Serotonin syndrome controversies: A need for consensus

Abstract

Serotonin syndrome (SS) is a drug-induced clinical syndrome resulting from increased serotonergic activity in the central nervous system. Although more than seven decades have passed since the first description of SS, it is still an enigma in terms of terminology, clinical features, etiology, pathophysiology, diagnostic criteria, and therapeutic measures. The majority of SS cases have previously been reported by toxicology or psychiatry centers, particularly in people with mental illness. However, serotonergic medications are used for a variety of conditions other than mental illness. Serotonergic properties have been discovered in several new drugs, including over-the-counter medications. These days, cases are reported in non-toxicology centers, such as perioperative settings, neurology clinics, cardiology settings, gynecology settings, and pediatric clinics. Overdoses or poisonings of serotonergic agents constituted the majority of the cases observed in toxicology or psychiatry centers. Overdose or poisoning of serotonergic drugs is uncommon in other clinical settings. Patients may develop SS at therapeutic dosages. Moreover, these patients may continue to use serotonergic medications even if they develop mild to moderate SS due to several reasons. Thus, the clinical presentation (onset, severity, and clinical features) in such instances may not exactly match what toxicologists or psychiatrists observe in their respective settings. They produce considerable diversity in many aspects of SS. However, other experts discount these new developments in SS. Since SS is a potentially lethal illness, consensus is required on several concerns related to SS.

Key Words: Serotonin; Serotonin syndrome; Serotonin toxicity; Selective serotonin reuptake inhibitors; Antidepressants; Cyproheptadine

Core Tip: Many recent papers have highlighted new developments in serotonin syndrome (SS). New clinical findings and clinical scenarios have emerged. Cases are now being reported from non-psychiatric and non-toxicological centers. SS can occur at therapeutic and stable doses. They create considerable diversity in various aspects of SS. Some experts, meanwhile, dismiss these recent advancements in SS. Because SS is a potentially fatal illness, there must be agreement on various issues of SS.

INTRODUCTION

Serotonin syndrome (SS) is a drug-induced clinical syndrome resulting from increased serotonergic activity in the central nervous system (CNS)[1]. In 1960, Oates and Sjostrand[2] were the first to report neurological symptoms caused by excessive tryptophan (serotonin)[2]. Insel et al[3] coined the term "serotonin syndrome" in 1982[3]. Although almost six decades have passed since the first description of SS, it remains an enigma in terms of terminology, prevalence, clinical symptoms, diagnostic criteria, and treatment measures. Recent reports have highlighted several new advancements in SS[4,5]. For a long period, the majority of SS reports were published by toxicology centers[6,7]. However, cases are now increasingly being reported from non-toxicology centers, such as perioperative settings, neurology clinics, cardiac settings, and pediatric clinics. Several new drugs have demonstrated serotonergic properties[8-10]. Historically, SS has been recognized as an acute clinical condition. However, several cases of sub-acute or chronic SS have recently been reported[11,12]. A few authors, though, are dismissive of these recent advances in SS[13]. Some experts have criticized several SS cases reported in peer-reviewed medical journals[13,14]. This review aims to shed light on the current state of controversy surrounding this potentially fatal clinical syndrome.

