Bipolar Disorder: Kowatch RA

Kowatch RA, Fristad M, Birmaher B, Wagner KD, Findling RL, Hellander M, Anonymous00051. · Department of Psychiatry, Cincinnati Children's Hospital Medical, OH 45267-0559, USA. · J Am Acad Child Adolesc Psychiatry. · Pubmed #15725966 No free full text.

Abstract: Clinicians who treat children and adolescents with bipolar disorder desperately need current treatment guidelines. These guidelines were developed by expert consensus and a review of the extant literature about the diagnosis and treatment of pediatric bipolar disorders. The four sections of these guidelines include diagnosis, comorbidity, acute treatment, and maintenance treatment. These guidelines are not intended to serve as an absolute standard of medical or psychological care but rather to serve as clinically useful guidelines for evaluation and treatment that can be used in the care of children and adolescents with bipolar disorder. These guidelines are subject to change as our evidence base increases and practice patterns evolve.

Post RM, Chang KD, Findling RL, Geller B, Kowatch RA, Kutcher SP, Leverich GS. · No affiliation provided · J Clin Psychiatry. · Pubmed #15291676 No free full text.

This publication has no abstract.

Pfeifer JC, Kowatch RA, DelBello MP. · The University of Cincinnati Medical Center, Cincinnati Children's Hospital Medical Center, Department of Psychiatry, MSB 7261, PO Box 670559, Cincinnati, Ohio 45267-0559, USA. · Expert Opin Pharmacother. · Pubmed #17956191 No free full text.

Abstract: The use of antipsychotics, particularly the atypical antipsychotics, has increased dramatically in child and adolescent populations over the last decade. This class of psychotropics has been used to treat a variety of psychiatric disorders in pediatric populations, including bipolar disorder (BPD). The present clinical guidelines for treating BPD in younger populations closely follow those for managing adult BPD, as reasoning for using the atypicals is many times initially based on the outcomes of adult studies and indications. As in adult populations, metabolic parameters such as body mass index, blood glucose levels and fasting lipid profiles should be routinely monitored throughout the course of treatment. Of the several studies undertaken thus far, it appears that atypical antipsychotics are efficacious in the treatment of pediatric BPD. However, the number of controlled studies demonstrating their efficacy in younger subjects is limited and further investigation is required to evaluate if effectiveness and potential for side effects differ significantly than that for adult populations.

Singh MK, DelBello MP, Kowatch RA, Strakowski SM. · Division of Bipolar Disorders Research, Department of Psychiatry, University of Cincinnati College of Medicine, 231 Bethesda Avenue, Cincinnati, OH 45267, USA. · Bipolar Disord. · Pubmed #17156157 No free full text.

Abstract: OBJECTIVES: Pediatric bipolar disorder (BPD) and attention-deficit hyperactivity disorder (ADHD) co-occur more frequently than expected by chance. In this review, we examine 4 potential explanations for the high rate of this common co-occurrence: (i) BPD symptom expression leads to overdiagnosis of ADHD in BPD youth; (ii) ADHD is a prodromal or early manifestation of pediatric-onset BPD; (iii) ADHD and associated factors (e.g., psychostimulants) lead to the onset of pediatric BPD; and (iv) ADHD and BPD share an underlying biological etiology (i.e., a common familial or genetic risk or underlying neurophysiology). METHODS: Peer-reviewed publications of studies of children and adolescents with comorbid BPD and ADHD were reviewed. RESULTS: There is a bidirectional overlap between BPD and ADHD in youth, with high rates of ADHD present in children with BPD (up to 85%), and elevated rates of BPD in children with ADHD (up to 22%). Phenomenologic, genetic, family, neuroimaging, and treatment studies revealed that BPD and ADHD have both common and distinct characteristics. While there are data to support all 4 explanations postulated in this paper, the literature most strongly suggests that ADHD symptoms represent a prodromal or early manifestation of pediatric-onset BPD in certain at-risk individuals. Bipolar disorder with comorbid ADHD may thus represent a developmentally specific phenotype of early-onset BPD. CONCLUSIONS: The etiology of comorbid BPD and ADHD is likely multifactorial. Additional longitudinal and biological studies are warranted to clarify the relationships between BPD and ADHD since they may have important diagnostic and treatment implications.

DelBello MP, Kowatch RA. · Department of Psychiatry, University of Cincinnati College of Medicine, OH 45267-0559, USA. · Dev Psychopathol. · Pubmed #17064436 No free full text.

