Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents

OBJECTIVE: Despite increasing use of psychotropic medications in children and adolescents, data regarding their efficacy and safety are limited. Endocrine and metabolic adverse effects are among the most concerning adverse effects of commonly used psychotropic medications. METHOD: Selective review of endocrine and metabolic effects of psychotropic medications in pediatric populations, with a focus on monitoring and management strategies. RESULTS: Because youth are still developing at the time of psychotropic drug exposure, most reference values need to be adjusted for gender and age. As in adults, youngsters receiving lithium require monitoring for thyroid dysfunction. Psychostimulants appear to cause mild reversible growth retardation in some patients, most likely because of decreased weight or slowing of expected weight gain; some patients may experience clinically significant reductions in adult height. Although still controversial, valproate use has been associated with an increased risk for polycystic ovary syndrome, in addition to causing weight gain. Although more data are required, children and adolescents appear to be at higher risk than adults for antipsychotic-induced hyperprolactinemia, weight gain, and possibly, associated metabolic abnormalities, which is of particular concern. CONCLUSIONS: Clinicians and caregivers need to be aware of potential endocrine and metabolic adverse effects of psychiatric medications. A careful selection of patients, choice of agents with potentially lesser risk for these adverse events, healthy lifestyle counseling, as well as close health monitoring are warranted to maximize effectiveness and safety.     

Second-generation antipsychotic medications in children and adolescents

OBJECTIVE: We reviewed available pediatric literature on second-generation antipsychotic medications to assess current evidence of efficacy and safety. METHOD: An English language MEDLINE search (1974-2003) was conducted using key words-atypical antipsychotics, children and adolescents, toxicity, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. Additional efficacy and safety data were obtained from drug manufacturers. RESULTS: We identified 176 reports, including 15 double-blind, controlled trials, 58 openlabel studies, 18 retrospective chart reviews, and 85 case series/reports. The majority of these studies (43%) were of risperidone. Evidence suggests that second-generation antipsychotics are efficacious in the treatment of psychosis, bipolar disorders, pervasive developmental disorders, and Tourette's Disorder, and are potentially useful in mental retardation, conduct disorder, and severe attention deficit hyperactivity disorder (ADHD). The most frequently reported side effects included cardiovascular effects, weight gain, sedation, sialorrhea, extrapyramidal signs, and hyperprolactinemia, although the relative frequencies of these untoward effects vary among medications. CONCLUSION: Although the evidence base for pediatric use of second-generation antipsychotics is expanding, the majority of available studies are anecdotal, or short-term, openlabel trials. Reports suggest that these compounds are effective for a variety of psychiatric disorders in children and adolescents, but additional double-blind, controlled studies are required to establish definitive efficacy. Although these medications appear to be well tolerated in short-term studies, long-term follow-up investigations and ongoing clinical monitoring are necessary to confirm their safety in this age group.     

The relevance of pharmacokinetic studies in designing efficacy trials in juvenile major depression

INTRODUCTION: Identifying evidence-based dosing strategies is a key part of new drug development in pediatric populations. Pharmacokinetic (PK) studies can provide important information regarding how best to dose medications in children and adolescents. Utilizing scientifically supported dosing strategies provides the best chance for any given drug to demonstrate both efficacy and acceptable tolerability in definitive, placebo-controlled studies. METHODS: Results of both PK studies and randomized, placebo-controlled efficacy trials (RPCTs) in juvenile major depressive disorder (MDD) are reviewed. The degree to which the medication dosing strategies that were employed in the efficacy studies were supported by the extant PK data is considered. Medications that are reviewed include fluoxetine, sertraline, paroxetine, citalopram, escitalopram, venlafaxine, nefazodone, and mirtazapine. RESULTS: In many instances, the dosing paradigms that were used in the RPCTs differed, sometimes substantially, from the dosing strategies that would have been supported based on the results of PK studies. CONCLUSIONS: Medication dosing regimens may have contributed to the failure of several RPCTs to show drug efficacy in the treatment of pediatric MDD. In addition, the doses of medication used in these RPCTs may also have contributed to the safety and tolerability concerns that have been raised with these drugs. PK and dose-ranging studies should be performed prior to the initiation of definitive efficacy trials so that empirically supported dosing strategies can be incorporated into the design of RPCTs of antidepressants in children and adolescents suffering from MDD.     

