Serotonin toxicity and malignant hyperthermia: role of 5-HT2 receptors.

EditorÐWe congratulate the authors on an excellent review of aspects of the pathophysiology of malignant hyperthermia (MH). They have explained the postulated role of serotonin in MH, in particular the role of peripheral 5-HT2 receptors, based on in vitro and in vivo animal work. There are important parallels between serotonin toxicity and MH, and this review adds to our understanding of the role of 5-HT2 receptors, peripheral and central, in both serotonin toxicity and MH. There is recent animal work that has de®ned the role of 5-HT2a receptors in serotonin toxicity, and reports of the use of 5-HT2 antagonists in the treatment that should make us rethink the conventional descriptions of serotonin toxicity, which were restated by Wappler and colleagues. Serotonin syndrome, better described as a spectrum of toxicity than a distinct syndrome, is characterised by: (i) neuromuscular hyperactivityÐhyperre ̄exia, clonus, myoclonus, tremor and rigidity; (ii) autonomic hyperactivityÐhyperpyrexia, tachycardia and diaphoresis; and (iii) altered mental statusÐagitation, anxiety, hypomania and confusion. While there are some similarities with neuroleptic malignant syndrome, the time course, neuromuscular features and autonomic features are usually quite distinct. Malignant hyperthermia is also a distinctly different condition, but some of the peripheral and autonomic features that occur with severe serotonin toxicity more closely resemble MH. This raises the possibility that peripheral 5HT2 receptors are involved in both conditions. Recent studies implicate 5-HT2a receptors in the pathophysiology of serotonin toxicity, not the 5-HT1a receptor which was initially thought to be involved. These studies have used an animal model of serotonin toxicity where rats were administered clorgyline, a monoamine oxidase inhibitor (MAOI), and 5hydroxyl-L-tryptophan (5-HTP). In the control group, the temperature increased to more than 40°C, and the rats exhibited behavioural changes including tremor, and died within 75 min. Animals pretreated with the potent 5-HT2a antagonist, ritanserin, and the atypical antipsychotic risperidone which has strong 5HT2a blocking action, had no rise in temperature, no behavioural changes and all survived. 5 Animals pretreated with high dose chlorpromazine and cyproheptadine, both 5-HT2 antagonists, all survived and had a suppression of the temperature rise. However, pretreatment with propranol, 5-HT1a receptor antagonist (as well as a beta blocker), dantrolene and haloperidol did not prevent death in any of the animals, although the ®rst two drugs did suppress the rise in temperature to some extent. 5 The lack of effect of dantrolene in these two studies 5 suggests that peripheral muscle effects play a lesser role in serotonin toxicity compared to MH, where dantrolene is more effective. The studies also do not support the use of propranolol or haloperidol in the treatment of serotonin toxicity. Clinical studies do, however, support the use of 5-HT2 antagonists, such as cyproheptadine, in the treatment of serotonin toxicity. The animal studies described by Wappler and colleagues also raise the possibility that peripheral 5-HT2 receptors may be involved in serotonin toxicity. In our experience, the main features of mild to moderate serotonin toxicity are hyperre ̄exia, clonus, tremor and autonomic features, with rarely any mental state changes. These neuromuscular features are similar to those described in the animal studies quoted by Wappler and colleagues which were elegantly demonstrated to be due to peripheral 5-HT2 receptor effects. Thus, neuromuscular features are an intrinsic part of serotonin toxicity, although whether this is mediated only via central 5-HT2a receptors or peripheral 5-HT2 receptors is unclear. In severe serotonin toxicity, which occurs almost exclusively when MAOIs (including reversible inhibitors of monoamine oxidase) or serotonin-releasing agents (e.g. MDMA or ecstasy) are combined with a selective serotonin reuptake inhibitor (SSRI), the condition is even more like MH with severe hyperpyrexia, rigidity and hypercapnia, requiring paralysis and sedation for effective management. Rhabdomyolysis and increased creatine kinase can also occur. Peripheral 5-HT2a receptors in skeletal muscle may be involved in these severe cases, resulting in a picture similar to MH. Serotonin toxicity is becoming increasingly common in many situations in medicine. It commonly occurs in overdoses of serotonergic agents, and drug interactions continue to be a problem. This can be a problem in perioperative patients, where a number of analgesics can induce serotonin toxicity in patients already taking SSRIs. The most important is pethidine, which is well reported as causing serotonin toxicity in patients on SSRIs. Tramadol may also be a problem, particularly in patients requiring longer term pain management. Thus, in the postoperative period, there is the possibility of both serotonin toxicity and MH occurring. Careful clinical assessment is needed to distinguish between these possibilities and allow appropriate treatment to be given.