Abstract: Despite the high prevalence rate, there have been relatively few controlled studies to systematically examine pharmacological treatments for children and adolescents with bipolar disorder. We review the differences in clinical characteristics between youth and adults with bipolar disorder and the extant literature of pharmacological treatments for children and adolescents with bipolar disorder, as well as discuss the effectiveness of pharmacological interventions for treating children and adolescents who are at familial risk for developing bipolar disorder. Although the number of controlled studies of youth with manic and mixed episodes is rapidly growing, there are few studies examining treatments for depression and the prevention of recurrent affective episodes in this population. Although children and adolescents with bipolar disorder commonly present with co-occurring psychiatric disorders, such as attention-deficit/hyperactivity disorder, there are limited data to guide the treatment of these patients. Recently, studies have begun to characterize prodromal manifestations of bipolar disorder and identify early intervention strategies for treating children and adolescents with an elevated risk for developing bipolar disorder.

Kowatch RA, Youngstrom EA, Danielyan A, Findling RL. · Department of Psychiatry, Cincinnati Children's Hospital Medical Center/University of Cincinnati Medical Center, Cincinnati, OH 45267, USA. · Bipolar Disord. · Pubmed #16403174 No free full text.

Abstract: OBJECTIVE: Using predetermined criteria for study quality and methods, a literature review and meta-analysis of seven reports about pediatric bipolar disorder (BPD) was conducted to determine if there is a consistent picture of the phenomenology and clinical characteristics of BPD in children and adolescents. METHODS: Searches were conducted in MedLine and PsycINFO using the terms mania, BPD, children and adolescents, and was limited to published articles in peer-reviewed journals. Seven reports were selected that met the following criteria: a systematic method for the elicitation and reporting of symptoms and clinical characteristics of subjects; subjects were interviewed by a trained researcher or clinician; ages 5-18 years; use of a diagnostic system, either DSM or RDC for categorization; a consensus method for the establishment of the diagnosis of BPD. RESULTS: Most DSM-IV symptoms of mania were common in the children and adolescents with BPD with the most common symptoms being increased energy, distractibility, and pressured speech. On average, four of five bipolar cases also showed threshold levels of irritable mood and grandiosity, and more than 70% of all cases showed elated/euphoric mood, decreased need for sleep, or racing thoughts. Roughly 69% of cases also showed poor judgment, whereas only half of bipolar cases demonstrated flight of ideas, and slightly more than one-third showed hypersexuality or psychotic features. CONCLUSIONS: The clinical picture that emerges is that of children or adolescents with periods of increased energy (mania or hypomania), accompanied by distractibility, pressured speech, irritability, grandiosity, racing thoughts, decreased need for sleep and euphoria/elation.

Kowatch RA, DelBello MP. · Department of Psychiatry and Pediatrics, University of Cincinnati Medical Center & Cincinnati Children's Hospital Medical Center, MSB 7261, PO Box 670559, Cincinnati, OH 45267-0559, USA. · Child Adolesc Psychiatr Clin N Am. · Pubmed #16321726 No free full text.

Abstract: Children and adolescents who have bipolar disorder often are encountered in clinical settings and frequently require treatment with mood stabilizers and atypical antipsychotics. New screening and diagnostic tools are available to aid in the diagnosis of bipolar disorder in children and adolescents. Additional data supporting the use of mood stabilizers and atypical antipsychotics in this population also are emerging. Combinations of existing psychotropics remain the most effective treatment of pediatric bipolar disorder at this point. This article reviews the phenomenology and clinical characteristics of pediatric bipolar disorder and current approaches to pharmacotherapy. It is becoming apparent that bipolar disorder is often a chronic disorder in children and adolescents, much like diabetes, and is best managed with a combination of medications and psychosocial therapy.

Danielyan A, Kowatch RA. · Cincinnati Children's Hospital Medical Center, OH 45267, USA. · Paediatr Drugs. · Pubmed #16220995 No free full text.

