 3), and 18% and 11% (P = 0.01), respectively, using Definition 2 (BPRS Total reduced 50%, BPRS psychosis items < or = 3, CGI-severity < or = 3).Conclusion: During 28 weeks of treatment, olanzapine-treated patients spent more cumulative time in remission than risperidone-treated patients. [ABSTRACT FROM AUTHOR]

: BackgroundThe purpose of this study was to develop prospective data on the effectiveness of combination pharmacotherapy of children and adolescents with bipolar disorder during a 6-month period of prospective, semi-naturalistic treatment.: MethodsThirty-five subjects, with a mean age of 11 years, were treated in the extension phase of this study after having received 6–8 weeks of acute treatment with a single mood stabilizer. The extension phase of this study lasted for another 16 weeks, for a total of 24 weeks of prospective treatment. During this study phase, subjects were openly treated, and they could have their acute-phase mood stabilizer switched or augmented with another mood stabilizer, a stimulant, an antidepressant agent, or antipsychotic agent, if they were assessed to be a nonresponder to monotherapy with their initial mood stabilizer.: ResultsDuring the extension phase of treatment, 20 of 35 subjects (58%) required treatment with one or two mood stabilizers and either a stimulant, an atypical antipsychotic agent, or an antidepressant agent. The response rate to combination therapy was very good, with 80% of subjects treated responding to combination therapy with two mood stabilizers after not responding to monotherapy with a mood stabilizer.: ConclusionsThis study suggests that children and adolescents with bipolar disorder are similar to adults with bipolar disorder, who also frequently require combination therapy. [Copyright &y& Elsevier]

Evaluates the neurohormonal and subjective mood response of children with anxiety disorders who were challenged with yohimbine. Uniform well tolerance to yohimbine in, and behavioral differences between, children with anxiety disorders and normal comparison children; Presence of a blunted growth hormone response to yohimbine in children with anxiety disorders.

Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off‐schedule, as including off‐schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical‐time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios. [ABSTRACT FROM AUTHOR]

The article presents brief information on the safety profile of semagacestat, a gamma-secretase inhibitor for Alzheimer's disease. It discusses that emphasis on mechanistically linked to g-secretase inhibition was made to assist in future development of g-secretase inhibitors. It further mentions that majority of safety findings are dedicated to g-secretase inhibition, and may be valuable to researchers developing g-secretase inhibitors.

Abstract: Signal detection methods were used to identify values of metabolic variables that predict development of prediabetes or diabetes before (moderators) or associated with treatment (mediators), utilizing data from two multi-center clinical trials of patients with schizophrenia, treated for 6 months with olanzapine (OLZ) or ziprasidone (ZIP). At baseline, participants were often overweight/obese (63% with a body mass index ⩾25.0kg/m2), dyslipidemic [more than one-third had elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations], and prediabetic (20%). Weight gain was significantly greater in OLZ-treated patients, as was accentuation of dyslipidemia. However, there were no significant correlations between weight gain and lipid changes from baseline to weeks 2, 4, 8 or to last observation. Type 2 diabetes developed in 4% and prediabetes in 18% of the population. Significant baseline predictors of diabetes were a HDL-C concentration <28mg/dL, or being ⩾58-years-old if HDL-C concentration was ⩾28mg/dL. Baseline plasma glucose concentration ⩾92mg/dL was the only significant predictor of developing prediabetes, accounting for 60% of cases. Post-treatment increments in plasma TG concentrations ⩾145mg/dL or ⩾59mg/dL were significant predictors of diabetes (23%) or prediabetes (27%), respectively. If the increase in TG was <145mg/dL, rapid weight gain ⩾6.1kg in 2weeks predicted development of diabetes (18%). These findings provide a quantitative approach to identify those at greatest treatment-associated risk to develop glucose intolerance, and emphasize the need to address co-morbid medical disorders in these patients. [Copyright &y& Elsevier]

