Serotonin Syndrome

Serotonergic Agents

Monoamine Oxidase (MAO) Inhibitors (see Monoamine Oxidase Inhibitors, [[Monoamine Oxidase Inhibitors]])

  • General Comments: MAO inhibition decreases serotonin degradation
  • Clorgyline
  • Furazolidone
  • Isoniazid (see Isoniazid, [[Isoniazid]])
  • Iproniazid
  • Isocarboxazide
  • Linezolid (see Linezolid, [[Linezolid]]): MAO inhibitor (MAO normally degrades serotonin in the brain) and decreases serotonin reuptake
    • FDA Alert (7/26/11): avoid use in conjunction with SSRI’s
  • Methylene Blue (see Methylene Blue, [[Methylene Blue]]): reversible MAO inhibitor (MAO normally degrades serotonin in the brain) and increases serotonin release from stored vesicles
    • FDA Alert (7/26/11): avoid use in conjunction with SSRI’s
  • Moclobemide
  • Nialamid(e)
  • Pargyline
  • Phenelzine (Nardil) (see Phenelzine, [[Phenelzine]])
  • Procarbazine (see Procarbazine, [[Procarbazine]])
  • Selegiline (Anipryl, L-Deprenyl, Eldepryl, Emsam, Zelapar) (see Selegiline, [[Selegiline]])
  • Toloxatone
  • Tranylcypromine

Opiates with Serotonergic Activity (see Opiates, [[Opiates]])

  • Dextromethorphan (see Dextromethorphan, [[Dextromethorphan]]): increases serotonin release from stored vesicles and serotonin reuptake inhibitor
  • Fentanyl (see Fentanyl, [[Fentanyl]]): serotonin reuptake inhibitor
  • Meperidine (Demerol) (see Meperidine, [[Meperidine]]): serotonin reuptake inhibitor
  • Methadone (see Methadone, [[Methadone]]): serotonin reuptake inhibitor
  • Pentazocine (Talwin) (see Pentazocine, [[Pentazocine]]): increases serotonin release from stored vesicles
  • Propoxyphene (Darvon) (see Propoxyphene, [[Propoxyphene]]): serotonin reuptake inhibitor
  • Tramadol (Ultram) (see Tramadol, [[Tramadol]]): phenylpiperidine series opioid, which functions as a serotonin reuptake inihibitor

Selective Serotonin Reuptake Inhibitors (SSRI) (see Selective Serotonin Reuptake Inhibitors, [[Selective Serotonin Reuptake Inhibitors]])

  • Citalopram (Celexa) (see Citalopram, [[Citalopram]])
  • Escitalopram (Lexapro) (see Escitalopram, [[Escitalopram]])
  • Fluoxetine (Prozac) (see Fluoxetine, [[Fluoxetine]])
  • Fluvoxamine (Luvox) (see Fluvoxamine, [[Fluvoxamine]])
  • Paroxetine (Paxil) (see Paroxetine, [[Paroxetine]])
  • Sertraline (Zoloft) (see Sertraline, [[Sertraline]])
  • Vilazodone (Viibryd) (see Vilazodone, [[Vilazodone]])

Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) (see Serotonin-Norepinephrine Reuptake Inhibitors, [[Serotonin-Norepinephrine Reuptake Inhibitors]])

  • Desvenlafaxine (Pristiq) (see Desvenlafaxine, [[Desvenlafaxine]])
  • Duloxetine (Cymbalta, Yentreve) (see Duloxetine, [[Duloxetine]])
  • Levomilnacipran (Fetzima)
  • Milnacipran (Dalcipran, Ixel, Savella)
  • Sibutramine (Meridia, Reductil)
  • Venlafaxine (Effexor) (see Venlafaxine, [[Venlafaxine]])

Tricyclic Antidepressants (see Tricyclic Antidepressants, [[Tricyclic Antidepressants]])