Terminology: Serotonin syndrome or serotonin toxicity

Some authors recommend using the term "serotonin toxicity" instead of SS because SS indicates an idiosyncratic reaction similar to neuroleptic malignant syndrome[15]. However, the term "syndrome" does not denote an idiosyncratic reaction or any pathophysiology for a specific medical condition. Syndrome means "a set of symptoms or signs" that occur together and indicate the presence of a specific disease. Because SS is caused by an excess of serotonin, a spectrum theory of serotonin toxicity (ST) has been proposed. The authors distinguish serotonin-related side effects (at therapeutic doses) from ST. They consider serotonin-related minor side effects as "serotonin effects". ST only happens at large dosages (above the therapeutic level)[13,15]. However, there are no studies differentiating "serotonin effects" from ST. Tremor is considered a minor serotonin effect. Nonetheless, tremor and hyperreflexia together satisfied the Hunter criteria for SS[16]. The co-occurrence of tremor and hyperreflexia in an individual taking serotonin medications at a therapeutic dose is serotonin effect, as per the spectrum theory of ST. The same combination of tremor and hyperreflexia, however, can be classified as ST if there is a history of excess serotonergic drug intake. Furthermore, there is no method to identify "excess" serotonin in a patient. SS differs from toxicity caused by other drugs. The values of serum serotonin are not specified to determine ST. Furthermore, as SS is a receptor-specific condition, serum serotonin levels alone might not be sufficient to diagnose it. No other toxidrome is described in the same way as the spectrum concept of ST. Side effects of anticholinergic medicines are not classified as "anticholinergic effects" and anticholinergic toxicity. Likewise, other toxidromes, such as those resulting from cholinergic medications or opioid or sympathomimetic poisoning, are not categorized in this manner. It is necessary to determine whether "serotonin effects" are a distinct entity or a component of mild SS. One reason for SS underdiagnosis is a lack of awareness about this life-threatening disorder. Therefore, it would be reasonable to remain with the more widely used term "serotonin syndrome". Furthermore, the doses of serotonergic drugs are not in the toxic range in many cases of SS.

Epidemiology: Uncommon or undiagnosed clinical condition

SS is widely considered a rare or uncommon syndrome. A single case report of SS is still being published in the literature. The true incidence of SS is not precisely known because it varies widely in the literature. It depends on what type of studies are conducted (database studies or retrospective or prospective studies), which diagnostic criteria are used for evaluation (Hunter criteria or Sternbach criteria or other criteria), which medications are evaluated (antidepressant medications vs others, or single agent vs group of medications, or therapeutic dose vs overdose), what types of clinical settings are used [outpatient vs inpatient vs intensive care unit (ICU) settings vs psychiatric ward vs survey vs post-marketing surveillance], which age group of patients are included (adults vs elderly), and what are the associated comorbid conditions [mental illness vs other illness (Table 1)][17-27].

Table 1 Epidemiological data regarding serotonin syndrome in different settings.

Ref.	Year	Type of study	Setting of the study	Criteria used	Serotonergic drugs	Person screened	Prevalence
Mackay et al[17]	1999	Post-marketing surveillance study	General population	Sternbach	Nefazodone-therapeutic dose	11834 patients on nefazodone	0.04%
Isbister et al[18]	2003	Retrospective	Toxicology centre	Sternbach	Moclobemide poisoning and serotonergic agent	21 patients with overdose	55%
Isbister et al[7]	2004	Retrospective	Toxicology centre	Sternbach-clinical	Five different SSRIs. Overdose	469 SSRI poisoning admissions	14%
Koury et al[19]	2015	Retrospective. Database registry	Hospital	Hunter	Fentanyl and serotonergic agent-therapeutic dose	4538 patients	0.09%
van Ewijk et al[20]	2016	Prospective	ICU	Hunter or Sternbach	Multiple serotonergic agents-therapeutic dose	delirious patients on serotonergic agents (44 patients)	16%
Nguyen et al[21]	2017	Retrospective. Databases	General population	ICD-9-CM	Serotonergic drugs- therapeutic dose	15 million	0.19% to 0.07%
Karkow et al[22]	2017	Retrospective case-control	Inpatients	Hunter or Sternbach	Linezolid vs linezolid+ serotonergic agent. Therapeutic dose	87 vs 261	0.4% vs 1.1%
Orlova et al[23]	2018	Retrospective. Database registry	General population	ICD-9	Triptans and antidepressant. Therapeutic dose	30928 person-years	0.006 to 0.023%
Prakash et al[24]	2021	Prospective	ICU	Hunter	Multiple drugs. Therapeutic dose.	All 309 ICU patients	7.8%
Erken et al[25]	2022	Retrospective	Geriatric department	Hunter	Antidepressants. Therapeutic dose	238 elderly (> 60 yr)	25%
Cooper et al[26]	2023	Retrospective	Toxicology centre	No criteria used	Various combinations of serotonergic drugs. Overdose	1978 overdoses in 1520 patients	13.6%
Di Salvo et al[27]	2024	Prospective	Psychiatric ward	Hunter	Serotonergic antidepressant agent. Therapeutic dose	133	12%

ICU: Intensive care unit; ICD-9-CM: International Classification of Diseases, clinical modification; SSRI: Selective serotonin reuptake inhibitors.

