Barbara L. Gracious

Combination Lithium and Divalproex Sodium in Pediatric Bipolarity

OBJECTIVE Lithium carbonate (Li) or divalproex sodium (DVPX) may be effective for some juveniles with bipolar disorder. Many youths with bipolar disorder do not respond to DVPX or Li monotherapy. An open-label study was conducted to examine the effectiveness of combination DVPX and Li therapy with youths diagnosed with bipolar disorder. METHOD Patients meeting DSM-IV criteria for bipolar I or bipolar II disorder, ages 5 to 17 years, were treated prospectively for up to 20 weeks with DVPX + Li. Assessments included the Young Mania Rating Scale (YMRS), Childrens Depression Rating Scale-Revised (CDRS-R), and the Childrens Global Assessment Scale (CGAS). The a priori definition of clinical remission utilized included four contiguous weekly ratings of YMRS </=12.5, CDRS-R </=40, CGAS >/=51, clinical stability, and no evidence of mood cycling. RESULTS Ninety patients (66 males, 24 females) were treated. Significant improvement (p <.0001) in all outcome measures was observed by week 8 as well as at the end of study. The mean time in study was 11.3 weeks. Forty-seven percent (n = 42) met a priori criteria for remission. CONCLUSIONS Symptoms of mania and depression in juvenile bipolar disorder may be safely and effectively treated acutely with DVPX + Li.

Discriminative Validity of a Parent Version of the Young Mania Rating Scale

OBJECTIVE To examine the usefulness of a parent report version of the Young Mania Rating Scale (P-YMRS) in distinguishing bipolar disorder from other mental health conditions in children and adolescents. METHOD Parents of 117 youths aged 5 to 17 years presenting to an outpatient research center completed an adapted Young Mania Rating Scale (P-YMRS). Eligible subjects underwent a diagnostic evaluation including a semistructured instrument (Schedule for Affective Disorders and Schizophrenia for School-Age Children) and also a clinical evaluation by a child and adolescent psychiatrist in more than 75% of the subjects. RESULTS Factor analyses of the P-YMRS suggested one dimension, with a total score showing acceptable internal consistency (alpha =.75). Logistic regressions discriminated bipolar mood disorder versus unipolar disorder, versus disruptive behavior disorder, and versus any other diagnosis. Classification rates exceeded 78%, and receiver operating characteristics analyses showed good diagnostic efficiency, with areas under the curve greater than 0.82. CONCLUSIONS The P-YMRS may be used to derive clinically meaningful information about mood disorders in youths.

Factor Structure of the Young Mania Rating Scale for Use with Youths Ages 5 to 17 Years

Assessed the factor structure of the Young Mania Rating Scale (YMRS). Youths presenting to a research program specializing in the pharmacological treatment of mood and disruptive behavioral disorders (N = 612) were administered a semistructured diagnostic interview. Based on the interview, youths were placed into diagnostic groups. Highly trained raters completed the YMRS for each youth. YMRS ratings were internally consistent (a = .91), and exploratory and confirmatory factor analyses yielded a 1-factor solution for boys and girls in both young (5 to 11 years) and older (12 to 17 years) subsamples. However, the young male group showed higher scores on several items as well as the total YMRS score. Results suggest that the YMRS total score can be meaningfully interpreted in child and adolescent samples.

