A double-blind comparison of valproate and lithium in the treatment of acute mania. Valproate in the treatment of acute mania. A placebo-controlled study. Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter study. European Valproate Mania Study Group. Comparative double blind clinical trial of phenytoin and sodium valproate as anticonvulsant prophylaxis after craniotomy: efficacy, tolerability, and cognitive effects. A placebo-controlled trial of valproate for agitation and aggression in Alzheimer's disease. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. A double-blind, placebo-controlled study of valproate for aggression in youth with pervasive developmental disorders. [Efficacy of sodium valproate in partial epilepsy. Crossed study of valproate and carbamazepine]. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group.
This study was carried out to compare the efficacy of lithium carbonate with that of valproate in acute mania and to determine whether pretreatment clinical characteristics, such as the presence of a mixed affective state, might predict a differential response to the two drugs.
                Twenty-seven patients meeting DSM-III-R criteria for acute manic episodes underwent a 3-week, randomized, double-blind, parallel-groups trial of treatment with lithium carbonate or valproate. Symptom severity was measured by using the Schedule for Affective Disorders and Schizophrenia, change version (SADS-C), the Global Assessment Scale (GAS), and the Brief Psychiatric Rating Scale (BPRS). Drug effects were compared by using repeated measures analysis of variance (ANOVA).
                At the end of the study, nine of 14 patients treated with valproate and 12 of 13 patients treated with lithium had responded favorably, as measured by changes in the SADS-C mania, BPRS, and GAS scores. Elevated pretreatment SADS-C depression scores were associated with good response to valproate. ANOVA revealed a significant interaction between drug and mixed affective state with respect to treatment response.
                Lithium and valproate were both effective in improving manic symptoms, and lithium was slightly more efficacious overall. Unlike the case with lithium, favorable response to valproate was associated with high pretreatment depression scores. Therefore, treatment with valproate alone may be particularly effective in manic patients with mixed affective states. We conducted a placebo-controlled, double-blind study of valproate, a drug originally developed as an antiepileptic, in 36 patients with acute manic episodes who had previously failed to respond to or to tolerate lithium carbonate. Treatment duration was 7 to 21 days, with no other psychotropic medications permitted except lorazepam up to 4 mg/d during the first 10 days of treatment. Serum valproate concentrations were measured three times weekly; an unblinded investigator then adjusted dosage to produce serum concentrations between 50 and 100 mg/L. Valproate proved superior to placebo in alleviating manic symptoms. The 17 patients randomized to active drug demonstrated a median 54% decrease in scores on the Young Mania Rating Scale as compared with a median 5.0% decrease among the 19 patients receiving placebo. On the 100-point Global Assessment Scale of overall psychiatric functioning, patients receiving valproate improved by a median of 20 points as compared with a zero-point change with placebo. Significant differences also emerged on the Brief Psychiatric Rating Scale and in the number of supplemental doses of lorazepam required by the patients in each group. Substantial antimanic effects appeared within 1 to 4 days of achieving therapeutic serum valproate concentrations. Adverse effects were infrequent, with no adverse effect appearing significantly more frequently with valproate than with placebo. We conclude that valproate represents a useful new drug for the treatment of manic patients. To compare the efficacy of sodium valproate administered as adjunct to neuroleptic medication for patients with acute mania with the efficacy of neuroleptics alone, the authors conducted a 21-day, randomized, double-blind, parallel-group, placebo-controlled trial. The study design closely reflected a clinical psychiatric setting in Europe where patients with acute mania commonly receive neuroleptic medication. In this trial, 136 hospitalized patients met the ICD-10 criteria for acute manic episodes; these patients received a fixed dose of 20 mg/kg of body weight of sodium valproate (Orfiril, Desitin Arzneimittel GmbH, Hamburg, Germany) orally, in addition to basic neuroleptic medication, preferably haloperidol and/or perazine. The primary outcome measure was the mean dose of neuroleptic