The incidence of SS in the population following an overdose of selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors is approximately 15%[7]. The incidence of SS was very high (> 55%) in patients with moclobemide poisoning, particularly when the drug was combined with another serotonergic agent[18]. The incidence of SS on therapeutic doses of different serotonergic drugs ranges from 0.006% to 25% (Table 1). So, the reported incidence of SS varies widely across the literature. The incidence of SS ranged from 0.19% to 0.07% in a retrospective review of 15 million people who had taken at least one serotonergic medication[21]. However, this study used International Classification of Diseases (ICD), clinical modification criteria for SS. There is no specific ICD-9 code for SS. SS is part of the larger category of "other extrapyramidal diseases and abnormal movement disorders" (ICD-9 code 333.99). Koury et al[19] performed a retrospective study on patients who received fentanyl and a serotonergic medication concurrently. Only 0.09% of patients (4 out of 4538) had SS[19]. Erken et al[25] examined 234 elderly patients (over 60 years old) who were taking antidepressants and had been admitted to a geriatric department. Sixty patients (25%) fulfilled Hunter criteria for SS[25]. Di Salvo et al[27] studied 133 consecutive patients who were admitted to the psychiatric inpatient unit and were using at least one serotonergic medication. Sixteen patients (12%) met the Hunter criteria for SS[27]. Van Ewijk et al[20] performed a prospective observational study to determine the prevalence of SS in delirious patients who had taken serotonergic drugs. The authors observed SS in 16% (7 out of 44) of the patients[20]. The treating physician did not diagnose any of these patients with SS. Similarly, Prakash et al[24], evaluated 309 consecutive patients who were admitted to the ICU for various reasons. Twenty-four patients (7.8%) met the Hunter criteria[24]. Interestingly, the treating physicians did not diagnose SS in any of the patients.

Unawareness regarding SS is common among physicians. Therefore, any prevalence study of SS should be interpreted with considerable caution. In one survey in 1999, SS was not recognized as a disease entity by 85% of general practitioners[17]. Even today, many practitioners are still unaware of SS. Just 31% of neurologists and 17% of psychiatrists were familiar with the Hunter criteria for SS in two different surveys[28,29]. Merely 11% of psychiatrists and 17% of neurologists recognized that clonus is one of the most distinctive characteristics of SS. The list of serotonergic drugs is expanding. There have also been reports of SS by food and herbal products[1,30,31]. The serotonergic properties of several medications are not known to physicians[28,29]. Despite the lack of rigorously established efficacy, cyproheptadine remains the recommended therapy for SS[1]. Only sixteen percent of the patients in the recently reviewed 56 fatal cases of SS received cyproheptadine[32]. Furthermore, just two of the patients received the appropriate recommended dosages. That could be a sign of unawareness regarding SS. Approximately 43% of all fatal SS cases were identified in just two nations, Finland and the United States[32]. It implies the underdiagnosis of fatal SS in other nations.

Physical examination for clonus is not a routine phenomenon in clinical practice[28,29]. Unfortunately, most studies on the prevalence of SS do not specify how many patients underwent clonus examinations. Therefore, a retrospective chart review or database registry cannot estimate the true incidence of SS. The majority of these studies-particularly the retrospective database studies-indicate that SS is an extremely uncommon clinical condition. On the contrary, prospective studies typically show a comparatively higher prevalence of SS. There are three prospective hospital-based studies in the literature[20,24,27]. Two studies measured the prevalence in people who had used serotonergic medications. van Ewijk et al[20] determined the prevalence of SS in delirious patients who had taken serotonergic drugs. The study identified SS in 16% of the cases[20]. Similarly, the prevalence was calculated in people who had used serotonergic medications in Di Salvo et al[27] observation. It was 12% of the patients (16 patients out of 133)[27]. In another study, the prevalence of SS among all inpatients in an ICU was 7.8%[24]. These prospective studies conducted in hospitals imply that SS may account for a substantial proportion of patients admitted to the ICU and psychiatry ward.

