Divalproex sodium augmentation of haloperidol in hospitalized patients with schizophrenia: clinical and economic implications.

Divalproex sodium has been approved for use in treating bipolar disorder. Its usefulness in schizophrenia has yet to be adequately assessed. Three days after initiating haloperidol treatment, patients who were hospitalized for an acute exacerbation of schizophrenia received either valproate augmentation (early-augmentation group) or continued to receive haloperidol alone (no-augmentation group). Patients in the no-augmentation group who failed to respond 14 days after the dose of haloperidol reached 20 mg/day received valproate augmentation (delayed-augmentation group). By day 14, the early-augmentation group improved 32.4% more than the no-augmentation group. Fifty percent of the patients in the no-augmentation group failed to respond to haloperidol alone for 2 weeks. They improved by 29% upon the addition of valproate. Compared with those who received no or delayed augmentation, the early-augmentation group required 44.8% fewer inpatient days from the initiation of haloperidol treatment. Patient response to treatment was particularly noted in suspiciousness, hallucinations, unusual thought content, and emotional withdrawal. Early augmentation with valproate may reduce the length of inpatient stays and provide substantially better therapeutic outcomes. It is, however, premature to recommend changes in the standard clinical management of schizophrenia on the basis of the data provided herein, in view of the small sample and open-label nature of the report.

Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic 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.

Critical review of GABA-ergic drugs in the treatment of schizophrenia.

GABA-ergic medications may have a potential role in the treatment of schizophrenia. Laboratory evidence has generally supported the ability of gamma-aminobutyric acid (GABA) to reduce dopaminergic activity and has suggested that GABA may be effective in combating hypofrontality by acting on mesoprefrontocortical tracts in patients resistant to treatment with antipsychotic drugs. Although the results of clinical trials of several GABA-ergic compounds have been inconclusive because of methodologic limitations and drug toxicity, benzodiazepines and valproate seem to be associated with favorable treatment outcomes, especially when combined with typical antipsychotic agents. This study concludes that further investigation of the use of GABA in schizophrenia is likely to improve the understanding of the psychopathology of this illness and to expand our treatment alternatives. Also provided are suggestions to enhance the design of future studies, improve the potential for favorable treatment outcomes, and assist in predicting patients' responses to GABA-ergic medications.

Immediate versus delayed visual memory task performance among schizophrenic patients and normal control subjects.

In an exploratory study, 10 schizophrenic patients and 10 normal control subjects performed immediate and delayed memory tasks, which were variants of previously developed continuous performance tests. Both tasks required participants to identify five-digit numbers which were repeated. Numbers were presented in series for 500 ms each and separated by a 500-ms time-out period. In the immediate memory task, subjects were to respond if a number was identical to the one that had immediately preceded it. The delayed memory task differed from the first task in that a longer delay (3.5 s) between stimuli was introduced, and during this delay distracter stimuli appeared. While normal control subjects performed accurately on both tasks (exceeding 80% correct detections), schizophrenic patients performed poorly, performing worse on the delayed memory task than on the immediate memory task. Rates of commission errors (responses made to similar, but not identical numbers) were nearly equal between groups on the immediate memory task, but on the delayed memory task normal control subjects made relatively more commission errors while schizophrenic patients made fewer commission errors. No differences in response latencies were observed between subject groups or tasks. This paradigm may prove useful in discriminating subtle differences in immediate and delayed memory capability among psychiatric populations and normal control subjects.

Glucocorticoid receptor binding in three different cell types in major depressive disorder: lack of evidence of receptor binding defect.

1. In order to further understand the apparent glucocorticoid resistance in major depressive disorder, circadian variation in cortisol concentration, dexamethasone suppression and glucocorticoid receptor binding in mononuclear leukocytes, polymorphonuclear leukocytes and cultured skin fibroblasts were measured in rigidly defined major depressive disorder patients and non-depressed psychiatric controls. 2. Mononuclear leukocytes binding to glucocorticoid correlated significantly with polymorphonuclear leukocytes binding to glucocorticoid, but both determinations failed to differentiate major depressive disorder and control subjects. 3. Initial and post-dexamethasone in vitro fibroblast binding to glucocorticoid was not different between major depressive disorder and non-depressed control subjects. 4. The phenomenon of glucocorticoid resistance in major depressive disorder remains unexplained.