Relationship of open acute mania treatment to blinded maintenance outcome in bipolar I disorder.

BACKGROUND: Most bipolar treatment guidelines recommend that acutely effective therapy be continued as maintenance treatment, unless contraindicated. No published studies have statistically evaluated the relationship between the outcomes in maintenance treatment and the principal acute agent. METHODS: Post-hoc analysis of prophylactic results obtained during a 12-month maintenance study in recently manic patients assessed the relationship between open treatment and randomized maintenance treatment. Patients were grouped according to mood stabilizer (if any) received on the last day of the open-label, stabilization phase (divalproex, lithium, or no mood stabilizer), and the mood stabilizer to which they were randomly assigned in the double-blind, maintenance phase (divalproex, lithium, or placebo). RESULTS: Patients treated with open-phase divalproex and randomized to divalproex maintenance therapy had a significantly longer period before development of a mood episode compared to those randomized to either placebo (Log-rank, p=0.05) or lithium (Log-rank, p=0.04), and better tolerability than those randomized to lithium. Patients treated with open-phase lithium showed no treatment-related differences in time to a mood episode after being randomized to lithium, divalproex, or placebo and tolerability was comparable in all groups. LIMITATIONS: Open treatment was selected by treating physicians, contributing to possible selection bias. More patients were randomized to divalproex than to lithium or placebo. The study was therefore better powered to detect divalproex effects. CONCLUSIONS: Acute response to divalproex predicted both superior prophylactic response and tolerability to divalproex, than to placebo (efficacy) and to lithium (efficacy and tolerability). Results could have implications for both clinical practice and clinical trial design.

ABT-089, a neuronal nicotinic receptor partial agonist, for the treatment of attention-deficit/hyperactivity disorder in adults: results of a pilot study.

BACKGROUND: This pilot study was designed to evaluate ABT-089, a neuronal nicotinic receptor partial agonist, as treatment for adult attention-deficit/hyperactivity disorder (ADHD). METHODS: Adults with ADHD received placebo, 2 mg, 4 mg, or 20 mg of ABT-089 for 2 weeks each in a randomized, double-blind, placebo-controlled, 4 x 4 Latin square design for a total of 8 weeks. In addition to the primary outcome, the Conner's Adult ADHD Rating Scale (CAARS), secondary rating scales, and neuropsychological and safety assessments were completed. RESULTS: A total of 11 adults with well-characterized ADHD completed this crossover study. ABT-089 b.i.d. was superior to placebo for the CAARS Total Symptom Score, which was the primary endpoint (placebo: 38.0 +/- 1.9; 2 mg b.i.d.: 32.2 +/- 1.9, one-tail p = .021; 4 mg b.i.d.: 33.2 +/- 1.9, p = .047; 20 mg b.i.d.: 33.5 +/- 1.9, p = .056). ABT-089 was also superior to placebo for the CAARS ADHD Index and Hyperactive/Impulsive scores and the Clinical Global Impression-ADHD Severity score. On the clinical efficacy endpoints, CAARS Total Symptom Score and CAARS Hyperactive/Impulsive score, a shallow inverted U-shaped dose-response curve was observed; however, the dose-response curve for attention and memory effects as measured by computerized cognitive testing seemed dose-linear. No clinically meaningful findings in safety assessments or side effect profile were observed. CONCLUSIONS: Data from this pilot study suggest that ABT-089 might be effective in treating adult ADHD and that it is well tolerated. On the basis of these promising results, larger, parallel-group ABT-089 studies of longer duration are warranted.

Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania.

OBJECTIVE: Several studies have shown that achieving adequate serum valproate levels is critical to rapid stabilization of acute mania, but estimates of the target therapeutic level have been imprecise. A post hoc analysis of pooled intent-to-treat data from three randomized, placebo-controlled studies of divalproex treatment for acute mania was performed to test a hypothesized linear relationship between serum concentration and response and to determine optimal blood levels for treatment of acute mania. METHOD: Subjects (N=374) were stratified into seven groups (six valproate serum level ranges and placebo), and effect size was determined for each. Linearity of dose response was tested with both parametric and nonparametric techniques. ANOVA was used to compare the response at each serum level range with that of placebo as well as the lowest valproate level (< =55.0 microg/ml). The mean serum valproate level was then determined for all subjects with an effect size greater than or equal to the maximal effect derived from linear modeling. RESULTS: The fit of blood level and response to a linear model was good. Efficacy was significantly greater than placebo beginning at the 71.4-85.0 microg/ml range and for all higher valproate levels; the 94.1-107.0 and >107.0 microg/ml groups were superior to the lowest valproate serum level group. The effect size associated with highest serum levels (>94 microg/ml) was 1.06 (0.59 after placebo correction). Subjects obtaining this effect or greater (N=84) had a mean serum level of 87.5 microg/ml. Blood levels in the lowest effective range were 60% more effective than placebo and in the higher ranges were 120% more effective. Tolerability appeared similar for all groups. CONCLUSIONS: The results of this study suggest that there is a linear relationship between valproate serum concentration and response and that the target blood level of valproate for best response in acute mania is above 94 microg/ml.

