Management of serotonin syndrome (toxicity)

Abstract

Serotonin syndrome (toxicity), resulting from an excessive accumulation of serotonin in the central nervous system, it can occur due to various factors such as the initiation of medication, overdose or drug interactions. Diagnosing serotonin toxicity presents challenges as there are no definitive criteria. This review delves into the pathophysiology, incidence, clinical assessment and management of serotonin toxicity, stressing the significance of promptly recognizing and managing severe cases. Diagnosis relies primarily relies on clinical assessment due to the absence of specific laboratory tests. The Hunter Serotonin Toxicity criteria are commonly utilized but have only been validated in the overdose setting. Assessing the severity of toxicity is crucial for guiding management decisions. Supportive care, discontinuation of causative agents and symptomatic treatment are prioritized in management. Mild toxicity often requires withdrawal or reduction of the serotonergic agent, while more severe toxicity requires more aggressive resuscitative and supportive care. Severe serotonin toxicity characterized by hyperthermia and rigidity requires aggressive supportive measures, including benzodiazepines, intubation, paralysis and active cooling. Animal studies suggest potential benefits of 5‐HT2A receptor antagonists in preventing hyperthermia and fatalities, but only at high doses. Their clinical effectiveness remains uncertain, and evidence is predominately from case series and case reports. Although commonly used, serotonin antagonists like cyproheptadine lack conclusive evidence of efficacy. Other serotonin antagonists such as chlorpromazine and olanzapine have been explored but evidence is limited to case reports. Hence, the cornerstone of treating severe cases does not lie in ‘antidote’ administration or even diagnosis but in effective early resuscitative and supportive care.

1. INTRODUCTION

Serotonin syndrome, more accurately serotonin toxicity (ST), results from an increase in intra‐synaptic central nervous system (CNS) serotonin. This can occur in the context of commencing, or an overdose of, a serotonergic agent or a drug–drug interaction. Toxicity is characterized by mental status changes, autonomic excitation and neuromuscular excitation. Signs and symptoms represent a spectrum of toxicity related to increasing serotonin concentrations in the CNS. There is no gold standard investigation or criteria to confirm its diagnosis, leading to concerns of misdiagnosis and fatal outcomes. In this review we will discuss the management of serotonin toxicity and that confirming the diagnosis and administering serotonin antagonists are not lifesaving. Rather, management should focus on ceasing the offending agent, supportive care, decreasing agitation with benzodiazepines and, in those with hyperthermia and rigidity, aggressive management of the hyperthermia and rigidity with intubation, paralysis and active cooling.

2. PATHOPHYSIOLOGY

Serotonin is synthesized from the amino acid tryptophan. It has central and peripheral effects with at least seven different families of serotonin receptors ¹ , ² Peripherally the serotonin system aids in the regulation of vascular tone and gastrointestinal motility. ² , ³ In the CNS, serotonin acts as a neurotransmitter with influences on mood, sleep, vomiting and pain perception. ² There are at least seven families of 5‐HT receptors (5‐HT1 to 5‐HT7), some of which have multiple subtypes. ¹ , ² It is likely that no single receptor is responsible for ST. However, stimulation of the 5‐HT1A and 5‐HT2A receptors have been implicated in ST. The 5‐HT1A receptors possibly contribute to some of the milder symptoms of ST including the neuromuscular features (hyperreflexia, clonus) and anxiety. ⁴ , ⁵ In contrast, activation of 5‐HT2A receptors is implicated in severe and lethal ST in animal studies, in which hyperthermia is the key feature. ⁶ , ⁷ However, the 5‐HT1A receptors have a higher affinity for serotonin (400–1000 times in animal models) compared to the low‐affinity 5‐HT2A receptors. ⁸ Hence at low concentrations the 5‐HT1A are occupied and with increasing 5‐HT concentrations, 5HT2A activation dominates resulting in more severe toxicity. ⁶ , ⁸ This is supported by animal and human studies that demonstrate that the hyperthermic effect induced by 5‐HT‐enhancing drugs is prevented by 5‐HT2A antagonists. ⁶ , ⁷ , ⁹ Animal studies have shown that a 40‐fold increase over baseline in extracellular CNS 5‐HT is required to observe behavioural ST in animals. ¹⁰ However, severe or lethal ST requires much larger increases in 5‐HT up to 1000‐fold over basal concentrations; typically this involves drug interactions with monoamine oxidase inhibitors (MAOIs). ⁹ , ¹¹ Furthermore, rat studies demonstrate that hyperactivity of the noradrenergic system occurs with severe/lethal serotonin toxicity, with noradrenaline concentrations increasing in the frontal cortex (>10× baseline), which may occur indirectly through mediation of 5‐HT2A receptors, or be a response to severe hyperthermia, hypertension or physical stress. ¹²

