Anticonvulsants

Carbamazepine and valproate are the best-studied psychotropic agents in this class. The bulk of available evidence supports the conclusion that they are likely to have anti-agitation efficacy essentially equivalent to other "effective" psychotropics. Carbamazepine has been examined in four placebo-controlled studies. Chambers, Bain, Rosbottom, Ballinger, and McLaren (1982) performed an eight-week crossover study in 19 women with mild agitation who also received antipsychotics: This brief report was negative. Tariot et al. (1994) performed a 12-week placebo-controlled pilot crossover study in 25 patients, showing encouraging effects on agitation and not other aspects of psychopathology. A more recent confirmatory parallel group study of six-weeks' duration in 51 patients also found a significant reduction in agitation using a mean dose of 300 mg/day (Tariot et al., 1998). Tolerabil-ity in these studies was generally good, with evidence of sedation and ataxia (Tariot et al., 1998; Tariot, Frederiksen, et al., 1995); there was an 8% dropout due to side effects in the larger confirmatory carbamazepine study. Finally, Olin, Fox, Pawluczyk, Taggart, and Schneider (2001) performed a six-week controlled study in 21 outpatients with BPSD associated with severe AD, who were treatment resistant to antipsychotics. Greater improvement was seen on the Clinical Global Impression of Change (CGIC) and the Brief Psychiatric Rating Scale (BPRS) hostility item with a trend for the hallucination item for the carbamazepine group over placebo. It is likely that side effects seen in other populations, such as rashes, more serious sedation, hematologic abnormalities, hepatic dysfunction, and altered electrolytes, for example, would be more evident with widespread use of this agent in the elderly, which may limit its use (Tariot, Frederiksen, et al., 1995). Further, it has considerable potential for significant drug-drug interactions. The carba-mazepine studies help provide proof-of-concept for the anti-agitation efficacy of anticonvulsants.

Valproic acid, which is also available as a significantly better tolerated enteric-coated derivative (divalproex sodium) has clinical effects generally similar to those achieved by carbamazepine in the treatment of mania. It is approved by the U.S. FDA for treatment of acute mania associated with bipolar disorder. Fourteen case reports or case series focus on use in patients with BPSD and describe a total of 202 subjects. In the aggregate, approximately two-thirds of these subjects were reported to show improved agitation, with valproate doses ranging from a general low of about 500 mg/day to a general maximal dose of 1,500 mg/day, with levels typically ranging from 20 to about 100 mcg/ml. Porsteinsson et al. (2001) reported on the first randomized, placebo-controlled, parallel group study of this agent, six weeks in length, in 56 nursing home residents who experienced dementia with agitation. The purpose of this study was not to prove efficacy but to establish effect size and clarify proper dosing to plan a larger definitive study. The average divalproex dose achieved in this study was 826 mg/day, resulting in an average level of about 46 mcg/ml. There was a 10% dropout rate due to adverse experiences. Despite the small sample size, the primary measure of agitation showed a near-significant reduction on valproate versus placebo, supported by similar results with CGIC. There were no changes in other behavioral measures. Tolerability was generally good: Serious adverse events occurred at a rate of 10% in both the drug and placebo groups, with milder side effects occurring more often in the drug group, chiefly consisting of sedation, mild gastrointestinal distress, mild ataxia, and expected mild ( but not clinically significant) decrease in platelet count (about 20,000/mm3).

A multicenter, randomized, placebo-controlled, six-week, parallel group study of divalproex sodium was conducted in patients with dementia and agitation who also met criteria for secondary mania (Tariot et al., 2001). This study was designed using an aggressive dosing and titration protocol, in which a target dose of 20 mg/kg/day was achieved in 10 days. This plan resulted in unacceptable sedation in roughly 25% of the drug-treated group and a relatively high dropout rate, leading to premature discontinuation of the study. The original sample size was 172 nursing home residents, with 100 completers at the time the study was suspended. While there was no significant drug-placebo effect on manic features, there was a significant effect of drug on agitation as measured by the Cohen-Mansfield Agitation Inventory (Cohen-Mansfield, 1986). Sedation occurred in 36% in the drug group versus 20% of the placebo group, and mild thrombocytopenia occurred in 7% of the drug group and none of the placebo-treated patients. There were no other drug-placebo differences in adverse effects. Side effects reported in the package insert include those described previously plus hair loss, mild thrombocytopenia, and hepatic or pancreatic dysfunction that can rarely be fatal. These more serious events have not been reported in the elderly and are more likely to be seen in children requiring multiple anticonvulsants. The available evidence would suggest use of a starting dose of about 125 mg p.o. b.i.d, increasing by 125 to 250 mg increments every five to seven days, with a maximal dose determined by clinical response, or where there is uncertainty, a serum level of about 60 to 90 mcg/ml.

There are no controlled studies of which we are aware of the newer anticonvulsants including lamotrogine, gabapentin, and topiramate, although at least two case reports and a retrospective case series suggest benefit with gabapentin (Hawkins, Tinklenberg, Sheikh, Peyser, & Yesavage, 2000; Regan & Gordon, 1997). Because anticonvulsants, as a class, are relatively well tolerated, based on years of experience in numerous clinical populations with other disorders, definitive trials showing efficacy and reasonable tolerability will very likely influence clinical practice in the future. Although beyond the scope of this chapter, there is considerable intriguing biological data addressing the mechanism of action of mood stabilizers, suggesting in particular that lithium and valproate, but not other agents, may have clinically relevant neuroprotective properties (Manji, Moore, & Chen, 2000). Further understanding of these issues may differentiate among available agents and also lead to the identification of new targets for therapy.

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