Impact of mood stabilizers and antiepileptic drugs on cytokine production in-vitro

Changes within the immune system have been reported to contribute to the pathophysiology of bipolar disorder and epilepsy. Interestingly, overlapping results regarding the cytokine system have been found for both diseases, namely alterations of interleukins IL-1β, IL-2, IL-4, IL-6, and tumor necrosis factor-α (TNF-α). However, the effect of mood stabilizers and antiepileptic drugs (AEDs) on these cytokines has not been systematically evaluated, and their effect on IL-17 and IL-22, other immunologically important cytokines, has not been reported. Therefore, we systematically measured levels of IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in stimulated blood of 14 healthy female subjects in a whole blood assay using the toxic shock syndrome toxin TSST-1 as stimulant. Blood was supplemented with the mood stabilizers or antiepileptic drugs primidone (PRM), carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), valproic acid (VPA), oxcarbazepine (OXC), topiramate (TPM), phenobarbital (PB), lithium, or no drug. IL-1β production was significantly decreased by PRM, CBZ, LEV, LTG, OXC, PB and lithium. IL-2 significantly decreased by PRM, CBZ, LEV, LTG, VPA, OXC, TPM and PB. IL-22 significantly increased by PRM, CBZ, LEV, OXC, TPM and lithium and decreased by VPA. TNF-α production significantly decreased under all applied drugs. The mechanism of action and side effects of mood stabilizers and AEDs may involve modulation of IL-1β, IL-2, IL-22 and TNF-α signaling pathways. IL-22 may be a research target for specific therapeutic effects of mood stabilizers and AEDs. These drugs might influence cytokine production by modulating ion channels and γ-aminobutyric acid (GABA) receptors of immune cells.