medication (after conversion into haloperidol-equivalents) for the 21-day study period. Severity of symptoms was measured using the Young Mania Rating Scale (YMRS), the Global Assessment Scale, and the Clinical Global Impression Scale. Intent-to-treat analysis was based on 69 patients treated with valproate and 67 patients who received placebo. Groups were comparable with regard to demographic and clinical baseline data. Premature discontinuations occurred in only 13% of the patients. The mean neuroleptic dose declined continuously in the valproate group, whereas only slight variations were observed in the placebo group; the difference was statistically significant (p = 0.0007) for study weeks 2 and 3. The combination of neuroleptic and valproate proved superior to neuroleptics in attempts to alleviate manic symptoms. The proportion of responders (a 50% improvement rate shown on the YMRS) was higher for the combination with valproate than for the group receiving only neuroleptics (70% vs. 46%; p = 0.005). Adverse events consisted of those known for valproate or neuroleptics; the only adverse event was asthenia, which occurred more frequently with the combination therapy. Valproate represents a useful adjunct medication for the treatment of acute manic symptoms. Valproate is beneficial because it allows the administration of fewer neuroleptic medications and produces improved and quicker remission of manic symptoms. To determine the efficacy, tolerability, and impact on quality of life and cognitive functioning of anticonvulsant prophylaxis with phenytoin or sodium valproate in patients after craniotomy.
                A prospective, stratified, randomised, double blind single centre clinical trial was performed, comparing two groups of 50 patients each, who underwent craniotomy for different pathological conditions and who were treated for 1 year after surgery with either 300 mg phenytoin/day or 1500 mg sodium valproate/day. During the study period patients were seen in the outpatient clinic at 1.5, 3, 6, and 12 months, when medical history, adverse events, and drug plasma concentrations were evaluated. Neuropsychological functioning and quality of life were assessed on the last three visits. In cases of a seizure an EEG was performed, drug plasma concentration assessed, and medication subsequently increased.
                Of the 100 included patients 14 (seven in each group) experienced one or more postoperative seizures. Severity of the seizures was comparable in the two groups. In all patients, drug plasma concentrations were in the low or subtherapeutic ranges at the time of the first postoperative seizure. Five patients in the phenytoin group and two in the valproate group had to stop their treatment due to drug related adverse events. Sixty patients completed the 12 month period. Analysis of neuropsychological and quality of life data showed no significant differences.
                For efficacy, tolerability, impact on cognitive functioning, and quality of life, no major differences were found between phenytoin and valproate prophylaxis. Valproate is an alternative for anticonvulsant prophylaxis in patients after craniotomy. To assess the efficacy and tolerability of valproate for the treatment of agitation and aggression in moderate-to-severe Alzheimer's disease (AD).
                This was a randomized, double-blind, placebo-controlled crossover trial of valproate in institutionalized AD patients. Patients were assessed with the Neuropsychiatric Inventory (NPI) and Cohen-Mansfield Agitation Inventory at baseline and after 6 weeks of treatment with valproate and placebo, with 2 weeks between phases to allow for placebo washout and tapering.
                Fourteen patients (8 male/6 female) aged 85.6 +/- 4.5 years with baseline Mini Mental State Examination scores of 4.5 +/- 4.6 and NPI agitation/aggression scores of 6.4 +/- 3.5 were randomized to treatment. NPI agitation/aggression treatment change scores significantly worsened during valproate treatment compared with placebo (Z = -2.03, p = 0.04). Tolerability of valproate was also poor, with patients experiencing a significantly greater mean number of adverse events during valproate therapy compared to placebo (Z = -2.82, p = 0.005).
                Valproate is not effective for the management of agitation in moderate-to-severe AD, and may be poorly tolerated in this population.
                Copyright (c) 2007 S. Karger AG, Basel. A 6-week double-blind, randomized, placebo-controlled trial was conducted to determine the efficacy of combined therapy with olanzapine and either valproate or lithium compared with valproate or lithium alone in treating acute manic or mixed bipolar episodes.