Therefore, even though SS only affects a small percentage of patients taking serotonergic medications, the actual number of SS patients is quite substantial. The use of pro-serotonergic drugs has increased over the last two decades worldwide. There has also been a rise in the duration of antidepressant medication ingestion in recent times. It is important to note that, in addition to depression, antidepressants are used to treat a variety of other diseases, including common conditions like headaches and other painful conditions. So, while the percentage of cases of SS due to serotonergic drug use may not increase, the actual number of cases of SS will undoubtedly rise. The first clinical review of SS in 1991 included only 38 patients[33]. In 2021, Prakash et al[32] noted a total of 127 cases of "fatal" SS in the literature[32]. So, the actual cases of SS in clinical practice are probably not uncommon.

Diagnostic accuracy of SS: Diagnosis is always provisional

Three criteria-the Hunter, Sternbach, and Radomski criteria-have been proposed for the diagnosis of SS[6,33,34]. The Hunter and Sternbach criteria are commonly used for diagnostic purposes[6,33]. The Sternbach criteria include ten symptoms, including mental-status changes, agitation, myoclonus, hyperreflexia, incoordination, diaphoresis, shivering, tremor, diarrhea, and fever[33]. Only three out of ten are required. The Hunter criteria include the following combinations of symptoms: (1) Spontaneous clonus; (2) tremor and hyperreflexia; and (3) inducible clonus or ocular clonus plus diaphoresis, agitation, or fever with rigidity (Table 2)[6]. Only one of these three is required according to the Hunter criteria. Both criteria include a history of ingestion of serotonergic agents and the exclusion of other etiologies.

Table 2 The Sternbach and Hunter criteria for serotonin syndrome.

The Sternbach’s criteria[33]	Hunter criteria[6]
1. A history of serotonergic agent ingestions	1. A history of serotonergic agent ingestions
2. Exclusion of other aetiologies	2. Exclusion of other aetiologies
3. Any three of the followings	3. Any of the following combinations
(i) Mental status changes	(i) Spontaneous clonus
(ii) Agitation	(ii) Hyperreflexia and tremor
(iii) Myoclonus	(iii) Inducible clonus or ocular clonus plus any of followings
(iv) Fever
(v) Hyperreflexia	(a) Diaphoresis
(vi) Diaphoresis	(b) Agitation
(vii) Shivering	(c) Fever and rigidity
(viii) Tremor
(ix) Diarrhoea,
(x) Incoordination

Although only a few symptoms are listed in both criteria, there are a wide range of symptoms and signs in SS (Table 3). Clinically, SS is characterized by a triad of cognitive impairment, autonomic hyperactivity, and neuromuscular abnormalities. This triad consists of more than 50 symptoms. So, the clinical characteristics of SS mimic a variety of disorders. The list of differential diagnosis is very long, and it is expanding[35]. So, the exclusion of all differential diagnosis is not possible for several reasons. Symptoms may disappear within 24-36 h of discontinuing the serotonergic drugs and starting other specific drugs[1]. However, death may occur within a few hours after hospitalization. In half of the fatal SS cases, death occurs within 24 h of the onset of symptoms[32]. Thus, within 24 h, some patients might make a full recovery, and some might die due to SS. Therefore, exclusion of all differential diagnoses is not possible within twenty-four hours (in a limited time) under either condition (recovery or death). So, the diagnosis will remain provisional. It is pointless to criticize any published case of SS.

Table 3 An overview of the clinical characteristics of serotonin syndrome in comparison to the Hunter and Sternbach criteria[5,16,24,32].

	Cognitive impairment	Neuromuscular abnormalities	Autonomic abnormalities	Miscellaneous /complications
Sternbach criteria	Agitation	Clonus, hyperreflexia, tremor	Diaphoresis, fever
Hunter criteria	Mental status changes. Agitation	Hyperreflexia, rigidity, tremor, incoordination, shivering	Diaphoresis, fever, diarrhoea
Other clinical features	Insomnia, anxiety, confusion, drowsiness, lethargy, seizures, coma. Psychosis, apathy, mania	Gait problems, dysarthria, myoclonus, babinski, trismus, paresthesias,body pain, headache, fatigue	Tachycardia, hypertension, hypotension, unstable blood pressure, palpitation dizziness, arrhythmia, mydriasis, nausea, vomiting, abdominal pain, hyperactive bowel, sexual dysfunctions, bladder dysfunctions	Rhabdomyolysis PRES, DIC, acute renal failure, Takotsubo cardiomyopath, Cardiogenic shock pulmonary oedema, ARDS, multi-organ failure

PRES: Posterior reversible encephalopathy syndrome; DIC: Disseminated intravascular coagulation; ARDS: Acute respiratory distress syndrome.