Relationship of mania symptomatology to maintenance treatment response with divalproex, lithium, or placebo.

Euphoric and mixed (dysphoric) manic symptoms have different response patterns to divalproex and lithium in acute mania treatment, but have not been studied in relationship to maintenance treatment outcomes. We examined the impact of initial euphoric or dysphoric manic symptomatology on maintenance outcome. Randomized maintenance treatment with divalproex, lithium, or placebo was provided for 372 bipolar I patients, who met improvement criteria during open phase treatment for an index manic episode. The current analysis grouped patients according to the index manic episode subtype (euphoric or dysphoric), and evaluated the impact on maintenance treatment outcome. The rate of early discontinuation due to intolerance during maintenance treatment was higher for initially dysphoric patients (N=249) than euphoric patients (N=123; 15.7 vs 7.3%, respectively; p=0.032). Both lithium (23.2%) and divalproex (17.1%) were associated with more premature discontinuations due to intolerance than placebo (4.8%; p=0.003 and 0.02, respectively) in the initially dysphoric patients. Among initially euphoric patients, treatment with lithium was associated with significantly more premature discontinuations due to intolerance compared to placebo (18.2 vs 0%; p=0.03), and divalproex was significantly (p=0.05) more effective than lithium, but not placebo in delaying time to a depressive episode. Initial euphoric mania appeared to predispose to better outcomes on indices of depression and overall function with divalproex maintenance than with either placebo or lithium. Dysphoric mania appeared to predispose patients to more side effects when treated with either divalproex or lithium during maintenance therapy.

Divalproex in the treatment of impulsive aggression: efficacy in cluster B personality disorders.

Impulsive aggressive behavior is common in psychiatric disorders and accounts for significant morbidity and mortality. However, little systematic treatment data exist from placebo-controlled trials for this symptom domain. This was a multicenter, randomized, double-blind, placebo-controlled study in which outpatients with a score of > or =15 on the Aggression scale of the Overt Aggression Scale-Modified (OAS-M) and who fulfilled DSM-IV criteria for Cluster B personality disorder (n=96), intermittent explosive disorder (n=116), or post-traumatic stress disorder (n=34) were randomized to divalproex sodium or placebo for 12 weeks duration. Based on average OAS-M Aggression scores over the last 4 weeks of treatment, a treatment effect was not observed in the intent-to-treat data set (combined across the three psychiatric disorders), but was observed in both intent-to-treat and evaluable data sets for patients with Cluster B personality disorders. In the Cluster B evaluable data set, statistically significant treatment differences favoring divalproex were also observed for component items of the OAS-M Aggression score, including verbal assault and assault against objects, as well as OAS-M Irritability score, and Clinical Global Impression (CGI)-Severity at multiple time points throughout the study. No treatment group difference was noted for overall premature discontinuation rate; however, across psychiatric diagnoses, 21 (17%) patients in the divalproex group prematurely discontinued because of an adverse event, as compared to 4 (3%) patients in the placebo group (p <0.001). While a treatment effect was not observed when all diagnostic groups were combined, in a large subgroup of patients with Cluster B disorders, divalproex was superior to placebo in the treatment of impulsive aggression, irritability, and global severity.

Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia.

