A growing body of literature has documented pediatric bipolar disorder to be a severely impairing form of psychopathology. However, concerns remain as to the inadequacy of the extant literature on its pharmacotherapy. Furthermore, treatment studies have not been systematically reviewed for treatment effects on core and associated symptoms. Thus, a systematic evaluation and synthesis of the available literature on the efficacy of antimanic pharmacotherapy for pediatric bipolar disorder on symptoms of mania, depression, and attention-deficit/hyperactivity disorder was undertaken.
A systematic search was conducted through PubMed from 1989 through 2010 for open-label and randomized controlled trials published in English on the pharmacotherapy of pediatric mania.
There have been 46 open-label (n = 29) and randomized (n = 17) clinical trials of antimanic agents in pediatric bipolar disorder encompassing 2,666 subjects that evaluated a range of therapeutic agents, including traditional mood stabilizers, other anticonvulsants, second-generation antipsychotics, and naturopathic compounds. This literature has documented that the available armamentarium has different levels of efficacy in the treatment of pediatric mania. Because all psychotropic classes are associated with important adverse effects, a careful risk-benefit analysis is warranted when initiating pharmacologic treatment with any of these compounds. In the limited data available, the effects of antimanic agents on depression and symptoms of attention-deficit/hyperactivity disorder have been, in general, modest. Few studies have evaluated the effects of antimanic agents in children younger than 10 years.
A substantial body of scientific literature has evaluated the safety and efficacy of various medicines and drug classes in the treatment of mania in pediatric bipolar disorder. More work is needed to assess the safety and efficacy of psychotropic drugs in children younger than 10 years, to further evaluate the efficacy of naturopathic compounds, and to further evaluate the effects of antimanic treatments for the management of depression and attention-deficit/hyperactivity disorder.
"Data are emerging from multiple large cross-sectional and longitudinal studies. Most influential are the ''EDSP-Bavarian Catchment'' study (Beesdo et al., 2009), the Course of Bipolar Youth study (Birmaher et al., 2006), the ''Stanley'' study (Findling et al., 2005), the Longitudinal Assessment of Manic Symptoms study (Findling et al., 2010), the Prepubertal and Early Adolescent Bipolar Disorder study (Geller et al., 1998), the Oregon Adolescent Depression Project (Lewinsohn, Klein, & Seeley, 1995), the ''Boston'' study (Wozniak et al., 2011), and the Assessing Bipolar Disorder: A Community-Academic Blend study (Youngstrom et al., 2005). Table 1 provides an overview of these studies' methodologies. "
[Show abstract][Hide abstract] ABSTRACT: The past 25 years has witnessed significant advances in our knowledge of Bipolar Spectrum Disorders (BPSD) in youth. Cross-sectional and longitudinal studies are clarifying the unique features of its pediatric presentation, including continuities and discontinuities across the spectrum of severity. Advances have been made, both in the pharmacological and psychological management of BPSD in youth. Current investigations may ultimately shed light on new treatment strategies. Future research is anticipated to be influenced by NIMH's Research Domain Criteria (RDoC). With this article, we summarize what is currently known about the basic phenomenology of pediatric BPSD, its clinical course, assessment and treatment, beginning with a summary of the major studies that have shed light on the topic. Next, we present a tally and content review of current research as an indicator of trends for the future. Then, we describe what we believe are important future directions for research. Finally, we conclude with implications for contemporary clinicians and researchers.
"Family and other studies document robust patterns of familiality (Schulze et al., 2006, Wozniak et al., 2010, Wozniak et al., 2012), a protracted course (Wozniak et al., 2011) and selective responsivity to antimanic agents (Smith et al., 2007, Correll et al., 2010, Liu et al., 2011). While it clearly affects both sexes, very few studies have addressed whether the sex of the proband influences the clinical presentation of pediatric bipolar disorder. "
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Since little is known as to whether sex differences affect the clinical presentation of pediatric BP-I disorder, it is an area of high clinical, scientific and public health relevance. METHODS: Subjects are 239 BP-I probands (65 female probands, 174 male probands) and their 726 first-degree relatives, and 136 non-bipolar, non-ADHD control probands (37 female probands, 99 male probands) and their 411 first-degree relatives matched for age and sex. We modeled the psychiatric and cognitive outcomes as a function of BP-I status, sex, and the BP-I status-gender interaction. RESULTS: BP-I disorder was equally familial in both sexes. With the exception of duration of mania (shorter in females) and number of depressive episodes (more in females), there were no other meaningful differences between the sexes in clinical correlates of BP-I disorder. With the exception of a significant sex effect for panic disorder and a trend for substance use disorders (p=0.05) with female probands being at a higher risk than male probands, patterns of comorbidity were similar between the sexes. Despite the similarities, boys with BP-I disorder received more intensive and costly academic services than girls with the same disorder. LIMITATIONS: Since we studied children referred to a family study of bipolar disorder, our findings may not generalize to clinic settings. CONCLUSIONS: We found more similarities than differences between the sexes in the personal and familial correlates of BP-I disorder. Clinicians should consider bipolar disorder in the differential diagnosis of both boys and girls afflicted with symptoms suggestive of this disorder.
"Interestingly, these effects were absent in cre-positive GSK3βflox mice. This observation is concordant with recent data showing an antidepressant-like effect of lentiviral vectors expressing siRNA targeted against GSK3β transcripts in the hippocampal dentate gyrus of stressed mice using these same behavioural paradigms . Therefore, it seems possible that the overall antidepressant-like effects of systemic GSK3β inhibition can be explained, at least in part, by an inhibition of this kinase in the dentate gyrus. "
[Show abstract][Hide abstract] ABSTRACT: Serotonin (5-HT) neurotransmission is thought to underlie mental illnesses, such as bipolar disorder, depression, autism and schizophrenia. Independent studies have indicated that 5-HT or drugs acting on 5-HT neurotransmission regulate the serine/threonine kinase glycogen synthase kinase 3β (GSK3β). Furthermore, GSK3β inhibition rescues behavioural abnormalities in 5-HT-deficient mice with a loss-of-function mutation equivalent to the human variant (R441H) of tryptophan hydroxylase 2. In an effort to define neuroanatomical correlates of GSK3β activity in the regulation of behaviour, we generated CamKIIcre-floxGSK3β mice in which the gsk3b gene is postnatally inactivated in forebrain pyramidal neurons. Behavioural characterization showed that suppression of GSK3β in these brain areas has anxiolytic and pro-social effects. However, while a global reduction of GSK2β expression reduced responsiveness to amphetamine and increased resilience to social defeat, these behavioural effects were not found in CamKIIcre-floxGSK3β mice. These findings demonstrate a dissociation of behavioural effects related to GSK3 inhibition, with forebrain GSK3β being involved in the regulation of anxiety and sociability while social preference, resilience and responsiveness to psychostimulants would involve a function of this kinase in subcortical areas such as the hippocampus and striatum.
Philosophical Transactions of The Royal Society B Biological Sciences 09/2012; 367(1601):2460-74. DOI:10.1098/rstb.2012.0094 · 7.06 Impact Factor
Michael R Markiewicz, R Bryan Bell, Tuan G Bui, Eric J Dierks, Ramon Ruiz, Savannah Gelesko, Phillip Pirgousis, Rui Fernandes
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