Hyperkinetic disorders may involve excess excitatory output from thalamus to cerebral cortex. Case-control, neurophysiological studies in persons with Tourette Syndrome (TS), Attention Deficit Hyperactivity Disorder (ADHD), and Obsessive-Compulsive Disorder (OCD) support this model. To compare the strength of association between motor cortex inhibition and tic, ADHD, and OCD severity in TS, we used transcranial magnetic stimulation to measure motor cortex inhibition in 36 children and adults with TS. Current symptom severity was assessed with standard clinical rating scales and compared with neurophysiological measures using correlational and multivariate regression analyses. Severity of ADHD symptoms and motor tics were associated significantly and independently with short interval intracortical inhibition (SICI) ( r2 = 0.50; F[2,27] = 13.7; P < 0.001), particularly in subjects not taking neuroleptics ( r2 = 0.68; F[2,17] = 17.8; P < 0.0001). The correlation of cortical disinhibition was greater with ADHD symptoms severity ( r = 0.53; P = 0.003) than with tic severity ( r = 0.42; P = 0.02), suggesting that in TS, the association between SICI and ADHD symptoms may be more consistent or direct than the association between SICI and tics. © 2004 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objective: To compare the tic suppression, electrocardiogram (ECG) changes, weight gain, and side effect profiles of pimozide versus risperidone in children and adolescents with tic disorders. Method: This was a randomized, double- blind, crossover (evaluable patient analysis) study. Nineteen children aged 7 to 17 years with Tourette's or chronic motor tic disorder were randomized to 4 weeks of treatment with pimozide or risperidone, followed by the alternate treatment after a 2-week placebo washout. The primary efficacy outcome measure was change in tic severity assessed by the Yale Global Tic Severity Scale (YGTSS). ECG results, weight gain, and side effects were also compared. Results: Compared to pimozide treatment, risperidone treatment was associated with significantly lower tic severity scores (YGISS: base-line 43.3 ± 17.5, pimozide 34.2 ± 14.2, risperidone 25.2 ± 13.6; p = .05). Weight gain during the 4-week treatment periods was greater for risperidone (mean 1.9 kg) than pimozide (1.0 kg). No patient suffered a serious adverse event, but 6 of 19 subjects failed to complete the protocol. Neither medication was associated with ECG changes. Conclusions: In this study, risperidone appeared superior to pimozide for tic suppression but was associated with greater weight gain. [ABSTRACT FROM AUTHOR]

Presents a study which evaluated mood responses of children with anxiety disorder (ANX) to clonidine challenge. Methodology used to conduct study; Comparison of elevated clonidine-stimulated growth hormone concentration to that of controlled concentration in ANX group; Evaluation of group with obsessive-compulsive disorder (OCD) and comparison of results to those of the ANX group; Discussion on findings.

Clinical trial outcomes for Alzheimer's disease are typically analyzed by using the mixed model for repeated measures (MMRM) or similar models that compare an efficacy scale change from baseline between treatment arms with or without participants' disease stage as a covariate. The MMRM focuses on a single-point fixed follow-up duration regardless of the exposure for each participant. In contrast to these typical models, we have developed a novel semiparametric cognitive disease progression model (DPM) for autosomal dominant Alzheimer's disease based on the Dominantly Inherited Alzheimer Network (DIAN) observational study. This model includes 3 novel features, in which the DPM (1) aligns and compares participants by disease stage, (2) uses a proportional treatment effect similar to the concept of the Cox proportional hazard ratio, and (3) incorporates extended follow-up data from participants with different follow-up durations using all data until last participant visit. We present the DPM model developed by using the DIAN observational study data and demonstrate through simulation that the cognitive DPM used in hypothetical intervention clinical trials produces substantial gains in power compared with the MMRM. [ABSTRACT FROM AUTHOR]

Introduction: The negative efficacy study examining the γ-secretase inhibitor semagacestat in mild to moderate Alzheimer's disease (AD) included a number of biomarkers of the disease as well as safety outcomes. We analyzed these data to explore relationships between drug exposure and pharmacodynamic effects and to examine the correlations among outcome measures. Methods: The study was a multicenter, randomized, placebo-controlled trial of two dose regimens of semagacestat and a placebo administered for 18 months to individuals with mild to moderate AD. Changes in measures of central and peripheral drug activity were compared between the three treatment groups using one-way analysis of variance. The relationship between changes in each of the outcome measures and measures of drug exposure and peripheral pharmacodynamic effect were assessed using Spearman's correlation coefficient. Results: Assignment to the active treatment arms was associated with reduction in plasma amyloid-β (Aβ) peptides, increase in ventricular volume, decrease in cerebrospinal fluid phosphorylated tau (p-tau) and several other laboratory measures and adverse event categories. Within the active arms, exposure to drug, as indicated by area under the concentration curve (AUC) of blood concentration, was associated with reduction in plasma Aβ peptides and a subset of laboratory changes and adverse event rates. Ventricular volume increase, right hippocampal volume loss and gastrointestinal symptoms were related to change in plasma Aβ peptide but not AUC, supporting a link to inhibition of γ-secretase cleavage of the amyloid precursor protein. Cognitive decline correlated with ventricular expansion and reduction in p-tau. Conclusion: These findings may inform future studies of drugs targeting secretases involved in Aβ generation. [ABSTRACT FROM AUTHOR]