Abstract: During recent years there has been a dramatic increase in the use of psychotropic medication for the treatment of bipolar disorder (BPD) in children. There is an emerging set of data to support this use.Mood stabilizers, including lithium and valproic acid (valproate sodium), have generally formed the mainstay of treatment in children and adolescents with BPD. However, the atypical antipsychotics, such as risperidone, aripiprazole, and quetiapine may be more effective as first-line treatment options and in some ways easier to use than the traditional mood stabilizers. As in adults, mood stabilization is often difficult to achieve in pediatric patients with BPD, and combined treatment with mood stabilizers and atypical antipscyhotics is commonly used. Data from controlled trials of psychotropic medications in children and adolescents with BPD are very limited, and hence, in the majority of cases physicians base their treatment decisions on data from case reports, case series, or open trials. More controlled studies of both monotherapy and polypharmacotherapy for BPD in children and adolescents are needed.

Kowatch RA, DelBello MP. · Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45267, USA. · Psychiatr Clin North Am. · Pubmed #15826738 No free full text.

Abstract: The identification and treatment of children and adolescents with a bipolar disorder is often challenging and difficult. Many of the psychotropic agents used to treat adults with bipolar disorder may also be-used to treat children and adolescents with these disorders. Further controlled trials using combination pharmacotherapy in children and adolescents with bipolar disorders are needed to advance the field of pediatric bipolarity and provide optimal care for these patients. There are multiple ongoing trials of mood stabilizers and atypical antipsychotics that will provide important controlled data that are currently lacking in the field.

Kowatch RA, DelBello MP. · Department of Psychiatry, Cincinnati Children's Hospital Medical Center, University of Cincinnati Medical Center, Ohio 45267, USA. · CNS Spectr. · Pubmed #12679742 No free full text.

Abstract: The clinical use of mood stabilizers and antipsychotics in children and adolescents with bipolar disorders has increased significantly over the past few years. These agents have multiple effects and interactions. This articles reviews the studies that support the use of mood stabilizers and atypical antipsychotics in children and adolescents with bipolar disorders and presents information on these agent's pharmacokinetics, dosing, and drug interactions.

Patel NC, DelBello MP, Bryan HS, Adler CM, Kowatch RA, Stanford K, Strakowski SM. · College of Pharmacy and Department of Psychiatry, University of Cincinnati, OH 45267-0004, USA. · J Am Acad Child Adolesc Psychiatry. · Pubmed #16540813 No free full text.

Abstract: OBJECTIVES: To investigate the effectiveness and tolerability of lithium for the treatment of acute depression in adolescents with bipolar disorder. We hypothesized that patients receiving open-label treatment with lithium during a 6-week period would experience a statistically and clinically significant decrease in depressive symptoms and tolerate lithium treatment fairly well. METHOD: Twenty-seven adolescents (12-18 years old) with an episode of depression associated with bipolar disorder type I received open-label lithium 30 mg/kg (twice-daily dosing), which was adjusted to achieve a therapeutic serum level (1.0-1.2 mEq/L). Effectiveness measures included the Children's Depression Rating Scale-Revised (CDRS-R) and Clinical Global Impressions Scale for Bipolar Disorder (CGI-BP). Adverse events were assessed weekly. RESULTS: Mean CDRS-R scores significantly decreased from baseline to endpoint (mean [SD] change = -25.5 (20.4); p < .001), resulting in a large effect size of 1.7. Response and remission rates (defined by a > or = 50% reduction in CDRS-R score from baseline to endpoint, and a CDRS-R score < or = 28 and a CGI-BP Improvement score of 1 or 2, respectively) were 48% and 30%. Side effects, which were generally mild to moderate in severity, included headache (74%), nausea/vomiting (67%), stomachache (30%), and abdominal cramps (19%). CONCLUSIONS: The findings of this study indicate that lithium may be effective and is relatively well tolerated for the treatment of an acute episode of depression in adolescents with bipolar disorder. Controlled studies of lithium in adolescent bipolar depression are needed.

Scheffer RE, Kowatch RA, Carmody T, Rush AJ. · Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8589, USA. · Am J Psychiatry. · Pubmed #15625202 links to  free full text

