Consoli, Angele, Deniau, Emmannuelle, Huynh, Christophe, Purper, Diane, Cohen, David

Treatments in child and adolescent bipolar disorders

The existence of bipolar disorder in adolescents is now clearly established. However, whether bipolarity exists in children is more controversial. We reviewed the literature on acute and prophylactic treatment of bipolar disorder in youths. The guidelines for the treatment of bipolar disorder in children and adolescents are generally similar to those applied in adult practice. But no evidence-based data support the use of mood stabilisers or antipsychotics since we only found two placebo-randomised controlled trials testing the efficacy of lithium in the paediatric literature. Therefore, we support the view that prescriptions should be limited to the most typical cases. In fact, the use of mood stabilisers or antipsychotics in the treatment of bipolar disorder in children and adolescents appears to be of limited use when a comorbid condition, such as attention deficit hyperactivity disorder, occurs unless aggressive behaviour is the target symptom. [References: 84]

European Child & Adolescent Psychiatry, 16(3) : 187-98

Findling, Robert L.,

Double-blind, placebo-controlled trial of divalproex monotherapy in the treatment of symptomatic youth at high risk for developing bipolar disorder

OBJECTIVE: To determine if divalproex sodium was superior to placebo in the treatment of symptomatic youths who suffer from a bipolar spectrum disorder and who also have a parent with a diagnosis of a bipolar illness. METHOD: Youths, ages 5 to 17 years, meeting DSM-IV criteria for bipolar disorder not otherwise specified (NOS) or cyclothymia who also had at least 1 biological parent with bipolar illness were randomly assigned in a double-blind fashion to receive treatment with either dival-proex sodium or placebo for up to 5 years. Study participation ended if the subject required additional clinical intervention, if the patient developed treatment-related adverse events, or if the participant was not adherent with study procedures. The primary outcome measure was time to study discontinuation for any reason. The study was conducted from August 1997 to April 2003. RESULTS: Fifty-six youths with a mean (SD) age of 10.7 (3.1) years were randomly assigned and received either divalproex sodium (N = 29) or placebo (N = 27). In spite of statistical power of 80% to detect hazard ratios of 2.2 or larger, the treatment groups did not significantly differ in survival time for discontinuation for any reason (p = .93) or discontinuation due to a mood event (p = .55). Changes in mood symptom ratings and psychosocial functioning from baseline to study discontinuation did not differ between groups (most significant p > .14). However, both groups did show improvements in mood symptoms and psychosocial functioning over time (all p values < .002). One patient, from the placebo group, ended study participation due to an adverse event. CONCLUSION: These results suggest that, although well tolerated, divalproex sodium does not produce clinically meaningful improvements in the treatment of symptomatic youths suffering from either bipolar NOS or cyclothymia who are at genetic risk for developing bipolar disorder.

Journal of Clinical Psychiatry, 68(5) : 781- 8

Brahm, Nancy C., Gutierres, Sheryl L., Carnahan, Ryan M.

Quetiapine for acute mania in bipolar disorder

PURPOSE: The efficacy and tolerability of quetiapine in the treatment of acute mania were reviewed. SUMMARY: Five randomized, placebo-controlled trials involving quetiapine as monotherapy or adjunct therapy in combination with either divalproex or lithium in the treatment of bipolar mania in either adolescents or adults were identified and reviewed. The primary outcome measure used in the trials was a change in Young Mania Rating Scale total scores. Monotherapy trials evaluated quetiapine, lithium, haloperidol, and placebo. Quetiapine was superior to placebo in both trials. Quetiapine and lithium showed comparable efficacy in one study, though lithium serum concentrations may have been suboptimal. Haloperidol was superior to quetiapine in efficacy at day 21 but similar at day 84. In the two trials evaluating quetiapine or placebo as adjunct therapy to lithium or divalproex, quetiapine was significantly more efficacious than placebo in one trial. In adolescents, quetiapine was more effective than placebo as an adjunct to divalproex. The most common adverse effects clearly attributable to quetiapine in these trials were somnolence and dry mouth. Quetiapine did not induce extrapyramidal effects, but weight gain was notable with the drug. CONCLUSION: While quetiapine treatment demonstrated efficacy in the majority of the studies, the robustness of its efficacy is questionable. The use of quetiapine as first-line therapy for acute mania is not recommended based on the available results and cost considerations. However, it may be a useful second-line agent, particularly when sensitivity to extrapyramidal symptoms limits treatment options. [References: 25]

American Journal of Health-System Pharmacy, 64(10) : 1045- 53

Weng, S., Tang, J., Wang, G., Wang, X., Wang, H.

