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Serotonin syndrome neuroleptic malignant syndrome

Date Created:    Last Modified:    Last Checked: Jan 2006

Neuroleptic malignant syndrome and serotonin syndrome serotonin toxicity differential diagnosis expert opinion

The distinction between NMS and ST (SS) is still giving rise to debate, but mostly confusion, in the literature. I have discussed and analysed some controversial published cases, as have Whyte and colleagues [1-15]. A more detailed comment on the value and (un)reliability of case reports generally has also been published [16]. There is a widespread perception that neuroleptic malignant syndrome symptoms somehow ‘trump’ or override symptoms of serotonin syndrome, and that serotonin syndrome cannot be diagnosed in the presence of neuroleptics. The origin and logic for this ‘ipse dixit’ assertion is unclear, but it appears to have become widely and uncritically accepted. This may be largely because of the misinformation perpetuated by poor case reports: readers who wish to learn about NMS and ST are advised to start with the major recent reviews by Caroff, Whyte et al and Gillman.

As I have reasoned elsewhere [8, 10] special evidence is required to logically justify assigning one illness or toxidrome a hierarchical precedence over another. There is no evidence that NMS is more strongly associated with neuroleptics than serotonin toxicity is with serotonergic drugs; indeed the opposite is the case because NMS is idiosyncratic, whereas ST is an inevitable form of poisoning. It is logical to make the diagnosis on the basis of the prevailing signs and a special argument is necessary to justify assigning a hierarchical precedence to one condition or feature, such as the previous administration of a neuroleptic. Bayesian theory indicates known ingestion of a serotonergic drug is the more important piece of data that would predict accurately the correct diagnosis in doubtful cases [17, 18], not previous ingestion of a neuroleptic, which is much less predictably or strongly associated with the occurrence of NMS following either over-dose or therapeutic administration.

Professor Whyte has recently summed up his experience of this differential diagnosis, which is that the two states are usually easily distinguished by ‘simple physical examination’ [19, 20]. The evidence that they are different and difficult to confuse in the majority of usual presentations is compelling. That does not deny there may be cases where a variety of drugs have been administered, often in large doses, resulting in complex pharmaco-dynamic and pharmaco-kinetic interactions producing moribund patients with pictures of mixed toxicity. Odd, and probably unreliable, case reports appear regularly in the serotonin toxicity and neuroleptic malignant syndrome literature. The Miyaoka report is an example. It is definitely not serotonin toxicity, it can hardly be interpreted as NMS either. The case described is said to have occurred 9 years prior to the report being written up and published, and five years after last reported contact with the patient [21].

NMS is a hypo-dopaminergic state, where progressive bradykinesia results in a state of immobilisation, akinesia and "stupor" accompanied by "lead pipe" rigidity, fever, autonomic instability [22-25]. It is unlikely to be a dose related phenomenon because, in contrast to ST, it is rare in association with over-doses [19] and shows a weak association with dose in normal use. Adityanjee [26, 27] discussed a spectrum concept of neuroleptic malignant syndrome some years ago. If there was a continuum between Parkinsonian side effects (to which everyone is susceptible in a dose-related way) and neuroleptic malignant syndrome, then intermediate cases would be very common and the proportion of those progressing to full NMS would be higher and dose related, as is the case with serotonin toxicity. Current evidence is insufficient to support or refute any particular pathophysiological model. Adityanjee, and others, have used the term spectrum concept in a different way to the usage the ST spectrum concept model. They use it to apply to the progression of symptoms in individual cases as apposed to the general pattern of progression seen in a representative sample. They appear to argue that a strict but arbitrary cut off, based on the severity of symptoms, is needed to maintain the usefulness of the NMS diagnosis. This notion has some logical difficulties, especially because there is no known, or even suggested, way of predicting whether progression to full-blown NMS will occur, perhaps because progression may depend on external or state dependant factors (e.g. ambient temperature and dehydration). It is a similar issue that persuades Whyte and I to prefer the term serotonin toxicity to serotonin syndrome and is discussed in the section on ‘spectrum concept’ and elsewhere [26, 28-34].

Some authors suggest that serotonin toxicity occurs with olanzapine and other neuroleptics and Kontaxakis also argues (from a review of published case reports) that neuroleptic malignant syndrome cases with olanzapine exhibit serotonin toxicity-like symptoms. It is thereby deduced that NMS and ST share a common pathophysiology and represent some sort of generic non-specific neuro-toxic syndrome. Both Isbister and I have pointed out the strong evidence that contradicts this notion. The idiosyncratic nature of NMS precludes pathophysiological comparison with ST in relation to the mechanism of action of the precipitating drugs even if the symptoms (as is proposed by Kontaxakis) were like ST. They are not (see ‘Defining toxidromes: serotonin toxicity and neuroleptic malignant syndrome: A comment on Kontaxakis et al’) so the proposal is weak in two ways. The reports of ST involving olanzapine (and citalopram) have been critisized by Whyte, Isbister and Gillman as not meeting the diagnostic criteria. These reports do not take adequate account of published data and can be confidently discounted [2, 8, 10, 19, 35-39].

Neither olanzapine, nor the other atypical neuroleptics, produce serotonergic side effects in therapeutic trials, or produce symptoms of ST when taken by them-selves in over-dose.