Abstract: OBJECTIVE: The purpose of this study was to determine whether adjunctive use of a psychostimulant (mixed amphetamine salts) was safe and efficacious for treatment of symptoms of attention deficit hyperactivity disorder (ADHD) in pediatric outpatients with bipolar I or bipolar II disorder and concurrent ADHD whose manic symptoms had been stabilized through treatment with divalproex sodium. METHOD: An 8-week open-label trial of divalproex sodium to control manic symptoms and to discern the effect of divalproex sodium on ADHD was followed by a 4-week randomized, double-blind, placebo-controlled crossover trial to determine if mixed amphetamine salts was safe and effective for treatment of ADHD symptoms. Patients in the crossover trial continued to receive divalproex sodium. Diagnoses, made by clinical interview, were confirmed with the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia. The Young Mania Rating Scale (for manic symptoms) and the Clinical Global Impression of improvement (for ADHD symptoms) were the primary outcome measures. RESULTS: Forty subjects ages 6-17 years with bipolar I disorder (77.5%) or bipolar II disorder (22.5%) and a Young Mania Rating Scale score > or =14 entered open treatment with divalproex sodium. With divalproex sodium, 32 subjects achieved > or =50% reduction in Young Mania Rating Scale baseline scores, but only three participants had significant improvement in ADHD symptoms. For the 30 subjects who entered the placebo-controlled crossover trial, mixed amphetamine salts was significantly more effective than placebo for ADHD symptoms. No significant side effects or worsening of manic symptoms was observed. CONCLUSIONS: Pediatric patients with bipolar disorder and concurrent ADHD can be safely and effectively treated with mixed amphetamine salts after their manic symptoms are stabilized with divalproex sodium. Divalproex sodium alone (8-week trial) is not an effective treatment for ADHD in the context of bipolar disorder.

Kowatch RA, Sethuraman G, Hume JH, Kromelis M, Weinberg WA. · Department of Psychiatry, Cincinnati Children's Hospital Medical Center and the University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA. · Biol Psychiatry. · Pubmed #12788243 No free full text.

Abstract: BACKGROUND: The purpose of this study was to develop prospective data on the effectiveness of combination pharmacotherapy of children and adolescents with bipolar disorder during a 6-month period of prospective, semi-naturalistic treatment. METHODS: Thirty-five subjects, with a mean age of 11 years, were treated in the extension phase of this study after having received 6-8 weeks of acute treatment with a single mood stabilizer. The extension phase of this study lasted for another 16 weeks, for a total of 24 weeks of prospective treatment. During this study phase, subjects were openly treated, and they could have their acute-phase mood stabilizer switched or augmented with another mood stabilizer, a stimulant, an antidepressant agent, or antipsychotic agent, if they were assessed to be a nonresponder to monotherapy with their initial mood stabilizer. RESULTS: During the extension phase of treatment, 20 of 35 subjects (58%) required treatment with one or two mood stabilizers and either a stimulant, an atypical antipsychotic agent, or an antidepressant agent. The response rate to combination therapy was very good, with 80% of subjects treated responding to combination therapy with two mood stabilizers after not responding to monotherapy with a mood stabilizer. CONCLUSIONS: This study suggests that children and adolescents with bipolar disorder are similar to adults with bipolar disorder, who also frequently require combination therapy.

Kowatch RA, Suppes T, Carmody TJ, Bucci JP, Hume JH, Kromelis M, Emslie GJ, Weinberg WA, Rush AJ. · Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas 75235-9070, USA. · J Am Acad Child Adolesc Psychiatry. · Pubmed #10846305 No free full text.

Abstract: OBJECTIVE: To develop effect sizes for 3 mood stabilizers--lithium, divalproex sodium, and carbamazepine--for the acute-phase treatment of bipolar I or II disorder, mixed or manic episode, in children and adolescents aged 8 to 18 years. METHOD: Forty-two outpatients with a mean age of 11.4 years (20 with bipolar I disorder and 22 with bipolar II disorder) were randomly assigned to 6 weeks of open treatment with either lithium, divalproex sodium, or carbamazepine. The primary efficacy measures were the weekly Clinical Global Impression Improvement scores and the Young Mania Rating Scale (Y-MRS). RESULTS: Using a > or = 50% change from baseline to exit in the Y-MRS scores to define response, the effect size was 1.63 for divalproex sodium, 1.06 for lithium, and 1.00 for carbamazepine. Using this same response measure with the intent-to-treat sample, the response rates were as follows: sodium divalproex, 53%; lithium, 38%; and carbamazepine, 38% (chi 2(2) = 0.85, p = .60). All 3 mood stabilizers were well tolerated, and no serious adverse effects were seen. CONCLUSIONS: Divalproex sodium, lithium, and carbamazepine all showed a large effect size in the open treatment of children and adolescents with bipolar I or II disorder in a mixed or manic episode.

