Pediatric Psychopharmacology Research Research Articles

Link Found Between Glutamate, Adolescent Bipolar Disorder

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessLink Found Between Glutamate, Adolescent Bipolar DisorderVabren WattsVabren WattsSearch for more papers by this authorPublished Online:17 Jul 2014https://doi.org/10.1176/appi.pn.2014.7a17AbstractGlutamte may serve as a potential biomarker to predict pathophysiologies of specific psychiatric disorders in youth.For decades, researchers have suggested that glutamate is the most prominent excitatory neurotransmitter in the brain, yet its specific role in psychiatric disorders is still unclear. To shed light on the actions of glutamate, a team of scientists from Massachusetts General Hospital investigated how dysregulation of the glutamatergic system can have negative consequences for mental health—in particular, bipolar disorder in children and adolescents. Andrea Spencer, M.D., hopes her systematic review of child and adolescent bipolar disorder will spark more researchers to examine the consequences of glutamatergic dysregulation on pediatric psychiatric disorders.Massachusetts General Hospital“There has been an increased interest in glutamatergic regulation in both adult and pediatric bipolar disorder,” Andrea Spencer, M.D., an instructor and researcher in psychiatry at Massachusetts General Hospital, said in an interview with Psychiatric News. “What is interesting for us as child and adolescent researchers is that glutamate is involved in the development of the brain.”As the major excitatory neurotransmitter, glutamate plays a critical role in brain function, adaptation of the brain in response to external stimuli, and brain maturation. Malfunction of the glutamatergic system has been associated with multiple psychiatric disorders, many of which have their onset in childhood, Spencer said. “We know that mood disorders often start in childhood,” she noted. “It is very important that we not only investigate the association of glutamate with the pathophysiology of adult bipolar disorder, but also investigate such association as it relates to pediatric bipolar disorder.”To explore whether such a link exists, Spencer and colleagues conducted a systematic review of the literature that examined glutamatergic dysregulation as it relates to all psychiatric disorders in children and adolescents. To meet inclusion criteria, the studies were required to have measured glutamatergic metabolites—glutamate, glutamine, or both—via magnetic resonance spectroscopy (MRS), a noninvasive method that detects protons of a chemical compound in a specified region of the brain.The results, which were presented at an APA annual meeting session in May titled “Advances in Pediatric Bipolar Research,” showed that decreased concentration of glutamatergic metabolites was consistently associated with children who had a diagnosis of bipolar disorder, compared with those without a bipolar disorder diagnosis. Metabolite levels were more likely to normalize in those who were administered medication as a treatment for the mood disorder.In addition, major depressive disorder in children was associated with low levels of glutamatergic metabolites, while other psychiatric disorders, such as attention-deficit/hyperactivity disorder and autism spectrum disorder, were found to be associated with elevated levels of glutamatergic metabolites. “It was important that we looked at all child and adolescent psychiatric disorders, because there can be so much overlap [such as in symptomatology] of the disorders,” Spencer explained. She said that the research approach was necessary to assess the potential for biomarkers—such as glutamate—to predict pathophysiologies of specific mental disorders in youth.Spencer noted that the current findings from her group have generated numerous hypotheses about glutamatergic regulation in bipolar illness and other psychiatric disorders that develop in childhood. “Right now we do not know a lot about the variability of glutamatergic metabolites in bipolar disorder. We really hope that this specific work will catalyze interest in examining glutamatergic regulation in child and adolescent psychopathology,” Spencer concluded.The research was supported by the Pediatric Psychopharmacology Research Council Fund. ■A video interview with Psychiatric News can be accessed here. ISSUES NewArchived

Pediatric psychopharmacological research in the post EU regulation 1901/2006 era.

Although the use of psychotropic medications in child and adolescent psychiatry in Germany is on the increase, most compounds are in fact prescribed "off-label" because of a lack of regulatory approval in these age groups. In 2007, the European Parliament introduced Regulation 1901/2006 concerning medicinal products in pediatric populations, with a subsequent amendment in the form of Regulation 1902/2006. The main aim of this legislation was to encourage research and clinical trials in children and adolescents, and thus promote the availability of medications with marketing authorization for these age groups. Furthermore, initiatives such as the European 7th Framework Program of the European Union now offer substantial funding for pediatric pharmacological research. At a recent Congress of the German Society for Child and Adolescent Psychiatry and Psychotherapy (DGKJP), experts from the field and the pharmaceutical industry held a symposium with lay representatives in order to discuss attitudes toward, and experience with, pediatric psychopharmacology research in Germany since 2007. Several areas of concern were identified. The present paper derives from that symposium and provides an overview of these opinions, which remain crucial to the field. A wider discussion of how to facilitate psychopharmacological research in Germany in order to optimize the treatment and welfare of children and adolescents with psychiatric disorders is now warranted.

