Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia. Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients. The effect of sodium valproate on tardive dyskinesia--revisited. Combined treatment of schizophrenic psychoses with haloperidol and valproate. Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia.
Experimental and clinical data suggest that GABA-ergic drugs such as valproate may have a potential role in the treatment of schizophrenia. The authors designed a 21-day prospective, double-blind, randomized, placebo-controlled pilot study of divalproex sodium as add-on treatment to haloperidol in 12 hospitalized patients with acute exacerbations of chronic schizophrenia. All patients received haloperidol 10 mg/day for 3 days and 15 mg/day for the remaining 18 days. In addition, five patients were randomly assigned to receive divalproex augmentation and seven to receive placebo. The divalproex dose was adjusted to a target serum concentration of 75 microg/mL for 2 weeks; placebo replaced divalproex during the third and last weeks to determine any carryover effect. Psychiatric rating scales were administered at baseline and on days 7, 14, and 21. Although the placebo group improved with haloperidol treatment, the divalproex group demonstrated greater improvement. On day 21, the divalproex group had greater improvement from baseline on the Clinical Global Impression Scale (p < or = 0.04), Brief Psychiatric Rating Scale (p < or = 0.13), and Schedule for Assessment of Negative Symptoms scores (p < or = 0.007). After divalproex withdrawal on day 15, a carryover effect was observed during week 3. The authors concluded that the addition of divalproex sodium to standard antipsychotic drugs may prove effective in relieving the symptoms of acute schizophrenia. Future studies may benefit from the design of this pilot study. However, it is premature to apply this augmentation strategy in the clinical setting just yet because of the small sample size and the likely heterogeneity of the disorder. The objective of this study was to compare the effects of carbamazepine (CBZ) and valproate (VPA) cotreatment on the plasma levels of haloperidol and on the psychopathologic outcome in schizophrenic disorders. In this controlled clinical trial, 27 patients with an ICD-10 diagnosis of schizophrenia (N = 24) or schizoaffective disorder (N = 3) were randomly assigned to receive 4 weeks of treatment with either haloperidol alone, haloperidol with CBZ, or haloperidol with VPA. Whereas the haloperidol dose remained stable, the antiepileptic drug doses were adjusted to achieve therapeutic plasma levels. Clinical state was rated by the Positive subscale of the Positive and Negative Syndrome Scale and the Inpatient Multidimensional Psychiatric Scale. The use of CBZ was associated with significantly lower haloperidol plasma levels and with a worse clinical outcome compared with antipsychotic monotherapy. VPA had no significant effect on either plasma levels or on psychopathology. Our results suggest that comedication with haloperidol and CBZ is associated with a high risk for treatment failure. This might be a result of a pharmacokinetic interaction on the hepatic level. The concomitant use of VPA with neuroleptic therapy is not impaired by clinically significant drug interactions, but it is not associated with a better outcome under our conditions. As a treatment for tardive dyskinesia, sodium valproate was tested in a double-blind placebo-controlled parallel group trial, with 6-week base-line observation period followed by 6 weeks of treatment. Sodium valproate was not found to be an effective treatment for either tardive dyskinesia or drug-induced Parkinsonism, and did not affect mental state or behaviour. In accordance with a previous study of adjuvant effects of the anticonvulsant carbamazepine (CBZ) on the neuroleptic treatment of schizophrenic psychoses, the effects of valproate (VPA) were tested in a randomly assigned double-blind, placebo-controlled study. Apart from a (statistically nonsignificant) psychopathological deterioration following discontinuation of VPA while on continuous neuroleptic mediation after four weeks and a statistically significant effect on "hostile belligerence", no overall therapeutic effects of the combination of haloperidol (HPD) with VPA were observed under controlled conditions. Unlike the results with CBZ, concomitant use of VPA led to an even higher consumption of haloperidol and biperiden and to a higher rate of extrapyramidal symptoms compared with the corresponding placebo group, although these differences did not attain statistical significance. In regard to use of the sedative neuroleptic chlorprothixene, there was a trend toward lower doses in the VPA group than in the placebo group. From these results, adjuvant effects like those of carbamazepine in the neuroleptic treatment of schizophrenic psychoses could not be confirmed for valproate in the present study. However, the trend toward lower doses of sedative medication and observed effects on "hostile belligerence" may indicate sedative and/or antimanic properties of valproate which have recently been demonstrated in several controlled studies. 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.
Based on currently available randomised trial-derived evidence, there are no data to support or to refute valproate as a sole agent for schizophrenia. There is some evidence for positive effects on aggression and tardive dyskinesia, but given that these results were based on only a single small study they cannot be considered robust. Given the paucity of the available database further large, simple well-designed and reported trials are necessary. Ideally these would focus on people with schizophrenia and aggression, on those with treatment resistant forms of the disorder and on those with schizoaffective disorders.