Comparison of the addition of siberian ginseng (acanthopanax senticosus) versus fluoxetine to lithium for the treatment of bipolar disorder in adolescents: A randomized, double-blind trial

Background: Bipolar disorder (BD) is a common, recurrent, and often life-long major psychiatric condition characterized by manic, depressive, and mixed episodes. Without treatment, there is substantial risk for morbidity and mortality, making BD a considerable public health problem. Objective: The purpose of this study was to compare the relative effectiveness and tolerability of Acanthopanax senficosus (A senficosus)-an herb that is derived from eleutherosides and polysaccharides found in the plant's root- versus fluoxetine added to lithium in the treatment of BD in adolescents. Methods: This was a double-blind, 6-week study. The patients were randomized into 2 treatment groups-A senticosus plus lithium (A senticosus group) and fluoxetine plus lithium (fluoxetine group). The patients underwent a baseline assessment using the 17-Item Hamilton Depression Rating Scale (HAMD-17) and the Young Mania Rating Scale (YMRS) during the screening period. Patients were scheduled for clinical visits at the end of weeks 1, 2, 4, and 6. At the end of the 6-week treatment period, each patient's condition was rated as follows: response (indicating an improvement of [greater-than or equal to]50% in the HAMD-17 score from baseline); remission (a HAMD-17 score of {precedes above single-line equals sign}7); and switching to mania (a YMRS score >16, and meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorders [Fourth Edition, Text Revision] for a manic episode). At each visit (with the exception of the enrollment visit), the patients were queried as to whether they experienced any health problems since the previous visit, a Treatment Emergent Symptom Scale assessment was completed, and the serum lithium concentration was analyzed. The patients were instructed to report adverse events (AEs) at any time during the study. AEs were also observed by the investigator(s) at clinical visits. Results: Seventy-nine Chinese adolescents were initially enrolled into the study. However, 76 adolescents were assessed for inclusion (45 females, 31 males; mean [SD] age, 15.4 [30.0] years; age range, 12-17 years) in the study. All included patients completed the study. After 6 weeks of treatment, the response rate between the A senticosus and the fluoxetine groups was similar (67.6% vs 71.8%, respectively). The remission rate between both groups was also similar (51.4% vs 48.7%). Analyzed by a general line model, the HAMD-17 scores revealed there was a significant time effect (F = 183.06; P < 0.01), but not a significant group effect (F = 0.99) or group-by-duration of treatment interaction (F = 0.779). Three patients in the fluoxetine group experienced switching to mania compared with no patient in the A senticosus group. AEs reported by patients in the A senticosus group were as follows: nausea, 2 (5.4%); rash, 1 (2.7%); and diarrhea, 1 (2.7%). AEs reported by patients in the fluoxetine group were as follows: nausea, 4 (10.3%); anxiety, 3 (7.7%); insomnia, 3 (7.7%); constipation, 1 (2.6%); and tinnitus, 1 (2.6%). Conclusion: Our study found no significant difference in these adolescents with BD treated with lithium plus adjunctive A senticosus or fluoxetine. All treatments were generally well tolerated. copyright 2007 Excerpta Medica, Inc.

Current Therapeutic Research - Clinical & Experimental., 68(4) : 280-290

Tohen, Mauricio, Kryzhanovskaya, Ludmila, Carlson, Gabrielle, Delbello, Melissa, Wozniak, Janet, Kowatch, Robert, Wagner, Karen, Findling, Robert, Lin, Daniel, Robertson-Plouch, Carol, Xu, Wen, Dittmann, Ralf W., Biederman, Joseph

Olanzapine versus placebo in the treatment of adolescents with bipolar mania.[see comment]

OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of olanzapine for the treatment of acute manic or mixed episodes associated with bipolar disorder in adolescents. METHOD: A 3-week multicenter, parallel, double-blind, randomized placebo-controlled trial was conducted at 24 sites in the United States and two sites in Puerto Rico. The participants were outpatient and inpatient male and female adolescents 13-17 years of age with an acute manic or mixed episode. Subjects received either olanzapine (2.5-20 mg/day [N=107]) or placebo (N=54). The mean change from baseline to endpoint in the Young Mania Rating Scale total score was the primary outcome measure. RESULTS: The mean baseline-to-endpoint change in the Young Mania Rating Scale total score was significantly greater for patients receiving olanzapine relative to patients receiving placebo, and a greater proportion of olanzapine-treated patients met response and remission criteria (44.8% versus 18.5% and 35.2% versus 11.1%, respectively). The mean baseline-to-endpoint weight change was significantly greater for patients receiving olanzapine relative to patients receiving placebo (3.7 kg versus 0.3 kg), and the incidence of treatment-emergent weight gain > or =7% of baseline was higher for olanzapine-treated patients (41.9% versus 1.9%). The mean baseline-to-endpoint changes in prolactin, fasting glucose, fasting total cholesterol, uric acid, and the hepatic enzymes aspartate transaminase and alanine transaminase were significantly greater in patients treated with olanzapine relative to patients receiving placebo. CONCLUSIONS: Olanzapine was effective in the treatment of bipolar mania in adolescent patients. Patients treated with olanzapine, however, had significantly greater weight gain and increases in the levels of hepatic enzymes, prolactin, fasting glucose, fasting total cholesterol, and uric acid.