To meet both criteria for SS, one must identify the ingestion of a serotonergic agent. However, the identification of serotonergic agents may not be easy for several reasons. More than 75 medications are known to have serotonergic effects and have been linked to the development of SS[1]. Physicians may be unaware of the serotonergic properties of various medicines[28,29]. The patient's mental state (altered behavior) may prevent them from providing a detailed history of drug ingestion. Hence, a diagnostic challenge is an inherent property of SS. Several cases of SS, published in peer-reviewed medical journals, have drawn criticism from some experts[13,14]. Chiew and Buckley reviewed the systematic review of the fatal SS published in a journal[13]. They claimed that several reported cases of fatal SS were not indeed SS. They noted that only 24% of the patients met the Hunter criteria. Unfortunately, they did not provide an alternative diagnosis for these cases. A few other experts are also critical of some cases of SS, published in peer-reviewed journals[14]. But, before criticizing the diagnosis of a condition for which there are many differential diagnoses and no specific laboratory test for diagnosis, we must be absolutely sure. Unless there is a clear misdiagnosis, we should stick with the author's original diagnosis. Nobody should challenge another person's diagnosis without giving them the opportunity to refute it.

Neuvonen et al[36] published five fatal cases of SS in "The Lancet". This case series lacks several information required to meet the Hunter criteria for SS. Only two patients met the Sternbach criteria[36]. Could we say that the Lancet published the wrong case series on fatal SS? Koury et al[19] assessed all admissions at Massachusetts General Hospital with a diagnosis of SS. Over a 10-year period, they discovered a diagnosis of SS in 292 cases. However, only six cases (out of 292) met the criteria for SS after a chart review[19]. This observation raises several questions regarding the diagnosis of SS. Did the treating physicians at a well-known hospital misdiagnose the cases of SS? Is a chart review sufficient to challenge the initial diagnosis? SS is considered an underdiagnosed condition. Why was it overdiagnosed here (6 vs 292)? If it was not SS, what was the most appropriate alternative diagnosis for these individuals? In this chart review, they calculated the incidence of SS in patients receiving fentanyl and serotonergic agents. The incidence was 0.09%. However, the incidence would be 6.4% if all cases were included. If you continue in this way, only 11 patients (29%) out of 38 patients included in Sternbach's review met the Hunter criteria for SS[33]. Similarly, 31% of the patients enrolled in the Dunkley et al[6] series (on which the Hunter criteria was developed), did not meet the Sternbach criteria[6]. Until a definitive laboratory test for SS is available, we must accept the diagnoses of others.

How much serotonin is "excess" to develop SS?

Although the Hunter criteria were developed in patients who had overdosed on single-agent SSRIs, the criteria state "in the presence of a serotonergic agent"[6]. The Sternbach criteria mention "Coincident with the addition of or increase in a known serotonergic agent to an established medication regimen"[33]. They do not suggest an overdose of serotonergic agent for the development of SS. Radomski et al[34] write, "Co-incidence with the addition or increase in a known serotonergic agent (to an established treatment regime)"[34]. There is no mention of an overdose for the development of SS. Boyer and Shannon[1] write, "Has a serotonergic agent been administered in the past five weeks?" So, according to Boyer and Shannon[1], a person can develop SS even if they have taken a serotonergic agent in the past five weeks[1]. However, a few experts think that "a large increase in CNS serotonin" within 24 h is the only cause of SS. Furthermore, they think that only a certain class of medicines, and only in overdose situations, can result in "a large increase in CNS serotonin"[13,37]. They think that SS cannot develop at a stable dose. Based on some animal model studies, they suggest that a rise in CNS serotonin up to three times does not cause SS. SS occurs only if CNS serotonin rises more than three times[38]. On this basis, they criticized several case studies published in peer-reviewed journals.

