Serotonin Syndrome Cristian Falup-Pecurariu Department of Neurology Faculty of Medicine, Transilvania University Brasov, Romania Introduction • the Serotonin Syndrome - medication induced condition • serotoninergic hyperactivity • administration of drugs that increase serotonergic transmission • in patients treated for depression (the most common group), bipolar affective disorder, obsessive-compulsive disorder, eating disorders with depression, Parkinson’s disease, migraines, HIV/AIDS, drugs abuse. • Potentially lethal • Incidence: - rising -↑ use of serotonergic drugs - many cases go unrecognized Ables AZ, Nagubilli R. Am Fam Physician. 2010 May 1;81(9):1139-42. Gordon, M. F., & Leder, A. N. Movement Disorder Emergencies, 2012; 217–239. Signs and symptoms of serotonin toxicity Neuromuscular: Autonomic: • Tremor • Mydriasis • Hyperreflexia • Diaphoresis • Clonus • Tachycardia • Tachypnea Mental status: • Agitation • Excitement • Restlessness • Confusion • Delirium Foong AL, Grindrod KA, Patel T, Kellar J. Can Fam Physician. 2018;64(10):720-727 Boyer EW, Shannon M. N Engl J Med. 2005 Mar 17;352(11):1112-20 Boyer EW, Shannon M. N Engl J Med. 2005 Mar 17;352(11):1112-20 Sternbach Criteria Hunter Criteria Inclusion Criteria Presence of serotonergic medication Presence of serotonergic medication Exclusion Criteria Presence of other possible disease etiologies (e.g., infection, substance None abuse and withdrawal) and/or recent addition (or increase in dose) of neuroleptic medication. At least three of the following signs/symptoms: Any of the following combinations of primary (1) or secondary (2) Mental status changes (confusion, hypomania) signs/symptoms: Agitation 1: Spontaneous clonus alone Myoclonus 1: Inducible clonus AND Signs 2: Agitation or diaphoresis And Hyperreflexia 1: Ocular clonus AND Symptoms 2: Agitation or diaphoresis Diaphoresis 1: Tremor AND Shivering 2: Hyperreflexia Tremor 1: Hypertonicity AND fever (temperature >38) AND Diarrhea Incoordination 2: Ocular clonus or inducible clonus Fever Francescangeli J et al. Int J Mol Sci. 2019 May 9;20(9):2288 Diagnosis Ables AZ, Nagubilli R. Am Fam Physician. 2010 May 1;81(9):1139-42 Boyer EW, Shannon M. N Engl J Med. 2005 Mar 17;352(11):1112-20 Pathophysiology Boyer EW, Shannon M. N Engl J Med. 2005 Mar 17;352(11):1112-20 Drugs MAOIs: Opiates: Serotonin precursors: SSRIs: For depression • Meperidine • L -tryptophan • Paroxetine • Trancylcypromine • Fentanyl • 5- • Sertraline • Phenelzine • Methadone hydroxytryptophan • Nialamid • Fluoxetine • Tramadol Triptans • Iproniazid • • Fluvoxamine • Isocarboxazid Dextromethorphan (controversial): • Citalopram • Pargyline (found in • Sumatriptan SNRIs: • Clorgiline antitussives) • Zolmitriptan • Venlafaxine • Moclobemide • Dextropropoxyphene • Rizatriptan • Milnacipran (reversible) • Pentazocine • Naratriptan • Toloxatone (reversible) Antihistamines: • Almotriptan • Duloxetine For Parkinson’s disease • Chlorphenamine • Frovatriptan • Sibutramine • Selegilene • Brompheniramine • Eletriptan Tricyclic antidepressants: For cancer Serotonin releasers: Miscellaneous: • Procarbazine • Clomipramine • Amfetamine • Lithium For infection • Imipramine • • Linezolid MDMA (ecstasy) • Furazolidone Sun-Edelstein C, Tepper SJ, Shapiro RE. Expert Opin Drug Saf. 2008 Sep;7(5):587-96 Francescangeli J et al. Int J Mol Sci. 2019 May 9;20(9):2288. Drugs implicated in severe SS Combinations of drugs: Individual drugs: • Trazodone+ buspirone • Fluoxetine+ sertraline • Almotriptan • Fluoxetine+ Tramadol • Eletriptan • Clomipramine+ MAO inhibitor as tranylcypromine, • Naratriptan fenelzine and benzatropine • Clomipramine+ trazodone • Rizatriptan • Clomipramine+ moclobemide • Sumatriptan • All SSRIs in combination with each other • Zolmitriptan • Venlafaxine+ lithium • Venlafaxine+ moclobemide • Dihydroergotamine • Dextromethorphan+ paroxetine • Clomipramine • Dextromethorphan+ moclobemide • Paroxetine • Venlafaxine+ fluoxetine • Venlafaxine+ mirtazapine • Ecstasy • Bromocriptine+ levodopa and carbidopa Bijl D. Neth J Med. 2004 Oct;62(9):309-13 Differential Diagnosis Francescangeli J et al. Int J Mol Sci. 2019 May 9;20(9):2288. Serotonin syndrome Neuroleptic malignant syndrome Cause of syndrome Dopamine agonist Serotonin Dopamine antagonists agonist Withdrawal of dopamine agonists Onset of signs and symptoms Within minutes to hours Gradually in days to weeks Resolution of symptoms Improves in <24 h Slower to resolve (average of 9 days) Hyperthermia >38.0°C/100.4 F 45% >90% Altered level of consciousness 50% >90% Autonomic dysfunction 50–90% >90% Muscle rigidity 50% >90% Leukocytosis 11% >90% Increased creatinine 15% >90% phosphokinase level Elevated liver transaminase 8% >75% Metabolic acidosis 9% Common Hyperreflexia Very common Rare Myoclonus Very common Rare Therapy: Dopamine agonists Exacerbate condition Improve Therapy: Serotonin antagonists May improve condition No effect Gordon, M. F., & Leder, A. N. Movement Disorder Emergencies, 2012; 217–239. Management Ables AZ, Nagubilli R. Am Fam Physician. 2010 May 1;81(9):1139-42 Foong AL, et al. 2018;64(10):720-727 Foong AL. et al. 2018;64(10):720-727 Gordon, M. F., & Leder, A. N. Movement Disorder Emergencies, 2012; 217–239 Conclusions • Serotonin syndrome is a potentially fatal condition caused by drugs of abuse, medications that affect serotonin metabolism. • Tremor or clonus and hyperreflexia should lead the clinician to consider the diagnosis of the serotonin syndrome. The Hunter Serotonin Toxicity Criteria are generally considered the most appropriate for diagnosing this disease. • The combination of an MAOI with an SSRI, and SNR or another MAOI is the most dangerous combination and the most likely to result in SS. • Differential diagnoses includes neuroleptic malignant syndrome, anticholinergic toxicity, malignant hyperthermia, antidepressant discontinuation syndrome • The most important treatment is prevention!.