American Journal of Psychiatry, 164(10) : 1547-56

Wagner, Karen Dineen, Kowatch, Robert A., Emslie, Graham J., Findling, Robert L., Wilens, Timothy E., McCague, Kevin, D'Souza, Joseph, Wamil, Artur, Lehman, Robert B., Berv, Douglas, Linden, David

A double-blind, randomized, placebo-controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents.[see comment][erratum appears in Am J Psychiatry. 2006 Oct;163 (10):1843]

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.

American Journal of Psychiatry, 163(7) : 1179-86

Robertson-Plouch, C.

Olanzapine useful in adolescent mania (Conference abstract)

Pharmacy & Therapeutics, 31(12) : 727

DelBello, Melissa P., Kowatch, Robert A., Adler, Caleb M., Stanford, Kevin E., Welge, Jeffrey A., Barzman, Drew H., Nelson, Erik, Strakowski, Stephen M.

A double-blind randomized pilot study comparing quetiapine and divalproex for adolescent mania

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.

Journal of the American Academy of Child & Adolescent Psychiatry, 45(3) : 305- 13

Barzman, Drew H., Delbello, Melissa P., Adler, Caleb M., Stanford, Kevin E., Strakowski, Stephen M.

The efficacy and tolerability of quetiapine versus divalproex for the treatment of impulsivity and reactive aggression in adolescents with co-occurring bipolar disorder and disruptive behavior disorder(s)

OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of quetiapine and divalproex for the treatment of impulsivity and reactive aggression in adolescents with co-occurring bipolar disorder and disruptive behavior disorders. METHOD: Patients were included in this post hoc analysis if they scored > or = 14 on the Positive and Negative Syndrome Scale (PANSS) Excited Component (EC) and > or = 4 on at least one of the PANSS EC items, had a current diagnosis of bipolar I disorder, manic or mixed episode, and had a lifetime and/or current diagnosis of a disruptive behavioral disorder (DBD) [conduct disorder (CD) or oppositional defiant disorder (ODD)]. Thirty-three (92%) of the 36 subjects with bipolar disorder and DBD met the PANSS EC inclusion criteria. These thirty-three adolescents were randomized to quetiapine (400-600 mg/day) or divalproex (serum level 80-120 microg/mL) for 28 days in this double- blinded study. The primary efficacy measure was change in PANSS Excited Component (EC) score over the study period and at each time point. RESULTS: Repeated measures analysis of variance (ANOVA) demonstrated statistically significant within-treatment-group effects for divalproex (baseline = 20.6, end point = 13.3, p < 0.0001) and quetiapine (baseline = 18.8, end point = 10.8, p < 0.0001) for the PANSS EC. There were no statistically significant treatment group differences in PANSS EC changes from baseline to end point scores (p = 0.7, d = 0.14). Mixed regression analyses (comparison of slopes, DAY*TREATMENT) revealed that there was no significant difference in the rate of improvement in the PANSS EC scores between the two treatment groups [F(1,31) = 0.78, p = 0.39, d = 0.28]. CONCLUSIONS: Quetiapine and divalproex showed similar efficacy for the treatment of impulsivity and reactive aggression related to co-occurring bipolar and disruptive behavior disorders in adolescents. Quetiapine and divalproex are both useful as monotherapy for the treatment of impulsivity and reactive aggression in adolescents with bipolar and disruptive behavior disorders. Placebo-controlled studies are necessary.

Journal of Child & Adolescent Psychopharmacology, 16(6) : 665- 70

Delbello, Melissa P., Findling, Robert L., Kushner, Stuart, Wang, Daniel, Olson, William H., Capece, Julie A., Fazzio, Lydia, Rosenthal, Norman R.

