Metabolism and excretion of mood stabilizers and new anticonvulsants

1. The mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA), have differing pharmacokinetics, structures, mechanisms of action, efficacy spectra, and adverse effects. Lithium has a low therapeutic index and is r enally excreted and hence has renally-mediated but not hepatically-mediated drug-drug interactions. 2. CBZ has multiple problematic drug-drug interactions due to its low thera peutic index, metabolism primarily by a single isoform (CYP3A3/4), active e poxide metabolite, susceptibility to CYP3A3/4 or epoxide hydrolase inhibito rs, and ability to induce drug metabolism (via both cytochrome P450 oxidati on and conjugation). In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, rendering it less susceptible to toxici ty due to inhibition of its metabolism. However, VPA can increase plasma co ncentrations of some drugs by inhibiting metabolism and increase free fract ions of certain medications by displacing them from plasma proteins. 3. Older anticonvulsants such as phenobarbital and phenytoin induce hepatic metabolism, may produce toxicity due to inhibition of their metabolism, an d have not gained general acceptance in the treatment of primary psychiatri c disorders. 4. The newer anticonvulsants felbamate, lamotrigine, topiramate, and tiagab ine have different hepatically-mediated drug-drug interactions, while the r enally excreted gabapentin lacks hepatic drug-drug interactions but may hav e reduced bioavailability at higher doses. 5. Investigational anticonvulsants such as oxcarbazepine, vigabatrin, and z onisamide appear to have improved pharmacokinetic profiles compared to olde r agents. 6. Thus, several of the newer anticonvulsants lack the problematic drug-dru g interactions seen with older agents, and some may even (based on their me chanisms of action and preliminary preclinical and clinical data) ultimatel y prove to have novel psychotropic effects.