To the Editor:
We would like to comment on the article “A Fatal Case of Serotonin Syndrome after Combined Moclobemide–Citalopram Intoxication” (1). The authors describe the postmortem determination of moclobemide and citalopram using a newly developed analytic technique. However, the conclusion that the patient they describe died from serotonin syndrome is not supported by conclusive clinical or toxicological evidence.
Serotonin toxicity is characterised by a triad of clinical features: (1) autonomic features; (2) neuromuscular changes; and (3) altered mental status (2). Sternbach’s criteria, the most commonly cited for the diagnosis (3), are based on clinical findings in patients taking agents that cause increased levels of serotonin in the central nervous system. Thus, being a clinical diagnosis, serotonin syndrome cannot be diagnosed postmortem, although it may be suspected, based on the presence of serotonergic agents in postmortem toxicological analyses.

The authors’ description of serotonin toxicity includes features not typically regarded as part of the syndrome, for example, generalized tonic-clonic convulsions (3), although myoclonic spasms and hypertonia may be mistaken for seizure activity. Some selective serotonin reuptake inhibitors, such as citalopram, and the selective serotonin and noradrenaline reuptake inhibitor venlafaxine are associated with seizures in overdose, apart from causing serotonin toxicity (4,5). Blood pressure lability is more characteristic of neuroleptic malignant syndrome (2). Although patients may ultimately die from cardiac arrest in severe cases, this is also not part of the syndrome. In such cases, the mechanisms leading to death are postulated to be uncontrolled rising temperature and hypoventilation caused by chest wall muscle rigidity.

In the case presented the only evidence of serotonin syndrome was excessive defecation (possible diarrhea), as judged by Sternbach’s criteria (3). Measurement of 5-hydroxy-indoleacetic acid (5-HIAA) (a metabolite of serotonin) or noradrenaline (NA) in the cerebrospinal fluid (CSF) would have been informative as there is good evidence from animal models that CSF NA levels are raised in serotonin toxicity (6). This has also been reported in one human case where the NA levels normalized once serotonin toxicity resolved (7).

A review of the literature refutes the assertion that serotonin toxicity has a high mortality (2,8). In our unit, some 204 cases of serotonin toxicity have been treated over the last 10 years with no resultant deaths. Although the untreated syndrome may be life-threatening, this is not as common as the authors suggest.

The intrinsic toxicity of citalopram and moclobemide, other than the combination producing serotonin syndrome, is not discussed. There is evidence that citalopram in overdose causes toxicity unrelated to serotonin toxicity (4). In the largest series of cases, doses > 600 mg were shown to be correlated with seizures and cardiac toxicity (QT prolongation) (4). The citalopram concentration in the case presented, 4.47 µg/mL, is within the range of levels determined in autopsy cases where citalopram alone was the cause of death—2.0 to 6.2 mg/kg (1.92 to 5.96 µg/mL) (9). Thus, there is no reason to assume that death was not from the intrinsic toxicity of citalopram.

Serotonin toxicity is becoming increasingly common and important in clinical toxicology, and a clear description of it is required if appropriate diagnoses are to be made.

Geoffrey K. Isbister1, Patricia McGettigan2,3, and Andrew Dawson1,3

1Department of Clinical Toxicology and Pharmacology, Newcastle Mater Hospital, Newcastle, Australia; 2Department of Medicine, Newcastle Mater Hospital, Newcastle, Australia; and 3Discipline of Clinical Pharmacology, University of Newcastle, Newcastle, Australia

References
 1. R. Dams, T.H.P. Benijts, W.E. Lambert, J.F. Van Bocxlaer, D. Van Varenbergh, C. Van Peteghem, and A.P. De Leenheer. A fatal case of serotonin syndrome after combined moclobemide–citalopram intoxication. J. Anal. Toxicol. 25: 147–151 (2001).

2. P.K. Gillman. The serotonin syndrome and its treatment. J. Psychopharmacol. 13: 100–109 (1999).

3. H. Sternbach. The serotonin syndrome. Am. J. Psychiatry 148: 705–713 (1991).

4. M. Personne, G. Sjöberg, and H. Persson. Citalopram overdose—review of cases treated in Swedish hospitals. J. Toxicol. Clin. Toxicol. 35: 237–240 (1997).

5. I.M.D.A.H. Whyte. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose (Abstract). J. Toxicol. Clin. Toxicol., in press.

6. K Nisijima, T. Yoshino, K. Yui, and S. Katoh. Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome. Brain Res. 890: 23–31 (2001).

7. K. Nisijima. Abnormal monoamine metabolism in cerebrospinal fluid in a case of serotonin syndrome. J. Clin. Psychopharmacol. 20: 107–108 (2000).

8. R. Lane and D. Baldwin. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J. Clin. Psychopharmacol. 17: 208–221 (1997).

9. K. Worm, C. Dragsholt, K. Simonsen, and B. Kringsholm. Citalopram concentrations in samples from autopsies and living persons. Int. J. Legal Med. 111: 188–190 (1998).

The Authors’ Reply:

The case report that we published in the Journal (1) primarily focuses on the analytical aspect of this intoxication. However, the comments of Isbister et al. on the concluded serotonin syndrome resulting from the combined moclobemide–citalopram intoxication are correct.

The fact that the victim was found nude in a basket was interpreted as the result of an altered mental state and hyperthermia. In our opinion, these observations together with the abundant defecation were three typical clinical features of a serotonin syndrome and justified our conclusion. However, as clinical evidence and conclusive toxicological data (5-HIAA and/or NA) are not available, a better conclusion would be that the cause of death was multiple drug intoxication, which very likely led to fatal serotonin syndrome.

Reference
 1. R. Dams, T.H.P. Benijts, W.E. Lambert, J.F. Van Bocxlaer, D. Van Varenbergh, C. Van Peteghem, and A.P. De Leenheer. A fatal case of serotonin syndrome after combined moclobemide-citalopram intoxication. J. Anal. Toxicol. 25: 147–151 (2001).