Status epilepticus associated with the combination of valproic acid and clomipramine

An epileptic patient well controlled on valproic acid (VPA) developed a prolonged episode of status epilepticus 12 days after initiation of 75 mg of clomipramine (CMI) to treat depression. Serum level of VPA in the emergency room was unchanged from her previous levels; serum level of CMI was very elevated despite the relatively small dose of CMI. A pharmacokinetic interaction between VPA, an enzyme inhibitor, and CMI has not been described but seemed to have occurred in this patient. Decreased metabolism of CMI and its metabolites, increased free CMI fraction, and precipitation of a nonlinear saturation kinetic state has been described when CMI was used concomitantly with other highly protein-bound, enzyme-inhibiting compounds. This case provides reasonable evidence that the combination of VPA and CMI may result in elevation of levels of CMI and possibly of its metabolites and may precipitate seizures in patients with an underlying predisposition. The elevated serum level of CMI at the time of the seizures, despite the relatively small oral dose of the drug, suggests that VPA may have inhibited its metabolism and/or elimination.