Wagner KD, Redden L, Kowatch RA, Wilens TE, Segal S, Chang K, Wozniak P, Vigna NV, Abi-Saab W, Saltarelli M. · University of Texas Medical Branch, USA. · J Am Acad Child Adolesc Psychiatry. · Pubmed #19325497 No free full text.

Abstract: OBJECTIVE: To compare the efficacy and safety of divalproex extended-release (ER) to placebo in a 28-day double-blind study of bipolar disorder in children and adolescents and evaluate the safety of divalproex ER in a 6-month open-label extension study. METHOD: In the double-blind study, 150 patients (manic or mixed episode, aged 10-17 years) with baseline Young Mania Rating Scale (YMRS) score of 20 or higher were randomized to once-daily placebo or divalproex ER, which was titrated to clinical response or serum valproate concentration of 80 to 125 microg/mL. Sixty-six patients enrolled in the extension study. RESULTS: In the double-blind study, a treatment effect was not observed with divalproex ER based on change in mean YMRS score (divalproex ER -8.8 [n = 74]; placebo -7.9 [n = 70]) or secondary measures. Divalproex was similar to placebo based on incidence of adverse events. Four subjects treated with divalproex ER and three treated with placebo discontinued because of adverse events. Mean ammonia levels increased in the divalproex ER group, but only one patient was symptomatic. In the long-term study, YMRS scores decreased modestly (2.2 points from baseline). The most common adverse events were headache and vomiting. CONCLUSIONS: The results of the study do not provide support for the use of divalproex ER in the treatment of youths with bipolar I disorder, mixed or manic state. Further controlled trials are required to confirm or refute the findings from this study.

Danielyan A, Pathak S, Kowatch RA, Arszman SP, Johns ES. · Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, D-3014, Cincinnati, OH 45229, United States. · J Affect Disord. · Pubmed #16822549 No free full text.

Abstract: BACKGROUND: Clinical information about bipolar disorder (BPD) in preschool-age (3-7 years old) children is extremely limited. This study examined clinical presentations, applicability of the DSM-IV diagnostic criteria, comorbidity, recovery and relapse rates, as well as some treatment strategies used in the management of BPD in preschoolers. METHODS: The charts of 26 outpatient children, ages 3-7, refereed to a child psychiatry outpatient clinic with mood and behavioral symptoms, were retrospectively reviewed. RESULTS: The majority of the patients were referred with the tentative diagnosis of ADHD but the most common diagnoses made by child and adolescent psychiatrists at the time of initial evaluation were BPD NOS (61.5%), followed by BPD I (26.9%), and mood disorder NOS (23.1%). Thirty-eight percent of the patients had one or more comorbid diagnoses. The most common presenting symptoms were irritability (84.6%) and aggression (88.5%). The most widely prescribed class of medications after diagnosis in the clinic was atypical antipsychotics and mood stabilizers. Twenty-six percent of the patients were treated with a combination of atypical antipsychotics and mood stabilizers. LIMITATIONS: Retrospective design; small sample size; lack of a comparison group. CONCLUSIONS: The course of BPD with onset in preschool years is complicated with high recovery and relapse rates. The questions of development of age-appropriate diagnostic criteria, long-term prognosis and treatment strategies used in this population require further intensive investigation.

Wagner KD, Kowatch RA, Emslie GJ, Findling RL, Wilens TE, McCague K, D'Souza J, Wamil A, Lehman RB, Berv D, Linden D. · Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77755-0188, USA. · Am J Psychiatry. · Pubmed #16816222 links to  free full text

Abstract: OBJECTIVE: This multicenter trial examined the efficacy and safety of oxcarbazepine in the treatment of bipolar disorder in children and adolescents. METHOD: A total of 116 outpatients 7 to 18 years of age with bipolar I disorder, manic or mixed, were recruited at 20 centers in the United States and randomly assigned to receive 7 weeks of double-blinded, flexibly dosed treatment with oxcarbazepine (maximum dose 900-2400 mg/day) or placebo. The primary efficacy measure was the mean change from baseline to endpoint in the Young Mania Rating Scale (YMRS), using the last-observation-carried-forward method. RESULTS: Oxcarbazepine (mean dose=1515 mg/day) did not significantly improve YMRS scores at endpoint compared with placebo [adjusted mean change: oxcarbazepine, -10.90 (N=55); placebo, -9.79 (N=55)]. Dizziness, nausea, somnolence, diplopia, fatigue, and rash were each reported in at least 5% of the patients in the oxcarbazepine group with an incidence at least twice that of the placebo group. The majority of adverse events were mild to moderate and occurred during the titration period. Eleven patients (19%) in the oxcarbazepine group discontinued the study because of adverse events, compared with two (4%) in the placebo group. CONCLUSIONS: Oxcarbazepine is not significantly superior to placebo in the treatment of bipolar disorder in youths. While the overall adverse event profile was similar to that reported for patients with epilepsy, the incidence of psychiatric adverse events for both the oxcarbazepine and placebo groups was higher than that reported for the epilepsy population.