In clinical trials, there always is the possibility to use data-driven adaptation at the end of a study. There prevails, however, concern on whether the type I error rate of the trial could be inflated with such design, thus, necessitating multiplicity adjustment. In this project, a simulation experiment was set up to assess type I error rate inflation associated with switching dose group as a function of dropout rate at the end of the study, where the primary analysis is in terms of a longitudinal outcome. This simulation is inspired by a clinical trial in Alzheimer’s disease. The type I error rate was assessed under a number of scenarios, in terms of differing correlations between efficacy and tolerance, different missingness mechanisms, and different probabilities of switching. A collection of parameter values was used to assess sensitivity of the analysis. Results from ignorable likelihood analysis show that the type I error rate with and without switching was approximately the posited error rate for the various scenarios. Under last observation carried forward (LOCF), the type I error rate blew up both with and without switching. The type I error inflation is clearly connected to the criterion used for switching. While in general switching, in a way related to the primary endpoint, may impact the type I error, this was not the case for most scenarios in the longitudinal Alzheimer trial setting under consideration, where patients are expected to worsen over time. [ABSTRACT FROM AUTHOR]

The article discusses a multinational phase 3 trial launched by Eli Lilly & Co. concerning semagacestat for treatment of Alzheimer's disease. The disease was documented on the basis of a score of 16 to 26 on the Mini-Mental State Examination. The institutional review board at each institution where the trial was done approved the research protocol. An illustration that shows screening, randomization, and follow-up during the first 76-week treatment period is provided.

The goal of this study was to identify the optimal combination of magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and cerebrospinal fluid (CSF) biomarkers to predict conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) dementia within two years, for enriching clinical trial populations. Data from 63 subjects in the Alzheimer's Disease Neuroimaging Initiative aMCI cohort who had MRI and FDG-PET imaging along with CSF data at baseline and at least two years clinical follow-up were used. A Bayesian classification method was used to determine which combination of 31 variables (MRI, FDG-PET, CSF measurements, apolipoprotein E (ApoE) genotype, and cognitive scores) provided the most accurate prediction of aMCI to AD conversion. The cost and time trade-offs for the use of these biomarkers as inclusion criteria in clinical trials were evaluated. Using the combination of all biomarkers, ApoE genotype, and cognitive scores, we achieved an accuracy of 81% in predicting aMCI to AD conversion. With only ApoE genotype and cognitive scores, the prediction accuracy decreased to 62%. By comparing individual modalities, we found that MRI measures had the best predictive power (accuracy = 78%), followed by ApoE, FDG-PET, CSF, and the Alzheimer's disease assessment scale-cognitive subscale. The combination of biomarkers from different modalities, measuring complementary aspects of AD pathology, provided the most accurate prediction of aMCI to AD conversion within two years. This was predominantly driven by MRI measures, which emerged as the single most powerful modality. Overall, the combination of MRI, ApoE, and cognitive scores provided the best trade-off between cost and time compared with other biomarker combinations for patient recruitment in clinical trial. [ABSTRACT FROM AUTHOR]

The goal of this study was to identify the optimal combination of magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and cerebrospinal fluid (CSF) biomarkers to predict conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) dementia within two years, for enriching clinical trial populations. Data from 63 subjects in the Alzheimer's Disease Neuroimaging Initiative aMCI cohort who had MRI and FDG-PET imaging along with CSF data at baseline and at least two years clinical follow-up were used. A Bayesian classification method was used to determine which combination of 31 variables (MRI, FDG-PET, CSF measurements, apolipoprotein E (ApoE) genotype, and cognitive scores) provided the most accurate prediction of aMCI to AD conversion. The cost and time trade-offs for the use of these biomarkers as inclusion criteria in clinical trials were evaluated. Using the combination of all biomarkers, ApoE genotype, and cognitive scores, we achieved an accuracy of 81% in predicting aMCI to AD conversion. With only ApoE genotype and cognitive scores, the prediction accuracy decreased to 62%. By comparing individual modalities, we found that MRI measures had the best predictive power (accuracy = 78%), followed by ApoE, FDG-PET, CSF, and the Alzheimer's disease assessment scale-cognitive subscale. The combination of biomarkers from different modalities, measuring complementary aspects of AD pathology, provided the most accurate prediction of aMCI to AD conversion within two years. This was predominantly driven by MRI measures, which emerged as the single most powerful modality. Overall, the combination of MRI, ApoE, and cognitive scores provided the best trade-off between cost and time compared with other biomarker combinations for patient recruitment in clinical trial. [ABSTRACT FROM AUTHOR]

