Correspondence

Fluoxetine

N Engl J Med 1995; 332:960-961April 6, 1995

Article

To the Editor:

In his review of fluoxetine (Nov. 17 issue),1 Dr. Gram failed to mention two studies of inpatients with major depression who had improvement with fluoxetine comparable to that with desipramine2 or imipramine3 and that an analysis of results from controlled studies of more than 1500 patients with mild, moderate, or severe depression revealed no differences in rates of response or remission between patients receiving fluoxetine and those receiving tricyclic antidepressant drugs.4 With regard to drug tolerance, a meta-analysis of 42 randomized, controlled studies examined rates of drug discontinuation due to lack of efficacy or side effects in patients receiving selective inhibitors of serotonin reuptake as compared with tricyclic antidepressants.5 The proportion of patients in the two groups who discontinued therapy because of lack of efficacy was similar, and fewer patients treated with inhibitors of serotonin reuptake discontinued therapy because of side effects. In an analysis of data from more than 1500 patients from comparative controlled studies, the rate of premature discontinuation of therapy due to adverse events was lower in patients treated with fluoxetine (17 percent) than in those treated with tricyclic antidepressants (31 percent).6 We think these data from studies not mentioned in the review help to explain the “popularity” (Dr. Gram's term) of fluoxetine.

Sharon L. Blomgren, M.D.
Gary D. Tollefson, M.D., Ph.D.
Lilly Research Laboratories, Indianapolis, IN 46285

6 References

1. 1

   Gram LF. Fluoxetine. N Engl J Med 1994;331:1354-1361
   Full Text | Web of Science | Medline

2. 2

   Bowden CL, Schatzberg AF, Rosenbaum A, et al. Fluoxetine and desipramine in major depressive disorder. J Clin Psychopharmacol 1993;13:305-311
   CrossRef | Web of Science | Medline

3. 3

   Beasley CM Jr, Holman SL, Potvin JH. Fluoxetine compared with imipramine in the treatment of inpatient depression: a multicenter trial. Ann Clin Psychiatry 1993;5:199-207
   CrossRef | Medline

4. 4

   Pande AC, Sayler ME. Severity of depression and response to fluoxetine. Int Clin Psychopharmacol 1993;8:243-245
   CrossRef | Web of Science | Medline

5. 5

   Montgomery SA, Henry J, McDonald G, et al. Selective serotonin reuptake inhibitors: meta-analysis of discontinuation rates. Int Clin Psychopharmacol 1994;9:47-53
   CrossRef | Web of Science | Medline

6. 6

   Pande AC, Sayler ME. Adverse events and treatment discontinuations in fluoxetine clinical trials. Int Clin Psychopharmacol 1993;8:267-269
   CrossRef | Web of Science | Medline

To the Editor:

Dr. Gram did not mention an important potential adverse effect of fluoxetine — hepatotoxicity. This drug is metabolized primarily by the liver. Serum aminotransferase concentrations increase in approximately 0.5 percent of patients receiving it,1 and several cases of toxic hepatitis during treatment with fluoxetine have been reported.2,3 We think that minor anomalies of liver-function tests occur more frequently,4 but they generally remain unreported. Special care should be taken to avoid adverse effects in patients with cirrhosis, because of their reduced rate of elimination of the drug. It is important to be aware of the potential hepatotoxicity of fluoxetine.

Agustin Castiella, M.D.
Pilar Lopez, M.D.
Juan I. Arenas, M.D.
Nuestra Señora de Aranzazu Hospital, 20080 San Sebastian, Spain

4 References

1. 1

   Cooper GL. The safety of fluoxetine -- an update. Br J Psychiatry Suppl 1988;153:77-86
   

2. 2

   Mars F, Dumasde la Roque G, Goissen P. Hépatite aigüe lors du traitement par la fluoxétine. Gastroenterol Clin Biol 1991;15:270-271
   Web of Science | Medline

3. 3

   Bobichon R, Bernard G, Mion F. Atteinte hépatique aigüe lors d'un traitement par la fluoxétine. Gastroenterol Clin Biol 1993;17:406-407
   Web of Science | Medline

4. 4

   Castiella A, Arenas JI. Fluoxetine hepatotoxicity. Am J Gastroenterol 1994;89:458-459
   Web of Science | Medline

Author/Editor Response

Dr. Gram replies:

To the Editor: In the review article, I mentioned some studies of hospitalized, depressed patients in which selective inhibitors of serotonin reuptake, including fluoxetine, were clearly less effective than tricyclic antidepressants. The common feature of these patients appears to be the presence of melancholic, endogenous types of depression. The three studies mentioned by Blomgren and Tollefson1-3 compared fluoxetine with tricyclic antidepressant drugs in patients with major depression of varying severity, some of whom were hospitalized. Although hospitalization and severity are often associated with symptoms of melancholic, endogenous depression, the number of such patients in the cited studies may have been small. The inadequate effect of selective inhibitors of serotonin reuptake in melancholic and profoundly depressed patients appears to be acknowledged by many clinicians.4 The efficacy of tricyclic antidepressant drugs in these patients may relate to the parallel effect of these drugs on both serotonergic and noradrenergic transmission.5

I pointed out that the rate of dropouts due to adverse events among patients treated with fluoxetine was lower than that among those treated with tricyclic antidepressant drugs in North American but not in European studies. Differences in settings, groups of patients, and the particular tricyclic antidepressant drug and dose may explain this difference. The cited study by Montgomery et al.6 deals with only a fraction of the comparative trials, and the criteria for their selection are unclear. The reanalysis of studies involving 1500 patients7 appears to correspond in large part to the North American studies of fluoxetine detailed in Table 2 of my article.

Despite worldwide use of fluoxetine in 10 to 15 million patients, the letters8,9 cited by Castiella et al. are the only reports of fluoxetine-associated hepatotoxicity that could be retrieved in an extensive Medline search. Among nearly 3000 patients receiving fluoxetine in clinical trials, about 0.5 percent had elevated serum hepatic-enzyme values, but none had clinically important liver dysfunction.8 There thus appears to be little reason to single out fluoxetine as a particularly hepatotoxic drug.

The rapid rise in the use of fluoxetine could not have been predicted from the documentation of its use in depression. A more general effect of selective inhibitors of serotonin reuptake on mental dysfunction through the serotonergic system may better explain the popularity of these agents. Depression may just be one symptom of this dysfunction, and extensive controlled and uncontrolled studies of fluoxetine have suggested a much broader spectrum of indications.

Lars F. Gram, M.D.
Odense University, DK-5000 Odense C, Denmark

9 References

1. 1

   Bowden CL, Schatzberg AF, Rosenbaum A, et al. Fluoxetine and desipramine in major depressive disorder. J Clin Psychopharmacol 1993;13:305-311
   CrossRef | Web of Science | Medline

2. 2

   Beasley CM Jr, Holman SL, Potvin JH. Fluoxetine compared with imipramine in the treatment of inpatient depression: a multicenter trial. Ann Clin Psychiatry 1993;5:199-207
   CrossRef | Medline

3. 3

   Pande AC, Sayler ME. Severity of depression and response to fluoxetine. Int Clin Psychopharmacol 1993;8:243-245
   CrossRef | Web of Science | Medline

4. 4

   Grey P. Fluoxetine and onset of its therapeutic effect. Am J Psychiatry 1993;150:984-984
   Web of Science | Medline

5. 5

   Gram LF, Reisby N, Ibsen I, et al. Plasma levels and antidepressive effect of imipramine. Clin Pharmacol Ther 1976;19:318-324
   Web of Science | Medline

6. 6

   Montgomery SA, Henry J, McDonald G, et al. Selective serotonin reuptake inhibitors: meta-analysis of discontinuation rates. Int Clin Psychopharmacol 1994;9:47-53
   CrossRef | Web of Science | Medline

7. 7

   Pande AC, Sayler ME. Adverse events and treatment discontinuations in fluoxetine clinical trials. Int Clin Psychopharmacol 1993;8:267-269
   CrossRef | Web of Science | Medline

8. 8

   Cooper GL. The safety of fluoxetine -- an update. Br J Psychiatry Suppl 1988;153:77-86
   

9. 9

   Mars F, Dumasde la Roque G, Goissen P. Hépatite aigüe lors du traitement par la fluoxétine. Gastroenterol Clin Biol 1991;15:270-271
   Web of Science | Medline

Citing Articles (3)

Citing Articles

1. 1

   Siegfried Kasper. (1997) Efficacy of Antidepressants in the Treatment of Severe Depression. Journal of Clinical Psychopharmacology 17, 19S-28S
   CrossRef

2. 2

   Stuart Dollow, Paul Timmings, Duncan Lamont. (1996) Antidepressant-associated fatal intrahepatic cholestasis. The Lancet 347:9010, 1268-1269
   CrossRef

3. 3

   Ronald Pies. (1995) One Foot on the Bandwagon?. Journal of Clinical Psychopharmacology 15:5, 303-305
   CrossRef