Patel NC, DelBello MP, Kowatch RA, Strakowski SM. · College of Pharmacy, Department of Psychiatry, University of Cincinnati College of Medicine, 3225 Eden Avenue, Cincinnati, OH 45267, USA. · J Child Adolesc Psychopharmacol. · Pubmed #16768640 No free full text.

Abstract: PURPOSE: The aim of this study was to explore relationships between the Children's Depression Rating Scale-Revised (CDRS-R) and Hamilton Rating Scale for Depression (HAM-D) in adolescent bipolar disorder. We hypothesized that CDRS-R and HAM-D scores would be significantly correlated and both scales would be sensitive to change resulting from treatment. METHODS: Data from a randomized, double-blind, placebo-controlled study of quetiapine with divalproex versus divalproex alone (n = 30) and an open-label study of lithium (n = 27) were used. Assessments using the CDRS-R and HAM-D were completed separately without any dependence on ratings from the alternate rating scale or specific order. All raters for symptom rating scales were blinded to the study for which they were completing a patient assessment and the intent to conduct these post hoc analyses and were different from those who performed diagnostic interviews. Relationships between these measures were assessed using the Pearson correlation coefficient, and receiver operator characteristic curves evaluated the ability of CDRS-R and HAM-D scores to predict the level of global improvement. RESULTS: The mean (+/- standard deviation) age of subjects was 15.0 +/- 1.6 years. Baseline CDRS-R and HAM-D scores were moderately correlated (r = 0.63; p < 0.001), while week 6 scores showed stronger correlation (r = 0.88; p < 0.001). Both measures showed significant main effects for time on treatment (CDRS-R: F(3.4,191.2) = 39.4, p < 0.001; HAM-D: F(3.9,217.9) = 38.5, p < 0.001). A CDRS-R score of 30.5 and HAM-D score of 7.5 represent the highest sensitivity and specificity in classifying responders and nonresponders. A 42.2% and 60.6% reduction in baseline CDRS-R and HAM-D scores, respectively, provided the highest sensitivity and specificity. CONCLUSIONS: Our preliminary results demonstrated that CDRS-R and HAM-D scores were significantly correlated, suggesting that either measure may be used to assess depressive symptoms in studies of adolescent bipolar disorder. Limitations to this study included a relatively small pooled sample, variation in clinician judgment, and study design not specific for the comparison of rating scales. Studies with methods specific to evaluate and compare these rating scales and larger patient samples from multiple treatment sites are needed to confirm these findings.

DelBello MP, Kowatch RA, Adler CM, Stanford KE, Welge JA, Barzman DH, Nelson E, Strakowski SM. · Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559, USA. · J Am Acad Child Adolesc Psychiatry. · Pubmed #16540815 No free full text.

Abstract: OBJECTIVE: To determine the comparative efficacy of quetiapine and divalproex for the treatment of adolescent mania. METHOD: Fifty adolescents (ages 12-18 years) with bipolar I disorder, manic or mixed episode, were randomized to quetiapine (400-600 mg/day) or divalproex (serum level 80-120 microg/mL) for 28 days for this double-blind study, which was conducted from July 2002 through January 2004. The primary efficacy measure was change in Young Mania Rating Scale (YMRS) score across the study period. RESULTS: Repeated measures analysis of variance using the last-observation carried forward data indicated no statistically significant group difference in YMRS scores across the 28 days of the study (p = 0.3). Mixed regression analyses (comparison of slopes) revealed that improvement in YMRS scores occurred more rapidly in the quetiapine than in the divalproex group for both the last-observation carried forward (p = 0.01) and observed data (p = 0.03). Response and remission rates were significantly greater in the quetiapine than in the divalproex group (p < .03). Rates of adverse events did not differ significantly between groups. CONCLUSIONS: The results suggest that quetiapine is at least as effective as divalproex in the treatment of acute manic symptoms associated with adolescent bipolar disorder; however, a quicker reduction of manic symptoms may occur with quetiapine as compared with divalproex. Quetiapine may be useful as monotherapy for the treatment of adolescents with manic or mixed episodes, although placebo-controlled studies are necessary.

