Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions

Abstract

Serotonin syndrome (SS) (also referred to as serotonin toxicity) is a potentially life-threatening drug-induced toxidrome associated with increased serotonergic activity in both the peripheral (PNS) and central nervous systems (CNS). It is characterised by a dose-relevant spectrum of clinical findings related to the level of free serotonin (5-hydroxytryptamine [5-HT]), or 5-HT receptor activation (predominantly the 5-HT1Aand 5-HT2Asubtypes), which include neuromuscular abnormalities, autonomic hyperactivity, and mental state changes. Severe SS is only usually precipitated by the simultaneous initiation of 2 or more serotonergic drugs, but the syndrome can also occur after the initiation of a single serotonergic drug in a susceptible individual, the addition of a second or third agent to long-standing doses of a maintenance serotonergic drug, or after an overdose. The combination of a monoamine oxidase inhibitor (MAOI), in particular MAO-A inhibitors that preferentially inhibit the metabolism of 5-HT, with serotonergic drugs is especially dangerous, and may lead to the most severe form of the syndrome, and occasionally death. This review describes our current understanding of the pathophysiology, clinical presentation and management of SS, and summarises some of the drugs and interactions that may precipitate the condition. We also discuss the newer novel psychoactive substances (NPSs), a growing public health concern due to their increased availability and use, and their potential risk to evoke the syndrome. Finally, we discuss whether the inhibition of tryptophan hydroxylase (TPH), in particular the neuronal isoform (TPH2), may provide an opportunity to pharmacologically target central 5-HT synthesis, and so develop new treatments for severe, life-threatening SS.

Case-Control Study of the Effects of Gut Microbiota Composition on Neurotransmitter Metabolic Pathways in Children With Attention Deficit Hyperactivity Disorder

“…In the folate metabolic pathway, a significant upregulation of the gene encoding 6-pyruvoyl-5,6,7,8-tetrahydropterin could promote the generation of tetrahydrobiopterin (BH4). However, tryptophan hydroxylase is a rate-limiting enzyme that catalyzes 5-HT synthesis, with oxygen and BH4 as substrates (Opladen et al, 2016;Scotton et al, 2019). Upregulation of the gene encoding 6-pyruvoyl-5,6,7,8-tetrahydropterin may lead to the conversion of excessive tryptophan into 5-HT in the intestinal tract, and 5-HT has difficulty crossing the BBB, resulting in decreased CNS 5-HT concentrations, which may contribute to ADHD.…”

Serotonin Syndrome in the Emergency Department

“…• Spontaneous clonus Serotonin antagonists include cyproheptadine, olanzapine, and chlorpromazine. These agents have 5-HT2a antagonistic activities, although data are both lacking and conflicting in support for their use in SS management [7][8][9]. With these treatment principles, SS can resolve within as early as 24 hours.…”

Adverse Drug Reactions, Intoxications and Interactions of Neuropsychotropic Medications

“…An adverse drug reaction is a response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis ADRs, drug interactions and pharmacogenetics often given Depth of information varies considerably between drugs ADRs, drug interactions, and pharmacogenetics listed but mostly not detailed References given sparingly Table 2 Differential diagnosis of the toxidromes presenting with agitation, delirium, or coma. This table is a modification of the excellent Table 3 (Scotton et al 2019), i.e., abrupt cessation of levodopa or DA agonists (Brunton et al 2017) Slower onset (days to weeks), resolves within 10 days with treatment Hyperthermia >41.1 C, tachycardia, hypertension, tachypnea Neuromuscular hypoactivity (lead pipe rigidity), bradykinesia, hypoactive bowel sounds Table 3. Desired effects (DXEs) and adverse drug reactions (ADRs) explained by pharmacologic target.…”