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Re: The dangers of antidepressants
- P Ken Gillman (12 March 2009)
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Fentanyl and serotonin toxicity
- P Ken Gillman, - (12 March 2009)
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The dangers of antidepressants
- Sandip Patel, Simon M Smith (17 October 2005)
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P Ken Gillman, Dr
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The authors are incorrect in their 'assertions'. Huge prospective case series of SSRI-alone overdoses show no fatalities from serotonin toxicity, and, indeed, very little other serious toxicity. There are not 'numerous published reports of fatalities involving SSRI alone', the references given (4,5) are misleading as they do not support those statements. SNRIs may be another issue, e.g. venlafaxine is definitely more toxic than most other new antidepressants: it also precipitates serotonin toxicity more frequently than SSRIs. But that is of peripheral relevance to anything in my review. It seems they have confused issues and forgotten I was talking specifically about ST, not other forms of morbidity or mortality. Likewise they are mistaken about 'Tricyclic antidepressants have an serotonin reuptake inhibition action, and can potentiate serotonin toxicity in SSRIs and opioids in a similar fashion'. Only clomipramine & imipramine are significant SRIs. More importantly, the evidence is that drugs with the same mechanism of action cannot potentiate each others effects, only have an additive effect the same as increasing the dose of one drug. Therefore mixtures of TCAs and SRIs do not precipitate serious ST. See: Gillman, PK, A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biological Psychiatry, 2006. 59: p. 1046-51. and Gillman, PK, Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British Journal of Pharmacology 2007. 151(6): p. 737-48. Epub 2007 Apr 30. Conflict of Interest:None declared |
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P Ken Gillman, dr -, -
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A previous review of serotonin toxicity (ST) with opioid analgesics in this journal 2 noted that there were some opioids that had no serotonin reuptake inhibitor (SRI) activity, and some that definitely did have, and those that did were associated with severe, potentially fatal, ST (e.g. tramadol, pethidine), if combined with monoamine oxidase inhibitors (MAOI). Data quantifying the affinity of opioids at the serotonin transporter were then, and still are, sparse: there is still no data on fentanyl and there remains a suspicion it may constitute a risk for precipitating ST if given to patients on an MAOI. Data relevant to this question have emerged from two retrospective surgical case series from units where methylene blue (MB) was routinely used in parathyroid surgery. These retrospective reviews were prompted by the observation of ‘CNS toxicity’ 4 7 in patients who were on SRIs pre- operatively. Investigation has since revealed that MB is a potent MAOI 6, which explains reports of ST with combinations of MB and SRIs (mostly antidepressant drugs like the SSRIs, but potentially including those opioids that are also SRIs) 3. These two case series totaled 325 patients who all had MB, 45/325 were on SSRIs pre-operatively: of those, 17/45 showed CNS toxicity after administration of MB. No case exhibited toxicity who had not been taking SSRIs pre-operatively. That indicates the CNS toxicity, which is probably ST 3, is due to an interaction between MB and SSRIs. However, this also constitutes an inadvertent but useful ‘experiment’ of the putative SRI potency of fentanyl which was used regularly in these cases. If fentanyl was a potent SRI it would be confidently predicted that it would cause serious ST if mixed with MAOIs (viz. MB, see 2) and these results indicate that did not happen. No case exhibited toxicity who had not been taking SSRIs pre-operatively, i.e. of the 280 cases (325-45) who had MB but no SRI pre-operatively, none showed toxicity, whereas 38% of those who took SRIs