Serotonin syndrome: a clinical review of current controversies

Serotonin syndrome is a state of increased central and peripheral serotonin (5-hydroxytryptamine) activity. Unless recognized and treated early, serotonin syndrome can lead to seizures, shock and death. Both substances with direct and indirect serotonergic activity can precipitate the syndrome. Serotonin syndrome can occur not only in psychiatric but also in non-psychiatric settings. Yet, clinicians may not be familiar with the condition. We explore some of the current controversies regarding serotonin syndrome. Specifically, we tested the following assumptions: (i) Despite being rare, serotonin syndrome is still clinically relevant; (ii) The Hunter criteria are the gold standard for diagnosing serotonin syndrome; (iii) Hyperthermia is common in cases of serotonin syndrome; (iv) Serotonin syndrome usually develops fast; (v) Severe serotonin syndrome usually or almost exclusively involves monoamine oxidase inhibitors. We found that (i) despite being rare, serotonin syndrome was clinically relevant, (ii) the Hunter criteria could not be regarded as the gold standard for the diagnosis of serotonin syndrome since they missed more cases than the other two diagnostic criteria systems (Sternbach and Radomski criteria), (iii) Serotonin syndrome could occur in the absence of an elevated temperature, (iv) fast onset could not be regarded as a reliable clinical sign of serotonin syndrome, and (v) absence of monoamine oxidase inhibitors treatment did not exclude a diagnosis of serotonin syndrome. Clinicians should bear in mind that in the context of relevant drug history, serotonin syndrome may still be possible in these circumstances.


Introduction
Serotonin syndrome (SS) is a state of increased central and peripheral serotonin (5-hydroxytryptamine) activity.It is a toxic state, most likely caused by stimulation of 5HT1A and 5HT2Areceptors in the central nervous system (CNS) (Boyer and Shannon, 2005).This toxic state can lead to extreme neuromuscular hy-perexcitability.Unless recognized and treated early, SS can lead to seizures, shock and death (Boyer and Shannon, 2005).Although serotonergic drugs are commonly used, SS is rare.Hence, it is not easily picked up in randomized controlled trials.Although SS can occur in psychiatric and non-psychiatric settings, physicians may not be familiar with this condition.One study from the UK showed that 85% of primary care physicians were not familiar with SS (Mackay et al., 1999).Primary care physicians often prescribe serotonergic drugs.Still, they are unlikely to witness SS in a clinic.Affected patients are much more likely to present to emergency services (Boyer and Shannon, 2005).
There is no gold-standard diagnostic test for SS.The diagnosis of SS is purely clinical.The diagnosis depends on signs and symptoms, identified through physical examination and history of exposure to serotonergic agents.There are three diagnostic criteria systems, Sternbach, Radomski and Hunter.All three criteria systems consider neuromuscular, autonomous and cognitive symptoms, albeit to a varying degree (Dunkley et al., 2003;Radomski et al., 2000;Sternbach, 1991) (Table 1).According to the developers, the Hunter criteria are superior to the Sternbach criteria (Dunkley et al., 2003).Hence, the Hunter criteria have widely been recommended as the gold standard of SS (Boyer and Shannon, 2005;Buckley et al., 2014).However, their superiority may have been substantially overstated.Therefore, we have challenged the notion that the Hunter criteria are the gold standard for the diagnosis for SS in previous work (Werneke et al., 2016).
All three criteria systems demand the presence of a serotonergic agent, without specifying this term further.The Sternbach and Radomski criteria also require the absence of a neuroleptic agent.Even this term, the respective developers did not specify further.Often, "neuroleptics'' is used interchangeably with "antipsychotics''.In the context of SS, this poses a dilemma with clozapine and second-generation antipsychotics, some of which act as 5HT2 antagonists, whereas others act as 5HT1A agonists (Schwartz and Stahl, 2011).As Sternbach and Radomski's criteria were developed before second-generation antipsychotics became mainstream, the requirement of absence of a neuroleptic agent may be above all applied to first-generation antipsychotics except clozapine (Werneke et al., 2016).It is acknowledged that a wide range of substances may cause SS (Table 2).However, the uncer-Table 1. Sternbach, Radomski and Hunter diagnostic criteria for the diagnosis of serotonin syndrome (Dunkley et al., 2003;Radomski et al., 2000;Sternbach, 1991).

