Serotonin Syndrome Toxicity Sue Henderson Definition Potentially life

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 • • • 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: 1. Overdose - 15% (Isbister et al, 2004 cited in Isbister, Buckley & White, 2007) 2. Adverse drug effect 3. Drug interaction 4. 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, 284287. 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.