This double-blind, randomized, multicenter study investigated the use of divalproex with an antipsychotic agent in patients hospitalized for acute exacerbation of schizophrenia. Patients (n = 249) who met DSM-IV criteria for schizophrenia were randomly assigned to receive olanzapine monotherapy, risperidone monotherapy, divalproex plus olanzapine, or divalproex plus risperidone for 28 days. Divalproex was initiated at 15 mg/kg/day and titrated over 12 days to a maximum dosage of 30 mg/kg/day. Olanzapine and risperidone, were, respectively, initiated at 5 and 2 mg/day and were titrated over the first 6 days to respective target fixed daily dosages of 15 and 6 mg/day. Improvements from baseline were observed at all evaluation points throughout the 28-day treatment period in the two combination therapy and the two antipsychotic monotherapy groups, with statistically significant treatment differences favoring combination therapy as soon as day 3 for Positive and Negative Syndrome Scale (PANSS) total score, derived Brief Psychiatric Rating Scale (BPRSd) total score, as well as PANSS and BPRSd subscales. These findings were confirmed in post hoc repeated-measures analyses of variance in which treatment differences favoring combination therapy were observed for PANSS total (p = 0.020) and PANSS positive scale scores (p = 0.002). Both combination therapy and antipsychotic monotherapy were well tolerated. Treatment with divalproex in combination with an atypical antipsychotic agent resulted in earlier improvements in a range of psychotic symptoms among acutely hospitalized patients with schizophrenia. Further evaluation is warranted to confirm these findings.

Maintenance efficacy of divalproex in the prevention of bipolar depression.

Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A randomized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of prestudy illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness.

A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder.

BACKGROUND: This study compared the efficacy, safety, and tolerability of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder. METHOD: This randomized, 12-week, double-blind, parallel-group, multicenter study included DSM-IV-defined bipolar disorder type I patients hospitalized for acute mania and randomly assigned to treatment with divalproex or olanzapine. After an inpatient period of up to 21 days, subjects were followed as outpatients. Dose adjustment was permitted during the inpatient period. Efficacy was assessed using change from baseline in Mania Rating Scale (MRS) score to day 21; other efficacy measures included the Brief Psychiatric Rating Scale, the Hamilton Rating Scale for Depression, and the Clinical Global Impressions-Part I, Severity of Illness scale. The primary safety endpoint was change from baseline in weight. Other safety and tolerability endpoints included spontaneous adverse event reporting and changes from baseline in laboratory measures and vital signs. RESULTS: 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomly assigned to treatment. No significant differences between groups were found for any efficacy variable for change from baseline to day 21. Mean MRS score changes from baseline to day 21 were -14.8 for divalproex and -17.2 for olanzapine (p =.210). A significantly (p <.05) greater proportion of olanzapine-treated subjects experienced somnolence, weight gain, edema, rhinitis, and speech disorder (slurred speech); no adverse events were significantly greater in the divalproex group. A number of laboratory measures also demonstrated significant treatment differences, but the clinical significance of many of these is uncertain. Mean body weight changes were significantly greater in the olanzapine group (+ 8.8 lb [+ 4.0 kg]) than the divalproex group (+ 5.5 lb [+ 2.5 kg], p <.050). One death occurred during the study (olanzapine group, diabetic ketoacidosis). CONCLUSION: No significant difference in efficacy was found between treatment groups. Divalproex was associated with a more favorable adverse event profile and significantly less weight gain than olanzapine.

The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder.

BACKGROUND: Previous studies have examined the safety and tolerability of oral-loaded divalproex sodium in the treatment of acute mania, but not the early efficacy of this dosing strategy. The purpose of this study was to evaluate the early efficacy of oral-loaded divalproex. METHOD: In this pooled analysis, 348 subjects from 3 randomized, double-blind, parallel-group, active- or placebo-controlled studies were used to compare the efficacy, safety, and tolerability of oral-loaded divalproex with standard-titration divalproex, lithium, olanzapine, or placebo. Subjects were inpatients diagnosed with acute mania associated with bipolar I disorder (DSM-III-R or -IV and SADS-Change Version). Patients were administered oral-loaded divalproex (20 or 30 mg/kg/day on days 1 and 2 followed by 20 mg/kg/day, and increased at physician's discretion), standard-titration divalproex initiated at 250 mg t.i.d. and titrated to 40-150 microg/mL, lithium (300 mg t.i.d. initial dose) titrated to 0.4 to 1.5 mEq/L, olanzapine (10 mg q.d. initial dose) up to 20 mg/day, or placebo. RESULTS: The results demonstrate an early efficacy advantage for oral-loaded divalproex compared to standard-titration divalproex at days 5, 7/8, and 10. Efficacy was improved over lithium on day 7/8. There were no efficacy differences between divalproex loading and olanzapine. Divalproex loading showed greater efficacy than placebo at all time points. Divalproex loading was as well tolerated or better tolerated than the other active treatments as measured by adverse events and changes in laboratory parameters. CONCLUSION: These results suggest the oral loading of divalproex leads to a more rapid antimanic effect when compared with standard-titration divalproex, lithium, or placebo and is better tolerated than olanzapine and as well tolerated as lithium or standard-titration divalproex.