did have toxicity. Thus, it can be reliably inferred that fentanyl is not a significant SRI in usual circumstances. This is also a reminder that MB is not just a dye, but a potent drug that acts as an MAO-A inhibitor at low nanomolar concentrations 6, and as a nitric oxide synthase (NOS) inhibitor at slightly higher concentrations (it blocks the formation of L-citrulline by NOS completely at 30 µM 5). Recent evidence indicates plasma levels in humans after intra-venous administration of only 0.75 mg kg-1 reach concentrations that would be expected to inhibit MAO-A 1 8 and patients receive doses of between 1 – 7.5 mg kg-1. Dr. P Ken Gillman 1. Burhenne J, Riedel KD, Rengelshausen J, Meissner P, Muller O, Mikus G, et al. Quantification of cationic anti-malaria agent methylene blue in different human biological matrices using cation exchange chromatography coupled to tandem mass spectrometry. J. Chromatogr. B. Biomed. Sci. App. 2008;863:273-82 2. Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br. J. Anaesth. 2005;95:434-441 3. Gillman PK. Methylene Blue implicated in potentially fatal serotonin toxicity. Anaesthesia 2006;61:1013-1014 4. Kartha SS, Chacko CE, Bumpous JM, Fleming M, Lentsch EJ, Flynn MB. Toxic metabolic encephalopathy after parathyroidectomy with methylene blue localization. Otolaryngol. Head Neck Surg. 2006;135:765-8 5. Mayer B, Brunner F, Schmidt K. Inhibition of nitric oxide synthesis by methylene blue. Biochem. Pharmacol. 1993;45:367-74 6. Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br. J. Pharmacol. 2007;152:946-51 7. Sweet G, Standiford SB. Methylene-blue-associated encephalopathy. J. Am. Coll. Surg. 2007;204:454-8 8. Walter-Sack I, Rengelshausen J, Oberwittler H, Burhenne J, Mueller O, Meissner P, et al. High absolute bioavailability of methylene blue given as an aqueous oral formulation. Eur. J. Clin. Pharmacol. 2009;65:179-89 Conflict of Interest:None declared |
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Sandip Patel, Emergency Physician Emergency Department, Wycombe Hospital, High Wycombe, Buckinghamshire, UK, Simon M Smith
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Dear Sir, We read with interest the article by Gilman (1) discussing dual drug induced serotonin toxicity. We are gratified to see an article highlighting this often unappreciated clinical problem. We would, however like to challenge the assertion made in this paper that "an overdose of an SSRI alone only produces a moderate degree of serotonin toxicity at worst, but with no serious sequelae or fatalities." Whilst it is true that the majority of Selective Serotonin Reuptake Inhbitor (SSRI) overdoses are benign (2,3), and most SSRI overdose fatalities are in the context of poly -drug overdoses, there are numerous published reports of fatalities involving SSRI or SNRI alone (4,5). We would also like to highlight that, in the United Kingdom, clomipramine is prescribed more frequently than all Monoamine Oxidase Inhibitors combined (5). Tricyclic antidepressants have an serotonin reuptake inhibition action, and can potentiate serotonin toxicity in SSRIs and opioids in a similar fashion (6). This paper reinforces the need for physicians to remain vigilant to the possibility of potentially fatal iatrogenic drug interactions. Yours faithfully, Sandip Patel Simon M Smith 1 P. K. Gillman. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br. J. Anaesth. 2005; 95: 434-441 2 Water FG, Bilden EF. Antidepressants. In: Marx JA (ed). Rosen’s Emergency Medicine. Mosby: St Louis, 2002; 2087-2102 3 Baca-Garcia, Diaz-Sastre C, Saiz-Ruiz J, de Leon J. How safe are psychiatric medications after a voluntary overdose? Eur Psychiatry. 2002 Dec;17(8):466-70 4 Banham NDG. Fatal venlafaxine overdose. Med J Aust 1998; 169: 445-8 5 Buckley NA, McManus PR. Fatal toxicity of serotinergic and other antidepressant drugs: analysis of UK mortality data. BMJ 2002; 325: 1332-3 6 Preskorn SH. Fatal drug-drug interaction as a differential consideration in apparent suicides.J Psychiatr Pract. 2002 Jul;8(4):233-8. Conflict of Interest:None declared |
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