Tau measurements in cerebrospinal fluid (CSF) are gaining acceptance as aids to diagnosis of Alzheimer's disease (AD) and differentiation from other dementias. Two ELISA assays, the INNOTEST® hTAU Ag and the INNOTEST® PHOSPHO-TAU(181P) for quantification of t-tau and p-tau181 respectively, have been validated to regulatory standards. Validation parameters were determined by repeated testing of human CSF pools. Specimens from Phase 2 studies of the γ-secretase inhibitor semagacestat and the therapeutic antibody solanezumab at baseline and following 12-14 weeks of treatment were also tested. Estimated intra-assay CV for repeated testing of 3 CSF pools were ≤11.5% and RE varied between -14.1% and +6.4%. Inter-assay CV for t-tau was <5% and RE was within ±8%. For p-tau181, inter-assay CV was <9% and RE was within ±2.5%. Total CV (intra-assay plus inter-assay) were below 10% for both analytes. Up to 20-fold dilutional linearity was demonstrated for both analytes. Stability of t-tau and p-tau181 was demonstrated in CSF during five freeze-thaw cycles at ≤-20°C and ≤-70°C and at 18-22°C for up to 24 h. Neither semagacestat nor solanezumab interfered with either assay. Inter-individual t-tau and p-tau181 concentrations were highly variable but intra-individual variations were small. These assays are suitable for analysis of CSF t-tau and p-tau181 in a single laboratory supporting multi-center AD clinical trials. No effect of treatment with semagacestat or solanezumab was observed in response to three months of drug administration. [ABSTRACT FROM AUTHOR]

Objective: The purpose of the present study was to evaluate the efficacy and tolerability of olanzapine long-acting injection for maintenance treatment of schizophren ia. Method: Outpatients with schizophrenia who had maintained stability on an oral regimen of olanzapine (10, 15, or 20 mgI day) for 4 to 8 weeks were randomly assigned to 24 weeks of double-blind treatment with "low" (150 mg every 2 weeks; N=140),"medium"(4O5mgevery4weeks; N=318), or "high" (300 mg every 2 weeks; N=141) doses of olanzapine long-acting injection; a very low reference dose of olanzapine long-acting injection (45 mg every 4 weeks; N=144); or their stabilized dose of oral olanzapine (N=322). Rates of and time to psychotic exacerbation were estimated using Kaplan-Meier methodology. Results: At 24 weeks, the majority of oral olanzapine-treated patients (93%), as well as most olanzapine long-acting injectiontreated patients receiving high (95%), medium (90%), low (84%), and very low doses (69%), remained exacerbation free, with the therapeutic 4-week regimen (medium dose) and pooled 2-week regimen (low and high doses) demonstrating efficacy similar to that of oral olanzapine as well as to each other. The three standard long-acting doses were superior to the very low reference dose based on time to exacerbation. Incidence of weight gain ⩾7% of baseline was 21% for oral olanzapine compared with 21%, 15%, 16%, and 8% for the high, medium, low, and very low olanzapine long-acting treatment groups, respectively. No clinically significant differences were observed between the long-acting injection and oral olanzapine groups in general safety parameters. Few injection-site reactions occurred (3%). Two patients experienced sedation and delirium consistent with olanzapine overdose following possible accidental intravascular injection. Conclusions: Olanzapine long-acting injection was efficacious in maintenance treatment of schizophrenia for up to 24 weeks, with a safety profile similar to oral olanzapine except for injection-related adverse events. [ABSTRACT FROM AUTHOR]

