Safety Information

Trans-Tasman Early Warning System - Alert Communication

Advice about serotonin syndrome

Information for consumers and caregivers
Information for healthcare professionals
Review Summary
What actions are Medsafe taking?
How to report adverse events
Further information

Serotonin syndrome (also referred to as serotonin toxicity) is a known adverse reaction associated with the use of many drugs, including selective serotonin reuptake inhibitor (SSRI) antidepressants (see Table 2 below).

Serotonin syndrome develops when there is excess serotonin in the central nervous system (brain). This can occur when:

starting or increasing the dose of a serotonergic medicine (drug that enhances the effects of serotonin such as some antidepressants),
taking two serotonergic agents together,
in overdose

Information for consumers and caregivers

The benefits of taking antidepressants outweigh the risk of harm in the majority of people.
Serotonin syndrome can occur when starting one of the medicines in Table 2, when increasing the dose, or when starting another medicine that increases serotonin levels.
Serotonin syndrome manifests as a combination of symptoms. Symptoms may include alterations of mental state (eg, confusion, anxiety and agitation), changes to voluntary muscle movement (eg, spasms, tremors and stiffness) and changes to internal body control systems (eg, raised body temperature, sweating, diarrhoea, rapid heart and breathing rate). Signs and symptoms are outlined in Table 1.
If you experience any symptoms suggestive of serotonin syndrome when taking an SSRI or another medicine as listed in Table 2 seek medical advice immediately.
Medsafe cannot give advice about an individual’s medical condition. If you have any concerns about a medicine you are taking Medsafe encourages you to talk to your healthcare professional.

Information for healthcare professionals

The overall benefit-risk of harm balance for serotonergic medicines remains positive.
Discuss the benefits and risk of harms of treatment with serotonergic medicines, including possible symptoms associated with serotonin syndrome, with patients before commencing therapy, with dose increases or with the addition of another serotonergic agent.
Serotonin syndrome diagnosis is based on ingestion of a serotonergic agent, presence of a combination of different symptoms and exclusion of other causes.
Symptoms may include alterations to mental status (eg, confusion, anxiety and agitation), autonomic changes (eg, hyperthermia, hypertension, tachypnoea, diaphoresis, diarrhoea and tachycardia) and neuromuscular effects (eg, clonus, tremors, hyperreflexia and hypertonia). The cardinal sign is clonus.
Symptoms of serotonin syndrome usually occur within hours to days of taking the medicine.
Treatment involves stopping the serotonergic agent and providing supportive care.
Report any adverse reactions to the Centre for Adverse Reactions Monitoring (CARM).

Review Summary

The Centre for Adverse Reactions Monitoring (CARM) recently received a report of a patient who experienced serotonin syndrome after taking their first dose of escitalopram, an SSRI. While this reaction is a predictable consequence of excess serotonin, this report to CARM highlights that this syndrome may occur after only one dose of an SSRI, without any other concomitant medication.

Onset and Treatment

In this case, the patient experienced symptoms within 24 hours of starting escitalopram. In other cases of serotonin syndrome reported to CARM, the majority also occurred within hours or days of starting or changing the dose of a serotonergic agent or the addition of another serotonergic agent.

Research shows that of those affected, approximately 75% experience symptoms within 24 hours of initiation, change in dose or overdose of the serotonergic agent [Boyer]¹.

Symptoms usually resolve within 24 hours with treatment [Volpi-Abadie]². Treatment involves stopping the serotonergic agent and providing supportive care.

Symptoms and Diagnosis

The symptoms of serotonin syndrome vary in severity, from mild symptoms that may not interfere with daily life to a potentially life-threatening condition characterised by severe hyperthermia (raised body temperature), muscle rigidity (stiffness) and multiple organ failure [Isbister³, Alusik⁴].

Diagnosis is based on drug history, physical examination and exclusion of other causes. The patient must be taking a serotonergic agent such as an SSRI and have at least three of the following range of symptoms [adapted from Volpi-Abadie², Isbister³].

Table 1: Signs and symptoms of serotonin syndrome

Alterations of mental state	Agitation or restlessness Confusion Anxiety
Autonomic effects (effects on functioning of internal organs)	Hypertension (raised blood pressure) Tachycardia (rapid heart rate) Hyperthermia (raised body temperature) Tachypnoea (rapid breathing) Mydriasis (dilation of the pupil) Diaphoresis (profuse sweating) Shivering Vomiting Diarrhoea Arrhythmia (irregular heart rate)
Neuromuscular effects (effects on nerves that control voluntary muscle movement)	Tremors Clonus (involuntary muscle spasms) Hyperreflexia (over responsive reflexes) Hypertonia (muscle rigidity)

Table 2: Medicines and drugs linked to serotonin syndrome (list not exhaustive)

Medicine/Drug Group	Examples
Selective Serotonin Reuptake Inhibitors (SSRIs)	Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Dapoxetine*
Tricyclic Antidepressants (TCAs)	Clomipramine, Imipramine, Amitriptyline, Nortriptyline
Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs)	Venlafaxine, Duloxetine
Atypical Antidepressants	Mirtazapine
Monoamine Oxidase Inhibitors (MAOIs)	Moclobemide, Phenelzine, Tranylcypromine
Opioid Analgesics	Pethidine, Fentanyl, Tramadol
Antimigraine Agents	Sumatriptan, Rizatriptan, Zolmitriptan
Antinausea Agents	Ondansetron, Granisetron
Herbal Products	St John's wort
Miscellaneous	Methylene Blue, Linezolid (antibiotic), Dextromethorphan (cough suppressant)

*Not indicated for depression

References

Boyer EW, Shannon M. 2005. The Serotonin Syndrome. New England Journal of Medicine 352:1112–1120.
Volpi-Abadie J, Kaye AM, Kaye AD. 2013. Serotonin Syndrome. The Ochsner Journal 13(4): 533-540.
Isbister GK, Buckley, NA, Whyte IM. 2007. Serotonin toxicity: a practical approach to diagnosis and treatment. Medical Journal of Australia 187(6): 361-365.
Alusik S, Kalatova D, Paluch Z. 2014. Serotonin syndrome. Neuroendocrinology Letters 35(4): 265-273.

What actions are Medsafe taking?

Medsafe is continuing to monitor reports of adverse events to SSRIs as with all medicines.

How to report adverse events

Online	Submit a CARM report Prescribers can also submit a report using the online reporting tool available in patient management software.
Paper	Download a consumer reporting form (Word Document, 61KB, 1 page) Download a healthcare professional reporting form (PDF, 292 KB, 2 pages) Submit completed forms by emailing CARMreport@health.govt.nz or mail (Medsafe, Ministry of Health, 133 Molesworth Street, Thorndon, Wellington, 6011).
Email	CARMreport@health.govt.nz

Medsafe cannot give advice about an individual’s medical condition. If you have any concerns about a medicine you are taking Medsafe encourages you to talk to your healthcare professional.