Empirical Examination of the Potential Adverse Psychological Effects Associated with Pediatric fMRI Scanning

Over the past decade, the number of functional magnetic resonance imaging (fMRI) studies has increased dramatically. As MRI scans may be anxiety provoking, performing them in a research setting, particularly with children already prone to anxiety, raises questions about ethics as well as methodological feasibility. It is essential to address these questions before expanding the use of this technique to clinical settings, or more widely in the context of pediatric psychopharmacology and biological psychiatry research. The current study investigates the psychological reactions of anxious and non-anxious children and non-anxious adults to an fMRI scan. Eighty-seven anxious children, 140 non-anxious children, and 98 non-anxious adults rated their emotional reactions to an fMRI scan. Results indicated that anxious and non-anxious children reported no greater anxiety after fMRI scanning than did adults. In addition, no age-related differences in distress were observed. These data demonstrate that anxious children, healthy children, and healthy adults have similar emotional reactions to fMRI scanning. The observed findings suggest that the potential for fMRI to produce anxiety should not impede its widespread use in clinical research, psychopharmacology, and biological psychiatry.

Long-Term Follow-Up Study of Patients With Refractory Obsessive-Compulsive Disorder

Long-Term Follow-Up Study of Patients With Refractory Obsessive-Compulsive Disorder

Child and adolescent schizophrenia: pharmacological approaches

Background: Childhood-onset schizophrenia is a serious, chronic and disabling illness that can significantly affect the quality of life of the affected individuals and their families. The affected children commonly show significant premorbid developmental impairment and social abnormalities that may provide an early clinical clue to pursue treatment. Until recent times, treatment approaches for childhood schizophrenia were derived from the adult population. However, given the unique developmental challenges in the pediatric population, this extrapolation may not hold true. Objective: This review encompasses and elaborates on the efficacy, safety and tolerability data available at present for both typical and atypical antipsychotics for treatment of childhood schizophrenia. Method: A literature search was conducted on PUBMED with special emphasis on double-blind placebo-controlled studies in childhood schizophrenia. Data from similar studies presented in recent meetings were also added to the review. Conclusions: Recent research in pediatric psychopharmacology has led to the Food and Drug Administration's approval of two atypical antipsychotics for the treatment of schizophrenia. Although data in this age group are still sparse, research in this unique population has grown over the years.

Research in child and adolescent psychopharmacology: recent accomplishments and new challenges

Research in pediatric psychopharmacology has expanded considerably in the last 10 years. Still, controversy remains about the effectiveness and safety of commonly used psychotropics and their role in child treatment, thus pointing to the need for more in-depth and targeted investigations. To review recent accomplishments and current limitations of pediatric psychopharmacology, and discuss approaches to further research. Selective review of the relevant literature and research in progress. Controlled clinical trials have been conducted in many common psychiatric disorders in children and adolescents, thus providing a basis on which evidence-based treatment guidelines can be constructed. Little innovation has, however, occurred in treatment development and testing. Safety concerns are prominent and have a major influence on clinical practice and drug utilization. While a research infrastructure has been successfully built for conducting pediatric clinical trials, important aspects such as long-term treatment effects, optimal sequencing and individualization of interventions, and integration of neuroscience findings into innovative, theory-driven treatment development remain to be addressed.

Child and Adolescent Psychopharmacology in the New Millennium: A Workshop for Academia, Industry, and Government

To give academic researchers, government officials, and industry scientists an opportunity to assess the state of pediatric psychopharmacology and identify challenges facing professionals in the field. Increased federal spending and the introduction of pediatric exclusivity led to large increases in pediatric psychopharmacology research in the 1990s. Despite the increase in research, concerns exist about methods and incentives for making new medications available for use in pediatric psychiatric disorders. In recognition of these concerns, the Duke Clinical Research Institute held a roundtable in September 2004. Participants from the National Institutes of Health, regulatory agencies, academia, and the pharmaceutical industry spoke about the effects of government regulations such as the U.S. Food and Drug Administration Modernization Act and the Pediatric Research Equity Act on pediatric research from academic, clinical, and industry perspectives, and bioethical considerations of such research. To ensure development of new drugs for treating psychiatric disorders in children and adolescents, we must address the challenges posed by the regulatory environment governing pediatric psychopharmacology research. Strategies were identified for improving the evidence base for psychopharmacologic interventions in youth before widespread use and for more effectively defining a research agenda for the future.