Abstract: Background: The objective of this retrospective chart review was to evaluate the phenomenology and response to divalproex in a sub-population of children admitted to an inpatient setting with severe impairing symptoms of irritability and aggression. In addition, we examined whether the symptomatology of this group was consistent with a pediatric divalproex-responsive bipolar spectrum disorder. Methods: The charts of 46 child and adolescent patients with prominent impulsive aggression with irritability admitted to a crisis stabilization center were assessed retrospectively. Impulsive aggressive symptoms were assessed for admission and discharge severity by two clinicians using the Overt Aggression Scale (OAS) and the Anger-Hostility Subscale of the SCL-90 (SCL-A), with overall functioning changes assessed using the Children''s Global Assessment Scale (C-GAS). Results: Statistically significant improvements were obtained for the group in the C-GAS, with significant decreases in the OAS and the SCL-A scores at discharge, following a maximal 14-day stay. No severe side effects were reported. All patients met the criteria for a potential pediatric bipolar phenotype. Limitations: This was a retrospective study without randomization or a control group. Additionally, the non-blinded design may have biased the raters concerning the effectiveness of divalproex for impulsive aggression. Conclusions: Our data are in line with divalproex response in children and adolescents with target symptoms of explosive temper and mood instability. Our data further suggest that such symptoms, coupled with impulsive aggression and irritability, as well as related manic symptoms, constitute a pediatric divalproex-responsive bipolar spectrum disorder. [Copyright &y& Elsevier]

We reference self-ratings and clinician ratings of childhood anxious symptoms to a third data source well delineated with regard to the pathophysiology of anxiety. A total of 36 children with anxiety disorders and other children were administered yohimbine, an alpha-sub-2-adrenoreceptor antagonist, in response to which anxiety-prone children have blunted output of growth hormone. We assessed neuroendocrine reactions. In general, participants who claimed anxiety that was unconfirmed by clinicians displayed anxiotypic neuroendocrine profiles, whereas those who denied anxiety detected by clinicians did not, suggesting self-report may have had the advantage over clinician ratings in some instances. Nuanced and contextualized conclusions in this area of work are needed. In response to the question "the illusion of mental health: in the mind of which beholder?," we answer "it depends on the sample and the syndrome under study." [ABSTRACT FROM AUTHOR]

Objective: To study the patterns of dietary supplement use in veterans with cancer. Design: Using a detailed questionnaire, a cross-sectional study was conducted to determine the patterns of dietary supplement use by patients with cancer. Setting/location: The study was conducted at the Hematology! Oncology Clinic at the VA Hospital in Cincinnati, OH. Subjects: Patients with malignancy who were attending the above clinic and willing to participate and sign a consent form were enrolled in the study. Outcomes/measures: The use of dietary supplements, the type, frequency, and reason for use was captured, along with the source of dietary supplements and perceived benefits. Results: Two hundred (200) veterans were surveyed, with a median age of 68 years (36-82). The type of malignancy included cancer of the genitourinary system (39.5%), lung (19.5%), gastrointestinal tract (14.5%), hematology system (16%), skin/head/neck (6.5%), and other (4%). One hundred and twenty-two patients (122) used dietary supplements (61%). Multi vitamins were the most commonly used dietary supplement reported by 98 patients (80.3%), followed by mineral use by 52 patients (40.6%). Ten (10) patients used herbal supplements. Patients who were employed and patients with higher education were more likely to use dietary supplements. Different reasons were given for dietary supplement use and 74% of the users reported perceived benefits, such as improved overall health and energy. While 38% of the patients did not disclose dietary supplement use to their physicians, 37.8% of them learned about dietary supplements from their physicians and 25% obtained their dietary supplements from the VA hospital. Conclusion: The use of dietary supplements is common among veterans with cancer. Health care professionals should inquire about them in a systematic fashion and he prepared to provide counseling to their patients about them. [ABSTRACT FROM AUTHOR]

