1. Serotonin Syndrome (Toxicity) Sue Henderson

2. Definition
Potentially life threatening adverse drug reaction caused by excessive serotonin in CNS (Dvir & Smallwood, 2008).

3. Role of Serotonin

4. Serotonin neurotransmission

5. 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).

6. Toxicity (combined bath, tap, plug)
Increase serotonin neurotransmission
Increased serotonin release
Increased serotonin synthesis
Inhibition of serotonin reuptake
“It’s when you combine two drugs with different mechanisms (taps and plugs) that you get into the really serious situations”
Decreased serotonin metabolism
Agonism of serotonin receptors

7. Triad Neuromuscular hyperactivity Autonomic hyperactivity
Altered mental status

8. Clinical Features Neuromuscular Autonomic Mental State Hyper-reflexia
Hyperthermia:
Agitation
Myoclonus
Mild C
Hypomania
Shivering
Severe > 38.5
Anxiety
Tremor
Tachycardia
Confusion
Hypertonia/ rigidity
Diaphoresis
Flushing
Mydriasis

9. Clinical Features
(Boyer & Shannon, 2005)

10. Causes of toxicity
All drugs that directly or indirectly increase serotonin due to:
Overdose - 15% (Isbister et al, 2004 cited in Isbister, Buckley & White, 2007)
Adverse drug effect
Drug interaction
Possible genetic contribution (enhanced sensitivity)
Overdose 15% - so genetic variability plays a part
Adverse drug effect
Drug interaction

11. Drug Groups Associated
Serotonin reuptake inhibitors
MAOI
Serotonin releasing agents
Miscellaneous (Isbister, Buckley & Whyte, 2007)

12. 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)

13. Monoamine oxidase inhibitors
Irreversible monoamine oxidase A inhibitors: Phenelzine, tranylcypromine
Reversible monoamine oxidase A inhibitors: Moclobemide
Others: linezolid (Isbister, Buckley & Whyte, 2007)

14. Serotonin releasing agents
Fenfluramine
Amphetamines
MDMA, ecstasy
Miscellaneous
Lithium
Tryptophan (Isbister, Buckley & Whyte, 2007)

15. Diagnostic Algorithm
(Boyer & Shannon, 2005)

16. 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

17. Spectrum of toxicity
(Boyer & Shannon, 2005)
(Boyer & Shannon, 2005)

18. 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).
Serotonin Antagonists:
Chlorpromazine S/E sedation which is useful S/E hypotension - ensure concurrent volume loading (IV fluids)
Cyproheptadine (anti-histamine anticholinergic characteristics) - can only be administered orally may not be useful in severe
Non selective serotonin antagonist such as atypical anti-psychotics – not as strong evidence base as others (Isbister, Buckley & Whyte, 2007)

19. References
Boyer, E. W., & Shannon, M. (2005). The serotonin syndrome. New England Journal of Medicine, 352(11),
Dvir, Y., & Smallwood, P. (2008). Serotonin syndrome: A complex but easily avoidable condition. General Hospital Psychiatry, 30,
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),