3. CAUSATIVE AGENTS

A variety of drugs have been implicated in causing serotonin toxicity, although not all cases are entirely justified. Plausible agents share a final common pathway that results in an elevation of serotonergic concentrations. ⁴ This can occur through mechanisms that either increase pre‐synaptic serotonin (i.e., increase 5‐HT production or inhibition of 5‐HT metabolism) or those that increase serotonin in the synapse (i.e., increase in 5‐HT release or inhibition of 5‐HT reuptake). ¹³ Serotonin toxicity typically presents in three clinical scenarios: shortly after initiating or escalating the dosage of a serotonergic agent, in overdose, or a drug–drug interaction, for example, combination of two serotonergic agents that increase serotonin concentration through different mechanisms. ¹³ Serotonin toxicity develops rapidly, typically starting shortly after the intake of a serotonergic agent, with symptoms becoming apparent within an hour in about 30% of patients, and within 6 h in 60%. ¹⁴

4. INCIDENCE

The true incidence of serotonin toxicity is unknown, and it is often stated that the true incidence is underestimated. However, this is because mild, moderate and severe ST are often considered as one entity. The causes, incidence and management of mild versus severe ST varies greatly. Mild ST or simply side effects of the medications are often labelled as ST and can occur on initiating any serotonergic agent. However, this is highly unlikely to cause severe toxicity. On the other hand, the occurrence of ST in overdose is easier to quantify for various serotonergic agents. Retrospective studies of selective serotonin reuptake inhibitor (SSRI) overdoses have shown that those ingesting only one serotonin reuptake inhibitor (SRI) developed ST in approximately 15% of cases, which was mild to moderate in severity and none developed severe toxicity. ¹⁵ , ¹⁶ Co‐ingestion of moclobemide in this group increased the risk of ST while co‐ingestions of 5‐HT2A antagonist such as olanzapine or risperidone decreased the probability of ST. ¹⁶ Studies in those overdosing on MAOIs showed that a combination of a MAOI (most commonly moclobemide) with SSRIs resulted in ST in almost half of cases and many developed at least moderately severe ST. ¹⁶ , ¹⁷ Severe and life‐threatening ST occurs almost exclusively in those ingesting a combination of MAOIs and another serotonergic agent (i.e., SSRI, serotonin and norepinephrine reuptake inhibitor [SNRI]).

5. FACTORS ASSOCIATED WITH SEROTONIN TOXICITY

There does not appear to be an association between ingested dose and risk of ST, at least for SSRIs and SNRIs in overdose. ¹⁶ The proportion of patients developing serotonin toxicity after small ingestions of 1 to 10 defined daily doses was about 12%, which only increased to about 20% for massive ingestions of 400 defined daily doses. This suggests that there are other factors which predispose individuals to ST, including genetic factors (i.e., polymorphism of SERT gene, 5‐HT2 receptors or CYP pathways). ⁴ , ¹⁸ , ¹⁹ , ²⁰ In addition, the combination of agents is the most important risk factor in causing severe ST, in particularly the combination of an SRI and a MAOI. ¹⁶ , ¹⁷ , ²¹

