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 neurotransmissionIncreased serotonin releaseIncreased serotonin synthesisInhibition of serotonin reuptake

Decreased serotonin metabolismAgonism of serotonin receptors

Triad

• Neuromuscular hyperactivity

• Autonomic hyperactivity

• 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/rigidity

Diaphoresis

Flushing

Mydriasis

Clinical Features

(Boyer & Shannon, 2005)

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)

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.