Sternbach criteria Radomski criteria Hunter criteria
Co-incidence with the addition of or increase in a known serotonergic agent to an established medication regimen, at least three of the following features present: Co-incidence with the addition or increase in a known serotonergic agent (to an established treatment regimen), and the development of at least four major or three major plus two minor symptoms: In the presence of a serotonergic agent and either

Clinical features, not an integral part of the underlying psychiatric disorder before commencing the serotonergic agent.
A neuroleptic drug had not been started or increased in dosage before the onset of the signs and symptoms listed above.
Other etiologies (e.g., infectious, metabolic or endocrine, substance abuse or withdrawal) have been ruled out.A neuroleptic drug had not been started or increased in dosage before the onset of the signs and symptoms listed above.* Incoordination and uncoordination are used interchangeably in the literature.
tainty about SS's exact pathophysiological mechanism has led to a controversy regarding which substances exactly can precipitate SS.For instance, it has been suggested that that severe SS "usually'' (Buckley et al., 2014;Isbister and Buckley, 2005) or "almost exclusively'' (Foong et al., 2018;Isbister and Buckley, 2005) involves monoamine oxidase inhibitors.

Methods
For this review, we used three methods: (i) a literature review, (ii) calculation of the expected number of SS cases per year from published statistics concerning antidepressant use, and (iii) quantitative analysis of a database of published SS cases collated from a previously conducted systematic review (Ott et al., 2019;Werneke et al., 2016;Wikström, 2019).

Literature review
We performed a literature search using the PubMed/Medline and Web of Science databases, using the search terms "serotonin syndrome'' and "serotonin toxicity'', "diagnostic criteria'', and "hyperthermia''.

Calculation of the expected number of serotonin syndrome cases per year
To assess SS's clinical relevance, we calculated the expected number of SS cases in several countries worldwide, for whom updated statistics on antidepressant use were available from the Organization of Economic Collaboration and Development (OECD).The OECD uses defined daily doses (DDD) of antidepressants (Code N06A according to the Anatomical Therapeutic Chemical (ATC) Classification System) per 1000 inhabitants per day 1 .DDDs provide an estimate of the proportion of a population treated daily with a particular drug or drug class.For instance, a DDD of 10/1000 inhabitants per day for a particular drug can be interpreted as 1% (10/1000) inhabitants receive this particular drug each day in that year.DDDs are most useful for drugs used chronically with a good agreement between the average prescribed daily dose (PDD) and DDD (WHO) 2 .The WHO states that DDDs only give  "a rough estimate of consumption and not an exact picture of actual use''3 .The WHO endorsed the ATC/DDD methodology for global use in 1996 as an international standard for drug utilization studies 3 .
Our estimate for the incidence of SS was based on US insurance claims data collated between 2008 and 2013 from two national datasets, (i) the Veterans Health Administration (VHA) dataset and (ii) the Intercontinental Marketing Services PharMetrics Plus (IMS) dataset (Nguyen et al., 2017).To determine the minimum and the maximum number of SS cases to be expected, we used the maximum and minimum incidence figures for 2013.We multiplied these with the estimated number of patients per year taking antidepressants.

Quantitative analysis of a database of published cases
To establish the causes of severe SS, we used our database of SS cases obtained from a systematic review of cases published on PubMed/Medline or Web of Science between 1 January 2004 and 31 December 2018.We used 1 January 2004 as a starting point because all three diagnostic criteria systems for SS had become available by that time.We used the search terms "serotonin syndrome'' or "serotonin toxicity'' to identify cases.We counted as severe cases that had either resulted in (i) intensive care, (ii) intubation, (iii) coma, or (iv) death.We analyzed the following variables: (i) symptoms associated with severe SS, (ii) speed of onset of SS, and (iii) substances thought to have precipitated severe SS.For a potential association between monoamine oxidase inhibitors (MAOI) and severe SS, we also calculated odds ratios (OR) and 95% confidence intervals (CI).The systematic review method underlying this database has been published in detail elsewhere (Ott et al., 2019;Werneke et al., 2016;Wikström, 2019).