A pilot controlled trial of topiramate for mania in children and adolescents with bipolar disorder

OBJECTIVE: To assess the efficacy of topiramate monotherapy for acute mania in children and adolescents with bipolar disorder type I. METHOD: This double-blind, placebo-controlled study was discontinued early when adult mania trials with topiramate failed to show efficacy. Efficacy end points included the Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale for Children, Children's Depression Rating Scale, Children's Global Assessment Scale, and Clinical Global Impressions-Improvement. RESULTS: Fifty-six children and adolescents (6-17 years) with a diagnosis of bipolar disorder type I received topiramate (n=29, 52%) or placebo (n=27, 48%). The only statistically significant differences in efficacy measures between treatment groups were the difference between slopes of the linear mean profiles of the YMRS (p=.003) using a post hoc repeated measures regression and the change in Brief Psychiatric Rating Scale for Children at day 28 (-14.9 versus-5.9, p=.048) using observed data. Adverse events with topiramate included decreased appetite, nausea, diarrhea, and paresthesia. CONCLUSIONS: Topiramate was well tolerated; however, the results are inconclusive because of premature termination resulting in a limited sample size. Adequately powered controlled trials are necessary to determine whether topiramate has efficacy in reducing symptoms of acute mania in children and adolescents.

Journal of the American Academy of Child & Adolescent Psychiatry, 44(6) : 539-47

Calabrese, Joseph R., Keck-Jr, Paul E., Macfadden, Wayne, Minkwitz, Margaret, Ketter, Terence A., Weisler, Richard H., Cutler, Andrew J., McCoy, Robin, Wilson, Ellis, Mullen, Jamie

A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression

OBJECTIVE: There is a major unmet need for effective options in the treatment of bipolar depression. METHOD: Five hundred forty-two outpatients with bipolar I (N=360) or II (N=182) disorder experiencing a major depressive episode (DSM-IV) were randomly assigned to 8 weeks of quetiapine (600 or 300 mg/day) or placebo. The primary efficacy measure was mean change from baseline to week 8 in the Montgomery-Asberg Depression Rating Scale total score. Additional efficacy assessments included the Hamilton Depression Rating Scale, Clinical Global Impression of severity and improvement, Hamilton Anxiety Rating Scale, Pittsburgh Sleep Quality Index, and Quality of Life Enjoyment and Satisfaction Questionnaire. RESULTS: Quetiapine at either dose demonstrated statistically significant improvement in Montgomery-Asberg Depression Rating Scale total scores compared with placebo from week 1 onward. The proportions of patients meeting response criteria (> or =50% Montgomery- Asberg Depression Rating Scale score improvement) at the final assessment in the groups taking 600 and 300 mg/day of quetiapine were 58.2% and 57.6%, respectively, versus 36.1% for placebo. The proportions of patients meeting remission criteria (Montgomery-Asberg Depression Rating Scale < or =12) were 52.9% in the groups taking 600 and 300 mg/day of quetiapine versus 28.4% for placebo. Quetiapine at 600 and 300 mg/day significantly improved 9 of 10 and 8 of 10 Montgomery-Asberg Depression Rating Scale items, respectively, compared to placebo, including the core symptoms of depression. Treatment-emergent mania rates were low and similar for the quetiapine and placebo groups (3.2% and 3.9%, respectively). CONCLUSIONS: Quetiapine monotherapy is efficacious and well tolerated for the treatment of bipolar depression.

American Journal of Psychiatry, 162(7) : 1351-60

Findling, Robert L., McNamara, Nora K., Youngstrom, Eric A., Stansbrey, Robert, Gracious, Barbara L., Reed, Michael D., Calabrese, Joseph R.

Double-blind 18-month trial of lithium versus divalproex maintenance treatment in pediatric bipolar disorder.[see comment]

OBJECTIVE: To determine whether divalproex sodium (DVPX) was superior to lithium carbonate (Li+) in the maintenance monotherapy treatment of youths diagnosed with bipolar disorder who had been previously stabilized on combination Li+ and DVPX (Li+/DVPX) pharmacotherapy. METHOD: Youths ages 5-17 years with bipolar I or II disorder were initially treated with Li /DVPX. Patients meeting remission criteria for four consecutive weeks were then randomized in a double-blind fashion to treatment with either Li+ or DVPX for up to 76 weeks. Study participation ended if the subject required additional clinical intervention or if the subject did not adhere to study procedures. RESULTS: Patients were recruited between July 1998 and May 2002. One hundred thirty-nine youths with a mean (SD) age of 10.8 (3.5) years were initially treated with Li+/DVPX for a mean (SD) duration of 10.7 (5.4) weeks. Sixty youths were then randomized to receive monotherapy with Li+ (n = 30) or DVPX (n = 30). The Li+ and DVPX treatment groups did not differ in survival time until emerging symptoms of relapse (p = .55) or survival time until discontinuation for any reason (p = .72). CONCLUSIONS: DVPX was not found to be superior to Li+ as maintenance treatment in youths who stabilized on combination Li +/DVPX pharmacotherapy.

Journal of the American Academy of Child & Adolescent Psychiatry, 44(5) : 409- 17