Effects of Valproate on Intracellular Calcium Ion Signaling: Implications for Mechanistic Research.

Objectives: Hyperactive intracellular calcium ion concentration ([Ca²⁺]_i) in peripheral cells of patients with bipolar disorder has been reported repeatedly. Reduction of intracellular calcium ion concentration has been found with the established mood stabilizers lithium and carbamazepine, but less reliably with valproate. This study examined whether inconsistent findings with valproate could be a function of the subjects studied.

Experimental design: Platelet [Ca²⁺]_i at baseline ([Ca²⁺]_B) and after stimulation with thrombin and platelet activating factor ([Ca²⁺]_S) was measured with and without incubation with therapeutic levels of valproate in mildly to moderately ill bipolar disorder patients (N = 14).

Principal observations: Prior to incubation with valproate, platelet [Ca²⁺]_B and [Ca²⁺]_S were generally lower than has been reported in studies of intracellular calcium ion concentration in bipolar disorder, consistent with at most moderate symptom severity and impairment. Incubation with valproate raised [Ca²⁺]_B somewhat, primarily in patients with lower initial [Ca²⁺]_B. Valproate incubation blunted the increase in [Ca²⁺]_i with platelet stimulation, but valproate did not alter final [Ca²⁺]_S, reflecting a smaller increase with valproate but a higher starting point (i.e., [Ca²⁺]_B) in valproate incubated cells.

Conclusions: Mixed results of studies of cellular actions of valproate on intracellular calcium signaling may be the results of use of subjects with milder illness and normal baseline signaling. Studies of animals and normal human subjects may be less informative about the potential mechanism of action of any psychotropic medication than studies of patients with sufficient severity of illness and abnormalities in the dimension of cellular function targeted by the medication.