Despite being rare, SS is still clinically relevant
The prevalence of SS remains unknown.Our best estimates stem from a US insurance claims study.In this retrospective cohort study of 15 million patients exposed to at least one serotonergic agent, the incidence for SS lay between 0.9 and 2.3/1000 individuals exposed in 2013 (Nguyen et al., 2017).The absolute number of cases may vary widely across the world, depending on the population size of a respective country.For instance, each year, there may only be three to six cases in Latvia, a country with a small population and low antidepressant use.However, there may be hundreds or up to a thousand cases per year in countries with large populations and/or high antidepressant use, such as Turkey, Germany or Canada (Table 3).Therefore, although SS is rare in relative terms, the number of cases can be substantial in absolute terms.This makes SS a clinically relevant condition.

The Hunter criteria are the gold standard for diagnosing SS
Our updated systematic review of published SS cases expanded our database from 299 to 412 cases collated from 350 articles.Of all 412 cases, 42% (173) had resulted in severe SS.Of all 173 severe cases, 13% (22) resulted in death.Our updated database's re-analysis showed that of all 412 SS cases, the Hunter criteria would have missed 37%.The Sternbach criteria would have missed 10%, and the Radomski criteria 24%.Of all 173 severe cases, the Hunter criteria would have missed 36%, and the Sternbach criteria would have missed 8% and the Radomski criteria 11%.In terms of missing cases SS overall and severe SS cases, the Hunter criteria performed worse than the Sternbach and Radomski criteria.

Hyperthermia is common in cases of SS
Our updated systematic case review, including only the 234 cases for whom a temperature was explicitly mentioned, 36% did not have a temperature > 38 • C (100.4 • F).Of the 128 severe cases with a temperature explicitly mentioned, 27% did not have a temperature > 38 • C (100.4 • F).Hence, SS can occur in the absence of an elevated temperature, even in severe course cases.

SS usually develops fast
Information on the onset speed was available for 314 of the 412 cases in the total sample and 122 of the 173 severe cases.Of the 314 cases in the total sample, 115 concerned surgical procedures, trauma care, overdoses or substance misuse and 199 concerning medical or psychiatric treatments.In the 115 cases relating to surgical procedures, trauma care, overdoses or substance misuse, 51% of all SS episodes presented within six hours and 17% after 24 hours.In the 199 cases relating to medical or psychiatric cases, 12% of all SS episodes presented within six hours and 65% after 24 hours.Of the 122 severe SS cases, 75 concerning surgical procedures, trauma care, overdoses or substance misuse and 47 concerning medical or psychiatric treatments.In the 75 severe cases relating to surgical procedures, trauma care, overdoses or substance misuse, 60% of all SS episodes presented within six hours and 9% after 24 hours.In the 47 severe cases relating to medical or psychiatric cases, 11% of all SS episodes presented within six hours and 62% after 24 hours.Our findings suggest that the speed of onset seems to depend on pharmacokinetic and pharmacodynamic factors.Therefore, fast onset cannot be regarded as a reliable clinical sign of SS.

Severe SS usually or almost exclusively involves MAOI
We explored this further using our updated systematic case review.We identified the top ten causes of severe SS as associated with any of the three diagnostic criteria systems and determined MAOI involvement for each cause.Of the 173 severe SS cases diagnosed by any of the three diagnostic criteria systems, only 41% (71) involved MAOI (Table 4).The odds ratio for MAOI involvement was 3.68 (CI 2.32-5.83;P < 0.001).As expected, most cases related to non-selective or selective MAOI-A inhibitors.Thus, our data confirm that MAOI is indeed significantly more frequently implicated in severe SS.But the absence of MAOI treatment does not exclude a diagnosis of SS.