Pharmacologic treatment of anxiety disorders in children and adolescents

This article reviews the pharmacologic treatment of anxiety disorders in children and adolescents. These disorders are quite common and can be considered a "silent epidemic" because they are more often reported by the children and adolescents than by their parents. Tricyclic antidepressants (TCAs), benzodiazepines, buspirone, and selective serotonin reuptake inhibitors (SSRIs) have been used to treat anxiety disorders in children and adolescents with varying degrees of success. Considering safety and efficacy, the SSRIs appear to be the first-line treatment for anxiety disorders in youth, but more studies are needed to confirm preliminary results. Tricyclic antidepressants and benzodiazepines may be considered when the child has not responded to SSRIs or when adverse effects have exceeded benefits. Although nonpharmacologic approaches for the treatment of anxiety in children and adolescents are beyond the scope of this article, their importance is to be underscored and they should be considered as part of the treatment plan. Over the next decade, research data will be generated regarding the treatment of anxiety disorders in youth. Ongoing research studies include the use of fluoxetine (B. Birmaher, personal communication, 1999) and fluvoxamine (J. Walkup, personal communication, 1999) for the treatment of generalized anxiety disorder, separation anxiety disorder, or social phobia; and buspirone for generalized anxiety disorder in children. Despite these efforts, there is a need for more studies to examine the safety and efficacy of different pharmacologic treatments, as well as longitudinal studies to monitor for long-term tolerability and side effects. Pharmacokinetic studies for children and adolescents will provide information on the metabolism and absorption of these medications and delineate the developmental differences between children and adolescents when compared to adults. Finally, and perhaps most importantly, studies that compare medication, psychosocial treatments, and their combination are needed.     

Treatment of children and adolescents with multiple sclerosis

The onset of multiple sclerosis is being increasingly recognized in children and adolescents. There are now approved immunomodulatory therapies for adults with multiple sclerosis. Treatment early in the disease course appears to have a greater impact on disease outcome, an issue of particular importance for children who face decades of multiple sclerosis disease activity. This review summarizes the multiple sclerosis therapies currently available, efficacy data available from studies of these medications in adults and limited information on the use of these medications in children. Future directions in multiple sclerosis therapeutics and specific issues relating to pediatric multiple sclerosis are discussed.     

Anxiolytics, adrenergic agents, and naltrexone

OBJECTIVE: To review extant data on the efficacy and safety of anxiolytic medications (benzodiazepines, buspirone, and other serotonin 1A agonists), adrenergic agents (beta-blockers and alpha 2-adrenergic agonists clonidine and guanfacine), and the opiate antagonist naltrexone that have been used to treat various psychopathologies in children and adolescents. To identify critical gaps in our current knowledge about these agents and needs for further research. METHOD: All available controlled trials of these medications in children and adolescents published in English through 1997 were reviewed. In addition, selected uncontrolled studies are included. RESULTS: The major finding, that there are virtually no controlled data that support the efficacy of most of these drugs for the treatment of psychiatric disorders in children and adolescents, is both surprising and unfortunate. For some drugs, e.g., buspirone and guanfacine, this is because no controlled studies have been carried out in children and/or adolescents. For other drugs, e.g., clonidine and naltrexone, most of the placebo-controlled studies have failed to demonstrate efficacy. CONCLUSIONS: The strongest recommendations for controlled studies of safety and efficacy in children and adolescents can be given for the following drugs: benzodiazepines for acute anxiety; buspirone (and newer serotonin 1A agonists as they become available) for anxiety and depression; beta-blockers for aggressive dyscontrol; guanfacine for attention-deficit/hyperactivity disorder; and naltrexone for hyperactivity, inattention, and aggression in autistic disorder.     

Pharmacotherapy of child and adolescent depression

Pediatric depression is a prevalent and recurrent condition that persists into adulthood and carries significant impairment, morbidity, and risk of mortality. Although there has been a surge of pediatric antidepressant studies in recent years, depression remains largely understudied, unrecognized, and untreated in children and adolescents. Few antidepressant trials have yielded positive results in pediatric depression. Regulatory agencies recently issued warnings against the use of selective serotonin reuptake inhibitors and newer antidepressants in depressed children and adolescents because of a possible link between their use and the appearance or worsening of suicidal ideation or attempts. The authors review data on efficacy and safety of antidepressants for the treatment of pediatric depression to provide treating clinicians with a basis on which to guide their treatment recommendations.     