6. SEROTONIN TOXICITY: CLINICAL ASSESSMENT

The classic triad of clinical features are neuromuscular excitation (e.g., clonus, hyperreflexia, myoclonus, rigidity), autonomic nervous system excitation (e.g., hyperthermia, tachycardia, mydriasis) and an altered mental state (e.g., agitation, confusion). ²² , ²³ The autonomic and mental state changes can be non‐specific while the neuromuscular excitation, especially clonus (including spontaneous, inducible and ocular clonus) is far more indicative of ST and the predominant clinical finding in the Hunter Serotonin Toxicity criteria. ²⁴

Clinical manifestations vary with increasing severity, ranging from mild side effects to moderate and severe toxicity (Figure 1). ²² , ²⁵ Severe ST presents with symptoms such as opisthotonus, sustained spontaneous clonus, truncal rigidity and hyperthermia. This will be severe hyperthermia with a temperature >40°C and is characterized by a rapidly rising temperature over a period of hours. ²⁶ Life‐threatening cases are distinguished by hyperthermia and increasing rigidity, particularly truncal rigidity which eventually impairs respiratory function. ²⁴

FIGURE 1.

Spectrum of serotonin toxicity and its management. ²² , ²⁵ Figure created with BioRender.com.

The diagnosis of ST is clinical, and there are currently no useful laboratory or neurophysiological tests to confirm excess concentrations of synaptic serotonin. Three diagnostic criteria (Sternbach, Radomski and Hunter) have been proposed, with the Hunter Serotonin Toxicity criteria being the most commonly utilized (Figure 2). ²³ , ²⁴ , ²⁶ All three criteria have undergone little validation, which has led to issues with misuse or misinterpretation of these criteria. ¹³ The symptoms listed in the Sternbach criteria are non‐specific and present in many other diagnoses and toxidromes. The Hunter Serotonin Toxicity criteria include symptoms more specific for ST, but there are issues with this too. The Hunter Serotonin Toxicity criteria were developed from an initial dataset of 473 single SSRI overdose patients and then validated in a second dataset of 2222 cases who ingested any serotonergic agent (including the initial derivation dataset). ²⁴ However, the Hunter Serotonin Toxicity criteria ‘in the presence of a serotonergic agent’ have now been extrapolated to patients on stable doses of a serotonergic agent or serotonergic antagonist. Hence, patients with tachycardia, hyperthermia and/or hyperreflexia side effects of therapeutic agents are being diagnosed with ST. ²⁷ Although this may be reasonable if it is labelled as mild, it should not be the indication for specific treatment and only withholding or decreasing the dose of serotonergic medications.

FIGURE 2.

Hunter Serotonin Toxicity Criteria. Flow diagram based on the Hunter Serotonin Toxicity criteria. Source: Figure reproduced with permission from Isbister et al. 2007. ²⁴ , ²⁵

This is clearly demonstrated in a recent prospective study of 309 intensive care unit (ICU) patients (over 6 months) in which 24 (7.8%) were reported to have met the Hunter Serotonin Toxicity criteria. ²⁸ The most common symptom of the criteria met was tachycardia and hyperreflexia in 22 of the 24 cases. Ondansetron (peripheral 5‐HT3 antagonist) was listed as the most common ‘serotonergic’ agent. The authors noted that no patient received a diagnosis of ST by the treating physician, instead chronic obstructive lung disease, metabolic encephalopathy and septicaemia were the most common diagnoses. ²⁸ The authors concluded that ST is underdiagnosed, rather than recognizing the problems with using the Hunter Serotonin Toxicity criteria in a heterogenous patient population, not necessarily using serotonergic drugs. Similarly, an ‘unexpected’ or ‘high incidence’ of ST has been reported in unwell patients. ²⁹ Importantly, most had an alternative diagnosis to explain their tachycardia, hyperthermia or delirium, and often the most common ‘offending’ serotonergic agents were opioids (principally fentanyl) and antiemetics (ondansetron and metoclopramide) in therapeutic doses. ²⁹ This has led to recent suggestions that the Hunter Serotonin Toxicity criteria should be updated to include the clinical scenario, important differential diagnoses, rather than assigning causation to numerous agents which are not necessarily serotonergic (i.e., serotonin antagonists such as ondansetron and many anti‐psychotics). ¹³ The Hunter Serotonin Toxicity criteria are better utilized for diagnosis in moderate to high‐risk patients (i.e., overdose of a serotonergic agent or drug interaction), for which it was originally developed, while lower risk patients require more stringent criteria including the exclusion of alternative diagnoses and definitive ingestion of a serotonergic drug (Table 1). ¹³