Randomized, placebo-controlled trial of flax oil in pediatric bipolar disorder

OBJECTIVES This clinical trial evaluated whether supplementation with flax oil, containing the omega-3 fatty acid alpha-linolenic acid (alpha-LNA), safely reduced symptom severity in youth with bipolar disorder. METHODS Children and adolescents aged 6-17 years with symptomatic bipolar I or bipolar II disorder (n = 51), manic, hypomanic, mixed, or depressed, were randomized to either flax oil capsules containing 550 mg alpha-LNA per 1 gram or an olive oil placebo adjunctively or as monotherapy. Doses were titrated to 12 capsules per day as tolerated over 16 weeks. Primary outcomes included changes in the Young Mania Rating Scale, Child Depression Rating Scale-Revised, and Clinical Global Impressions-Bipolar ratings using Kaplan-Meier survival analyses. RESULTS There were no significant differences in primary outcome measures when compared by treatment assignment. However, clinician-rated Global Symptom Severity was negatively correlated with final serum omega-3 fatty acid compositions: %alpha-LNA (r = -0.45, p < 0.007), % eicosapentaenoic acid (EPA) (r = -0.47, p < 0.005); and positively correlated with final arachidonic acid (AA) (r = 0.36, p < 0.05) and docosapentaenoic acid (DPA) n-6 (r = 0.48, p < 0.004). The mean duration of treatment for alpha-LNA was 11.8 weeks versus 8 weeks for placebo; however, the longer treatment duration for alpha-LNA was not significant after controlling for baseline variables. Subjects discontinued the study for continued depressive symptoms. CONCLUSIONS Studies of essential fatty acid supplementation are feasible and well tolerated in the pediatric population. Although flax oil may decrease severity of illness in children and adolescents with bipolar disorder who have meaningful increases in serum EPA percent levels and/or decreased AA and DPA n-6 levels, individual variations in conversion of alpha-LNA to EPA and docosahexaenoic acid as well as dosing burden favor the use of fish oil both for clinical trials and clinical practice. Additionally, future research should focus on adherence and analysis of outcome based on changes in essential fatty acid tissue compositions, as opposed to group randomization alone.

Antipsychotic Medications for Children and Adolescents

Antipsychotic medications are commonly prescribed to children and adolescents. These medications, however, are not only prescribed for young patients with psychosis, but are often prescribed for youths with a variety of psychiatric disorders. Despite the fact that psychiatric illness in the pre-adult era is not rare, few controlled clinical trials have examined the short-term safety and efficacy of these agents in youths with psychosis. There are even fewer data regarding the long-term safety and efficacy of these agents in psychotic children and adolescents. As new antipsychotics become available, the study of these agents in youngsters with a variety of psychiatric illnesses may become an exciting new avenue for research.

Elevated Thyrotropin in Bipolar Youths Prescribed Both Lithium and Divalproex Sodium.

OBJECTIVE To examine the effect of combined lithium and divalproex sodium on thyroid-stimulating hormone (TSH) levels in children and adolescents with bipolar disorders and to identify risk factors for lithium-induced hypothyroidism. METHOD Bipolar youths aged 5 to 17 years participating in an open-label clinical trial received treatment with lithium and divalproex sodium for up to 20 weeks. TSH levels were measured at baseline and at the end of the study. Subjects were divided into two groups for analysis: group 1 had TSH levels of less than 10.0 mU/L at the end of the study and group 2 had TSH levels of 10.0 mU/L or more at end of the study. RESULTS Twenty of the 82 subjects (24.4%) showed TSH elevations of at least 10 mU/L within an average exposure of less than 3 months. The mean baseline TSH level for group 2 was significantly higher than for group 1 (2.97 [SD = 1.48] versus 2.05 [SD = 0.89], p <.05). Mean lithium levels at the end of the study were 1.00 mEq/L for group 2 compared to 0.76 mEq/L for group 1 (t = -2.41, p =.019). CONCLUSIONS Lithium is associated with significant rates of thyrotropin elevation in bipolar youths. Factors associated with elevation in TSH in lithium-treated subjects include a higher baseline TSH level and a higher lithium level. Close monitoring of thyroid function in children and adolescents taking lithium is recommended.

The rationale, design, and progress of two novel maintenance treatment studies in pediatric bipolarity.

ABSTRACT Introduction: There are no definitively established acute or maintenance treatments for juvenile bipolar disorder. Method: Two randomized, blind, maintenance clinical trials in children and adolescents with bipolar disorders are ongoing at the University Hospitals of Cleveland/Case Western Reserve University Stanley Clinical Research Center for bipolar disorder. The first is comparing the safety and effectiveness of lithium carbonate (Li+) to divalproex sodium (VPA) for up to 76 weeks in youths with stabilized bipolar illness (type 1 or 2). The second study is designed to compare the efficacy of VPA to placebo in the acute management of subsyndromal symptoms of bipolar disorder (‘cyclotaxia’) and the prevention of the full syndrome in children at risk. Both studies use the prospective life-chart method as an outcome measure. Results: Sixty-six youths have received study medication as part of the trial that is comparing Li+ to VPA as a maintenance therapy. In addition, 32 youths have received blinded treatment as part of the ‘cyclotaxia’ prevention study. Combination Li+A/PA treatment appears generally well tolerated and seems to have robust anti-manic and antidepressant effects. Discussion: Since the blind has not been broken on either of these clinical trials, conclusions about the maintenance effectiveness of either VPA or Li+ in youths with bipolar disorder type 1 or 2 cannot be made yet. Similarly, it is unclear whether VPA is superior to placebo in genetically high-risk youths with cyclotaxia. The final results of these trials should provide valuable information about the treatment of juvenile bipolar disorders.

