An Open-Label Pilot Study of Duloxetine in Patients With Irritable Bowel Syndrome and Comorbid Major Depressive Disorder.

Major depressive disorder (MDD) and irritable bowel syndrome (IBS) frequently co-occur, yet treating their comorbid presentation is challenging. Low-dose tricyclic antidepressants are efficacious for IBS, but higher doses to treat depressive symptoms present tolerability problems, whereas selective serotonin reuptake inhibitors are more tolerable but show inconsistent efficacy for IBS. If efficacious, serotonin-norepinephrine reuptake inhibitors like duloxetine would provide a useful alternative. We explored efficacy, tolerability, and time to onset of action of duloxetine in comorbid IBS-MDD in an open-label, 12-week trial. Repeated-measures mixed-effects regression analysis with the intent-to-treat sample assessed rate of change of the clinician-administered Gastrointestinal Symptoms Rating Scale, Montgomery-Åsberg Depression Rating Scale, and other clinician-administered and self-report scales. Seventeen Hispanic adults with current MDD and comorbid IBS meeting Rome III criteria entered the study. Medical and laboratory assessment ruled out alarm symptoms and signs inconsistent with IBS. Duloxetine led to significant improvement in Gastrointestinal Symptoms Rating Scale and Montgomery-Åsberg Depression Rating Scale scores and 71.4% and 64.3% intent-to-treat response rates for IBS and MDD, respectively. Abdominal pain severity decreased by 56%. Contrary to expectation of rapid analgesic effects, based on duloxetine studies for neuropathic pain, both IBS and MDD symptoms improved gradually; differences in slopes of improvement were nonsignificant. Duloxetine was moderately well tolerated at a mean endpoint dose of 60 mg/d. Study limitations include the lack of placebo control, modest sample size, single ethnic group, and high attrition rate. Duloxetine efficacy for comorbid IBS-MDD should be studied under placebo-controlled conditions with larger and more diverse samples.

Morphological features of the neonatal brain following exposure to regional anesthesia during labor and delivery.

INTRODUCTION: Recent animal and human epidemiological studies suggest that early childhood exposure to anesthesia may have adverse effects on brain development. As more than 50% of pregnant women in the United States and one-third in the United Kingdom receive regional anesthesia during labor and delivery, understanding the effects of perinatal anesthesia on postnatal brain development has important public health relevance. METHODS: We used high-resolution magnetic resonance imaging (MRI) to assess the effects of regional anesthesia during labor and delivery as part of a larger study of perinatal exposures on the morphological features of the neonatal brain. We mapped morphological features of the cortical surface in 37 healthy infants, 24 exposed and 13 unexposed to regional anesthesia at delivery, who were scanned within the first 6 weeks of life. RESULTS: Infants exposed to maternal anesthesia compared with unexposed infants had greater local volumes in portions of the frontal and occipital lobes bilaterally and right posterior portion of the cingulate gyrus. Longer durations of exposure to anesthesia correlated positively with local volumes in the occipital lobe. CONCLUSIONS: Anesthesia exposure during labor and delivery was associated with larger volumes in portions of the frontal and occipital lobes and cingulate gyrus in neonates. Longitudinal MRI studies are needed to determine whether these morphological effects of anesthesia persist and what their consequences on cognition and behavior may be.

A double-blind, placebo-controlled study of atomoxetine in young children with ADHD.

OBJECTIVE: To evaluate the efficacy and tolerability of atomoxetine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in 5- and 6-year-old children. METHODS: This was an 8-week, double-blind, placebo-controlled randomized clinical trial of atomoxetine in 101 children with ADHD. Atomoxetine or placebo was flexibly titrated to a maximum dose of 1.8 mg/kg per day. The pharmacotherapist reviewed psychoeducational material on ADHD and behavioral-management strategies with parents during each study visit. RESULTS: Significant mean decreases in parent (P = .009) and teacher (P = .02) ADHD-IV Rating Scale scores were demonstrated with atomoxetine compared with placebo. A total of 40% of children treated with atomoxetine met response criteria (Clinical Global Impression-Improvement Scale indicating much or very much improved) compared with 22% of children on placebo, which was not significant (P = .1). Decreased appetite, gastrointestinal upset, and sedation were significantly more common with atomoxetine than placebo. Although some children demonstrated a robust response to atomoxetine, for others the response was more attenuated. Sixty-two percent of subjects who received atomoxetine were moderately, markedly, or severely ill according to the Clinical Global Impression-Severity Scale at study completion. CONCLUSIONS: To our knowledge, this is the first randomized controlled trial of atomoxetine in children as young as 5 years. Atomoxetine generally was well tolerated and reduced core ADHD symptoms in the children on the basis of parent and teacher reports. Reductions in the ADHD-IV Rating Scale scores, however, did not necessarily translate to overall clinical and functional improvement, as demonstrated on the Clinical Global Impression-Severity Scale and the Clinical Global Impression-Improvement Scale. Despite benefits, the children in the atomoxetine group remained, on average, significantly impaired at the end of the study.

