Serotonin syndrome controversies: A need for consensus

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.

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

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.