In Erken et al[25] study on antidepressant-induced SS, the average calculated dose of fluoxetine was 34.85 mg/d[25]. While it was marginally more than that of the control group (28.17 mg/d), it remained within therapeutic ranges. The authors made no mention of any recent increase or addition of serotonergic agents. In Di Salvo et al[27] study, 16 patients were diagnosed with SS in a psychiatric inpatient unit[27]. All patients received serotonergic agents within therapeutic ranges. About 56% of the patients were on a single serotonergic agent. There were no changes in recent medications in about 60% of the cases. In fact, in two cases, the dosage of serotonergic medications was reduced. Pedavally et al[39] reviewed 33 ICU patients with SS. Only seven patients (21%) had drug overdoses[39]. Thirteen patients (39%) got SS only after being hospitalization. In a prospective observation in an ICU setting, 24 of 309 patients (7.8%) satisfied the Hunter criteria[24]. None of the patients received an overdose of any serotonergic drugs. These studies show that a single serotonergic drug at a therapeutic and stable dose can induce severe SS. In addition to these cases, there are several case reports of moderate-to-severe SS due to a single serotonergic agent at a therapeutic and stable dose. Only 18 (32%) patients in the review of 56 fatal SS cases showed evidence of serotonergic agent overdose. Moreover, seven (13%) patients had been on stable therapeutic doses[32]. You cannot dismiss all of these cases whose clinical features and other circumstances were consistent with SS simply because they were on stable doses.

Recently, Keith et al[40] reported SS-like presentation in two patients with SARS-CoV-2 infection; both patients responded to cyproheptadine[40]. None of the patients received any serotonergic agents. One patient in the Prakash et al[24] study (in the ICU setting) met the Hunter criteria and responded to cyproheptadine[24]. However, the treating doctors did not get a history of serotonergic substance ingestion. Wu and Hill[41] reported a case of SS that overlapped with the features of catatonia due to the abrupt withdrawal of clozapine[41]. There was no history of serotonergic agent ingestion. There was a suggestion that serotonergic hyperactivity could result from clozapine withdrawal. Bhatia et al[42] reported a case of SS due to cyproheptadine withdrawal (the patient was on a stable dose of sertraline)[42]. Similar to this, SS occurred after discontinuing olanzapine in a patient who was also receiving duloxetine[43]. Salimnia et al[44] reported a patient on a stable dose of a serotonergic drug. SS was precipitated by the excessive ingestion of pineapple juice[44]. The authors proposed that SS was triggered by CYP450 inhibition by pineapple juice. Patel and Marzella described a case of SS in a patient on a stable dose of a serotonergic drug[30]. SS was precipitated by the ingestion of excess food products. Warner et al[31] reported a case of SS in which they believe turmeric enhanced the serotonergic properties of other serotonergic drugs[31]. Several food products (especially those with high tryptophan) and herbal products are known to have serotonergic properties. Tryptophan is the precursor to serotonin and is abundant in many foods. Several over-the-counter medications are known to have serotonergic properties. Several simple painkillers, such as aspirin, acetaminophen, ibuprofen, and rofecoxib, are known to increase serotonin[45]. A study showed that paracetamol's antinociceptive effects are mediated by 5-HT1A/1B receptors[46]. There are several non-pharmacologic strategies (physical exercise, exposure to sunlight, and positive emotions) that may increase brain serotonin function[47]. Thus, a variety of factors influence brain serotonin. All of these might not be enough to produce SS by themselves. However, we think it could sometimes exacerbate the serotonergic effects of a "stable dose" of other serotonergic drugs, which could lead to SS.

