PsychoTropicalResearch, serotonin and serotonin syndrome research.
Serotonin Syndrome - Introduction
Serotonin Syndrome - Introduction
Date Created: 14/1/1999 Last Modified: 02/09/2003 Last Checked: 02/09/2003
Morbidity and fatalities as a result of serotonin toxicity are occurring with increasing frequency.
The combination that does this to the greatest extent is that of a monoamine oxidase inhibitor -MAOI (that includes the ‘RIMA’, moclobemide) if combined with any drug that acts as a serotonin reuptake inhibitor, whether it is ‘selective’ (like the SSRIs) or not.
Those drug combinations are likely to produce serious toxicity that may lead to fatal outcomes. Fatal outcomes have been reported in dozens of published reports in peer reviewed medical journals. A larger but unknown number of cases have gone unreported.
Venlafaxine, clomipramine, imipramine, milnacipran, sibutramine and duloxetine are serotonin reuptake inhibitors and are therefore just as problematic as the selective serotonin reuptake inhibitors (SSRIs). Some narcotic analgesics are serotonin reuptake inhibitors and are therefore also dangerous, these are:-- pethidine, tramadol, dextromethorphan, dextropropoxephene and pentazocine.
Most other serotonergic combinations, like those used therapeutically (eg an SSRI plus Lithium, or an MAOI plus Lithium) do boost serotonin levels enough to cause a noticeable increase in serotonin-related side effects, but not enough to cause serious morbidity from serotonin toxicity.
At the moment the term serotonin syndrome is being used in the literature in an unhelpful way. I have argued in various publications *** that serotonin toxicity is best regarded as a spectrum of increasing side effects building up to ‘toxicity’ and that these manifestations are related to the degree of elevation of brain serotonin levels.
What is presently loosely referred to as serotonin syndrome is a spectrum of increasingly severe serotonin related effects. At some point side effects become severe enough to describe as toxicity.
The key features that would define serotonergic toxicity from side effects.
Clinicians may like to remember that the evidence clearly indicates that mortality and serious morbidity only occur following the large elevations of serotonin that result when both monoamine oxidase inhibitors (MAOIs) and serotonin reuptake inhibitors (SRIs) are combined together.
'Milder' degrees of serotonin-related side effects that may meet 'definitions' for serotonin syndrome do ocurr with monotherapy at therapeutic doses and are not uncommon; for instance tremor, shivering and hyperreflexia may be seen. This has been reviewed by both Lejoyeaux and Gillman.
Serotonergic side effects that are mild, but sufficient to meet the arbitrary 'Sternbach' criteria, seem to occur in about 10% of over-doses with a single serotonergic drug, but there have been no deaths and no severe cases. The latest prospectively gathered figures for the incidence of serotonin syndrome from Dr Whyte's group are:-- SSRIs 45 of 233 (19.3%) compared to venlafaxine 15 of 51(29.4%). It is beginning to look as though venlafaxine is more prone to cause serotonin syndrome, but those figures are not significant to the P = 0.05 level.
The only fatalities have occurred with combinations of an MAOI (or RIMA) with an SRI.
***
Gillman, P.K., Serotonin Syndrome: History and Risk. Fundamental and Clinical Pharmacology, 1998. 12(5): p. 482-491. [Review]
Gillman, P.K., The serotonin syndrome and its treatment. Journal of Psychopharmacology, 1999. 13(1): p. 100-9. [Review]
Gillman, P.K., Serotonin syndrome: clomipramine too soon after moclobemide. International Clinical Psychopharmacology, 1997. 12: p. 339-342. [Review]
Gillman, P.K. and S. Hodgens, Serotonin syndrome following SSRI mono-therapy. Human Psychopharmacology, 1998. 13: p. 525-526.
Gillman, P.K., Comments on "Serotonin syndrome during treatment with paroxetine and risperidone". J Clin Psychopharmacol, 2001. 21(3): p. 344-5.
All text ©Dr Ken Gillman MRC Psych - PsychoTropical Research®
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