CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity.

Methylene blue has only recently been noted to cause severe central nervous system toxicity. Methylene blue is used for various conditions, including, intravenously, in methemoglobinemia, vasoplegia and as an aid to parathyroidectomy (at doses of 1-7.5 mg kg(-1)). This review of the current evidence concludes that 13 of 14 of the reported cases of CNS toxicity were serotonin toxicity that met the Hunter Serotonin Toxicity Criteria. That has important preventative and treatment implications. Serotonin toxicity is precipitated by the monoamine oxidase inhibitor (MAOI) property of methylene blue interacting with serotonin reuptake inhibitors. Serotonin toxicity is reviewed, using the lessons inherent in the methylene blue story and experience, to illustrate how the mechanisms and potency of serotonergic drugs interact to determine severity. Recent human data showed that an intravenous dose of only 0.75 mg kg(-1) of methylene blue produced a peak plasma concentration of 500 ng ml(-1) (1.6 µM), indicating that the concentration in the central nervous system reaches a level that inhibits monoamine oxidase A. That is consonant with the actual occurrence of severe serotonin toxicity in humans at the dose of only 1 mg kg(-1). It seems that all proposed uses of methylene blue entail levels that block monoamine oxidase, so cessation of serotonin reuptake inhibitors should be very carefully considered before using methylene blue.

Neuroleptic malignant syndrome: mechanisms, interactions, and causality.

This review focuses on new data from recent publications concerning how compounding interactions between different thermoregulatory pathways influence the development of hyperthermia and/or neuroleptic malignant syndrome (NMS), and the fundamental issue of the presumed causal role of antipsychotic drugs. The formal criteria for substantiating cause-effect relationships in medical science, established by Hill, are applied to NMS and, for comparison, also to malignant hyperthermia and serotonin toxicity. The risk of morbidities related to hyperthermia is reviewed from human and experimental data: temperatures in excess of 39.5°C cause physiological and cellular dysfunction and high mortality. The most temperature-sensitive elements of neural cells are mitochondrial and plasma membranes, in which irreversible changes occur around 40°C. Temperatures of up to 39°C are "normal" in mammals, so, the term hyperthermia should be reserved for temperatures of 39.5°C or greater. The implicitly accepted presumption that NMS is a hypermetabolic and hyperthermic syndrome is questionable and does not explain the extensive morbidity in the majority of cases, where the temperature is less than 39°C. The thermoregulatory effects of dopamine and acetylcholine are outlined, especially because they are probably the main pathways by which neuroleptic drugs might affect thermoregulation. It is notable that even potent antagonism of these mechanisms rarely causes temperature elevation and that multiple mechanisms, including the acute phase response, stress-induced hyperthermia, drugs effects, etc., involving compounding interactions, are required to precipitate hyperthermia. The application of the Hill criteria clearly supports causality for drugs inducing both MH and ST but do not support causality for NMS.

Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review.

The US Food and Drug Administration (FDA) have suggested that fatal serotonin syndrome (SS) is possible with selective serotonin reuptake inhibitors (SSRIs) and triptans: this warning affects millions of patients as these drugs are frequently given simultaneously. SS is a complex topic about which there is much misinformation. The misconception that 5-HT1A receptors can cause serious SS is still widely perpetuated, despite quality evidence that it is activation of the 5-HT2A receptor that is required for serious SS. This review considers SS involving serotonin agonists: ergotamine, lysergic acid diethylamide, bromocriptine, and buspirone, as well as triptans, and reviews the experimental foundation underpinning the latest understanding of SS. It is concluded that there is neither significant clinical evidence, nor theoretical reason, to entertain speculation about serious SS from triptans and SSRIs. The misunderstandings about SS exhibited by the FDA, and shared by the UK Medicines and Healthcare products Regulatory Agency (in relation to methylene blue), are an important issue with wide ramifications.

Serotonin toxicity associated with the use of linezolid: a review of postmarketing data.

