THE EFFECTS OF SODIUM VALPROATE ON DISTURBED BEHAVIOR IN DEMENTIA (1994)

Behavioral changes in dementia are among the predictive variables used to refer a patient for nursing home placement.1 This finding suggests that intervention and treatment of disturbed behavior in dementia might delay or prevent long-term institutionalization of the patient. When managing disturbed behavior in dementia, the strategy should be based on a combination of psycho- and pharmacotherapeutic strategies. As drugs of first choice, benzodiazepines and neuroleptics are best studied. However, in many patients (up to 80%) they seem to be ineffective or not appropriate because of side-effects.2 In our hospital, the anticonvulsant sodium valproate is used as third choice medication to treat disturbed behavior in dementia when benzodiazepines and neuroleptics have proven to be ineffective. Sodium valproate is preferred to carbamazepine because of the better side-effect profile in the elderly. Sodium valproate is reported to be a gamma-aminobutyric acid (GABA) agonist, to inhibit corticotropin-releasing factor production, and to lower Cortisol in Cushing's disease.3, 4 Animal studies have shown that after stress, sodium valproate augments 5-hydroxy-indoleacetic acid (5-HIAA) levels in rats.5 These mechanisms might explain the positive effect of sodium valproate in aggressive behavior, since studies on neurochemical aspects of aggressive behavior report an inverse relation between aggressive behavior and brain GABA levels, an inverse correlation between impulsive aggressive behavior and cerebrospinal-fluid levels of serotonin metabolite 5-HIAA and a positive relation between aggressive behavior and brain noradrenergic turnover.6 In Alzheimer disease, an association between aggressive behavior and serotonin-reduction has been reported.7 Retrospectively, the records of patients admitted between 1989 and 1992 were examined for sodium valproate prescription. Included were patients with disturbed behavior who met the DSM-III-R criteria for dementia. Excluded were patients with other psychiatric diagnoses, epilepsia (history of/or epileptic EEG activity), and history of cerebrovascular accident. Effect was scored in 3 classes: zero effect or initial effect but relapse during admittance, partial effect during admittance, and complete disappearance of disturbed behavior. A total of 590 records were screened for sodium valproate prescription, resulting in 48 records. After inclusion and exclusion, the data of 23 patients (14 M, 9 F; mean age 79 and 82 years, respectively) were analyzed. All patients had been treated with benzodiazepines and/or neuroleptics without effect. Patients were diagnosed as suffering from dementia (DSM-III-R): Alzheimer type dementia (n = 13: 1 early; 5 moderate and 7 severe), multi-infarction dementia (n = 2: both early types), M. Pick (n = 1: severe), and dementia NOS (n = 7: 2 moderate and 5 severe). The prescribed dose of sodium valproate varied between 2 × 120 mg and 2 × 600 mg daily, with a mean dose of 481.3 ± 248.3 mg/day. No difference was found between responders and nonresponders concerning the mean dose. Determination of plasma levels of sodium valproate was performed in 6 patients (4 responders; 2 nonresponders). A positive relation was found between dose and plasma levels. Remarkably, plasma levels in 3 out of 4 responders were below the therapeutic window in epilepsy. The effects of sodium valproate in the 23 patients are shown in Table 1. In 26% of the patients, the disturbed behavior was completely abolished. Response defined as a long-term reduction of the type of disturbed behavior lasting until discharge was seen in 52% of the patients. No differences could be found in response between the various types of dementia nor between the stages of dementia. The apparent sex difference can largely be explained by the higher incidence of physical aggressive behavior in males in this study (M = 8; F = 1). This type of behavior showed the best response with sodium valproate. The effects of sodium valproate related to the various types of disturbed behavior are presented in Table 2. Restless behavior and physically aggressive and verbally aggressive behavior showed a good response. Two types of disturbed behavior were seen in 8 men and 2 women. Six of them were full responders. Two men had 3 types of disturbed behavior. In both cases, sodium valproate was effective on all 3 types of disturbed behavior. Side-effects, drowsiness (n = 2) and ataxia (n = 1), occurred in 3 patients. In two responders, a decrease of the given dosage led to disappearance of the side-effects, and the disturbed behavior did not reappear. In our retrospective analysis, sodium valproate seems to be effective in the treatment of physically aggressive, verbally aggressive, and restless behavior in dementia. Due to the methodological problems (blinding, control group, retrospective classification of the type of disturbed behavior) no definite conclusions can be drawn. However, it is suggested that sodium valproate in a dose of 2 × 240 mg/day might be effective in the treatment of aggressive behavior in dementia.