Grand-mal seizure in a combined amitriptyline and paroxetine treatment

A thirty year old female patient was treated with a combined drug therapy of amtriptyline, paroxetine and valproic acid in the course of severe depression. Improvements of the depressive symptoms but no remission were achieved under this regime. A reduction of valproic acid was followed by a grand mal seizure. The control of drug plasma levels showed normal results for paroxetine and valproic acid, slightly elevated levels for amitriptyline, but severely elevated levels for nortriptyline, a metabolite of amitriptyline. The medication was therefore changed; the above mentioned drugs were replaced by escitalopram and reboxetine. The result was a complete remission of depressive symptoms in the patient and there occurred no further drug-induced side-effects. The explanation for the observed side effects lies in the competitive inhibition of drug metabolism between nortriptyline and paroxetine in the liver, since both substances are metabolized by the same isoenzyme of the cytochrome P450 system. In addition, there is a genetic polymorphism known for the responsible cytochrome isoenzyme 2D6. About 7 to 10 percent of the middle European population are poor metabolizers with reduced activity of the CYP2D6 isoenzyme. In accordance with this example the risks of combined antidepressive treatment, including tricyclic antidepressants, shall be discussed.