The open-label treatment of attention-deficit/hyperactivity disorder in 4- and 5-year-old children with beaded methylphenidate.

OBJECTIVE: The aim of this study was to assess the effectiveness and tolerability of a long-acting methylphenidate (MPH) formulation, beaded MPH (B-MPH), for treatment of attention-deficit/hyperactivity disorder (ADHD) in 4- and 5-year-old children. METHOD: Eleven children (9 boys and 2 girls) with ADHD received 4 weeks of B-MPH treatment in a single-site, open-label pilot study. Medication dosing was flexible, with titration to a maximum of 30 mg/day. A brief education session on behavior management was offered to parents at each treatment visit. RESULTS: Subjects experienced a mean decrease of 1.09 (standard deviation [SD]=0.73, p<0.01) on the Swanson, Nolan, and Pelham Questionnaire (SNAP-IV) ADHD composite score to an end point of 1.18 (SD=0.64). Subjects demonstrated mean decreases in scores of inattention of 1.01 (SD=0.85, p<0.01) and in hyperactivity/impulsivity of 1.17 (SD=0.74, p<0.01), with end point scores of 1.10 (SD=0.61) and 1.26 (SD=0.77), respectively. The Clinical Global Impressions-Severity (CGI-S) scale showed a statistically significant improvement from a baseline mean of 5 to the final visit mean of 3.36 (p<0.01). At the final visit, the mean daily B-MPH dose was 17.73 mg. Subjects did not experience any statistically significant changes in weight, blood pressure, or pulse during the study. The most common adverse event was decreased appetite. CONCLUSION: B-MPH was safe and effective for the treatment of ADHD in the 4- and 5-year-olds participating in this study.

Smokers' response to combination bupropion, nicotine patch, and counseling treatment by race/ethnicity.

BACKGROUND: Evidence on how to tailor nicotine dependence treatment to specific race/ethnic groups is limited. The present study investigated responses to established smoking cessation treatments among African American, Hispanic, and White adults. METHODS: Participants were 559 smokers (126 African American, 73 Hispanic, and 360 White). All received treatment for eight weeks with open-label bupropion, the nicotine patch, and individual counseling. The dependent variable was tobacco abstinence during the last four weeks of treatment. The independent variables were race/ethnicity and other known predictors of abstinence, including sex, age, smoking history (nicotine dependence level, number of cigarettes smoked daily, serum cotinine level and expired carbon monoxide, number of past quit attempts, and age when daily smoking began), confidence in ability to stop smoking, body mass index, psychological status, and psychiatric history (past major depression and alcohol dependence). RESULTS: The total proportion of abstainers in the sample was 53%, with proportional differences by race/ethnicity (Whites 60%, African Americans 38%, Hispanics 41%). Compared to Whites, the odds ratios (OR) for quitting, adjusted for moderators of race/ ethnicity and other predictors of abstinence, were significantly lower among African Americans (OR .44, 95% confidence interval 195% CI] .27-.72) and Hispanics (OR .46, 95% CI .26-.81). CONCLUSION: Disparity in smoking cessation treatment outcome among African American and Hispanic smokers compared to Whites implies that the burden of tobacco-related illness will continue to fall disproportionately among minority racial/ethnic groups. Gaining knowledge on the effectiveness of nicotine dependence treatments and on the factors that facilitate or impede a successful response by minority smokers is a public health priority.

A randomized trial of bupropion and/or nicotine gum as maintenance treatment for preventing smoking relapse.

AIM: To investigate the efficacy of maintenance treatment with bupropion and/or nicotine gum for reducing smoking relapse. DESIGN, SETTING AND PARTICIPANTS: A 48-week study was conducted at a university-based smoking cessation clinic between February 2001 and October 2005. A total of 588 smokers received bupropion and nicotine patch in 8 weeks of open-label treatment (OLT); 289 abstainers during the last 4 weeks of OLT were randomized in double-blind placebo-controlled fashion to one of four arms for 16 weeks of maintenance treatment (MT) followed by 24 weeks of non-treatment follow-up (NTFU). INTERVENTION: Bupropion (300 mg/day) and 2 mg nicotine gum, used alone or combined, and comparable placebo pill and placebo gum. Behavioral counseling at all visits. OUTCOME: Time to relapse (TTR) from randomization. Relapse is defined as the first 7 consecutive days of smoking. Abstinence verified by carbon monoxide

Olfactory deficits, cognition and negative symptoms in early onset psychosis.