TABLE 1.

Modified diagnostic criteria to diagnose clinically significant serotonin toxicity (the serotonin toxidrome).

Drug history	Serotonergic drug a poisoning/overdose OR drug–drug interaction of two serotonergic agents a	Initiation or increase in dose of a serotonergic agent or agent that decreases metabolism of serotonergic agent. This includes recreational drug use.	On a stable dose of a serotonergic medication. c
Clinical probability of ST given drug history	Very likely (high risk)	Likely (moderate risk)	Unlikely (other diagnosis much more likely)
Exclusion criteria		● Other aetiologies ruled out b ● A neuroleptic drug had not been started or increased in dosage prior to the onset of the signs and symptoms listed below.
ST criteria Patient must meet any one of these criteria.	● Spontaneous clonus ● Inducible clonus AND (agitation OR diaphoresis) ● Ocular clonus AND (agitation OR diaphoresis) ● Tremor AND hyperreflexia ● Hypertonic AND temperature >38°C AND (ocular clonus OR inducible clonus) ● Lower limb rigidity AND temperature >38°C	● Spontaneous clonus ● Inducible clonus AND (agitation OR diaphoresis) ● Ocular clonus AND (agitation OR diaphoresis) ● Tremor AND hyperreflexia ● Hypertonic AND temperature >38°C AND (ocular clonus OR inducible clonus) ● Lower limb rigidity AND temperature >38°C	● Spontaneous clonus ● Ocular clonus AND (agitation OR diaphoresis) ● Hypertonia/rigidity AND temperature >38°C AND (ocular clonus OR inducible clonus c )

^a Serotonergic agent that increases pre‐synaptic serotonin concentrations or amplifies serotonergic effects. Not a 5HT antagonist or agonists or peripheral 5HT agents, that is, ondansetron.

^b Other aetiologies such as infectious, metabolic, or endocrine, substance abuse or withdrawal. Concurrent assessment and management of other aetiologies and serotonin toxicity may be required.

^c This group requires a highly specific sign.

Abbreviation: ST, serotonin toxicity.

Source: Table reproduced with permission from Chiew et al 202213

Further concerns regarding the Hunter Serotonin Toxicity criteria extend to its potential inability to diagnose individuals with severe rigidity, which were not well represented in the derivation cohort. ³⁰ Although the full dataset revealed that individuals with severe, life‐threatening toxicity universally presented with severe rigidity compromising respiration, the criteria only included hypertonia as a clinical criterion alongside temperature and clonus. ²⁴ Extreme muscle rigidity might not always manifest as elicitable clonus or hyperreflexia. ³¹ , ³² Hence in those ingesting an MAOI and a serotonergic agent, it is important to recognize rigidity as a sign of severe toxicity (Table 1).