Post RM, Kowatch RA. · Biological Psychiatry Branch, National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bldg. 10, Rm. 3S329, 10 Center Drive, Bethesda, MD 20892, USA. · J Clin Psychiatry. · Pubmed #16426098 No free full text.

Abstract: OBJECTIVE: To describe new data on the incidence and impact of childhood- and adolescent-onset bipolar illness and make recommendations to help accelerate the acquisition of knowledge in this area. DATA SOURCES: Two large, multicenter out-patient studies in adults with DSM-IV bipolar disorder-the Systematic Treatment Enhancement Program for Bipolar Disorder and the Bipolar Collaborative Network-were the primary sources of retrospective data on age at onset. STUDY SELECTION: We focused on the 2 retrospective studies because they supplied more immediate data on age at onset and long-term prognosis than current prospective studies. DATA SYNTHESIS: The 2 studies revealed that 15% to 28% of adults experienced an onset of their illness prior to age 13 years. Those with childhood versus adult onset had a more severe, complicated, and adverse course of bipolar illness, assessed retrospectively and confirmed prospectively during naturalistic treatment. The time lag from onset of first symptoms to first treatment was strongly inversely related to age at onset and averaged 16.8 +/- 10 years in those with childhood onset. Recommendations include defining temporary consensus threshold criteria for each bipolar subtype and their prodromes; conducting studies using less onerous than traditional designs, including randomized open comparisons to acquire preliminary data in this age cohort; and forming clinical and academic treatment outcome networks to more quickly acquire treatment outcome data in this understudied population. CONCLUSIONS: The data reveal a very substantial rate of childhood-onset bipolar illness, extraordinary delays in onset to first treatment, and a very adverse long-term outcome. Several approaches to accelerating the rate of acquisition of treatment outcome data in this cohort are outlined.

Barzman DH, DelBello MP, Kowatch RA, Warner J, Rofey D, Stanford K, Rappaport K, Daniels JP, Strakowski SM. · Cincinnati Children's Hospital Medical Center, Division of Child and Adolescent Psychiatry, and Department of Psychiatry, University of Cincinnati College of Medicine, Ohio 45267, USA. · J Child Adolesc Psychopharmacol. · Pubmed #16379513 No free full text.

Abstract: OBJECTIVE: The aim of this study was to assess topiramate as adjunctive treatment in children and adolescents hospitalized with bipolar disorders. METHODS: Medical records of all children and adolescents with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV-TR) (APA, 2000) diagnosis of bipolar disorder, type I, hospitalized for an acute manic, mixed, or depressive episode, were reviewed. The primary outcome measure was the Clinical Global Impression-Severity (CGI-S) score. RESULTS: Twenty-five (25) children and adolescents received topiramate, with a mean final dose of 126 mg/day (range, 25-350 mg). Overall CGI-S scores significantly improved from 5.3+/-1.0 to 3.5+/-0.7, and mania CGI-S scores decreased from 5.4+/-1.0 to 3.3+/-0.9. Sixteen (16) of 25 (64%) bipolar patients were classified as responders (defined by an endpoint overall CGI-I score of less than or equal to 2). No serious adverse events occurred during treatment. Of 25 patients evaluated, 1 (4%) experienced mild sedation while treated with topiramate. CONCLUSIONS: Preliminary results of this retrospective chart review suggest that adjunctive topiramate may be associated with improvements in children and adolescents hospitalized for an acute manic, mixed, or depressive episode. Randomized and controlled trials with adjunctive topiramate in this population are needed to further explore this observation.

Barzman DH, DelBello MP, Kowatch RA, Gernert B, Fleck DE, Pathak S, Rappaport K, Delgado SV, Campbell P, Strakowski SM. · Bipolar and Psychotic Disorders Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA. · J Child Adolesc Psychopharmacol. · Pubmed #15662152 No free full text.