Ethical considerations in psychopharmacological research involving children and adolescents.

Increased community utilization of psychotropic medications among children has brought attention to pediatric psychopharmacology research and associated ethical issues. To discuss ethical aspects of child participation in psychopharmacology protocols. Selective review of relevant scientific and regulatory literature. Efficacy and safety of psychotropics in children cannot be entirely inferred from adult data and direct participation of children in research is necessary. Child research must follow special regulations that are in addition to those common to all human research. For research with prospect of direct benefit, a critical factor is whether the risk/benefit ratio is favorable to the participating child. For research without such a prospect, the concepts of minimal risk and minor increase over minimal risk apply. However, the interpretation and application of these principles to specific protocols vary across settings and among ethics committees. Thus far, little empirical investigation has been conducted on children and parents' motivation for research participation, effectiveness of the informed consent and assent procedures, possibility of persistent consequences of exposure to experimental treatments and placebo, and validation of the concepts of minimal risk and minor increase over minimal risk. Research on human subject issues relevant to child participation is a promising approach to improving ethical methods and procedures of pediatric psychopharmacology.

Prescribing of psychotropic medications for children by Australian pediatricians and child psychiatrists.

To describe the pattern of prescribing of psychotropic medications for Australian children. Australia-wide cross-sectional postal survey conducted in 2000. All registered general pediatricians and child and adolescent psychiatrists. The survey was completed by 435 general pediatricians and 187 child and adolescent psychiatrists (response rates 72% and 70%, respectively). Stimulants and clonidine were the most frequently prescribed medications. Seventy-two percent of practitioners reported that they had prescribed a combination of medications. Frequent combinations included a stimulant and clonidine (64% of pediatricians, 51% of child psychiatrists) and a stimulant and a selective serotonin reuptake inhibitor (SSRI; 29% of pediatricians, 36% of child psychiatrists). Pediatricians were more likely than child psychiatrists to report prescribing clonidine for sleep problems (67% vs 36%). Child psychiatrists were more likely than pediatricians to report prescribing SSRIs (93% vs 75%) and mood stabilizers (45% vs 11%) for depression, and SSRIs (74% vs 50%) and tricyclic antidepressants (37% vs 12%) for obsessive compulsive disorder. Off-label prescribing (indication or age not included in the product information) was reported by 40%. Over 5% of practitioners in this study had prescribed clonidine, methylphenidate, dexamphetamine, and typical neuroleptics for children under 3 years of age. A broad range of psychotropic medications are being prescribed for Australian children, with some medication groups being prescribed frequently. Combinations of psychotropic medications are used regularly, and there is some prescribing for very young children. The safety and efficacy of several of the agents prescribed have not been adequately researched in children. There is an urgent need for pediatric psychopharmacology research to inform current prescribing practice.

Pediatric Psychopharmacology

This paper reviews research in pediatric psychopharmacology over the past decade. The authors first discuss social, economic, and other influences on pediatric psychopharmacology research and prescribing patterns including changing models of childhood psychopathology, increased government funding, and changes in industry regulations. Definitions are offered for current research terminology including efficacy, effectiveness, and adverse events. Design trends and new approaches to outcome measurement are also presented. New data from the last 10 years of research is reviewed for each major class of psychotropic agents. Criteria for inclusion in the review are presented and include aspects of study design (placebo‐controlled, large sample size), source of funding (government funded vs. industry), and vision (creative applications). Data for short‐term efficacy, long‐term efficacy, effectiveness, and safety and adverse events are discussed for each class of medication, although for many, there remains little empirical data. Findings for stimulants, selective serotonin reuptake inhibitors, neuroleptics, alpha‐adrenergic agonists, mood stabilizers, buproprion, secretin, naltrexone, immune therapies, and natural supplements are all presented. Finally, the authors offer some speculations regarding the future of pediatric psychopharmacology research.

