Interaction between valproic acid and antidepressants/antipsychotics

A combination therapy of the anticonvulsant drug valproic acid and antidepressant as well as antipsychotic drugs is not uncommon. In the literature studies on drug-drug interactions between valproic acid and antidepressants or antipsychotics are rare. The authors assessed their TDM database for cases receiving a co-medication of valproic acid and amitriptyline, doxepin, venlafaxine and clozapine and compared these to matched control samples of patients without valproic acid co-medication regarding the serum concentration of the mentioned antipsychotic and antidepressant drugs by U-tests.

The combination of amitriptyline and valproic acid (n = 33) led to a significant increase of amitriptyline (+59%) and nortriptyline (+123%) serum concentrations and to a significant decrease in nortriptyline/amitriptyline ratio (1.30 ± 0.90 vs. 0.86 ± 0.45). A co-medication of valproic acid in doxepin treated patients (n = 16) significantly increased the concentration of doxepin (+134%) and N-doxepin (+116%). Whereas venlafaxine serum concentration was not elevated by a combination with valproic acid (n = 41), the serum level of O-desmethylvenlafaxine was significantly higher (+27%). Patients with a co-medication of valproic acid and clozapine (n = 30) exhibit a significant lower N-clozapine serum concentration (–52%) and in females also a lower clozapine serum concentration was revealed (–51%).

Besides CYP2C9 inhibition of amitriptyline, doxepin and O-desmethylvenlafaxine also inducing properties of valproic acid via CYP3A4 must be considered which result in a decrease of N-clozapine and also clozapine in females.