Objective: To investigate psychosocial effects of a 6-month pilot multidisciplinary weight-management program for young females. Methods: Participants (n=57), ages 8-15, completed the Revised Children's Manifest Anxiety Scale (RCMAS) and Self-Perception Profile for Children (SPPC) at baseline, 6 months, and 12 months. Results: Positive changes were noted in the scores of both surveys. Significant decreases occurred in the RCMAS mean Total Anxiety and Worry/Oversensitivity scores; significant increases were found in the SPPC mean Social Acceptance and Athletic Competence scores. Conclusions: Enrollment in multifaceted weight-management programs that include stress management and social support may reduce anxiety level and enhance self-perception. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine changes in bone mineral density/bone mineral content (BMD/BMC) in obese female adolescents (Tanner stages 2 to 4) pursuing a weight reduction program. This was a prospective pilot clinical investigation involving 92 obese females screened to meet inclusion criteria and required to participate in a 6-month weight loss intervention. Baseline, 6 months, and 12 months measurements were taken for total body/lumbar spine BMD/BMC and percentage body fat. Survey instrumentation included the following: calcium food frequency/24-hour dietary recall, physical activity, and psychological assessments for anxiety/self-esteem. Changes in bone measurements were compared with changes in body weight measurements using multiple linear regression. Other potentially confounding variables analyzed included bone area, calcium intake, baseline Tanner stage, activity level, and height. Total body/lumbar spine BMD/BMC changes were found to be most significantly correlated with weight changes in the subject population. Although mean weight increased, the rate of increase per a given height velocity slowed to an appropriate height for weight ratio. Individuals who lost weight did not lose BMD/BMC; however, the rate of growth declined when compared with all study subjects whose bone growth rate was consistent with normal weight female adolescents. In this study, weight changes were strongly related to bone measurement changes in an obese adolescent female population. Dietitians counseling obese young girls are encouraged to emphasize the importance of a healthy weight loss program with optimal calcium intake and inclusive of weight-bearing exercises. J Am Diet Assoc. 2003;103:369-372. [Copyright &y& Elsevier]

Rationale: Dopaminergic systems are involved in the pathophysiology of alcohol use disorders, but there is little research investigating the role of these systems in adolescents. Objectives: In this study, we investigated dopaminergic systems in adolescents with alcohol abuse by determining neuroendocrine and behavioral responses to dopaminergic drug challenges. Methods: Twenty-six participants (11 with DSM IV alcohol abuse and 15 controls) were enrolled in the study. Neuroendocrine and behavioral response to the dopaminergic indirect agonist methylphenidate (10 mg) and the direct agonist pergolide (50 mcg), were examined. The primary response measures were spontaneous eye-blink rate, plasma prolactin (PRL), and growth hormone (GH). Additionally, participants completed a visual analog mood scale (VAMS). Results: The rate of increase in plasma GH level was blunted for adolescents with alcohol abuse compared to the control group, after methylphenidate administration [t=-2.75, P=0.0066, 95% confidence interval (CI) -0.3, -0.048]. The rate of decrease in PRL level after pergolide administration was greater in adolescents with alcohol abuse as compared to the control group (t=-3.05, P=0.0028, 95% CI -0.01923, -0.00409). Adolescents with alcohol abuse rated themselves as less "energized" in comparison to the control group after methylphenidate (rate difference=-0.4, P=0.0231). Conclusions: This preliminary study suggests that adolescents with alcohol abuse may have a differential response to dopaminergic agonists, as also reported for adults with alcohol use disorders. Further studies investigating gender differences, and other neurotransmitter systems are needed to understand the differential dopaminergic response in adolescents with alcohol use disorders. [ABSTRACT FROM AUTHOR]

Summary: Purpose: Lamotrigine (LTG), a newer antiepileptic drug (AED), has activity against both partial-onset and generalized seizures. Its reported benefits for behavior, and its effectiveness in Lennox–Gastaut syndrome and other forms of refractory epilepsy, make it a logical choice for treatment of epilepsy in tuberous sclerosis complex (TSC). We present our experience with LTG therapy of epilepsy in 57 patients with TSC. Methods: Patients fulfilled the diagnostic criteria for clinically definite TSC. LTG was initiated and increased until improvement in seizure frequency was noted, intolerable side effects occurred, or maximal doses were reached. Seizure frequency and behavioral changes were recorded during LTG therapy and compared with those prior to the introduction of LTG. Results: Twenty-four (42%) were seizure free, and 21 (37%) had a >50% reduction in seizure frequency. Eighteen (32%) had subjectively improved behavior and/or alertness with daily activities. Thirty-eight (67%) had no change in this regard, whereas one (2%) became worse. Responders were more likely to not have a history of infantile spasms, and to have experienced only partial seizures (p < 0.05). Otherwise no phenotypic correlations with response were apparent. Conclusions: Among patients with TSC and epilepsy, LTG was effective and well tolerated, including as initial monotherapy. Improved alertness and behavior were apparent in many patients. The incidence of side effects is similar to that reported for other pediatric populations with symptomatic partial epilepsy. The usefulness of LTG in TSC may relate to an underlying defect of glutamatergic neurotransmission in partial epilepsy. [ABSTRACT FROM AUTHOR]