The first line of both criteria for SS mentions "a history of ingestion of serotonergic agents". However, due to cognitive impairment, the patient might not be able to provide an accurate history of ingesting serotonergic medications. Moreover, the list of serotonergic agents is extensive and continually growing. For a variety of reasons, it might not be possible for every patient and doctor to check this list in an emergency setting. In the Prakash et al[24] series, only 50% of the patients reported having taken serotonergic medications at the time of admission in an ICU setting[24]. It might not be appropriate to search extensively for "excess serotonin" in an emergency setting. Given that the condition may be fatal, it can be treated as SS if the patient fulfils any criteria for SS. The most important thing is discontinuing serotonergic agents and not starting any other drug with serotonergic properties[1]. Cyproheptadine is a generally safe medication that can be administered empirically[48]. If there is no improvement in 24 h, it can be discontinued.

SS in toxicology centers vs SS in non-toxicology centers

The majority of earlier studies were published by toxicology or psychiatry centers. SS cases are now being reported from a variety of clinical settings, including medical ICUs, surgical ICUs, pediatric ICUs, medical inpatient units, neurology inpatient units, headache clinics, and several other clinical settings. Overdoses or poisonings of serotonergic agents constituted the majority of the cases observed in toxicology or psychiatry centers. Overdoses or poisonings from serotonergic drugs mainly occur in patients with mental disorders. The diagnosis in such cases may be straightforward. Apart from psychiatric illnesses, serotonergic drugs are used for a variety of other reasons, such as headache disorders, any painful conditions, paralysis, and associated depression with other major medical disorders. In contrast to those suffering from psychiatric disorders, these patients typically do not intentionally overdose or poison themselves. These patients may concurrently receive several other classes of serotonergic medications. Furthermore, these patients may continue to use serotonergic medications, even if they develop mild to moderate SS. In the case series from ICU settings by Pedavally et al[39] and Prakash et al[29], the doctor continued or added serotonergic medications in suspected cases of SS[24,39]. Thus, the clinical presentation (onset, severity, and clinical features) in such instances may not exactly match what toxicologists or psychiatrists observe in their respective settings. An acute overdose or poisoning will undoubtedly result in the sudden onset of symptoms. On the other hand, when we take serotonergic agents at a stable dose or gradually increase them, serotonin accumulates slowly, causing symptoms to appear gradually. In the recent past, several cases of chronic, sub-acute, or delayed onset SS have been reported in the literature[11,12].

Toxicologists and psychiatrists frequently observe SS as a result of overdose or poisoning. It does, however, occur at therapeutic doses in other clinical settings. The symptoms will be acute and severe because of the overdose. The diagnosis is easy (because of the history of overdose) at the toxicology center. The primary differential diagnosis in such cases is other toxidromes. However, diagnosis is challenging in other clinical settings, and the list of differential diagnoses is extensive here[35]. Moreover, the patient can continue to use serotonergic medications despite having signs of SS. And sometimes, even doctors will add new serotonergic medications. SS is a "syndrome on syndrome". It develops on top of a pre-existing disease for which serotonergic medications have been prescribed. As a result, in addition to SS, the patients will exhibit symptoms associated with a pre-existing disease. It will create diagnostic confusion. Such diagnostic issues are common in SS cases seen in non-toxicology or non-psychiatric settings.

Typical serotoninergic drugs vs other drugs with serotonergic properties

Recently, Chiew and Buckley suggested a modification in the diagnostic criteria for SS[13]. The most important aspect of the suggestion was the precise description of serotonergic drugs. On the pattern of drug ingestion, they divided it into three groups: (1) Serotonergic drug poisoning/overdose or drug–drug interaction of two serotonergic agents-ST very likely; (2) Initiation or increase in dose of a serotonergic agent or agent that decreases metabolism of serotonergic agent. This includes recreational drug use - ST likely; and (3) on a stable dose of a serotonergic medication-ST unlikely. There are several "shortfalls" in this suggestion. They have not presented any new data. They have not analyzed all the cases reported in the literature. Instead of clinical symptoms, the level of diagnosis-very likely, likely, and unlikely-is based on the pattern or quantity of drug ingestion. This suggestion simply denied the development of SS at a stable dose. This suggestion is just an assumption. There is no study to support this. On the contrary, there are several case studies and case reports suggesting SS at the stable dose. They ignored all these cases. As discussed above, several cases of chronic or sub-acute onset SS have been described in the literature. Recently, Janowski and colleagues from the Mayo Clinic reported 11 patients with chronic SS (duration of symptoms: 1.5 months to 12 years)[11]. In an analysis of cases registered in the French pharmacovigilance database, 12.5% of patients (14 out of 112) experienced SS after 5 wk of their last serotonergic drug modification[49]. SS development at a stable dose is a reality. You cannot make such a recommendation until you have a strong prospective, multi-centric study.

