Clinical Toxicology Unit, Prince of Wales Hospital, Randwick, Australia.
NSW Poisons Information Centre, The Children's Hospital at Westmead, Westmead, Australia.
Clin Toxicol (Phila). 2022 Feb;60(2):143-158. doi: 10.1080/15563650.2021.1993242. Epub 2021 Nov 22.
Serotonin syndrome (toxicity) describes adverse drug effects from toxic amounts of intra-synaptic central nervous system serotonin. A wide range of drugs have been implicated to cause serotonin toxicity, not all justifiably. The plausible agents all have a final common pathway resulting in a substantial increase in central nervous system serotonergic neurotransmission. Serotonin toxicity is characterized by neuromuscular excitation, mental status changes, and autonomic dysregulation. Signs and symptoms represent a spectrum of toxicity (mild to life-threatening) related to increasing serotonin concentrations. As there is no consensus on the threshold for "toxicity" or diagnostic criteria, the true incidence of serotonin toxicity is unknown. The incidence in overdose is easier to quantify and is reasonably common in serotonergic antidepressant overdoses. In a large case series of overdoses, moderate serotonin toxicity occurred in 14% of poisonings with a selective serotonin reuptake inhibitor. While half those ingesting a monoamine oxidase inhibitor in combination with a serotonergic agent in overdose exhibit at least moderately severe serotonin toxicity. In contrast, the incidence of serotonin toxicity in those on therapeutic serotonergic agents appears to be very low.
To provide a narrative review of the current diagnostic criteria, utilizing case reports of fatalities to evaluate how many meet the various diagnostic criteria and propose practical solutions to resolve controversies in diagnosis.
A review of serotonin toxicity diagnostic criteria in the English literature was completed by searching Embase and PubMed from January 1990 to July 2021 for the keywords "serotonin syndrome/toxicity" paired with "diagnostic criteria" or "diagnosis." Also, fatal cases of serotonin toxicity identified from a recent systematic review were independently examined to determine what diagnostic criteria were met and whether serotonin toxicity or another cause was most likely.
Serotonin toxicity is a clinical diagnosis, four diagnostic criteria (Sternbach, Serotonin Syndrome Scale, Radomski, and Hunter) have been proposed. However, the Serotonin Syndrome Scale has not been validated in patients with serotonin toxicity and only utilized in those on a serotonergic agent. The remaining three criteria are utilized more widely but have undergone little refinement or validation.
Shortfalls with diagnostic criteria can be illustrated by examining case fatalities. Of 55 fatal cases reviewed, 12 (22%) were unlikely to be serotonin toxicity. Sternbach and Radomski criteria were met by 25 (45%), 20 (36%) had insufficient data reported and 10 (18%) met an exclusion criterion. Few had sufficient information reported to determine whether Hunter Criteria were met, with only 13 (24%) documented as meeting the criteria, the remaining 42 (76%) had insufficient data.
As serotonin toxicity is a clinical diagnosis, issues arise when basing the diagnosis on symptom criteria alone, without considering whether the drug/s ingested increase central nervous system serotonin or whether there is an alternative diagnosis. This has resulted in case reports and government warnings for drugs that cannot plausibly cause significant serotonin toxicity (e.g., ondansetron and antipsychotics). We propose when assessing for a serotonin toxidrome, both the causative agent(s) and clinical scenario is considered to determine the likelihood of serotonin toxicity. Then the clinical features assessed, those with a moderate to high prior probability (e.g., serotonergic drug-drug interaction, overdose, recent initiation or increase in dose of serotonergic agent/s) could be diagnosed based on the Hunter criteria. However, those with a low probability (e.g., stable therapeutic doses of a serotonergic agent) require more specific and stringent criteria. Finally, we propose a minimum dataset for case reports/series of serotonin toxicity.
More complete and accurate reporting of serotonin toxicity cases is required in the future, to avoid further misleading associations that are physiologically implausible.
血清素综合征（毒性）描述了中枢神经系统血清素毒性的不良药物作用，这种毒性来自于中枢神经系统内突触的血清素。许多药物已被牵连导致血清素毒性，但并非所有药物都有合理的依据。可能的药物都有一个最终的共同途径，导致中枢神经系统血清素能神经传递的实质性增加。血清素毒性的特征是神经肌肉兴奋、精神状态改变和自主神经失调。症状和体征代表与血清素浓度增加相关的毒性谱（从轻度到危及生命）。由于没有关于“毒性”或诊断标准的共识，因此血清素毒性的真实发生率是未知的。在过量用药的情况下，更容易量化发病率，而且在血清素类抗抑郁药过量用药中相当常见。在一项大剂量中毒的病例系列中，选择性血清素再摄取抑制剂中毒的患者中有 14%出现中度血清素毒性。而在与单胺氧化酶抑制剂联合使用的血清素能药物过量的患者中，有一半以上至少出现中度严重的血清素毒性。相比之下，在使用治疗性血清素能药物的患者中，血清素毒性的发病率似乎非常低。
提供当前诊断标准的叙述性综述，利用致命病例报告评估有多少符合各种诊断标准，并提出解决诊断争议的实用解决方案。
通过在 Embase 和 PubMed 上搜索 1990 年 1 月至 2021 年 7 月的“血清素综合征/毒性”和“诊断标准”或“诊断”这两个关键词，检索血清素毒性诊断标准的英文文献。还从最近的一项系统综述中独立检查了致命的血清素毒性病例，以确定符合哪些诊断标准，以及最有可能是血清素毒性还是其他原因。
血清素毒性是一种临床诊断，已经提出了四项诊断标准（斯特恩巴赫、血清素综合征量表、拉多姆斯基和亨特）。然而，血清素综合征量表尚未在血清素毒性患者中进行验证，仅用于使用血清素能药物的患者。其余三个标准使用得更广泛，但几乎没有经过细化或验证。
通过检查病例的致命性，可以说明诊断标准的不足。在 55 例致命病例中，有 12 例（22%）不太可能是血清素毒性。25 例（45%）符合斯特恩巴赫和拉多姆斯基标准，20 例（36%）报告的资料不足，10 例（18%）符合排除标准。很少有足够的信息来确定亨特标准是否符合，只有 13 例（24%）被记录为符合标准，其余 42 例（76%）报告的资料不足。
由于血清素毒性是一种临床诊断，当仅根据症状标准进行诊断，而不考虑所摄入的药物是否增加中枢神经系统血清素或是否有其他诊断时，就会出现问题。这导致了一些病例报告和政府对不能合理引起严重血清素毒性的药物（如昂丹司琼和抗精神病药物）的警告。我们建议在评估血清素毒性时，同时考虑致病药物和临床情况，以确定血清素毒性的可能性。然后评估临床特征，那些具有中高度先验概率的（例如，血清素能药物-药物相互作用、过量、最近开始或增加血清素能药物剂量）可以根据亨特标准进行诊断。然而，那些具有低概率的（例如，稳定的治疗剂量的血清素能药物）需要更具体和严格的标准。最后，我们提出了一个血清素毒性病例报告/系列的最小数据集。
未来需要更完整和准确地报告血清素毒性病例，以避免进一步产生生理上不合理的误导性关联。