7. MANAGEMENT

There are often concerns that failure to recognize ST or misdiagnosis will result in a missed opportunity to administer a ‘lifesaving’ serotonin antagonist. However, what is more important is failure to understand the potentially rapid progression of ST and inadequately managing the rigid, hyperthermic patient, regardless of the cause. Even if the diagnosis remains unclear, the clinician should withhold serotonergic agents and provide aggressive supportive care, as with any patient with severe hyperthermia and muscle rigidity. ³³

Management of ST is determined by its severity (Figure 1). ⁴ Those with mild toxicity require reduction or cessation of serotonergic agents and symptomatic treatment with benzodiazepines. For those with moderate to severe toxicity, supportive care is imperative. Severe toxicity requires aggressive resuscitative care, active and rapid cooling, decreasing muscle activity (i.e., benzodiazepines, paralysis) and anticipating complications, particularly severe muscle rigidity impeding respiration. ²⁵ , ³⁴

Although often used, there is limited human data and no controlled studies examining the use of serotonin antagonists in the treatment of ST. The use of these in case reports is most commonly in patients with mild to moderate toxicity to alleviate symptoms. ²⁷ , ³⁵ , ³⁶ , ³⁷ Their clinical effect is likely due to their sedative actions, but they do not appear to decrease the duration of toxicity or underlying neuromuscular toxicity. ³⁸ Although some authors claim serotonin antagonists are to be used in severe toxicity or useful to confirm the diagnosis, this has never been shown. ³⁶ , ³⁹ , ⁴⁰ The focus of management should instead be on identifying those developing worsening or severe toxicity characterized by a rapidly rising temperature >39°C and muscle rigidity. ST will often resolve within 24 h of discontinuing the serotonergic agent and initiating supportive care. However, drugs with long half‐lives or active metabolites may cause more persistent symptoms in severe cases, and require a longer duration of sedation, paralysis and mechanical ventilation. ⁴¹

Benzodiazepines are commonly used in the management of ST for their anxiolytic and sedating properties. A retrospective study of 1010 ST patients from the ToxIC registry, an international database of prospectively collected cases seen by medical toxicologists, found the majority were treated with benzodiazepines 67% (n = 677) and only 15% (n = 153) with cyproheptadine. In this case series only 29 cases (3%) were documented to have hyperthermia (temp >40°C) and rigidity was reported in 140 (14%). ⁴² Rat studies have demonstrated that pre‐treatment with diazepam 10 and 20 mg/kg attenuated hyperthermia, but only delayed death, compared with potent 5‐HT2A antagonists. ¹¹ This means that benzodiazepines are useful for symptomatic treatment of mild to moderate ST, in which anxiety and agitation are the most clinically important features. In severe toxicity, more aggressive treatment is required, including paralysis and cooling. ⁶

Uncontrolled hyperthermia from drug toxicity is associated with significant morbidity and mortality, regardless of the aetiology. It can cause rhabdomyolysis, liver failure, disseminated intravascular coagulation and multi‐organ failure. ³⁴ In animal models, lowering temperature has been shown to indirectly downregulate 5‐HT2A receptors in the CNS and reduce overall serotonin concentrations. ⁴³ Management of toxin‐induced hyperthermia involves sedation to reduce muscle hyperactivity (intravenous benzodiazepines), active cooling (fans with water sprays, ice packs, cooling blankets or ice‐water submersion), and in severe cases paralysis and ventilation. ³⁴ In those patients with a temperature >39°C with agitation, an altered level of consciousness, rigidity or not responding to initial treatment to cool, early paralysis and intubation are essential. Furthermore, it should not be assumed that all hyperthermic responses from less specific ‘serotonergic drugs’ are mediated by 5‐HT2A receptors. Hyperthermia associated with methylenedioxymethamphetamine (MDMA), for example, has shown to be more responsive to a D1 dopamine antagonist than a 5‐HT2A antagonist. ⁶ , ⁴⁴

8. SEROTONIN ANTAGONIST

As 5‐HT2A receptor activation is implicated in severe ST, various 5‐HT2A receptor antagonists have been proposed for its management. However, the data are limited to animal studies and human data to case reports and retrospective case series. Cyproheptadine and chlorpromazine have been the most researched, but other 5‐HT2A receptor antagonists such as olanzapine and risperidone have also been used clinically.

