A Placebo-Controlled Trial of Valproate for Agitation and Aggression in Alzheimer’s Disease

Abstract

Background/Aims: To assess the efficacy and tolerability of valproate for the treatment of agitation and aggression in moderate-to-severe Alzheimer’s disease (AD). Methods: 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. Results: 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). Conclusion: Valproate is not effective for the management of agitation in moderate-to-severe AD, and may be poorly tolerated in this population.

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

“…In patients with mild to moderate AD, divalproex treatment (10-12 mg/kg/day) did not delay the emergence of agitation and cognitive impairment and, more alarmingly, was found to accelerate brain volume loss with significant toxic effects (Tariot et al, 2011). VPA treatment was also found to be ineffective for the management of agitation and aggression in older patients with moderate to severe AD (Herrmann et al, 2007). Of note, most of these reports used fixed doses and had few data on VPA's effects on the pathogenesis or neuropathology of AD.…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…It inhibits GSK3β, but has additional effects by acting as a transcriptional modulator through the inhibition of HDACs, and by reducing excitotoxicity 110,113 . While valproate might not be suited for the management of agitation in dementia 114 , longer-term studies are necessary to be able to judge its neuroprotective effects. PP1/PP2A phosphatase inhibition is a possible strategy to boost phosphorylation of mHtt in HD and reduce its toxicity 108 .…”

Symptomatic and Nonamyloid/Tau Based Pharmacologic Treatment for Alzheimer Disease

“…Individual practitioners may use practice-based evidence to guide their therapeutic decisions. Several recent trials suggest that use of valproate to treat agitation has no superiority over placebo and is associated with substantial toxicity Herrmann et al 2007). Early trials suggested the benefit of carbamazepine as a treatment for agitation (Tariot et al 1998).…”