Discussion
In this review, we have challenged five commonly held assumptions about serotonin syndrome.We showed that (i) despite being rare, SS was still clinically relevant, (ii) the Hunter criteria could not be regarded as the gold standard for the diagnosis of SS since they missed substantial numbers of cases, (iii) SS could occur in the absence of an elevated temperature, (iv) fast onset could not be regarded as a reliable clinical sign of SS, and (v) absence

The origin of the three diagnostic criteria sets for serotonin syndrome
To understand why the Hunter criteria achieved gold standard status for the diagnosis of SS, it is helpful to recall how all three diagnostic criteria systems came about.The Sternbach criteria were developed in 1991, based on 38 psychiatric cases (Sternbach, 1991).In 2000, Radomski et al. (2000) suggested a new classification building on Sternbach criteria.They expanded the underlying evidence to 62 cases, adding 24 further published cases.They also suggested that symptoms should be divided into major and minor symptoms.Radomski et al. (2000) added rigidity (hypertonicity) as a major criterion and insomnia, dilated pupils, tachycardia, tachy-or dyspnea, diarrhea, and hyper-hypotension as minor criteria.Uncoordination was another minor symptom in Radomski criteria, corresponding to the criterium of incoordination in the Sternbach criteria.Radomski et al. (2000) recognized that SS varied in severity and might manifest itself as mild, fullblown and toxic states.A third classification system, the Hunter criteria, was proposed in 2003.The Hunter criteria were derived from 473 cases of single serotonin-reuptake inhibitor (SSRI) overdoses.The derived criteria were then tested (validated) on 2222 cases of overdoses with any serotonergic drug.Prior to the validation exercise, rigidity was added as an additional symptom.The Hunter criteria firmly shifted SS's focus to neuromuscular symptoms, particularly to clonus in various forms (Dunkley et al., 2003).

Taking diagnostic criteria to the test
The variability of symptoms between the three diagnostic systems has raised which system is the best.One major concern of the Sternbach criteria has been their potentially low specificity.For instance, a possible symptom constellation could consist of mental status changes, agitation and fever.This constellation is commonly found in many medical conditions.Yet, it is important to remember that the Sternbach criteria require the presence of a serotonergic agent, absence of a neuroleptic agent and the ruling out of other possible etiologies.
According to their developers, the Hunter criteria have better sensitivity and specificity than the Sternbach criteria (Dunkley et al., 2003).Therefore, the Hunter criteria have widely been recommended as the gold standard of SS (Boyer and Shannon, 2005;Buckley et al., 2014), but their sensitivity and specificity may have been substantially overstated.The derivation dataset, from which the Hunter criteria were generated, was also part of the validation data set, on which the Hunter criteria then were tested.21% of all cases in the validation dataset had also been used to derive Hunter criteria.Given the magnitude of potential bias, the claim that Hunter criteria were more sensitive (84% vs. 75%) and more specific (97% vs. 96%) (Dunkley et al., 2003) than Sternbach criteria cannot be upheld (Werneke et al., 2016).Only re-analysis of the original validation set with the derivation cases' exclusion could unambiguously settle this question.The developers of the Hunter criteria themselves point out that their criteria would require validation in other settings (Dunkley et al., 2003).This, to our knowledge, has not occurred.Another concern is the exclusive reliance of Hunter criteria on overdoses for derivation and validation.In overdoses, symptoms are likely to be much more clearcut and severe.Other cases with more discrete symptoms may be missed (Werneke et al., 2016).The Hunter criteria requirement of the presence of clonus in its various forms or a combination of tremor and hyperreflexia for SS diagnosis may also be too narrow.For instance, patients who have developed substantial rigidity may have become too constrained in their ability to move (Boyer and Shannon, 2005).Clonus and hyperreflexia may not be visible in patients in whom peripheral polyneuropathy masks upper motor neuron signs (Prakash et al., 2014).
There is substantial variability of symptoms sampled in the three classification systems.Of all symptoms, five symptoms appear in all three criteria sets.Seven are shared by two of the three criteria sets.Six symptoms are only found in one of either diagnostic criteria set.In our previous systematic review of 299 SS cases, we showed that agreement beyond chance lacked between the Hunter and Sternbach criteria and between the Hunter and Radomski criteria (Werneke et al., 2016).