The affinity for these agents to bind to the 5‐HT2A receptors varies greatly (Table 2) with sertindole, ketanserin and risperidone having the greatest affinity for 5‐HT2A receptors. However, sertindole and ketanserin have only been used experimentally in animals, and are not available for human use. The other clinically available drugs chlorpromazine and cyproheptadine have less affinity for the 5‐HT2A receptors. ³⁶ All these drugs show an affinity for the 5‐HT1A receptors two to three orders of magnitude less than the 5‐HT2A receptor. ⁴⁵

TABLE 2.

Blockade of 5‐HT2A receptors by various drugs.

Drug	Affinity at 5HT2A
Cyproheptadine	100
Chlorpromazine	71
Olanzapine	25
Risperidone	170
Ketanserin a	178
Sertindole a	260

Note: Affinity = 10⁻⁷ × 1 / Kd, where Kd = equilibrium dissociation in molarity.

^a Used experimentally in animals (adapted from Gillman ³⁶ ).

Despite limited evidence, many have suggested that the administration of 5‐HT2A serotonin antagonists is ‘warranted’ even in suspected cases of ST, as empiric treatment, ²⁸ , ⁴⁶ or used in cases of severe toxicity as ‘lifesaving’ antidotes. ⁴⁷ Even more problematic is when these agents are utilized to confirm the diagnosis of ST. It is important to evaluate the evidence for these agents, such as what percentage of 5‐HT2A receptor blockage is required to alleviate symptoms or prevent hyperthermia or death, what percentage blockade these agents achieve, the time to onset of antagonism and does it improve clinical outcomes (i.e., mortality, complications, length of stay or symptoms)?

8.1. Animal Data

Animal studies, predominantly in rats, have explored 5‐HT2A receptor antagonists for ST. ⁷ , ¹² These have shown that blocking 85%–90% of 5‐HT2A receptors is necessary to prevent ST‐related hyperthermia and death. ⁷ Nisijima et al. tested various treatments for severe ST in rats, including pimpamperone (20 mg/kg) and ritanserin (3 mg/kg), potent 5HT2A receptor antagonists, cyproheptadine (5 and 10 mg/kg), chlorpromazine (20 and 40 mg/kg), propranolol (5HT1A antagonist), and dantrolene (20 mg/kg). ¹² All drugs were administered intraperitoneally 15 min prior to serotonergic agent administration. Ritanserin and pimpamperone prevented death and hyperthermia, with lower noradrenaline increases compared to placebo, whereas chlorpromazine (20 mg/kg), cyproheptadine (5 mg/kg), dantrolene and propranolol did not prevent death, and all rats developed hyperthermia to 40°C and high noradrenaline concentrations. At higher doses of cyproheptadine (10 mg/kg) and chlorpromazine (40 mg/kg), the rats survived. Hence these animal studies demonstrate if administered prior to the serotonergic agent, only after very high doses is substantial receptor blockade achievable to prevent death. ¹²

8.2. Human Data

8.2.1. Cyproheptadine

Cyproheptadine, a first‐generation histamine‐1 receptor blocking agent with non‐specific antagonist properties at 5‐HT1A and 5‐HT2 receptors, is only available orally. Definitive evidence of its effectiveness is lacking, with limited data from case reports and series. Dosage variation and inconsistent outcomes are notable, with no clear association between cyproheptadine administration and improved medical outcomes or reduced length of symptoms. ²⁷ , ²⁸ , ³⁸ , ⁴² , ⁴⁶ There are multiple reports of patients with mild to moderate toxicity, treated with cyproheptadine with resolution of symptoms in 1–2 h. ³⁵ , ³⁷ However, initial doses administered vary greatly, typically from 4 to 12 mg and even higher doses have been given. ³⁵ , ³⁷ However, there are cases receiving 16 mg with no response ³⁶ and cases of fatality despite cyproheptadine. ⁴⁸ Or cases with severe toxicity having maximal resuscitative care (i.e., intubation, cooling, other sedative agents) and an effect often attributed to cyproheptadine. ³⁶ , ⁴⁹ The large variation in response may be attributed to a variety of factors including: the spectrum of toxicity treated, the variable levels of 5‐HT2A receptor blockade needed to alleviate symptoms and the initial recommended dose of cyproheptadine (typically 12 mg may be suboptimum to achieve adequate 5‐HT2A receptor blockade and that doses of about 30 mg are required). ³⁶ , ⁵⁰

