Serotonin syndrome

Correspondence to Dr Stuart Maitland, Clinical & Translational Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, Tyne and Wear, UK; [email protected]

Key learning points

• Serotonin syndrome can be life threatening in patients with new or altered serotonergic therapy.

• Clinicians should be aware to the cardinal features of altered mental state, autonomic hyperactivity and neuromuscular abnormalities.

• Fever indicates severe disease requiring urgent inpatient monitoring and assessment.

What is serotonin syndrome?

The serotonin syndrome is a life-threatening adverse drug reaction resulting from excess serotonergic agonism due to interactions between multiple drugs, poisoning or less commonly due to therapeutic action of a single drug.

Aetiology/pathophysiology

Serotonin, or 5-hydroxytryptamine (5-HT), is a neurotransmitter produced from L-tryptophan (see figure 1). 5-HT receptors comprise 14 receptor subtypes, divided into seven groups (5-HT1–5-HT7).¹ Serotonergic neurons are found throughout the nervous system, both peripheral and central (primarily the midline raphe nuclei of the brainstem). 5-HT receptors are expressed in the uterus, heart, gastrointestinal tract, blood vessels and platelets.²

Serotonergic neurons have many functions and are involved in regulating affect, food intake, wakefulness, thermoregulation, vascular tone, nausea, pain, sexual behaviour, nociception and motor tone (figure 1).² 5-HT receptor agonists include ‘triptans’ (eg, sumatriptan used to treat migraine) and metoclopramide (prokinetic agent for managing nausea), although neither of these are likely to cause serotonin syndrome.³ Antagonists include ondansetron (treatment of nausea), as well as cyproheptadine (used to control the symptoms of carcinoid or serotonin syndrome).⁴ There are also many other drugs which are involved at various stages of the serotonergic pathway, which can cause serotonin syndrome (table 1).

Table 1

Causative agents for serotonin syndrome

Increase in serotonin production L-tryptophan Inhibition of serotonin metabolism Phenelzine Moclobemide Selegiline Linezolid Methylthioninium chloride Increase in serotonin release Amphetamines Methylphenidate Serotonin receptor agonism Buspirone Lithium

Inhibition of serotonin reuptake SSRIs MAOIs (eg, tranylcypromine) Tricyclic antidepressants Venlafaxine Trazodone Dextromethorphan Tramadol Pethidine Fentanyl Duloxetine Bupropion St John’s wort

Adapted with permission from Thanacoody 2016.¹²

Underlined agents have stronger evidence for severe serotonin syndrome based on pharmacovigilance.⁷

MAOI, monoamine oxidase inhibitors; SSRIs, selective serotonin reuptake inhibitors.

Many drugs that either interact directly with 5-HT receptors or are involved in the synthesis or metabolism of 5-HT are implicated in serotonin syndrome, including monoamine oxidase...