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Letter to the Editor   |    
Treating Depression in Schizophrenia
BRIAN C. LUND, PHARM.D.; PAUL J. PERRY, PH.D.; DEL D. MILLER, PHARM.D., M.D.
Am J Psychiatry 2001;158:1528-1528. doi:10.1176/appi.ajp.158.9.1528

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.

Siris SG: Depression in schizophrenia: perspective in the era of "atypical" antipsychotic agents. Am J Psychiatry 2000; 157:1379-  1389
 
Ferslew KE, Hagardorn AN, Harlan GC, McCormick WF: A fatal drug interaction between clozapine and fluoxetine. J Forensic Sci 1998; 43:1082-  1085
 
Spina E, DeDomenico P, Ruello C, Longobardo N, Gitto C, Ancione M, DiRosa AE, Caputi AP: Adjunctive fluoxetine in the treatment of negative symptoms in chronic schizophrenic patients. Int Clin Psychopharmacol  1994; 9:281-285
[PubMed]
[CrossRef]
 
Silver H, Shmugliakov N: Augmentation with fluvoxamine but not maprotiline improves negative symptoms in treated schizophrenia: evidence for a specific serotonergic effect from a double-blind study. J Clin Psychopharmacol  1998; 18:208-211
[PubMed]
[CrossRef]
 
Salokangas RKR, Saarijarvi S, Taiminen T, Kallioniemi H, Lehto H, Niemi H, Tuominen J, Ahola V, Syvalahti E: Citalopram as an adjuvant in chronic schizophrenia: a double-blind placebo-controlled study. Acta Psychiatr Scand  1996; 94:175-180
[PubMed]
[CrossRef]
 
Lee MS, Kim YK, Lee SK, Suh KY: A double-blind study of adjunctive sertraline in haloperidol-stabilized patients with chronic schizophrenia. J Clin Psychopharmacol  1998; 18:399-403
[PubMed]
[CrossRef]
 
Buchanan RW, Kirkpatrick B, Bryant N, Ball P, Breier A: Fluoxetine augmentation of clozapine treatment in patients with schizophrenia. Am J Psychiatry 1996; 153:1625-  1627
 
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References

Siris SG: Depression in schizophrenia: perspective in the era of "atypical" antipsychotic agents. Am J Psychiatry 2000; 157:1379-  1389
 
Ferslew KE, Hagardorn AN, Harlan GC, McCormick WF: A fatal drug interaction between clozapine and fluoxetine. J Forensic Sci 1998; 43:1082-  1085
 
Spina E, DeDomenico P, Ruello C, Longobardo N, Gitto C, Ancione M, DiRosa AE, Caputi AP: Adjunctive fluoxetine in the treatment of negative symptoms in chronic schizophrenic patients. Int Clin Psychopharmacol  1994; 9:281-285
[PubMed]
[CrossRef]
 
Silver H, Shmugliakov N: Augmentation with fluvoxamine but not maprotiline improves negative symptoms in treated schizophrenia: evidence for a specific serotonergic effect from a double-blind study. J Clin Psychopharmacol  1998; 18:208-211
[PubMed]
[CrossRef]
 
Salokangas RKR, Saarijarvi S, Taiminen T, Kallioniemi H, Lehto H, Niemi H, Tuominen J, Ahola V, Syvalahti E: Citalopram as an adjuvant in chronic schizophrenia: a double-blind placebo-controlled study. Acta Psychiatr Scand  1996; 94:175-180
[PubMed]
[CrossRef]
 
Lee MS, Kim YK, Lee SK, Suh KY: A double-blind study of adjunctive sertraline in haloperidol-stabilized patients with chronic schizophrenia. J Clin Psychopharmacol  1998; 18:399-403
[PubMed]
[CrossRef]
 
Buchanan RW, Kirkpatrick B, Bryant N, Ball P, Breier A: Fluoxetine augmentation of clozapine treatment in patients with schizophrenia. Am J Psychiatry 1996; 153:1625-  1627
 
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