Letter to the editor: Reply to Legare et al.

With interest we read the recent publication ‘Increasing the clozapine:norclozapine ratio with co-administration of fluvoxamine to enhance efficacy and minimize side effects of clozapine therapy’ by Legare et al. [1]. Of course, we agree on the superior efficacy of clozapine in treatment resistant schizophrenia which renders it gold-standard for refractory schizophrenia. However the statement that a clozapine:norclozapine ratio of two or more via co-administration of fluvoxamine would lead to a reduction of side effects is to our knowledge not proven and even potentially harmful. There is ample evidence that clozapine plasma levels above 350 lg/L are more effective than lower levels [2,3], but efficacy is unrelated to the norclozapine level. Norclozapine (desmethyl-clozapine) has failed to demonstrate any therapeutic activity in clinical trials [4]. Adding fluvoxamine can possibly enhance efficacy of lower dosages of clozapine, as stated in the title, it is however highly unlikely that side effects will be minimized as is also stated in the title. There is one study stating that addition of fluvoxamine inhibited weight gain, raise in glucose and cholesterol levels, however these were not statistically different [5]. On the other hand, increasing clozapine plasma levels by co-administration of fluvoxamine can result in sometimes dramatic side effects, e.g. seizures [6], especially since clozapine levels can increase very quickly to toxic levels. We therefore recommend to increase the dose of clozapine gradually over several weeks until blood levels of clozapine are above 350 lg/L.