Selective serotonin reuptake inhibitors for children and adolescents

The controlled studies of selective serotonin reuptake inhibitors (SSRIs) in pediatric psychopharmacology research lag behind the controlled studies of SSRIs in adults. As a result, widespread use of SSRIs in the treatment of child and adolescent psychiatric disorders is in stark contrast to the paucity of research data. Recent changes in the research climate (including support from the National Institute of Mental Health, the Food and Drug Administration, and industry) have encouraged welldesigned SSRI studies in pediatric psychopharmacology, and will ultimately provide needed information to guide treatment. This paper reviews the best available data from pediatric SSRI trials, including 10 double-blind placebo-controlled trials, and two abstracts of open-label continuation studies of SSRIs associated with large pediatric efficacy studies. Adverse events (AEs) of SSRIs in children and adolescents are discussed in reference to available pediatric studies. Recent pharmacokinetic studies of SSRIs in children and adolescents are reviewed. Future SSRI research strategies are also discussed.     

Pharmacotherapy of depressed children and adolescents: current issues and potential directions.

The recent deliberations by the U.S. Food and Drug Administration (FDA) regarding the relationship between antidepressants and suicidality in children have incited debates about the safety of these medications for the treatment of pediatric depression. In light of these events, this review discusses four issues pertaining to pharmacotherapy for pediatric depression. First, we summarize pertinent data from randomized controlled trials of antidepressants for pediatric depression. These data provide strong support for fluoxetine and modest support for the other antidepressants. Second, we examine the outcome of the FDA meta-analysis of the data on antidepressant-induced suicidality, with specific emphasis on the methodological limitations of this analysis. Third, we consider the collective implications of the antidepressant efficacy and suicidality data on clinical practice. Specifically, we present several compelling arguments that justify the continued use of antidepressants for pediatric depression, despite the inherent limitations of these medications. Finally, we review several pathophysiological factors that might provide insights into treatment response and impact the design of future pharmacotherapy studies of depression. These factors relate to diagnostic heterogeneity, developmental consistency, and psychobiology. Potentially novel pharmacotherapies are also discussed.     

Inflammatory Bowel Disease in Children: Psychological and Psychiatric Issues

The overlap between inflammatory bowel disease (IBD) and psychiatric disorders has been studied extensively. We reviewed the limited literature targeting the complex relationship between IBD and psychiatric disorders in children and adolescents. Findings from this review were compared with findings from available studies in adults. Results reflecting an association between IBD and psychiatric illnesses were observed in children and adolescents and were consistent with results in adults. In adults with IBD, many studies have reflected the advantages of psychotherapeutic treatment, including faster recovery, improved quality of life, and reduced health care use. Unfortunately, such studies are scarce in the child and adolescent population. Psychopharmacologic studies also are limited in adult and pediatric populations. At this time, the literature on treatment of the pediatric IBD population remains minimal, and the need to study screening and treatment modalities is critical.     

The treatment of anxiety disorders in children and adolescents.

Anxiety disorders are the most common psychiatric conditions in the pediatric population, with prevalence estimates ranging from 5-18%. Children and adolescents with excessive anxiety often meet diagnostic criteria for a number of disorders within the DSM-IV. Unfortunately, the current diagnostic system is controversial because of high rates of symptom overlap, comorbidity with other psychiatric disorders, and lack of biological markers that would support a more empirical anxiety nosology. Treatment strategies for pediatric anxiety disorders have important historical roots. Several controlled studies of cognitive-behavioral therapy (CBT) demonstrate efficacy for pediatric anxiety disorders. In contrast, no controlled psychopharmacology studies have demonstrated efficacy in children and adolescents with anxiety disorders, except obsessive-compulsive disorder; however, several large, methodologically sound psychopharmacotherapy trials are underway for pediatric anxiety disorders. This update will review the current status of psychosocial and psychopharmacologic treatment of pediatric anxiety disorders. In addition, a brief discussion of nosology, epidemiology, and developmental course of anxiety is included. Preliminary psychopharmacology treatment and CBT treatment algorithms are presented for pediatric anxiety disorders, based on the best available data. Recommendations for future research directions are also discussed.     

