PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs. Serotonin toxicity: linezolid.

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Serotonin toxicity: linezolid

Serotonin toxicity: linezolid

Date Created:    Last Modified:    Last Checked: Jan 2006

Linezolid, a new anti-biotic, is similar to moclobemide as a competitive and reversible inhibitor of monoamine oxidase, except it is non-selective (blocks MAO-A and B) [1]. Linezolid is a reversible non-selective MAOI anti-microbial (available for IV use, which may increase potential risk). Its potency in tyramine pressor tests appears is similar to moclobemide, which itself was a by-product of a search for a new anti-microbial by Roche (I seem to recall, refs?).

At present, there seems no doubt that linezolid has sufficient potency as an MAOI to be capable of precipitating significant serotonin toxicity. This being the case it can be confidently predicted that it is only a matter of time before someone experiences life threatening serotonin toxicity with a combination of linezolid with an SRI.

Linezolid’s emerging story in connection with serotonin toxicity has striking parallels with the moclobemide story. At present it does not appear that a better and more rapid assessment of its risk of precipitating serotonin toxicity is being achieved. I have already commented on this life-threatening issue. No animal work re linezolid and SSRI interactions has yet been done, and only a small number of cases of co-administration in a human phase 1 trial. There are now enough reports of serotonin toxicity with linezolid in phase 4 clinical use [2-14] to make further action to clarify the situation desirable.

The following information provided from Pfizer illustrates that the appropriate symptoms were not looked for in the preliminary work carried out.

“A phase I, randomised, placebo-controlled, parallel group study was conducted to evaluate the potential for pharmacodynamic drug interaction between paroxetine hydrochloride and linezolid. All patients were given paroxetine hydrochloride 20 mg daily on days 1-7 and 40 mg daily on days 8-11 in open-label manner. Linezolid 600 mg orally every 12 hours (12 patients) or placebo (6 patients) were administered in blinded manner on days 5-11.

Eighteen healthy male and female volunteers were analysed for pharmacokinetic, pharmacodynamic and safety assessments. No significant changes in temperature were noted between linezolid and placebo-treated patients. Mean heart rate values ranged from 61 to 80 beats per minute in the placebo group and 61 to 78 in the linezolid group. Mean systolic and diastolic blood pressure ranged from 115 to 132 and 76 to 85 mmHg in the placebo group, respectively. In the linezolid group, mean systolic and diastolic blood pressure ranged from 113 to 124 and 72 to 80 mmHg, respectively.

No clinically significant differences in vital signs, physical findings, or laboratory findings were noted. No signs of enhanced serotonergic response or serotonin syndrome were observed in any patient.”

This has a familiar ring to anyone who has read the Roche / Dingemanse material, or reviewed Hawley’s experience (see section on moclobemide). If you do not know what to look for you are somewhat less likely to find anything.

The linezolid product information (PI) is an echo of the Roche (moclobemide) story. The current US PI could in my opinion be much improved to better inform and assist doctors in avoiding the dangers. Preliminary investigations persuaded some people that moclobemide was not implicated in serious serotonin toxicity. That was a grave misjudgement (no pun intended). Unfortunately pharmaceutical companies are organisations that have difficulties involving their mental sets of secrecy, denial, coping with contrary evidence, conflict of interests etc, sadly to the disadvantage of patients, doctors and probably themselves. Until a clearer picture emerges, and more data re the MAOI potency of linezolid is obtained, it may be assumed that linezolid, if mixed with SRIs, or releasers, will produce fatal serotonin toxicity.

The Pfizer company, post take-over of Pharmacia who developed linezolid, do not appear to fully appreciate the nature and seriousness of the potential interaction. They have not carried out (or have declined to reveal) appropriate interaction investigations: there is insufficient data about MAOI potency (say compared to moclobemide) nor comprehensive data about SRI interactions. When one considers the ongoing problem with moclobemide / SRI serotonin toxicity (see section on moclobemide) this demonstrates the difficulties that continue in educating people about serotonin toxicity. I communicated with Pfizer about this in mid 2003 and again in Jan 2005. Their response has not yet been encouraging, nor indicative of a satisfactory understanding of the problem. I have published contributions alerting to the potential interactions [15-17].

Note that linezolid is potentially more dangerous than moclobemide for two reasons:

  1. Linezolid is non-selective ie blocks MAO A and B, whereas moclobemide blocks only MAO-A
  2. Linezolid is available as an intra-venous preparation.

References

1. Cantarini, M.V., et al., Effect of oral linezolid on the pressor response to intravenous tyramine. Br J Clin Pharmacol, 2004. 58(5): p. 470-5.
2. Morales, N. and H. Vermette, Serotonin syndrome associated with linezolid treatment after discontinuation of fluoxetine. Psychosomatics, 2005. 46(3): p. 274-5.
3. Debellis, R.J., et al., Linezolid-associated serotonin syndrome after concomitant treatment with citalopram and mirtazepine in a critically ill bone marrow transplant recipient. J Intensive Care Med, 2005. 20(6): p. 303-5.
4. Morales-Molina, J.A., et al., Linezolid-associated serotonin syndrome: what we can learn from cases reported so far. J Antimicrob Chemother, 2005.
5. Sorbello, A., et al., Post-Marketing Reports of Serotonin Syndrome Associated With Linezolid. FDA, 2005.
6. Bergeron, L., M. Boule, and S. Perreault, Serotonin Toxicity Associated with Concomitant Use of Linezolid. Annals of Pharmacotherapy, 2005.
7. Thomas, C.R., et al., Serotonin syndrome and linezolid. J Am Acad Child Adolesc Psychiatry, 2004. 43(7): p. 790.
8. Jones, S.L., E. Athan, and D. O'Brien, Serotonin syndrome due to co-administration of linezolid and venlafaxine. Journal of Antimicrobial Chemotherapy, 2004. 54: p. 289-290.
9. Tahir, N., Serotonin syndrome as a consequence of drug-resistant infections: an interaction between linezolid and citalopram. Journal of the American Medical Directors Association, 2004. 5(2): p. 111-3.
10. Hachem, R.Y., et al., Myelosuppression and serotonin syndrome associated with concurrent use of linezolid and selective serotonin reuptake inhibitors in bone marrow transplant recipients. Clin Infect Dis, 2003. 37(1): p. e8-11.
11. Aga, V.M., N.E. Barklage, and J.W. Jefferson, Linezolid, a monoamine oxidase inhibiting antibiotic, and antidepressants. Journal of Clinical Psychiatry, 2003. 64(5): p. 609-11.
12. Lavery, S., et al., Linezolid and serotonin syndrome. Psychosomatics, 2001. 42(5): p. 432-4.
13. Bernard, L., et al., Serotonin syndrome after concomitant treatment with linezolid and citalopram. Clin Infect Dis, 2003. 36(9): p. 1197.
14. Wigen, C.L. and M.B. Goetz, Serotonin syndrome and linezolid. Clin Infect Dis, 2002. 34(12): p. 1651-2.
15. Gillman, P.K., Linezolid and serotonin toxicity. Clinical Infectious Diseases, 2003. 37: p. 1274-5.
16. Gillman, P.K., Moclobemide and the risk of serotonin toxicity (or serotonin syndrome). Central Nervous System Drug Reviews, 2004. 10: p. 83-85.
17. Gillman, P.K., Comment on: Serotonin syndrome due to co-administration of linezolid and venlafaxine. Journal of Antimicrobial Chemotherapy, 2004. 54: p. 844-845.