To the Editor: We applaud the efforts of Samuel G. Siris, M.D. (1), in summarizing the perplexing and heterogeneous literature regarding depressive symptoms in patients with schizophrenia. We add a discussion of drug interactions to Dr. Siris’s article, from the perspectives of both safety and efficacy. Regarding safety, many antidepressant medications have the potential of producing clinically important increases in antipsychotic plasma concentrations. One notable example is the addition of fluoxetine to clozapine therapy, which can increase clozapine plasma concentrations by more than 50% and has resulted in at least one reported fatality (2).

Interactions of antidepressants and antipsychotics also play a role in the interpretation of clinical studies. Dr. Siris pointed out the encouraging results involving adjunctive selective serotonin reuptake inhibitors (SSRIs) in treating the negative symptoms of schizophrenia (1). An observation from a review of controlled studies is that studies with positive findings have primarily used fluoxetine or fluvoxamine (3, 4) agents that are notorious for increasing the plasma concentrations of many antipsychotics. In contrast, the results of controlled studies with sertraline and citalopram, which have less propensity to cause interactions, have been negative (5, 6).

The onset of depressive symptoms in patients with schizophrenia may often be the first clinical evidence of relapse (1). This presents an interesting clinical quandary. If an inhibiting antidepressant, such as fluoxetine, is taken and depressive symptoms disappear, has one successfully treated a depressive syndrome with an antidepressant or has one staved off an impending relapse of schizophrenia by increasing antipsychotic plasma concentrations by means of a drug interaction?

Dr. Siris also made the important observation that he knows of no studies that have investigated antidepressants as adjuncts to atypical antipsychotics in depressed patients with schizophrenia. Studies that have used fluoxetine to augment clozapine treatment have not shown any improvement in positive, negative, or depressive symptoms (7). In light of these considerations, we emphasize caution in the addition of antidepressants to antipsychotic treatments and recommend monitoring antipsychotic plasma concentrations where potential interactions exist.