The idea that both neuroleptic malignant syndrome and serotonin toxicity are a manifestation of a common non-specific spectrum disorder is inexplicably at odds, not only with the clear difference of symptoms, but also with the reliable observation that serotonin toxicity is a form of toxicity to which everyone is liable, whereas NMS is an idiosyncratic reaction. It is difficult to reconcile these observations with views expressed by Fink and others [40, 41].

Features differentiating serotonin toxicity and NMS

From: [1, 19, 20, 42, 43]

• ST, rapid onset and rapid progression in association with serotonergic drugs. NMS, slow onset and progression, in association with neuroleptics.
• ST, hyperkinesia (agitation) and hyperreflexia / clonus, pyramidal rigidity. NMS, bradykinesia and extrapyramidal rigidity.
• ST, a manifestation of toxicity. NMS, an idiosyncratic reaction to therapeutic dosages.
• ST, rigidity is a terminal developement. NMS, rigidity is a prodromal symptom.

Sternbach made suggestions [44]about diagnostic criteria, which were reasonable initially, but were unvalidated proposals derived from a selected sample. Sternbach’s review has now been superceeded by the more reliable data from Professor Whyte’s HATS data published in a series of seminal papers. Sternbach noted the likelihood of reporting bias in his series, but that qualification has received insufficient subsequent attention. It is also appropriate to review his other suggestion— the exclusion criteria that ‘previous ingestion of a neuroleptic should be an exclusion criteria for a diagnosis of ST’. This is an illogical diagnostic standpoint because there are no a priori grounds for those features assuming a hierarchical precedence over, either known ingestion of serotonergic drugs, or signs of serotonin toxicity. A special argument is necessary to logically justify assigning a hierarchical precedence to one feature over another, such as the previous ingestion of a particular drug: such a case of prior probability is strong for serotonergic drugs, especially mixtures of monoamine oxidase inhibitors and selective serotonin reuptake inhibitors, but non-existant for neuroleptics. [13, 14, 45].

The discriminating signs of clonus, myoclonus, hyperreflexia, agitation, tremor and shivering and fever make it difficult to confuse the typical case of serotonin toxicity with NMS or drug withdrawal or intoxication with other drugs such as anti-muscarinic drugs.

As Professor Whyte has written re NMS and ST: [1, 42]

“In my capacity as a general physician to the local psychiatric hospital and as a clinical pharmacologist who takes referrals of drug related problems, I have managed over 50 patients with Neuroleptic Malignant Syndrome over the last 12 years. From this clinical experience and the literature, I have compiled a table comparing the clinical features of Serotonin Syndrome with those of Neuroleptic Malignant Syndrome….. “From this comparison it can be seen that while there are several features in common, a full physical examination and clinical assessment makes it almost impossible to confuse the two diagnoses. A similar table and conclusions have been recently published by Gillman (Gillman, PK., The Serotonin Syndrome at its treatment. Journal of Psychopharmacology. Vol 13 (1): 1999, pp 100-109)”

It seems that it is mostly psychiatrists who subscribe to the opinion that NMS and ST are ‘virtually indistinguishable’ and this may be because they do not usually have involvement in the care of these seriously ill patients in the intensive care units where they are treated by physicians and toxicologists.

References

1. Whyte, I.M., Serotonin syndrome complicating the treatment of recurrent depression. Current Therapeutics, 1999. 40: p. 6-7.
2. Isbister, G.K., F. Downes, and I.M. Whyte, Olanzapine and serotonin toxicity. Psychiatry and Clinical Neurosciences, 2003. 57(2): p. 241-2.
3. Isbister, G.K. and I.M. Whyte, Atypical presentation of risperidone toxicity. Veterinary and Human Toxicology, 2002. 44(2): p. 118-9.
4. Isbister, G.K., A.H. Dawson, and I.M. Whyte, Comment: neuroleptic malignant syndrome associated with risperidone and fluvoxamine. Annals of Pharmacotherapy, 2002. 36(7): p. 1294.
5. Whyte, I.M. and G.K. Isbister, Misdiagnosis of myoclonus in antidepressant induced serotonin excess. Veterinary and Human Toxicology, 2001. 43(6): p. 375-6.
6. Isbister, G.K., A.H. Dawson, and I.M. Whyte, Comment: serotonin syndrome and 5-HT2A antagonism. Annals of Pharmacotherapy, 2001. 35(12): p. 1143-4.
7. Isbister, G.K., I.M. Whyte, and A.J. Smith, Olanzapine overdose. Anaesthesia, 2001. 56(4): p. 400-1.
8. Gillman, P.K., Defining toxidromes: serotonin toxicity and neuroleptic malignant syndrome: A comment on Kontaxakis et al. Archives of General Hospital Psychiatry, 2004. http://www.general-hospital-psychiatry.com/content/2/1/10/comments#41454.
9. Gillman, P.K., Treatment with 5-HT2A antagonists may prevent fatalities from serotonin toxicity. European Psychiatry, 2004: p. e-pub.
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45. Gillman, P.K., Defining toxidromes: serotonin toxicity and neuroleptic malignant syndrome: A comment on Kontaxakis et al. Archives of General Hospital Psychiatry, 2004: p. http://www.general-hospital-psychiatry.com/content/2/1/10/comments#41454.

All text ©Dr Ken Gillman MRC Psych - PsychoTropical Research®


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