BACKGROUND: Smell identification deficits (SID) are common in adult schizophrenia, where they are associated with negative symptoms and lower intelligence. However, smell identification has not been examined in adolescents with early onset psychosis, wherein diagnosis is often obscure, and there are few prognostic predictors. METHOD: We examined smell identification, diagnosis, neuropsychological performance and symptoms in 26 well characterized adolescents with early onset psychosis, age 11-17 years. RESULTS: SID existed in the sample and were more common in patients with schizophrenia and psychotic depression than in patients with psychosis NOS and bipolar disorder. As in adults, SID were significantly associated with greater negative symptoms and lower verbal IQ. However, the associations of verbal IQ (and other verbal tasks) to smell identification in this pediatric sample were explained by the relation of both of these types of variables to negative symptoms. CONCLUSIONS: SID existed across this sample of youths with psychotic disorder, and were specifically related to typical characteristics of schizophrenia, such as negative symptoms and lower intelligence, but not to features of bipolar disorder, such as grandiosity. SID is a characteristic of early onset psychosis that may be useful for prognostic purposes.

A pharmacokinetic/pharmacodynamic study comparing a single morning dose of adderall to twice-daily dosing in children with ADHD.

OBJECTIVE: To determine the pharmacokinetic and pharmacodynamic properties of once-daily versus twice-daily doses of Adderall. METHOD: Following a 1-week wash-out, 12 subjects with attention-deficit/hyperactivity disorder (ADHD) entered a double-blind crossover study comparing two conditions: QD (10 mg of Adderall at 7:30 a.m. and placebo at noon) or BID (10 mg of Adderall at 7:30 a.m. and at noon). At two sites, cohorts of six subjects each were assessed on two different days by a 12-hour laboratory school protocol. Plasma concentrations of d- and l-amphetamine, vital signs, teacher ratings of classroom behavior on the SKAMP, and 10-minute Math Test performance were measured repeatedly over 12 hours. An analysis of variance used center, subject-within-center, condition, and time-after-second-dose as independent variables. RESULTS: The pharmacokinetic profiles revealed similar morning concentrations of d- and l-amphetamine. However, concentrations were twice as high in the afternoon for BID as QD. The two conditions showed similar pharmacodynamic profiles in the morning, although improvement in math performance and behavior was maintained into the afternoon only in the BID condition (p <.05). CONCLUSIONS: This study suggests that twice-daily dosing of Adderall may be an effective strategy for afternoon control of attention and deportment for children with ADHD.

Review of safety assessment methods used in pediatric psychopharmacology.

OBJECTIVE: Elicitation is an essential and critical step in ascertaining adverse events (AEs). This report reviews elicitation methods used in published clinical trials of psychopharmacological agents in children. METHOD: Pediatric psychopharmacology reports were reviewed for safety methods in the Medline database. Studies were included if they were published 1980 or later, provided data on AEs, and described the ascertainment methodology used for determining them. RESULTS: A review of 196 pediatric psychopharmacology articles depicting safety assessments in clinical studies over the past 22 years revealed that there was no common method used for eliciting or reporting AE data. CONCLUSION: The current inconsistency in safety data ascertainment is a major limitation that likely impairs the ability to promptly and accurately identify drug-induced AEs. Research on how best to standardize safety methods should be considered a priority in pediatric psychopharmacology.

Developing methodologies for monitoring long-term safety of psychotropic medications in children: report on the NIMH conference, September 25, 2000.

OBJECTIVE: To improve the methods for long-term assessment of drug-associated side effects and advance knowledge of the safety profile of psychotropic medications in children and adolescents. METHOD: A multidisciplinary, interactive workshop was hosted by the National Institute of Mental Health (NIMH) and the Research Units on Pediatric Psychopharmacology network. Participants were experts in child and adolescent psychiatry, psychopharmacology, pharmacoepidemiology, and statistics from academia, the pharmaceutical industry, the Food and Drug Administration (FDA), and the NIMH. Evaluation of drug safety was examined from five perspectives: research design and methods, industry, regulatory requirements, bioethics, and practice settings. For each of these areas, special emphasis was placed on identifying barriers and generating solutions. RESULTS: A major obstacle is the lack of standardization of the methods used for collecting safety data. The limitations of both randomized clinical trials and passive postmarketing surveillance in assessing long-term safety were recognized. The need to consider alternative approaches, such as registries and trend analysis of population-based databases, was highlighted. Recommendations were proposed together with possible approaches to implementation. CONCLUSIONS: A concerted effort by academic researchers, industry, FDA, practitioners, and NIMH is needed to standardize methods and lay the foundations for systematic research on the long-term safety of psychotropic medications in children.