In ST studies, less than 15% received serotonin antagonists. ²⁴ , ⁴² Only one study has attempted to examine the difference in outcomes in those receiving cyproheptadine versus those who did not, for ST. ³⁸ Nguyen et al. conducted a retrospective review of 288 probable ST cases over 11.5 years, of which 68 received cyproheptadine and 220 did not, despite 138 recommendations to administer cyproheptadine. The most common ingested agents were SSRIs (56%), SNRIs (21%), and atypical antipsychotics (18%). Eight deaths occurred (two received cyproheptadine), with all patients receiving other supportive therapies like benzodiazepines, IV fluids, intubation and sedation. There was no significant association between cyproheptadine administration and serious medical outcomes or hospitalization. ³⁸

Overall, the use of cyproheptadine in life‐threatening ST lacks compelling evidence over aggressive supportive care measures. It may provide symptomatic relief in mild to moderate toxicity but its benefit over other supportive care has not been proven. Currently there is no evidence that its use in life threatening toxicity is of any benefit over aggressive resuscitative care.

8.2.2. Other 5HT2A antagonist (chlorpromazine and olanzapine)

A major limitation of cyproheptadine use in the severely affected patient is that it is only available as an oral preparation, hence, the recommendation to use chlorpromazine as a 5HT2A antagonist because it can be given parenterally. However, evidence of its effectiveness is limited to case reports, which have detailed alleviation of symptoms soon after administration in patients with moderate toxicity. ³⁶ , ³⁷ , ⁴⁷ , ⁵¹ , ⁵² Doses used vary from 12.5 to 100 mg intramuscular or intravenously. ³⁶ In cases of severe toxicity, the response has been variable with reports of good and poor responses and deaths despite use of chlorpromazine. ³⁶ , ⁵³ The main adverse effects are hypotension and sedation. Many guidelines recommend the use of intravenous chlorpromazine in severe toxicity but there is very limited evidence (animal only) to support whether it has a benefit over good supportive care and whether it can improve hyperthermia or rigidity. Similarly to cyproheptadine, its use may be to alleviate symptoms in moderate cases, but this has yet to be demonstrated in human studies. The use of olanzapine (5 to 10 mg) for ST has been reported in even fewer cases than cyproheptadine and chlorpromazine. ⁵⁴

9. CONCLUSION

The important aspect in managing ST is recognizing its potential for rapid progression and adequately treating severe symptoms, such as hyperthermia and muscle rigidity, irrespective of the underlying cause. While there is often a concern regarding the missed opportunity of administering serotonin antagonists, the focus should be on providing aggressive supportive care, benzodiazepines, treating complications and withholding serotonergic agents. Management strategies are determined by the severity of toxicity, with mild cases typically requiring cessation of serotonergic agents and symptomatic treatment, and severe cases necessitating intensive supportive care, including rapid cooling and muscle activity reduction. Despite their frequent use, serotonin antagonists like cyproheptadine lack definitive evidence of effectiveness, and their role in improving outcomes remains uncertain. Furthermore, the variability in dosing and response to cyproheptadine underscores the need for cautious interpretation of its efficacy. The management of ST should prioritize aggressive supportive care over empiric use of serotonin antagonists, with further research needed to establish their role in improving patient outcomes in those with moderate to severe toxicity.

CONFLICT OF INTEREST STATEMENT

The authors report no conflicts of interest.

Chiew AL, Isbister GK. Management of serotonin syndrome (toxicity). Br J Clin Pharmacol. 2025;91(3):654‐661. doi: 10.1111/bcp.16152