                The primary objective was to evaluate the efficacy of olanzapine (5-20 mg/d) vs placebo when added to ongoing mood-stabilizer therapy as measured by reductions in Young Mania Rating Scale (YMRS) scores. Patients with bipolar disorder (n = 344), manic or mixed episode, who were inadequately responsive to more than 2 weeks of lithium or valproate therapy, were randomized to receive cotherapy (olanzapine + mood-stabilizer) or monotherapy (placebo + mood-stabilizer).
                Olanzapine cotherapy improved patients' YMRS total scores significantly more than monotherapy (-13.11 vs -9.10; P = .003). Clinical response rates (> or = 50% improvement on YMRS) were significantly higher with cotherapy (67.7% vs 44.7%; P< .001). Olanzapine cotherapy improved 21-item Hamilton Depression Rating Scale (HAMD-21) total scores significantly more than monotherapy (4.98 vs 0.89 points; P< .001). In patients with mixed-episodes with moderate to severe depressive symptoms (DSM-IV mixed episode; HAMD-21 score of > or = 20 at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared with 1.57 for monotherapy (P< .001). Extrapyramidal symptoms (Simpson-Angus Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale) were not significantly changed from baseline to end point in either treatment group. Treatment-emergent symptoms that were significantly higher for the olanzapine cotherapy group included somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech.
                Compared with the use of valproate or lithium alone, the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes. The aim of this study was to study valproate efficacy and safety for aggression in children and adolescents with pervasive developmental disorders (PDD).
                In this prospective double-blind, placebo-controlled study, 30 subjects (20 boys, 10 girls) 6-20 years of age with PDD and significant aggression were randomized and received treatment with valproate (VPA) or placebo (PBO) for 8 weeks as outpatients. Mean VPA trough blood levels were 75.5 mcg/mL at week 4 and 77.8 mcg/mL at week 8.
                No treatment difference was observed statistically between VPA and PBO groups. The Aberrant Behavior Checklist--Community Scale (ABC-C) Irritability subscale was the primary outcome measure (p = 0.65), and CGI--Improvement (p = 0.16) and OAS (p = 0.96) were secondary outcome measures. Increased appetite and skin rash were significant side effects. Only 1 subject was dropped from the study owing to side effects, notably a spreading skin rash, which then resolved spontaneously. Two subjects receiving VPA developed increased serum ammonia levels, one with an associated parent report of slurred speech and mild cognitive slowing. Poststudy, of 16 VPA and PBO subjects receiving VPA, 10 subjects demonstrated sustained response, 4 of whom later attempted taper, with significant relapse of aggression.
                The present negative findings cannot be viewed as conclusive, partly owing to the large placebo response, subject heterogeneity, and size of the groups. Larger studies are needed to expand upon these findings. An open response-conditional cross-over study of valproate versus carbamazepine has been done in previously untreated patients with partial seizures. Thirty-one patients entered the study. Nineteen were followed up to one year. It appeared that valproate was at least as effective as carbamazepine: at one year, 11 patients were seizure-free on valproate and only 8 were seizure-free on carbamazepine. Furthermore no side-effect was noted in valproate therapy, whereas carbamazepine was stopped in 2 patients because of skin rashes. The efficacy of sodium valproate in partial epilepsy remains controversial. It is of course limited when given as co-therapy in severe epilepsies, uncontrolled with other major antiepileptic drugs. However in naive patients, with recent and previously untreated partial epilepsies, a one-drug treatment with valproate appears to be as effective as carbamazepine or phenytoin. It has less unwanted side-effects and should be prescribed as first line treatment. Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy.
                A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n = 372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia-Change Version subscale scores for depression and mania, and Global Assessment of Function scores.
                The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores.
                The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.
In view of the equivocal findings of this review, conclusions about the efficacy and acceptability of valproate compared to placebo and lithium cannot be made with any degree of confidence. With current evidence, patients and clinicians would probably wish to use lithium before valproate for maintenance treatment. At present, the observed shift of prescribing practice to valproate is not based on reliable evidence of efficacy