Current research highlights in child and adolescent psychopharmacology

Recent efforts to stimulate research in pediatric psychopharmacology have resulted in increased interest in the effects of psychotropic medications in children and adolescents. This interest is reflected in the number of studies that have been reported or initiated during the past year. As a means of providing a brief update on the progress of child psychopharmacology, research reports either published or presented at national meetings in 1999 are selectively reviewed here. Relevant initiatives recently started under the sponsorship of the National Institute of Mental Health (NIMH) are also reviewed. Most studies have been directed at testing treatments of attention deficit hyperactivity disorder (ADHD), but also studies of the selective serotonin reuptake inhibitors in patients with obsessive compulsive disorder, depression, and anxiety disorders are well represented. The efforts of NIMH to focus on effectiveness research and direct comparisons of pharmacologic, psychosocial, and combined treatment modalities are apparent in recent initiatives in ADHD and depression. Research of treatments for youths with bipolar disorder, schizophrenia, autism, and eating disorders is still scanty and in urgent need of expansion.

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 well-designed 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.

Medication development and testing in children and adolescents. Current problems, future directions.

Progress in pediatric psychopharmacological research has suffered notable delay, especially compared with the achievements in adult psychopharmacology. Although safety and efficacy of the use of many psychotropic agents in children remain largely unproved, their pediatric use has been increasing and their widespread off-label prescribing by practitioners has raised some important concerns. The National Institute of Mental Health, in cooperation with the Food and Drug Administration and leading researchers, has coordinated systematic efforts to identify the major obstacles to research in pediatric psychopharmacology and to propose feasible solutions. In 1995, a conference cosponsored by the national Institute of Mental Health and the Food and Drug Administration gathered more than 100 research experts, family and patient advocates, and representatives of mental health professional associations. Participants met in working groups focused on specific aspects of child research and reached consensus on various recommendations. Each of the various aspects relevant to conducting research in this area (methodological, ethical, legal, regulatory, financial, and family or community context) presents specific challenges, which are herein outlined. Recommendations for possible solutions are presented, some of which are being implemented. Because data about drug safety and efficacy in adults can rarely be extrapolated to children, there is no substitute for pediatric psychopharmacological research. Successful strategies for overcoming the many obstacles with which this research has to contend must enlist the concerted efforts of all the relevant parties (investigators, clinicians, industry, federal agencies, ethicists, families, and community representatives).

Regulatory Issues in Pediatric Psychopharmacology

Labeling claims for the effectiveness of drugs in the treatment of psychiatric illnesses in children and adolescents must be based on data from adequate and well-controlled investigations. The preferred design for demonstrating the effectiveness of a drug in pediatric psychopharmacology is generally a placebo-controlled trial. Safety information in labeling may be derived from more diverse sources. The Food and Drug Administration (FDA) has taken several steps to encourage more informative labeling of drugs for pediatric use, including a recent labeling initiative that emphasizes the possibility of extrapolating effectiveness data from adult studies to pediatric populations under appropriate circumstances. This recently finalized regulation requires pharmaceutical sponsors to reexamine existing data for their drugs to determine whether there is a sufficient basis for modifying labeling for pediatric use. Included in this new rule is a reminder that in certain situations the FDA may require new pediatric studies, thereby signaling the FDA's determination to improve labeling for the pediatric use of drugs. Improved preclinical models for predicting drug effects on growth and development, as well as improved clinical methods for detecting such changes, need to keep pace with the expansion of research in pediatric psychopharmacology.

Psychiatric syndromes in adolescent substance abusers

Conduct disorder, major depressive episode, and the combination of attention deficit, hyperactivity, and impulse disorder were the most prevalent diagnoses after detoxification among 57 adolescents consecutively referred to an inpatient facility for treatment of substance abuse and other concurrent psychiatric disorders.

Manic-depressive variant syndrome of childhood: a preliminary report

The author describes the specific diagnostic entity of manic-depressive variant syndrome of childhood and outlines the five essential diagnostic criteria (affective storms, family history of significant affective dysfunction, hyperactivity, chronically disturbed personal relationships, and absence of psychotic thought disorder) and the five secondary criteria (sleep disturbances, minimal brain dysfunction, abnormal EEG, enuresis, and neuropathology). In the four cases reported, the children, when properly diagnosed, responded well to lithium therapy. The author points out the need for further study of this syndrome. Precautions about the use of lithium in children under age 12 are crucial, as is the need for continuing psychotherapy for parents and child.