Serotonin Syndrome (Toxicity)

Sue Henderson
 Definition
• Potentially life threatening adverse drug
reaction caused by excessive serotonin in
CNS (Dvir & Smallwood, 2008).
Role of Serotonin
Serotonin neurotransmission
 Cause: Serotonin toxicity
Pharmacological agents:
• Increase serotonin neurotransmission
• Increased serotonin synthesis
• Decreased serotonin metabolism
• Increased serotonin release
• Inhibition of serotonin reuptake
• Agonism of serotonin receptors (Dvir & Smallwood,
2008).
Toxicity (combined bath, tap, plug)
Increase serotonin neurotransmission
Increased serotonin release
Increased serotonin synthesis
Inhibition of serotonin reuptake

Decreased serotonin metabolism

Agonism of serotonin receptors
 Triad
1. Neuromuscular hyperactivity
2. Autonomic hyperactivity
3. Altered mental status
 Clinical Features
Neuromuscular Autonomic Mental State
Hyper-reflexia Hyperthermia: Agitation
Myoclonus Mild 38.5 C Hypomania
Shivering Severe > 38.5 Anxiety
Tremor Tachycardia Confusion
Hypertonia/ Diaphoresis
rigidity
Flushing
Mydriasis
Clinical Features

(Boyer &
Shannon,
2005)
 Causes of toxicity
All drugs that directly or indirectly
increase serotonin due to:
1. Overdose - 15% (Isbister et al, 2004 cited in Isbister, Buckley & White,
2007)

2. Adverse drug effect

3. Drug interaction

• Possible genetic contribution (enhanced

sensitivity)
 Drug Groups Associated
• Serotonin reuptake inhibitors
• MAOI
• Serotonin releasing agents
• Miscellaneous (Isbister, Buckley & Whyte, 2007)
Serotonin Reuptake Inhibitors
• SSRIs: Fluoxetine, fluvoxamine,
paroxetine, citalopram, sertraline,
escitalopram
• Other antidepressants: Venlafaxine,
clomipramine, imipramine,
• Opioid analgesics: pethidine, tramadol,
fentanyl, dextromethorphan
• St. John’s Wort (Isbister, Buckley & Whyte, 2007)
 Monoamine oxidase inhibitors
• Irreversible monoamine oxidase A
inhibitors: Phenelzine, tranylcypromine
• Reversible monoamine oxidase A
inhibitors: Moclobemide
• Others: linezolid (Isbister, Buckley & Whyte, 2007)
 Serotonin releasing agents
• Fenfluramine
• Amphetamines
• MDMA, ecstasy

Miscellaneous
• Lithium
• Tryptophan (Isbister, Buckley & Whyte, 2007)
Diagnostic Algorithm

(Boyer &
Shannon,
2005)
 Prevention
• Avoid serotonergic drugs but if not
possible minimize use of serotonergic
drugs (Isbister, Buckley & Whyte, 2007)
• Avoid MAOI (to prevent severe toxicity)
(Isbister, Buckley & Whyte, 2007) but if not possible

ensure a 2 week washout between

stopping a MAOI and starting an SSRI
Spectrum of toxicity

(Boyer &
Shannon,
2005)
 Treatment
Mild
• Discontinue all serotonergic agents
• Supportive care: Cooling, IV fluids (Hydration,
facilitate diuresis)
• Benzodiazepines (prevent agitation)
Moderate
• Above + Serotonin antagonists (blockers)
Severe
• Above + intubation, paralysis & sedation (Dvir &
Smallwood, 2008).
 References
Boyer, E. W., & Shannon, M. (2005). The
serotonin syndrome. New England Journal of
Medicine, 352(11), 1112-1120.
Dvir, Y., & Smallwood, P. (2008). Serotonin
syndrome: A complex but easily avoidable
condition. General Hospital Psychiatry, 30, 284-
287.
Isbister, G. K., Buckley, N. A., & Whyte, I. M.
(2007). Serotonin toxicity: A practical approach
to diagnosis and treatment. Medical Journal of
Australia, 187(6), 361-365.