Selective serotonin reuptake inhibitors and depression in the child and adolescent

Child and adolescent depression is a serious psychiatric disorder with a considerable impact on psychosocial functioning, and an associated risk of mortality due to suicide. The potential interest of selective serotonin reuptake inhibitors (SSRI) for child and adolescent depression treatment is now well recognized. Since a recent date, this class of antidepressants is recommended as first-line medication (18, 24). Open studies have shown a response rate to SSRI from 60% to 75% and their efficiency was demonstrated through a controlled trial of high methodological quality, conducted by Emslie et al. in 1997 (10). The side effects of SSRI are generally mild and seldom require to discontinue the treatment. Research on this domain is tending toward increasing data on the efficacy, safety and pharmacokinetics of SSRI on children and adolescents. The different SSRI specificities and the potentialisation of these compounds by a molecule of the same class, or by other medications (lithium, buspirone, triodothyronine), are currently studied. It seems useful to us to do a review of this category of antidepressants, even though data are incomplete; it has not gone through AMM approval in children below the age of 15, but it appears to be efficient and promising.     

Mood disorders in children and adolescents: psychopharmacological treatment.

Mood disorders are the leading causes of morbidity and mortality in children and adolescence. As a result, many adolescents are treated with psychopharmacologic agents such as antidepressants and mood stabilizers. To date, research into the safety and efficacy of these medications has lagged behind clinical practice. Several controlled trials of antidepressants in this population have recently been completed or are ongoing, yet few controlled trials of mood stabilizers have been conducted. Although acute efficacy of antidepressants is being addressed, many questions remain about pharmacological treatment of early-onset mood disorders. This article will focus on unmet research needs for the psychopharmacologic treatment of child and adolescent mood disorders.     

Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents

Although second-generation antipsychotics (SGAs) are used increasingly in children and adolescents, data on the effectiveness and safety in pediatric populations are still sparse. Much of the safety information is derived from studies conducted in adults. This derivation is problematic because children and adolescents are exposed to SGAs during a phase of unparalleled physical and psychologic development that can affect pharmacokinetic and pharmacodynamic drug actions, efficacy, and side-effect patterns. This article presents an overview of SGA-related side effects in children and adolescents and strategies to monitor health outcomes effectively in youngsters receiving SGAs.     

Panic disorder in children and adolescents: a review.

OBJECTIVE: Panic disorder has been considered an adulthood disorder that does not occur in children or adolescents. The authors' goals were to critically review the available evidence for panic attacks and/or panic disorder in children and adolescents, to review the limited data on the biological basis of panic disorder as it has been studied in children and adolescents, to discuss the possible treatment approaches for panic disorder in children, and to suggest potential opportunities for further research on panic disorder in children. DATA COLLECTION: Sixty-three articles pertaining to panic disorder in children and adolescents were critically reviewed. These articles included retrospective histories of adults with panic disorder, clinical case reports of children and adolescents with panic disorder, studies of psychiatrically referred children and adolescents, reports from epidemiologic community and school samples of children and adolescents, studies of children and adolescents at risk for psychiatric disorder, reports of panic-like symptoms in pediatric patients, family studies of panic, studies of the biological basis of panic in adults, and studies of treatment for panic. FINDINGS: There is strong evidence that panic disorder occurs in children and adolescents and that its clinical presentation in this population is similar to that found in adults. CONCLUSIONS: Extending the many adult studies of panic disorder to children and adolescents would be extremely fruitful. Like adults with panic disorder, many children and adolescents are brought to emergency and medical clinics for the physical symptoms of unrecognized panic disorder.     

