Jane Fried

Imipramine in adolescent major depression: plasma level and clinical response

ABSTRACT Thirty‐four adolescents with mean age 14.25 years who met RDC criteria for major depressive disorder as assessed with the K‐SADS, were treated for 6 weeks on a fixed schedule of imipramine hydrochloride titrated to a dosage of 5.0 mg/kg/day except as limited by side effects. Mean dose was 246 mg/day (4.5 mg/kg/day). In spite of good indications of compliance with treatment only 44% of the adolescents improved to the level of no or only slight depressed mood or anhedonia, though most had less depressive symptomatology at the end of treatment. There was neither a linear nor curvilinear relationship between total plasma level of IMI plus DMI and clinical response, despite a wide range of both plasma level (77 ng/ml to 986 ng/ml) and outcome. Adolescents with associated separation anxiety had significantly poorer response to treatment of their depressive disorder than those with major depression alone. Poor response was also weakly associated with being female, having endogenous subtype of depression, and having higher plasma IMI (but not DMI) level. In the context of similar studies of IMI on depression in other age groups, it is hypothesized that high levels of sex hormones during adolescence and young adulthood may interfere with IMIs antidepressant effects. It is concluded that other types of antidepressants should be tested in adolescents with major depression.

Sustained release methylphenidate: pharmacokinetic studies in ADDH males.

Methylphenidate is widely used in the treatment of school-age children with attention deficit disorder with hyperactivity (ADDH). It is available in a short-acting (MPH) and a long-acting (MPH-SR) preparation. Nine males with ADDH participated in a 1-day pharmacokinetic study following a single morning dose of 20 mg. MPH-SR. Data are presented on MPH-SRs half-life (T 1/2), peak concentrations achieved (Cmax) and the time to the peak plasma concentrations (Tmax). Similar data were gathered from a second group of eight ADDH males treated with a higher, single morning dose of standard, short-acting MPH. After adjusting for dose differences, comparisons of the two sets of plasma concentration curves suggest that MPH-SR has a longer Tmax, but that it does not reach the same Cmax as an identical dose of standard MPH.

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.

MAOIs in adolescent major depression unresponsive to tricyclic antidepressants.

Abstract Many adolescents with major depressive disorder have at most partial response to standard tricyclic antidepressants despite appropriate dosage and adequate length of treatment. This paper reports a series of 23 such adolescents who were treated with monoamine oxidase inhibitors (MAOIs). Seventy-four percent of this group achieved good or fair antidepressant response, 57% had both good or fair response and continued dietary compliance. There were few serious side effects. Special attention must be paid to subject selection for treatment with MAOIs because of the risk of impulsive or accidental dietary transgression. This retrospective chart review strongly suggests the need for controlled studies of MAOI treatment in adolescents with tricyclic antidepressant refractory major depression.

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.

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.

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.

Psychometrics of Neurological Soft Signs

OBJECTIVE To examine the psychometrics of neurological soft signs in young children. METHOD In a sample of 42 children from the community, two examiners simultaneously rated soft signs using a standardized examination. A subsample (n = 33) was reexamined twice over the next week to estimate test-retest reliability. RESULTS Total score exhibited acceptable internal consistency as well as interrater and test-retest reliability. Psychometrics for individual items appeared less satisfactory than for the total score. DISCUSSION Although examiners can reliably rate a variety of soft signs, more research examining test-retest reliability is needed. A reliable examination might be useful in future efforts to document the neuropsychiatric correlates of soft signs.

Relative Safety of Single Versus Divided Dose Imipramine in Adolescent Major Depression

Abstract Twenty-nine adolescents with Major Depressive Disorder were treated with imipramine on a t.i.d. dosage schedule for 3 weeks titrating to a maximal 5.0 mg/kg/day as limited by side effects (X = 4.5 ± 0.7). They were then randomly divided into two groups: 16 received their total dose at 10 P.M., after standard divided doses at 7 A.M. and 3 P.M. that same day, and then no more imipramine during the subsequent 24 hours, whereas 13 continued t.i.d. dosage. EKG and plasma TCA levels in both groups were serially examined over the next 24 hours. There were no significant differences between groups in the per subject means or maxima of any EKG parameter. These data suggest that a once daily dosage schedule for imipramine is safe in adolescents once they are at steady rate. Although there was a strong relationship between the tricyclic plasma levels and EKG parameters throughout the day, EKG parameters cannot be used to predict plasma levels—there was wide variation in this relationship between individuals, and even within individual adolescents the plasma level could change over a wide range without any change in EKG parameters.

Improving the methods for evaluating the safety of psychotropic medications in children and adolescents

Abstract Background: Given the considerable importance of drug safety in children and adolescents and the potential effects of psychotropic medications on growth rates and developing central neurotransmitter systems, there is a need for valid methods for detecting possible drug-induced adverse events during prolonged exposure. Objectives: The aims of this study were to discuss challenges involved in the collection of safety information on psychotropic medications when administered to children and adolescents and suggest methods for improving existing approaches. Methods: Current methods for collecting and assessing safety data during pediatric psychopharmacological trials are critiqued and possible alternatives reviewed. Results: Methods used for collecting and assessing drug safety data remain less sophisticated than efficacy evaluations. Multisite trials, although demonstrating statistical power to detect placebo/active drug differences, remain too small to detect infrequent but serious drug-related adverse events. Other active surveillance approaches, such as long-duration follow-up studies and clinical epidemiological studies, using case-control, cohort designs, or trend analysis of population-based treatment data must be used. Conclusions: Research is needed to standardize the basic ascertainment approaches, definitions of adverse events, lists of preferred terms, and recording procedures to a common core battery. A possible approach to developing and testing these procedures is proposed. Then more detailed lists of drug-related adverse events can be added, which can be study specific. The increasing use of psychotropic medications in youths should be accompanied by increased efforts to standardize the ascertainment of drug-related adverse events.