Understanding the core symptoms of serotonin syndrome
Some symptoms, such as clonus, myoclonus and hyperthermia, require particular attention since their definitions can be ambiguous.

Clonus or myoclonus?
Clonus, the defining symptom of Hunter's criteria, is not included in the other two systems.The Sternbach and Radomski criteria list myoclonus instead (Radomski et al., 2000;Sternbach, 1991).Sometimes, the terms "clonus'' and "myoclonus'' are used interchangeably and incorrectly.Both symptoms are an expression of neuronal hyperexcitability.Yet, they are not the same.Myoclonus relates to brief, sudden contractions of agonist and antagonist muscles.Such can originate at any level of the CNS (Lozsadi, 2012).Clonus, however, relates to rhythmic muscle contraction as an exaggerated stretch reflex.The cause of clonus is unknown but tends to be associated with upper motor neuron lesions and hyperreflexia (Boyraz et al., 2016;Zimmerman et al., 2020).In practice, both myoclonus and clonus are often referred to as "jerks''.This highlights the need to describe symptoms accurately and correctly.If "strange jerking movements'' are interpreted as clonus, a case

Elevated body temperature -the cut-off point
There is no single cut-off point for elevated body temperature.Body temperature is subject to individual variability.The temperature recorded may also depend on the measurement method and timing.Rectal temperature tends to be about 0.5 • C (0.9 • F) higher than an oral temperature (Bijur et al., 2017).Afternoon temperature may, on average, be 0.3 • C (0.5 • F) higher than morning temperature (Harding et al., 2019).In women, ovulation also increases temperature between 0.28 • C (0.5 • F) and 0.56 • C (1.0 • F) in the second half of the menstrual cycle (Shilaih et al., 2018).Environmental factors may also change body temperature.A large study of 35488 patients presenting at a routine outpatient appointment examined the variability of normal body temperature.Patients presenting out of hours, suffering from an infection or receiving antibiotics were excluded.In this study, the mean temperature was 36.6 • C (97.9 • F), with a 95% range from 35.7 • C (96.3 • F) to 37.3 • C (99.1 • F), and a 99% range from 35.3 • C (95.5 • F) to 37.7 • C (99.9 • F) (Obermeyer et al., 2017).The Sternbach criteria and Radomski criteria do not give a cut-off point for elevated temperature (Radomski et al., 2000;Sternbach, 1991).The Hunter criteria refer to a temperature > 38 • C (100.4 • F) (Dunkley et al., 2003).The problem of temperature definition also arises in the context of severe SS.Again, the Sternbach and Radomski criteria do not offer any cut-off point (Radomski et al., 2000;Sternbach, 1991).Radomski et al. (2000) suggest that in severe states, the temperature can exceed 40 • C (104 • F).In their discussion of the Hunter criteria, Dunkley et al. suggest that a temperature ≥ 38.5 • C (101.3 • F) indicates severe serotonin toxicity (Dunkley et al., 2003).Finally, Boyer and Shannon (2005) suggest core temperatures as high as 40 • C (104 • F) in SS of moderate severity.In life-threatening cases, core temperatures of ≥ 41.1 • C (106 • F) may occur.