The pathophysiology of SS is still evolving. Boyer and Shannon[1] write, "No single receptor appears to be responsible for the development of the serotonin syndrome"[1]. They consider that the 5-HT2A receptor is the principal receptor implicated in SS. However, some authors believe that overstimulation of 5HT1A receptors is primarily responsible for the major symptoms of SS. There is a suggestion that 5-HT1A receptors are probably not as important as previously believed in human SS (compared to animal studies)[50]. It is essential to recognize the constraints of animal studies. The development of SS has also been linked to a number of other neurotransmitters besides serotonin. N-methyl-D-aspartate receptor antagonists, and gamma-aminobutyric acid, and dopaminergic receptors are also involved in the pathogenesis of SS[1]. It has been proposed that a balance between the serotonergic and dopaminergic pathways may determine the risk of developing SS. So, the exact pathophysiology for the development of SS is complex and unclear. There are still a lot of unanswered questions regarding SS. Therefore, in this potentially fatal situation, any comments or suggestions should be made with caution. A few experts believe that SS occurs only with a certain class of drugs. If some medications do not fit into that group, they reject the diagnosis of even a typical case of SS[13]. A few triptans, in addition to their strong affinity for 5-HT1B/1D receptors, show modest affinity for 5-HT1A receptors, which may lead to mild-to-moderate SS. There are numerous case reports of triptan-induced SS in the literature[45]. However, some authors don’t believe about this. Lasmiditan, a recently approved antimigraine medication, usually acts on 5-HT1F. However, there have been reports of SS after taking lasmiditan[51]. It implies that SS can develop even with drugs that do not typically affect 5-HT2A and 5-HT1A but do affect other 5HT receptors. Several antiepileptic drugs, especially sodium valproate and lamotrigine, have serotonergic properties[52]. Even Boyer and Shannon[1] listed sodium valproate as one of the drugs causing SS. There are several reports of SS caused by valproate in the literature. Several studies have demonstrated the serotonergic properties of sodium valproate. But a few authors continued to criticize this concept and do not believe that sodium valproate causes SS. Despite criticism from experts that a few medicines, such as sodium valproate, ondansetron, metoclopramide, bupropion, and mirtazapine, do not induce SS, the literature continues to publish such reports. It indicates that drugs with even mild serotonergic properties may induce SS. It is also possible that the serotonergic system is activated by other different mechanisms or neurotransmitters. There is a need to reach consensus on this issue.

Cyproheptadine response: Is it diagnostic of SS?

Cyproheptadine is the recommended therapy for moderate and severe SS. However, there are conflicting reports regarding the response to cyproheptadine in patients with SS. The discrepancy in response may be due to varying doses and delayed initiation of the drug. A study discovered that 30 mg of cyproheptadine is required to block 85%-95% of the brain’s 5HT2A receptors[53]. Therefore, the case series that administered a higher initial dose (12 to 32 mg) in the first 24 h showed a positive response[54,55]. Conversely, the case series that administered a lower dose did not demonstrate any beneficial response. SS develops on top of a pre-existing disorder[56]. A patient may experience symptoms from both a pre-existing illness and SS. Since the patient may need separate medication for a pre-existing illness, the patient's symptoms may only partially respond to cyproheptadine. So, even a partial response to cyproheptadine can be suggestive of SS.

CONCLUSION

The concept of SS continues to evolve. Recent reports have highlighted several new developments. New findings have been emerging. Apart from psychiatric illnesses, serotonergic drugs are used for a variety of other reasons. The clinical presentation (onset, severity, and clinical features) in these cases may differ from what toxicologists or psychiatrists see in their respective settings. The concept of SS is changing. However, other experts dismiss these recent advancements in SS. Considering the magnitude of the use of serotonergic agents in the general population across the world, there is a need to reach consensus on several matters related to SS.