Psychiatric comorbidity in children and adolescents

PURPOSE OF REVIEW: This review critically discusses recent research findings on psychiatry comorbidity in children and adolescent persons. RECENT FINDINGS: Several epidemiological studies have confirmed previous findings in relation to the high rates of psychiatric comorbidity in children and adolescents. In particular, psychiatric comorbidity has been detected in children with substance abuse, and with conduct and oppositional defiant, anxiety and attention deficit-hyperactivity disorders. These studies have also investigated the impact comorbidity has on symptom presentation, outcome and service utilization. Although the presence of concurrent psychiatric disorders in children and adolescents is well established, there has been limited research on the need for different treatment modalities in children suffering from more than one disorder. SUMMARY: It is widely accepted that children and adolescents frequently present with more than one psychiatric diagnosis. The substantial variation in psychiatric comorbidity found in the literature may be due to the different methods of data collection as well as to the classification system used. Whether children and adolescents fulfil diagnostic criteria for a mixed condition (International Classification of Diseases-10) or multiple disorders (Diagnostic and Statistical Manual of Mental Disorders-IV), it is important that the concurrent psychopathology be recognized and treated.     

The selective serotonin reuptake inhibitors controversy in the treatment of depression in children

Antidepressants are widely prescribed for children and adolescents, although data regarding their safety and efficacy are limited. The objective of this article is to review the origins of the controversy regarding the current use of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents. Two chief concerns drive the controversy: 1) the discovery of an increased risk of suicidal behaviors in those treated with SSRIs and 2) the efficacy of SSRIs in childhood and adolescent major depression is unclear. Various factors may account for the reported differences in outcomes for SSRI treatment in children and adolescents compared to adults. The past decade has shown a significant drop in the rate of adolescent suicide, which coincides with the onset of the use of these medications. Therefore, a reduction in the use of SSRIs in children and adolescents should be considered carefully.     

Psychoactive medication prescribing practices for U.S. children: gaps between research and clinical practice

OBJECTIVE: To determine national pediatric prescribing practices for psychotropic agents and to examine these practices in view of the available evidence concerning their safety and efficacy in this age group. METHOD: Prescribing data from 2 national databases based on surveys of office-based medical practices were determined and reviewed vis-à-vis available safety and efficacy evidence. RESULTS: Data indicate that levels of psychotropic prescribing in children and adolescents are greatest for stimulants, resulting in nearly 2 million office visits and 6 million drug "mentions" in 1995. Selective serotonin reuptake inhibitors were the second most prescribed psychotropic agents, while anticonvulsant mood stabilizers (prescribed for a psychiatric reason), tricyclic antidepressants, central adrenergic agonists, antipsychotics, benzodiazepines, and lithium were also prescribed for a substantial number of office visits. Comparison of prescribing frequencies with available safety and efficacy data indicates significant gaps in knowledge for commonly used agents. CONCLUSIONS: Most psychotropic agents require further sustained study to ensure appropriate health care expenditures and vouchsafe children's safety. Recommendations for researchers, parents, federal agencies, and industry are offered as a means to accelerate the pace of research progress.     

Selective serotonin re-uptake inhibitors for children and adolescents

Objectives: 1) To briefly review the scientific basis for the use of selective serotonin re-uptake inhibitors (SSRIs) in children and adolescents. 2) To review the current data on the efficacy, safety and tolerability in children and adolescents. Method: A Medline search back to 1990 was conducted. Review articles and double blind, placebo controlled trials were critically reviewed. Additional hand searches were performed with key journals and in specific areas of interest for this paper. Results: Most of the published papers are from North America. There is an increasing use of SSRIs in child and adolescent psychiatry. The main disorders studied are mood and anxiety disorders. The data supporting efficacy is still limited. The most robust data is the treatment of OCD and depression. Conclusion: Taking the limited data together with clinical experience and with adult studies, there is a valuable role for SSRIs as a component of treatment for various child and adolescent psychiatric disorders.

     

A review of the growing evidence base for pediatric psychopharmacology

This article provides an update of pediatric psychopharmacologic treatment evidence and focuses on six classes of medications in pediatric populations: psychostimulants, mood stabilizers, SSRIs, tricyclic antidepressants, antipsychotic agents, and other agents. The evidence is organized by disorder so that it is most useful to practicing clinicians. We begin each section with a brief introduction and summary of the findings published before January 1998. Priority is given to clinical trials that use random assignment and use of a comparison group (ie, placebo-control, head-to-head comparison, or cross-over design). Serious concerns remain about the efficacy and safety of many of these agents for use in children and adolescents. While a great progress is being made, there is clearly much work left to be done.