Elevated body temperature -fever, hyperpyrexia or hyperthermia?
Elevated temperature is not only a matter of degree but also of nature.Generally speaking, core temperature is regulated by the hypothalamus.Still, causes for elevated temperature may differ.Two pathophysiological mechanisms lead to elevated body temperature.Hyperpyrexia refers to a high body temperature in the context of a pyrogen-mediated upregulation of the hypothalamic thermostat.Pyrogens, such as bacterial lipopolysaccharides, interleukin 1 or tumor necrosis factor α induce prostaglandin E2.These pyrogens raise the temperature set-point in the anterior hypothalamus.Hyperthermia, however, does not involve any pyrogens.Hyperthermia is a state of uncontrolled heat production and/or impaired heat dissipation without any upregulation of the hypothalamic thermostat (Rehman and deBoisblanc, 2014).Whether the elevated temperature is due to hyperpyrexia, i.e., high fever, or hyperthermia is not only theoretical but also of practical relevance.It is crucial for the choice of method for temperature reduction.
In SS, the elevated temperature is thought to arise from uncontrolled heat production, i.e., hyperthermia.Here, the hyperthermia is thought to be due to increased muscle activity.This results from hyperexcitability and direct serotonergic effects on the muscle (Boyer and Shannon, 2005;Rehman and deBoisblanc, 2014;Wappler et al., 2001).The 5HT2 receptor's role has been suggested since 5HT2 antagonists have been shown to prevent hyperthermia in animal experiments (Isbister and Whyte, 2002).As pyrogens are not at play, the elevated temperature may not be reducible by antipyretic drugs.Instead, treatment requires physical cooling measures.
The term fever, albeit confined to hyperpyrexic states, is often used loosely.For instance, Sternbach (1991) uses the term "fever'' for his criteria.Contextually though, it becomes clear hyperthermia is meant.Radomski et al. (2000), building on the Sternbach criteria, also refer to fever.The Hunter criteria refer to a temperature > 38 • C (Dunkley et al., 2003).Notably, the absence of hyperthermia does not exclude SS.

Time to onset: fast or slow?
It has been generally accepted that-SS develops fast (Boyer and Shannon, 2005).In our previous work, we have already put this claim in question (Werneke et al., 2016).Our results show that the speed of onset of SS depends on drug administration and dose.SS may develop fast in the context of overdoses or in surgical or intensive care settings, in which serotonergic agents may be administered quickly.SS may develop slowly in medical and psychiatric settings, in which serotonergic drugs are often slowly introduced or cross-tapered.

Substances associated with serotonin syndrome
All three diagnostic criteria systems require the presence of a serotonergic agent without giving a specific definition (Dunkley et al., 2003;Radomski et al., 2000;Sternbach, 1991).Pragmatically, a serotonergic agent may be defined as a substance capable of leading to excess serotonin activity (Boyer and Shannon, 2005).Sternbach (1991) and Radomski et al. (2000) suggested that SS might be due to activation of the central 5HT1A receptor based on animal experiments findings.Other evidence from animal experiments has pointed towards 5HT2A agonism (Isbister and Whyte, 2002;Nisijima et al., 2000).This is further supported because cyproheptadine, an antihistamine with strong 5HT2 antagonistic effects (Kapur et al., 1997), is recommended for the treatment of SS (Boyer and Shannon, 2005).This implies that the withdrawal of substances with 5HT2 antagonistic properties could also cause SS (Harmouche, 2018;Stevenson et al., 2013).Ultimately though, no single receptor seems to be responsible for the development of SS (Boyer and Shannon, 2005).Serotonin toxicity may be caused by an increase in serotonin's intrasynaptic concentration in the central nervous system (CNS) (Dunkley et al., 2003).
Clinicians may associate serotonergic drugs with mainly psychiatric treatments.However, many other substances also have serotonergic properties, including somatic medicines, recreational drugs and complementary remedies (Table 2) (Boyer and Shannon, 2005;Buckley et al., 2014;Truedson et al., 2020).For instance, some opiates, such as pethidine (meperidine) and tramadol, can inhibit serotonin reuptake.Not only some antidepressants but also several somatic medicines can act as MAOI, either type A or type B. Examples of MAOI-A include methylene blue and linezolid.Methylene blue is used to treat methemoglobinemia and as a contrast dye used in specific surgical procedures.Linezolid is used as an antibiotic against methicillin-resistant Staphylococcus aureus (MRSA).Examples of MAOI-B include selegiline (L-deprenyl), rasagiline, and safinamide to treat Parkinson's disease.