Psychosis in mania: specificity of its role in severity and treatment response.

BACKGROUND: Psychosis is a prominent characteristic of manic episodes. We investigated relationships between the presence of psychotic features, the severity of the manic syndrome, and syndrome severity's response to treatment. METHOD: 179 subjects meeting Research Diagnostic Criteria for a manic episode of bipolar I disorder were hospitalized for acute manic episodes and treated in a randomized trial of lithium, divalproex sodium, or placebo. Factor and cluster analyses were carried out using the clinician-rated Schedule for Affective Disorders and Schizophrenia, Change version (SADS-C) and the nurse-rated Affective Disorder Rating Scale (ADRS). RESULTS: Subjects with psychotic features had significantly (p < .005) greater overall impairment (lower Global Assessment Scale [GAS] scores) but did not differ in severity of mania scores compared with those without psychotic features. Psychosis factor scores correlated significantly (p < .000001) with GAS scores but not with mania scores. Baseline psychosis factor scores did not correlate with subsequent treatment-associated change in mania scores, but change in mania scores during treatment correlated significantly (p < .000001) with change in the psychosis factor. Changes in psychosis factor scores correlated significantly with changes in mania rating scale scores regardless of treatment. CONCLUSIONS: Psychotic features as a component of manic episodes contribute substantially to overall impairment. Treatments that successfully treat mania also reduce psychosis scores.

An open-label trial of divalproex in children and adolescents with bipolar disorder.

OBJECTIVE: This study evaluated the safety and effectiveness of divalproex sodium (Depakote ) in the treatment of youths with bipolar disorder. METHOD: Forty bipolar disorder patients aged 7 to 19 years, with a manic, hypomanic, or mixed episode, enrolled in an open-label study of divalproex (2-8 weeks), followed by a double-blind, placebo-controlled period (8 weeks). RESULTS: Twenty-two subjects (61%) showed > or =50% improvement in Mania Rating Scale (MRS) scores during the open-label period. Significant ( <.001) improvements from baseline were seen for mean scores of all efficacy measures, including the MRS, Manic Syndrome Scale, Behavior and Ideation Scale, Brief Psychiatric Rating Scale, Clinical Global Impressions Severity scale, and Hamilton Rating Scale for Depression. Of the 23 subjects who discontinued the study during the open-label period, 6 (15%) discontinued for ineffectiveness, 6 (15%) for intolerance, 6 (15%) for noncompliance, and 6 (15%) for other reasons. Adverse events were generally mild or moderate in severity, with the most common being headache, nausea, vomiting, diarrhea, and somnolence. Laboratory data results were unremarkable. Too few subjects participated in the double-blind period for statistical analysis. CONCLUSION: This study provides preliminary support for the safety and effectiveness of divalproex in the treatment of bipolar disorder in youths.

Adjunctive divalproex and hostility among patients with schizophrenia receiving olanzapine or risperidone.

OBJECTIVE: This study compared the specific antihostility effects of atypical antipsychotic monotherapy (olanzapine or risperidone) with that of combination treatment with divalproex sodium among patients with schizophrenia experiencing an acute psychotic episode. METHODS: A total of 249 inpatients with schizophrenia were randomly assigned to receive olanzapine plus placebo, olanzapine plus divalproex, risperidone plus placebo, or risperidone plus divalproex in a double-blind, 28-day multicenter trial. The target daily dose was 15 milligrams for olanzapine, 6 milligrams for risperidone, and up to 30 milligrams per kilogram (minimum, 15 milligrams per kilogram) for divalproex. The hostility item of the Positive and Negative Syndrome Scale (PANSS) was the principal outcome measure. Covariates included the PANSS items reflecting positive symptoms of schizophrenia (delusions, suspiciousness/persecution, grandiosity, unusual thought content, conceptual disorganization, and hallucinatory behavior). RESULTS: Combination treatment with risperidone or olanzapine plus divalproex was associated with different scores on the hostility item of the PANSS compared with antipsychotic monotherapy. Combination therapy had a significantly greater antihostility effect at days 3 and 7 than monotherapy. This result was not seen beyond the first week of treatment, but there was a trend toward a difference in effect for the entire treatment period. The effect on hostility appears to be statistically independent of antipsychotic effect on other PANSS items reflecting delusional thinking, a formal thought disorder, or hallucinations. CONCLUSIONS: Divalproex sodium may be useful as an adjunctive agent in specifically reducing hostility in the first week of treatment with risperidone or olanzapine among patients with schizophrenia experiencing an acute psychotic episode.

