Correspondence

Correction

Obesity

N Engl J Med 1998; 338:64-65January 1, 1998

Article

To the Editor:

In their article on obesity, Rosenbaum et al. (Aug. 7 issue)1 characterize sibutramine, currently undergoing regulatory review as a drug for the treatment of obesity, as having both catecholaminergic and serotonergic agonist effects. Sibutramine, in fact, is not an agonist at catecholamine or serotonin receptors but instead acts by inhibiting the reuptake of serotonin and norepinephrine at central synapses. Thus, sibutramine's mode of action is similar to that of other monoamine-reuptake inhibitors such as venlafaxine (an inhibitor of serotonin and norepinephrine reuptake) and fluoxetine (a selective serotonin-reuptake inhibitor). The mode of action of drugs that alter appetite by enhancing central monoamine activity has several implications. For instance, primary pulmonary hypertension has been associated with certain appetite-suppressant drugs2 (e.g., fenfluramine), as well as other drugs (e.g., cocaine), that act by causing monoamine release.3 Rosenbaum et al. characterize the implicated anorectic drugs as reuptake inhibitors. In fact, monoamine-reuptake inhibitors that do not cause monoamine release, such as tricyclic antidepressant drugs, selective serotonin-reuptake inhibitors, and serotonin- and norepinephrine-reuptake inhibitors, have not been associated with an increased risk of primary pulmonary hypertension or neurotoxicity 4 or with the cardiac valvulopathy reported by Connolly et al.5 Given the diversity of the satiety-enhancing drugs currently being developed, attention to the details of the mechanism of action may be even more important in the future.

Timothy B. Seaton, M.D.
Carl M. Mendel, M.D.
Steven P. Weinstein, M.D., Ph.D.
Knoll Pharmaceutical, Parsippany, NJ 07054

5 References

1. 1

   Rosenbaum M, Leibel RL, Hirsch J. Obesity. N Engl J Med 1997;337:396-407
   Full Text | Web of Science | Medline

2. 2

   Abenheim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996;335:609-616
   Full Text | Web of Science | Medline

3. 3

   Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol 1997;17:208-221
   CrossRef | Web of Science | Medline

4. 4

   McCann UD, Seiden LS, Rubin LJ, Ricaurte GA. Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine: a systematic review of the evidence. JAMA 1997;278:666-672
   CrossRef | Web of Science | Medline

5. 5

   Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337:581-588
   Full Text | Web of Science | Medline

To the Editor:

The excellent review of obesity contains a contradiction. The authors say that insulin causes weight gain because it increases the expression of neuropeptide Y messenger RNA, with subsequent central appetite stimulation. They later say that insulin reduces food intake by inhibiting the expression of neuropeptide Y, and in another section, insulin is said to increase the expression of leptin in adipose tissue. Can the authors clarify the role of insulin in the stimulation or inhibition of food intake?

Elliott Eisenbud, M.D.
6403 Coyle Ave., Carmichael, CA 95608

Author/Editor Response

The authors reply:

To the Editor: We appreciate the letter from Seaton et al. concerning the mode of action of sibutramine. We wished to note only that sibutramine has agonist actions in both serotonin and catecholamine systems. The full delineation of the exact mode of action of centrally active anorexiant drugs will undoubtedly receive increased scrutiny because some of these drugs may be neurotoxic,1 cause primary pulmonary hypertension, and cause valvular heart disease.2 Since our review was published, the Food and Drug Administration (FDA) and Wyeth–Ayerst Laboratories, acting on the concern about these possible adverse effects, have removed fenfluramines from the market.

We thank Dr. Eisenbud for his careful reading of the text. On page 401 (left-hand column), the statement, “The expression of neuropeptide Y mRNA is increased by insulin and glucocorticoids,” is incorrect. It should read, “The expression of neuropeptide Y mRNA is increased by androgens and glucocorticoids and decreased by leptin, insulin, and estrogen.”

There are two other errors. First, on page 397 (right-hand column), the statement suggesting that lesions of the median forebrain bundle are equivalent to those of the ventromedial hypothalamus is incorrect. Lesions of the median forebrain bundle are more likely to induce anorexia in a manner similar to that of lesions of the lateral hypothalamus. Second, on page 403, in the third sentence under the heading “Drug Therapy,” fenfluramine should be dexfenfluramine. Dexfenfluramine was approved by the FDA in 1996, but fenfluramine was approved in 1973.

Jules Hirsch, M.D.
Rudolph L. Leibel, M.D.
Michael Rosenbaum, M.D.
Rockefeller University, New York, NY 10021

2 References

1. 1

   McCann UD, Seiden LS, Rubin LJ, Ricaurte GA. Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine: a systematic review of the evidence. JAMA 1997;278:666-672
   CrossRef | Web of Science | Medline

2. 2

   Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;335:581-588
   Full Text | Web of Science