BACKGROUND: Linezolid is the first oxazolidinone antimicrobial marketed in the United States. It exhibits monoamine oxidase (MAO) type A and MAO type B inhibitory effects. The concomitant administration of nonselective MAO inhibitors or MAO-A inhibitors with drugs that increase serotonin concentrations is associated with serotonin toxicity. METHODS: We requested from the US Food and Drug Administration all postmarketing adverse event reports regarding linezolid that included serotonin toxicity or any report describing cognitive or behavioral symptoms and autonomic and neuromuscular excitability. We assessed the case summaries obtained from the Adverse Event Reporting System database for serotonin toxicity. A case of serotonin toxicity was defined as having the following: (1) linezolid as the primary suspect drug; (2) concurrent administration of > or =1 secondary suspect drug known to increase serotonin concentrations in the central nervous system; and (3) serotonin toxicity, as defined by the modified Hunter Serotonin Toxicity Criteria or by the reporter. RESULTS: Twenty-nine cases were classified as serotonin toxicity. Patients' ages ranged from 17-83 years, and the ratio of females to males was 1:1. The most common class of drugs received concurrently with linezolid was selective serotonin reuptake inhibitors (26 of 43 patients). Thirteen patients required an intervention to prevent permanent impairment or required hospitalization for the adverse event. CONCLUSION: The use of linezolid with medications that increase concentrations of serotonin in the central nervous system may result in serotonin toxicity. Prescribers must weigh risks and benefits of this combination. Patients and prescribers should be cognizant of signs and symptoms of serotonin toxicity and should initiate appropriate measures if such symptoms develop.

A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action.

Data now exist from which an accurate definition for serotonin toxicity (ST), or serotonin syndrome, has been developed; this has also lead to precise, validated decision rules for diagnosis. The spectrum concept formulates ST as a continuum of serotonergic effects, mediated by the degree of elevation of intrasynaptic serotonin. This progresses from side effects through to toxicity; the concept emphasizes that it is a form of poisoning, not an idiosyncratic reaction. Observations of the degree of ST precipitated by overdoses of different classes of drugs can elucidate mechanisms and potency of drug actions. There is now sufficient pharmacological data on some drugs to enable a prediction of which ones will be at risk of precipitating ST, either by themselves or in combinations with other drugs. This indicates that some antidepressant drugs, presently thought to have serotonergic effects in animals, do not exhibit such effects in humans. Mirtazapine is unable to precipitate serotonin toxicity in overdose or to cause serotonin toxicity when mixed with monoamine oxidase inhibitors, and moclobemide is unable to precipitate serotonin toxicity in overdose. Tricyclic antidepressants (other than clomipramine and imipramine) do not precipitate serotonin toxicity and might not elevate serotonin or have a dual action, as has been assumed.

A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status.

A systematic review of published work concerning mirtazapine was undertaken to assess possible evidence of serotonergic effects or serotonin toxicity (ST) in humans, because drug toxicity and interaction data from human over-doses is an useful source of information about the nature and potency of drug effects. There is a paucity of evidence for mirtazapine having effects on any indicator of serotonin elevation, which leads to an emphasis on ST as an important line of evidence. Mirtazapine is compared with its analogue mianserin, and other serotonergic drugs. Although mirtazapine is referred to as a dual-action 'noradrenergic and specific serotonergic drug' (NaSSA) little evidence to support that idea exists, except from initial microdialysis studies in animals showing small effects; those have not subsequently been replicated or substantiated by independent researchers. Also, new data indicate its affinity for Alpha 2 adrenoceptors is not different to mianserin. It appears to exhibit no serotonergic symptoms or toxicity in over-dose by itself, nor is there evidence that it precipitates ST in combination with monoamine oxidase inhibitors, as would be expected if it raises intra-synaptic serotonin levels. Mirtazapine has no demonstrable serotonergic effects in humans and there is insufficient evidence to designate it as a dual-action drug.