A randomized, placebo-controlled, multicenter study of divalproex sodium extended-release in the acute treatment of mania.

OBJECTIVE: Divalproex sodium extended-release (ER) was examined for the treatment of acute mania in adults in 2 randomized, placebo-controlled clinical trials. One study demonstrated statistically significant improvements in mania symptoms compared to placebo, while an earlier study did not. Results of the earlier study are presented here. METHOD: A total of 225 DSM-IV-diagnosed bipolar I disorder patients were randomly assigned in a 2:1 ratio to 21 days of double-blind treatment with divalproex ER (n = 147) or placebo (n = 78). The daily divalproex ER dosage was initiated at 20 mg/kg. The primary efficacy variable was the change from baseline to final evaluation in Mania Rating Scale (MRS) score. Subjects were discontinued from the study if they were discharged from the hospital or if they met prespecified improvement criteria. The study was conducted from May 1998 to July 1999 at centers in the United States. RESULTS: There was no statistically significant difference in MRS score change from baseline to final for patients treated with divalproex ER compared with those treated with placebo. With the exception of back pain and constipation, adverse event rates between placebo and divalproex ER were very similar. A large proportion of patients prematurely discontinued study treatment (divalproex ER: 83%, placebo: 82%). The mean daily dose of divalproex ER was 2,211 mg with a mean maximum serum valproic acid concentration of 77.9 microg/mL. CONCLUSIONS: The results of the current study did not demonstrate statistically significant improvement in mania symptoms associated with divalproex ER treatment compared to placebo. A number of methodological considerations may have contributed to the negative findings, including allowance for early study discontinuation and lower than optimal dosing. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00060905.

A double-blind, randomized, placebo-controlled trial of divalproex extended-release in the treatment of bipolar disorder in children and adolescents.

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.

Divalproex ER combined with olanzapine or risperidone for treatment of acute exacerbations of schizophrenia.

The objective of this study was to evaluate the efficacy and safety of divalproex sodium extended release (divalproex ER) vs placebo in combination with olanzapine or risperidone for the treatment of acute exacerbations of schizophrenia. In this 12-week, randomized, double-blind, parallel-group, multi-center trial, a total of 402 patients were randomized and treated; 103 received olanzapine/placebo, 99 received olanzapine/divalproex ER, 101 received risperidone/placebo, and 99 received risperidone/divalproex ER. Divalproex ER was initiated on day 1 at 20 mg/kg per day q AM and was titrated to clinical effect on days 3, 7, and 10, not to exceed a maximum dosage of 35 mg/kg per day. Olanzapine and risperidone were initiated at 5 and 2 mg/day q PM, respectively, increased to 10 and 4 mg/day on day 3, and increased to fixed target doses of 15 and 6 mg/day on day 6. No significant treatment difference was demonstrated between the combination therapy and antipsychotic monotherapy groups on the primary efficacy variable of the mean change from baseline to day 14 last observation carried forward on the Positive and Negative Syndrome Scale (PANSS) total score, although antipsychotic monotherapy did demonstrate superiority to combination therapy on the PANSS Negative subscale at several time points. Combination therapy also failed to show an advantage over antipsychotic monotherapy at day 84 on the PANSS total score. Most adverse events observed in the study were mild to moderate in severity, and the overall number of adverse events did not differ significantly between the combination therapy groups and their corresponding antipsychotic monotherapy group.

Long-term safety of divalproex sodium extended-release in children and adolescents with bipolar I disorder.