The study objective was to determine if serotonergic challenge with oral racemic fenfluramine would differentiate between childhood anxiety disorders in comparison to normal controls. Subjects were 24 children with anxiety diagnoses (DSM-IIIR) by structured interview, and 14 normal controls (ages 7 – 14 years) matched for age and sex. All subjects were given a standard challenge dose of d,1-fenfluramine (1 mg/kg) followed by serial assessments of cardiovascular, neurohormonal, and mood parameters over a five hour period. In response to fenfluramine, controls demonstrated increases in subjective anxiety and systolic blood pressure relative to anxious subjects. Fenfluramine was safely tolerated and did not induce panic symptoms in any subject. Exaggerated prolactin response to fenfluramine differentiated an obsessive – compulsive disorder (OCD) subset from both controls and other anxiety disorders. Fenfluramine challenge differentiates anxious children from healthy controls by elevated anxiety ratings and systolic blood pressure in controls. Increased prolactin response to fenfluramine discriminates children with obsessive – compulsive disorder from both healthy children and children with other anxiety diagnoses. As adults with OCD appear to demonstrate a blunted prolactin response to fenfluramine challenge, the serotonin pathways involved may differ between ‘early’ and ‘late’ onset disorder, or the serotonin substrates tapped by this challenge may change over time. Copyright © 2000 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Comparison of disease progression between placebo-group patients from randomised controlled trials (RCTs) and real-world patients can aid in assessing the generalisability of RCT outcomes. This analysis compared outcomes between community-dwelling patients with mild Alzheimer's disease (AD) dementia from two RCTs (pooled European (EU) data from EXPEDITION and EXPEDITION 2) and similar patients from the EU GERAS observational study. Methods: Data from placebo-group patients with mild AD dementia from the RCTs (EU countries only) were compared with data from GERAS patients with mild AD dementia. Between-group differences for changes over 18 months were analysed for cognition, functioning, neuropsychiatric symptoms, health-related quality of life (HRQoL) and caregiver time using propensity score-adjusted models. A sensitivity analysis compared EU/North American (EU/NA) EXPEDITION patients with GERAS patients. Results: EU EXPEDITION patients (n = 168) were younger than GERAS patients (n = 566) (mean (standard deviation, SD) age 71.9 (7.4) versus 77.3 (6.9) years; p < 0.001) and were more likely to use AD treatment (95% versus 84%; p < 0.001). Cognitive performance was similar at baseline in both populations, although GERAS patients showed greater functional impairment (p = 0.005) and lower HRQoL (p < 0.05). At 18 months, no statistically significant differences between EXPEDITION (n = 133) and GERAS (n = 417) patients were observed for changes in cognitive, functional, neuropsychiatric and HRQoL outcomes. Least squares mean (95% confidence interval) change in caregiver time (hours/month) spent on instrumental activities of daily living (iADL; 29.22 (19.16, 39.27) versus 3.20 (−11.89, 18.28), p = 0.001) and supervision (66.59 (47.49, 85.69) versus 3.04 (−25.39, 31.48), p < 0.001) showed greater increases in GERAS than EXPEDITION. In the sensitivity analysis, changes in neuropsychiatric and HRQoL scores and caregiver time spent on basic ADL were also significantly greater in GERAS than in EU/NA EXPEDITION patients. Conclusions: Patients with mild AD dementia participating in the EU EXPEDITION RCTs and the GERAS observational study showed a similar decline in cognitive, functional and neuropsychiatric symptoms over 18 months, whereas changes in caregiver time measures were significantly greater in GERAS. Results indicate the importance of using similar regions when comparing real-world and RCT data. Trial registration: ClinicalTrials.gov NCT00905372 EXPEDITION. Registered 18 May 2009. ClinicalTrials.gov NCT00904683 EXPEDITION 2. Registered 18 May 2009. [ABSTRACT FROM AUTHOR]

Demonstrates that cystic and nodular pulmonary changes consistent with lymphangioleimyomatosis (LAM) and multifocal modular pneumocyte hyperplasia are common in women with tuberous sclerosis (TSC). Prospective characterization of the prevalence, clinical presentation and genetic basis of lung disease in TSC.