Severe serotonin syndrome and monoamine oxidase inhibitors
In our results, we have challenged the assumption that severe SS "usually'' (Buckley et al., 2014;Isbister and Buckley, 2005) or "almost exclusively'' (Foong et al., 2018;Isbister and Buckley, 2005) involves MAOI.MAOI are classified according to three pharmacological criteria, (i) affinity to subtype of the enzyme (isoenzyme), (ii) selectivity, and (iii) reversibility (Table 5).There are two forms of MAO, MAO-A and MAO-B.Both MAO-A and MAO-B metabolize dopamine and tyramine.However, MAO-A is relatively selective for the metabolism of norepinephrine and serotonin (Lotufo-Neto, 1999) with an about ten-fold higher affinity for serotonin than MAO-B (Finberg, 2014).Reversibility refers to the ease with which the MAOI can be displaced from the enzyme.Irreversible MAOI cannot be displaced from the enzyme.They essentially stay put for the lifetime of the molecule of about 14 to 28 days and deactivate the enzyme during this time (Lotufo-Neto, 1999).Reversible MAOI may clear the enzyme within a day.For instance, for moclobemide, a reversible MAOI-A, MAO-A inhibition rises to 80% within two hours of administration and lasts between eight and ten hours.After 24 hours, the MAO-A activity is completely restored.Judged on the pharmacological properties alone, irreversible MAOI with a high affinity for MAO-A, irrespective of selectivity, will carry the highest risk of SS, followed by reversible MAOI-A.Reversible MAOI-B should carry the lowest risk of SS.
Despite non-selective and selective MAOI-A having strong serotonergic properties, there is no logical reason why other serotonergic drugs could not cause SS.Neither were the three diagnostic criteria exclusively derived from MAOI.In the original 38 Sternbach criteria cases, 85% involved MAOI.However, the Hunter criteria were derived from single SSRI overdoses with any cases due to other serotonergic drugs being expressly excluded.The Hunter criteria added rigidity prior to the validation to not miss severe cases with rigidity in whom clonus or hyperreflexia was not demonstrable (Dunkley et al., 2003).These may most likely have included some SS cases caused by MAOI.Generally, SS may occur when levels of serotonin rise.Levels can rise with dose increases, the addition of serotonergic drugs or withdrawal of serotonin antagonists.Hyperserotonergic states can even arise with impairment of metabolism (e.g., via cytochrome P 450 system) or elimination (Ott et al., 2019).

Conclusions
The diagnosis of SS is based on clinical symptom constructs rather than an objective gold standard.Our understanding of the pathophysiological mechanism behind SS remains limited.As SS is rare, it is challenging to study.The three currently available diagnostic criteria systems only partly overlap and agree with each other.More work is needed to improve the method for diagnosing SS to increase sensitivity and specificity.Higher sensitivity minimizes false negatives and hence the likelihood of missing SS and its potentially life-threatening consequences.Higher specificity minimizes false positives so that clinicians do not unnecessarily withhold medications patients need.Equally, our current limited understanding of the underlying pathophysiology has led to a controversy concerning the substances that could cause SS.Serotonergic substances other than MAOI may more frequently be involved than commonly suggested.Clinicians should bear in mind that in the context of relevant drug history, SS may still be a differential diagnosis even (i) it is a rare occurrence, (ii) the Hunter criteria are not met, (iii) there is no elevated temperature, (iv) the onset is slow, and (v) MAOI are not involved.

Table 3 . Antidepressant use (ACT code N06A) and expected number of cases of serotonin syndrome per year (Nguyen et al., 2017). Country Antidepressant users in Population size Patients using Expected number of cases of serotonin syndrome based on % of the population a in millions antidepressants (×1000) incidence number/1000 exposed to serotonergic agents b
Nguyen et al. 2017he Organization for Economic Cooperation and Development (OECD), estimated from defined daily dose (DDD) /1000 inhabitants per day.https://stats.oecd.org/Index.aspx[accessedOctober28].bEstimated byNguyen et al. 2017: Minimum incidence: 0.9/1000 , maximum incidence: 2.3/1000 c Provisional d Break in statistical time series.Such occurs when there is a change in the standards for defining and observing a variable over time.e Estimate f Difference in methodology of MAOI treatment did not exclude a diagnosis of SS.

Table 5 . Commonly used monoamine oxidase (MAO) inhibitors by subtype, selectivity and reversibility.
Not clear from the literature.maymeet Hunter's criteria.If "strange jerking movements'' are interpreted as myoclonus, though, a case may meet the Sternbach or Radomski criteria, but not the Hunter criteria.