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-HT_1A and 5-HT_2A subtypes), 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.

Keywords: Serotonin syndrome; neuroleptic malignant syndrome; novel psychoactive substances; serotonin toxicity; toxidromes; tryptophan hydroxylase inhibitors.

Figure 1.

Mechanisms of serotonin syndrome: (1) Increased levels of L-tryptophan will lead to increased levels of endogenous 5-HT; a step catalysed by the enzyme tryptophan hydroxylase 2 (TPH2). (2) Increased presynaptic concentrations of 5-HT due to inhibition of serotonin metabolism by MAOIs. (3) Increased 5-HT release by drugs including amphetamines and their derivatives, cocaine, MDMA, and levodopa. (4) Direct or indirect activation of postsynaptic 5-HT_1A receptors. (5) Direct or indirect antagonism of postsynaptic 5-HT_2A receptors is thought to enhance the effect of 5-HT_1A agonists. (6) Increased synaptic levels of 5-HT due to inhibition of the SERT by reuptake inhibitors such as SSRIs, and TCAs. MAOIs indicate monoamine oxidase inhibitors; MDMA, 3,4-methylenedioxy-methamphetamine; SERT, serotonin reuptake transporter protein; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressant.

Figure 2.

The spectrum of clinical features in serotonin syndrome. GCS indicates Glasgow Coma Scale. Source: Buckley et al.

Figure 3.

The Hunter Serotonin Toxicity Criteria: for diagnosing serotonin syndrome. Note that the requirement for the presence of some form of neuromuscular excitation, the sine qua non for a diagnosis of serotonin syndrome. *The presence of temperature ⩾38.5°C and/or marked hypertonia or rigidity (especially truncal) indicates severe SS with a risk of progression with respiratory compromise.