Dear Editor

I report the case of a young man with depression who had severe anticholinergic side effects when reboxetine was added to fluoxetine. No similar reports were found either on MEDLINE or on the Institute for Scientific Information’s electronic database on pharmacology.

A 40-year-old man with major depressive disorder (and no other medical disorders) had stable improvement with fluoxetine 10 mg daily for 2 months, although 20 mg daily caused insomnia. To treat low energy level, reboxetine 2 mg daily was added to fluoxetine. The following day, this patient had urinary retention, pain on urination and ejaculation, dry mouth, constipation, sweating, and marked insomnia. Symptoms persisted during the following 4 days. Reboxetine was discontinued on day 5, and symptoms disappeared on day 6.

The close temporal association between symptoms and reboxetine treatment (terminal half-life of elimination 13 hours) suggests a causal link. It is unlikely that the small dose of reboxetine alone caused the severe symptoms reported in a young, healthy man: a pharmacokinetic interaction with fluoxetine—leading to higher reboxetine levels and more anticholinergic side effects—seems more likely. Metabolism of reboxetine is mediated by CYP3A4 (1). Reboxetine cytochrome (1A2, 2C, 2D6, 3A4) inhibitory potential is insignificant (2), and fluoxetine inhibitory potential of CYP3A4 is moderate (2), but norfluoxetine is a more potent CYP3A4 inhibitor than fluoxetine (3). In healthy volunteers, fluoxetine has not had significant effects on the pharmacokinetics of reboxetine (4).

However, pharmacokinetic interactions are likely in clinical practice because fluoxetine and norfluoxetine are inhibitors of CYP3A4, the main metabolic pathway of reboxetine. Reboxetine, a potent and selective noradrenaline reuptake inhibitor, has low affinity for muscarinic receptors (5). In clinical trials of reboxetine versus imipramine, reboxetine caused similar proportions of anticholinergic effects (dry mouth, urinary retention, constipation, blurred vision, tachycardia) (6,7). Anticholinergic effects may be related to increased adrenergic activity (8). This case report suggests that caution must be used when combining reboxetine with fluoxetine, even in young, healthy persons.

References

1. Wienkers LC, Allievi C, Hauer MJ, Wynalda MA. Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes. Drug Metab Dispos 1999;7:1334–40.
2. DeVane CL. Differential pharmacology of newer antidepressants. J Clin Psychiatry 1998;59(suppl 20):85–93.
3. Caccia S. Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokinetic implications. Clin Pharmacokinet 1998;4:281–302.
4. Fleishaker JC, Herman BD, Pearson LK, Ionita A, Mucci M. Evaluation of the potential pharmacokinetic/pharma-
codynamic interaction between fluoxetine and reboxetine in healthy volunteers. Clin Drug Invest 1999;18:141–50.
5. Dostert P, Benedetti MS, Poggesi I. Review of the pharmacokinetics and metabolism of reboxetine, a selective noradrenaline reuptake inhibitor. Eur Neuropsychopharmacol 1997;7(suppl 1):23S–35S.
6. Katona C, Bercoff E, Chiu E, Tack P, Versiani M, Woelk H. Reboxetine versus imipramine in the treatment of elderly patients with depressive disorders: a double-blind randomized trial. J Affect Disord 1999;55:203–13.
7. Berzewski H, Van Moffaert M, Gagiano CA. Efficacy and tolerability of reboxetine compared with imipramine in a double-blind study in patients suffering from major depressive episodes. Eur Neuropsychopharmacol 1997;(suppl 1):37S–47S.
8. Lefkowitz RJ, Hoffman BB, Taylor P. Neurotransmission. The autonomic and somatic motor nervous systems. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Goodman Gilman A, editors. Goodman & Gilman’s The pharmacological basis of therapeutics, ninth ed. New York: McGraw-Hill; 1996. p 105–39.

Franco Benazzi, MD
Forli, Italy

Dear Editor

The serotonin syndrome (SS) has been reported following administration of any drug or combination of drugs that has the net effect of increasing serotonergic neurotransmission. The SS is idiosyncratic—it may occur in toxicity (for example, in overdose with selective serotonin reuptake inhibitors [SSRIs]) or in potentially lethal combinations (for example, an SSRI and a monoamine oxidase inhibitor). Uncommonly, it occurs at therapeutic doses (1). The following is the first report of the SS in a subject receiving subtherapeutic doses of sertraline.

Ms AP, a 43-year-old woman,  presented to the emergency room (ER) 3 days after beginning sertraline 25 mg daily for depression (2 doses taken). She had underlying moderate to severe mental retardation (MR) and high blood pressure (well controlled with hydrochlorothiazide 50 mg daily).

In the preceding month, she had lost her job as a packer at a local factory, a position she had held for 18 years. Her parents, with whom she lived, noted disturbed appetite and sleep (with mild weight loss and some difficulties falling asleep). She missed her former work colleagues, with whom she had socialized. In addition to sadness and anhedonia, her anxiety had also increased.

On the morning of her presentation, the patient had awakened with palpitations and chest pain. ER assessment noted a short and obese female who became progressively lethargic. Her cheeks were flushed and she was diaphoretic. Bedside vitals were as follows: blood pressure 140/70, pulse 116, and temperature 37.7ºC. An immediate