Divalproex Might Shrink the Brain
Patients with Alzheimer disease showed brain atrophy and cognitive problems in the first year of receiving divalproex.
Divalproex sodium has been hypothesized to have neuroprotective properties and is often prescribed for neuropsychiatric disorders like epilepsy, bipolar disorder, and migraine, as well as off-label for behavioral problems. Preclinical studies have suggested that divalproex sodium may have neuroprotective effects. In this report, researchers focus on the medication’s effect on brain volume and cognition in a subset of patients with mild-to-moderate Alzheimer disease (AD) enrolled in a 24-month, multicenter, placebo-controlled clinical study of divalproex for AD (JW Psychiatry Aug 29 2011). The study’s findings were negative for prevention of agitation.
Eighty-nine participants had baseline and 12-month magnetic resonance imaging results of sufficient quality to analyze. At 12 months, those on divalproex had significantly smaller mean volumes of whole brain, ventricles, and hippocampi than placebo recipients. Clinically, Mini-Mental State Examination (MMSE) scores, a secondary measure, were significantly lower with divalproex than with placebo at 6 and 12 months; scores were correlated with annualized hippocampal volume changes. MMSE differences disappeared at 18 and 24 months.
Comment: These findings are certainly of concern to clinicians using divalproex in patients with AD. The mechanism, currently unknown, might involve hepatotoxicity, hyperammonemia, osmotic changes, or neurotoxicity. Other important questions remain for example, whether the atrophy is reversible or whether these findings are specific to AD patients or occur in other populations, including patients with bipolar disorder or epilepsy. This study also demonstrates the importance of investigating the relevance of preclinical findings to humans. Because atrophy was correlated with lower cognition (as measured by the MMSE), clinicians who wish to conservatively treat patients showing cognitive adverse effects on divalproex could simply substitute another medication.
Jonathan Silver, MD