Prevalence of overweight and obesity in adolescents with severe mental illness: a cross-sectional chart review.

OBJECTIVE Pediatric obesity (body mass index [BMI] > or = 95th percentile for sex and age) and overweight (BMI > or = 85th percentile < 95% percentile) are priority public health targets for the prevention of diabetes and cardiovascular disease. We examined the prevalence and risk of overweight and obesity in adolescents with serious mental disorders. METHOD Height, weight, demographic, diagnostic, and treatment data were reviewed for 114 adolescents attending a partial hospitalization program over 18 consecutive months between January 2003 and July 2004. Sample data were compared to normative National Health and Nutrition Examination Survey data and regional county data for BMI. Unadjusted odds ratios and their 95% CIs were calculated for each categorical risk factor using the chi-squared test. A logistic regression model was conducted to detect the effects of these risk factors on the occurrence of overweight and obesity. RESULTS The combined prevalence of overweight and obesity was 55.4% (n = 63); the prevalence for obesity alone was 30% (n = 34), approximately double the rate in national and county norms. Lack of private insurance, smoking, and antidepressant and antipsychotic treatment were associated with overweight and obese status. CONCLUSIONS Adolescents with severe mental illness are at increased risk for overweight and obesity. Identification of elevated BMI, associated risk factors, and efforts to prevent weight gain should begin at initiation of mental health treatment.

The Importance of Taking a History of Over-the-Counter Medication Use: A Brief Review and Case Illustration of “PRN” Antihistamine Dependence in a Hospitalized Adolescent

Over-the-counter (OTC) and prescription medication abuse has been rapidly increasing, yet publications on OTC abuse in adolescents are limited. We present a brief literature review and a novel report of antihistamine dependence emerging after admission in an adolescent, subsequently treated with naltrexone. This case highlights the need to take a thorough history of OTC, herbal, and prescription drug use from parents and patients separately and repeatedly, at initial presentation, and again if withdrawal symptoms emerge. General strategies for combating OTC and prescription abuse are given.

Nutritional and Safety Outcomes from an Open-Label Micronutrient Intervention for Pediatric Bipolar Spectrum Disorders

OBJECTIVE The purpose of this study was to report the safety, tolerability, and serum micronutrient concentrations and their correlations with mood changes from an 8 week pilot feasibility study of a 36 ingredient multinutrient supplement, EMPowerplus (EMP+), for pediatric bipolar spectrum disorders (BPSD). METHODS Ten children ages 6-12 received EMP+ escalating from one to four capsules t.i.d., with four children increased to the maximum suggested dose, five capsules t.i.d. Outcome measures were micronutrient concentrations in serum and red blood cells, vital signs, body mass index (BMI), dietary intake (Food Frequency Questionnaire and 24 hour dietary recall interview), and mood and global functioning ratings. RESULTS Seven children (70%) completed the study. Three (30%) terminated early for tolerability and compliance issues. Adverse effects were mild and transient, and chiefly consisted of initial insomnia or gastrointestinal (GI) upset. No differences occurred in BMI (p = 0.310) or waist-hip ratio (WHR; p = 0.674) pre- to postsupplementation. Four of the tested serum vitamin concentrations increased from pre- to postsupplementation: vitamin A-retinol, vitamin B6, vitamin E-α-tocopherol; and folate (all p<0.05). The increase in serum 25-OH vitamin D approached significance (p = 0.063). No differences were found in dietary intake pre- to postsupplementation, suggesting that blood nutrient level increases were caused by EMP+. CONCLUSIONS In this open prospective study, short-term use of EMP+ in children with BPSD appeared safe and well-tolerated, with a side effect profile preferable to first-line psychotropic drugs for pediatric bipolar spectrum disorders. A double-blind, randomized clinical trial is feasible, appears safe, and is warranted by open-label clinical outcomes and plausible mechanisms of action, combined with documentation of increased serum concentrations of specific micronutrients.