Abstract: OBJECTIVE: The aim of this retrospective chart review was to evaluate the effectiveness and tolerability of aripiprazole for the treatment of children and adolescents with bipolar disorders. METHODS: The medical charts of all children and adolescents with a DSM-IV diagnosis of bipolar disorder, type I, type II, not otherwise specified (NOS), or schizoaffective disorder, bipolar type, and who were treated with aripiprazole were reviewed by two child and adolescent psychiatrists who independently confirmed their DSM-IV diagnoses, severity, and the improvement of illness using the Clinical Global Impression (CGI) Severity and Improvement scores for bipolar disorder (CGI-BP) and the Clinical Global Assessment Scale (CGAS). RESULTS: Thirty patients who were treated with aripiprazole were identified (mean starting dose=9 +/- 4 mg/day, mean final dose=10 +/- 3 mg/day). The overall response rate, defined by a CGI-Improvement score of < or = 2 at endpoint, was 67%. There was a statistically significant improvement in CGAS scores (48 +/- 11 to 65 +/- 11, signed rank = 191, p <0.0001) and CGI-S scores (4.2 +/- 0.8 to 2.8 +/- 1.0, signed rank=-172, p <0.0001, effect size=1.90) from baseline to endpoint. No serious adverse events were identified. Common side effects were sedation (n=10, 33%), akathisia (n=7, 23%), and gastrointestinal disturbances (n=2, 7%). Baseline and endpoint weights were available for 14 (47%) of the patients. Change in weight ranged from +5 to -21 kg and 12 (86%) of 14 patients lost weight (mean weight loss was 3 +/- 6 kg). CONCLUSIONS: This retrospective chart review suggests that aripiprazole may be effective and well tolerated for children and adolescents with bipolar disorders. Controlled studies of aripiprazole for the treatment of pediatric bipolar disorder are necessary.

Wilke M, Kowatch RA, DelBello MP, Mills NP, Holland SK. · Imaging Research Center and Department of Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. · Psychiatry Res. · Pubmed #15246455 No free full text.

Abstract: Bipolar disorder is an increasingly recognized cause of significant morbidity in the pediatric age group. However, there is still a large degree of uncertainty regarding the underlying neurobiological deficits. In this preliminary study, we performed automated volumetric studies and whole-brain voxel-based morphometry (VBM) on gray matter. Imaging data from 10 adolescents with bipolar disorder were compared with data from 52 age- and gender-matched healthy controls. Previously defined brain parcellations and optimized VBM protocols were used, based on custom-made pediatric reference data. An additional, exploratory whole-brain comparison was also implemented. The volumetric region-of-interest study revealed significantly greater gray matter volume in central gray matter structures bilaterally (including the basal ganglia and the thalamus) and the left temporal lobe in the bipolar group. VBM confirmed bilaterally larger basal ganglia. Localized gray matter deficits in bipolar subjects were found in the medial temporal lobe, orbito-frontal cortex, and the anterior cingulate, confirming and extending earlier studies.

DelBello MP, Kowatch RA, Warner J, Schwiers ML, Rappaport KB, Daniels JP, Foster KD, Strakowski SM. · Bipolar and Psychiatric Disorders Research Program, Department of Psychiatry, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267, USA. · J Child Adolesc Psychopharmacol. · Pubmed #12625992 No free full text.

Abstract: OBJECTIVE: The objective of this study was to evaluate the effectiveness, safety, and tolerability of the anticonvulsant agent, topiramate, as adjunctive treatment for children and adolescents with bipolar disorders. METHODS: The outpatient medical charts of children and adolescents with a Diagnostic and Statistical Manual of Mental Disorders (4th ed.) diagnosis of bipolar disorder, type I or II, and who were treated with topiramate were retrospectively reviewed by two child and adolescent psychiatrists using the Clinical Global Impression (CGI) scale and the Clinical Global Assessment Scale (CGAS). Separate CGI ratings were made for mania and overall bipolar illness. RESULTS: Twenty-six patients (mean age 14 +/- 3.5 years) with bipolar disorder, type I (n = 23) or II (n = 3), who had been treated (mean duration 4.1 +/- 6.1 months) with topiramate (mean dose 104 +/- 77 mg/day) were identified. Response rate (defined by a CGI-Improvement score of < or = 2 at endpoint) was 73% for mania and 62% for overall illness. CGAS scores significantly improved from baseline to endpoint. No serious adverse events were reported. CONCLUSIONS: Although controlled trials are necessary, this retrospective study suggests that topiramate is effective and well tolerated as an adjunctive treatment for children and adolescents with bipolar disorder.