OBJECTIVE: The objective of this open-label study was to assess the safety of divalproex sodium extended-release in the treatment of children and adolescents with acute mania associated with bipolar I disorder. METHODS: This was a 6-month, Phase 3, open-label study in healthy subjects aged 9-17 years with a current Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition, Text Revision (DSM-IV-TR) diagnosis of bipolar I disorder manic or mixed episode. Divalproex sodium extended-release (DVPX-ER) was initiated at 15 mg/kg per day on day 1 (not to exceed 750 mg/day) with increases allowed to a maximum of 35 mg/kg per day. Study visits were conducted on day 1 and at months 1, 2, 3, and 6. Assessments included standard safety evaluations and appropriate rating scales for clinical effect. RESULTS: A total of 226 subjects were enrolled; 109 subjects completed the study. The most common adverse events were weight gain (16%), nausea (9%), and increased appetite (8%). Nonsymptomatic elevations of mean ammonia levels in plasma were observed. The mean Young Mania Rating Scale (YMRS) decreased 12.4 from baseline to final visit; small improvements were seen in behavior and caregiver stress ratings. CONCLUSIONS: DVPX-ER was generally well tolerated in children and adolescents with acute mania, with a side-effect profile similar to that observed in adults.

A randomized, placebo-controlled, multicenter study of divalproex sodium extended release in the treatment of acute mania.

OBJECTIVE: The efficacy and safety of divalproex sodium extended release (divalproex ER) were evaluated in patients hospitalized for acute mania associated with bipolar I disorder, manic or mixed type (DSM-IV-TR criteria). METHOD: Following screening and washout of psychotropic medications, 377 patients were randomly assigned in a 1:1 ratio to 21 days of double-blind treatment with divalproex ER (N = 192) or placebo (N = 185). Daily dosage was initiated at 25 mg/kg, increased 500 mg on day 3, and adjusted to serum valproate concentrations of 85 to 125 microg/mL. The Mania Rating Scale (MRS) was used to assess efficacy. Patients remained hospitalized at least 15 days during blinded treatment. The study was conducted from April 2003 to May 2004. RESULTS: Improvement from baseline on the MRS was significantly greater among patients who received divalproex ER compared with placebo at the first on-treatment rating assessment, day 5, and all subsequent ratings through day 21 (p = .013). Furthermore, the proportion of patients achieving at least 50% improvement from baseline in MRS was significantly higher in patients receiving divalproex ER (48%) than in patients receiving placebo (34%) (p = .012). Five of the 11 MRS items improved significantly more in patients receiving divalproex ER than placebo: less need for sleep (p

Relationship between serum valproate and lithium levels and efficacy and tolerability in bipolar maintenance therapy.

Background. In spite of widespread recognition of the importance of maintenance treatment for bipolar disorder, there are relatively few available well-designed clinical trials that have provided rigorous evidence for the efficacy of specific agents. One approach used effectively in analyses of lithium studies has been the stratification of efficacy and tolerability results based on serum drug concentrations. Therefore, we conducted a similar analysis of the efficacy of divalproex or lithium, based on serum concentrations in the maintenance treatment of bipolar I disorder in a recent 12-month placebo-controlled trial. Methods. This was a post-hoc analysis of results obtained in a 12-month, double-blind, placebo-controlled trial of divalproex and lithium involving 372 patients (intent-to-treat). The patient set was stratified into four therapeutic drug concentration ranges (Non-therapeutic, Low Therapeutic, Medium Therapeutic, and High Therapeutic) for both divalproex and lithium. Efficacy measures were Kaplan-Meier survival analyses of time to discontinuation for any reason, time to discontinuation for a protocol-defined manic episode, and time to discontinuation for a manic or depressive episode. Results. Significant differences between divalproex at the Medium Therapeutic range (75-99.9 µg/ml) and placebo were demonstrated in Kaplan-Meier survival results for discontinuation for any reason (median survival time: divalproex, 8 months; placebo, 4 months; P<0.05) and for discontinuation for a manic or depressive episode (median survival time: divalproex, 8 months; placebo, 3 months, P=0.003). At 12 months, the proportion of divalproex-treated patients (Medium Therapeutic range) who did not discontinue for a protocol-defined manic episode (85%) was higher than the proportion of lithium (Medium Therapeutic range; 70%) or placebo-treated (83%) patients. Conclusions. Divalproex at the Medium Therapeutic range provided significantly better bipolar maintenance treatment response than placebo in survival analyses, suggesting a possible serum concentration target range for clinicians in providing optimal treatment response. The value of this analytic approach, used for the first time here for divalproex, is discussed, along with a call for further research into optimal therapeutic drug levels.