Recent in-vitro data indicate that depletion of neural cells of myo-inositol by virtue of down-regulation of the high-affinity sodium-myo-inositol co-transporter (SMIT) may be a common mechanism of action of the mood stabilizers lithium, valproate and carbamazepine. The authors sought to investigate whether or not down-regulation of SMIT also occurs in vivo in bipolar patients. Expression of SMIT mRNA was measured in neutrophils of bipolar patients either unmedicated or treated with lithium salts or valproate and in neutrophils of unmedicated, matched healthy controls using quantitative real-time PCR. The content of SMIT mRNA was significantly reduced in neutrophils of lithium-treated bipolar patients compared to controls and to untreated bipolar patients. Untreated bipolar I patients but not bipolar II patients exhibited a significantly higher expression of SMIT mRNA than controls. Neutrophils of bipolar I patients treated with valproate exhibited a significantly lower expression of SMIT mRNA than untreated bipolar I patients but did not differ from controls. These results suggest that lithium and valproate down-regulate SMIT mRNA in vivo in patients. In addition the data provide first evidence that up-regulation of SMIT might be associated with an increased risk for bipolar I disorder.