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.

How can we improve the assessment of safety in child and adolescent psychopharmacology?

OBJECTIVE: To identify approaches to improving methods for assessing tolerability and safety of psychotropic medications in children and adolescents. METHOD: Strengths and limitations of current methodology were reviewed and possible alternatives examined. RESULTS: Research on the validity of safety evaluation has been extremely limited. No evidence-based "gold standard" exists. Clinical trials remain the best design to establish causality, but sample size limitations prevent the detection of infrequent, though serious, adverse events. Other designs, such as cohort and case-control studies, and approaches, such as mining of large databases, must be considered. CONCLUSION: The current lack of methodological standardization across studies prevents generalizations and meta-analyses. Because the issues relevant to drug safety are diverse, a variety of methodological approaches and instruments are needed. It is, however, possible to adopt standard basic definitions of adverse events, degree of severity, ascertainment methods, and recording procedures, as a common "core," to which more specific assessment instruments can be added. Systematic empirical testing and validation of safety methodology is needed.

The relevance of prolonged QTc measurement to pediatric psychopharmacology.

OBJECTIVE: To consider the relevance of prolonged QTc (QT interval corrected for rate) to pediatric psychopharmacology. METHOD: The authors reviewed publications on QTc prolongation and publications on sudden death in Medline from 1968 to November 2002. RESULTS: The search yielded more than 20,000 publications. Review manuscripts with clinical recommendations outnumber the few pediatric studies of QTc duration during treatment. Most reviews have been published in the past 5 years, during a time when the Food and Drug Administration restricted five psychotropic medications because of QTc prolongation (sertindole: not approved; thioridazine, mesoridazine, and droperidol: black-box warning; and ziprasidone: bolded warning) and nine somatic medications because of QTc prolongation. CONCLUSION: Pretreatment screening, careful selection of psychotropic and/or somatic medication combinations, and recognition of QTc prolongation in electrocardiographic tracings during treatment with medications that prolong QTc are important components of clinical practice.

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.

Searching for moderators and mediators of pharmacological treatment effects in children and adolescents with anxiety disorders.

OBJECTIVE: To examine whether age, gender, ethnicity, type of anxiety disorder, severity of illness, comorbidity, intellectual level, family income, or parental education may function as moderators and whether treatment adherence, medication dose, adverse events, or blinded rater's guess of treatment assignment may function as mediators of pharmacological treatment effect in children and adolescents with anxiety disorders. METHOD: The database of a recently reported double-blind placebo-controlled trial of fluvoxamine in 128 youths was analyzed. With a mixed-model random-effects regression analysis of the Pediatric Anxiety Rating Scale total score, moderators and mediators were searched by testing for a three-way interaction (strata by treatment by time). A two-way interaction (strata by time) identified predictors of treatment outcome. RESULTS: No significant moderators of efficacy were identified, except for lower baseline depression scores, based on parent's (but not child's) report, being associated with greater improvement (p < .001). Patients with social phobia (p < .05) and greater severity of illness (p < .001) were less likely to improve, independently of treatment assignment. Blinded rater's guess of treatment assignment acted as a possible mediator (p < .001), but improvement was attributed to fluvoxamine, regardless of actual treatment assignment. Treatment adherence tended to be associated (p = .05) with improvement. CONCLUSIONS: In this exploratory study, patient demographics, illness characteristics, family income, and parental education did not function as moderators of treatment effect. Social phobia and severity of illness predicted less favorable outcome. Attribution analyses indicated that study blindness remained intact. The presence of concomitant depressive symptoms deserves attention in future treatment studies of anxious children.

Insomnia in children: when are hypnotics indicated?

Insomnia in children is a nonspecific impairing symptom that may be the result of normal developmental changes, psychosocial duress, a sleep disorder, a psychiatric disorder, other medical disorders, substance misuse, or an adverse effect of medication. Careful clinical assessment of insomnia in children may include the use of symptom rating scales, laboratory testing, or other medical assessment. Short- and long-term treatment of insomnia in children involves management of etiological factors and associated syndromes. Controlled treatment studies of pediatric insomnia are limited to <10 published studies of psychosocial and/or psychopharmacological treatment in young children. Directive parent education and behavior modification techniques have been effective in short-term treatment of insomnia in young children, and may be the preferred treatment of extrinsic insomnia, as well as an important adjunctive treatment of any insomnia symptoms. Two benzodiazepines [flurazepam and delorazepam (chlordesmethyldiazepam)], one antihistamine (niaprazine) and one phenothiazine [alimemazine (trimeprazine)] have been shown to be effective in the short-term treatment of insomnia in young children, although none of these agents have US Food and Drug Administration approval for pediatric insomnia. Short-acting benzodiazepines may have a role in the brief treatment of pediatric insomnia associated with an anxiety or mood disorder, psychosis, aggression, medication- induced activation, or anticipatory anxiety associated with a medical procedure. However, tachyphylaxis and risk of misuse preclude the long-term use of benzodiazepines for the treatment of insomnia in children. Newer hypnotics, which appear better tolerated than the benzodiazepines in studies of adults, may have a role when combined with psychosocial treatments of pediatric insomnia. Treatment of intrinsic pediatric insomnia may additionally involve chronotherapy or medical management.