Chapter 6 138 ABSTRACT Objectives: We present an elderly, bipolar patient with a high free concentration of VPA but (sub) therapeutic total concentration VPA due to hypoalbuminemia (14-25g/l) leading to reversible severe cognitive impairment. Methods: Valproic acid (VPA) is largely bound to serum proteins (80-95%) particularly albumin, with a saturable binding capacity. In hypoalbuminemic patients, protein binding of VPA will decrease and the pharmacologically active free concentration may increase, even to toxic levels. Results: There was an association between dosage increase of VPA, total VPA blood levels (68mg/l, reference 40-120mg/l), the concentration of the unbound VPA (37.5mg/l, reference 4-12mg/l) and cognitive impairment (MMSE 20/30; MoCA 15/30) increasing to reversible severe cognitive impairment comparable to a Global Deterioration Scale (GDS) of 6. Six weeks after dechallenge of VPA her cognitive and conative functioning recovered to preVPA levels (MMSE 27/30, MoCA 27/30, GDS 1). Conclusions: In standard therapeutic drug monitoring, total VPA concentrations are generally measured instead of unbound VPA concentrations due to analytical difficulties, a lack of established reference ranges and (inter)national guidelines not requiring the measurement of free fractions. This case points out that hypoalbuminemia demands regular monitoring of the free concentration of VPA to prevent unnecessary side effects and toxicity. We recommend measuring albumin during VPA use particularly in patients at risk of hypoalbuminemia; including those with nephrotic syndrome, liver disease or older adults.
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