  • General Comments: these agents decrease serotonin reuptake
  • Amitriptyline (Tryptomer, Elavil) (see Amitriptyline, [[Amitriptyline]])
  • Clomipramine (Anafranil) (see Clomipramine, [[Clomipramine]])
  • Desipramine (Norpramin, Pertofrane) (see Desipramine, [[Desipramine]])
  • Doxepin (Adapin, Sinequan) (see Doxepin, [[Doxepin]])
  • Imipramine (Tofranil, Janimine, Praminil) (see Imipramine, [[Imipramine]])
  • Nortriptyline (Pamelor, Aventyl, Norpress) (see Nortriptyline, [[Nortriptyline]])
  • Protriptyline (Vivactil) (see Protriptyline, [[Protriptyline]])
  • Trimipramine (Surmontil) (see Trimipramine, [[Trimipramine]])

Triptans (see Triptans, [[Triptans]])

  • General Comments: 5HT receptor stimulation
  • Almotriptan (Axert, Almogran)
  • Avitriptan (BMS-180,048)
  • Donitriptan (F-11356)
  • Eletriptan (Relpax)
  • Frovatriptan (Frova, Migard, Frovamig)
  • Naratriptan (Amerge, Naramig)
  • Rizatriptan (Maxalt)
  • Sumatriptan (Imitrex, Imigran, Cinie, Illument, Migriptan) (see Sumatriptan, [[Sumatriptan]])
  • Zolmitriptan (Zomig)

Other

  • 5-Hydroxytryptophan (see 5-Hydroxytryptophan, [[5-Hydroxytryptophan]])
    • Epidemiology: possibly etiologic, when used in combination with MAO inhibitors or Selective Serotonin Reuptake Inhibitors (SSRI) (see Selective Serotonin Reuptake Inhibitors, [[Selective Serotonin Reuptake Inhibitors]])
  • Amphetamine (see Amphetamine, [[Amphetamine]])
    • Pharmacology: increases serotonin release from stored vesicles and decreases serotonin reuptake
  • Aripiprazole (Abilify) (see Aripiprazole, [[Aripiprazole]])
    • Epidemiology: serotonin syndrome has been reported when used in conjunction with lamotrigine and cocaine [MEDLINE]
    • Pharmacology: partial agonist at 5-HT1A receptor and antagonist at serotonin reuptake transporter
  • Bath Salts (see Bath Salts, [[Bath Salts]])
    • Pharmacology: increased synaptic concentrations of dopamine, serotonin, and norepinephrine
  • Buproprion (Wellbutrin, Zyban) (see Bupropion, [[Bupropion]])
    • Pharmacology: non-SSRI and non-TCA norepinephrine-dopamine reuptake inhibitor
  • Buspirone (Buspar) (see Buspirone, [[Buspirone]])
    • Pharmacology: 5HT receptor stimulation
  • Carbamazepine (Tegretol) (see Carbamazepine, [[Carbamazepine]])
    • Pharmacology: 5HT receptor stimulation and decreases serotonin reuptake
  • Cocaine (see Cocaine, [[Cocaine]])
    • Pharmacology: increases serotonin release from stored vesicles and decreases serotonin reuptake
  • Codeine (see Codeine, [[Codeine]])
    • Pharmacology: increases serotonin release from stored vesicles
  • Ecstasy (MDMA, E, X, XTC, Molly, Mandy) (see Ecstasy, [[Ecstasy]])
    • Pharmacology: increases serotonin release from stored vesicles
  • Ginseng (see Ginseng, [[Ginseng]])
  • Lamotrigine (Lamictal) (see Lamotrigine, [[Lamotrigine]])
    • Epidemiology: serotonin syndrome has been reported when used in conjunction with aripiprazole and cocaine [MEDLINE]
    • Pharmacology: weak inhibitory effect on 5-HT3 receptor
  • Levodopa (see Carbidopa-Levodopa, [[Carbidopa-Levodopa]])
    • Pharmacology: increases serotonin release from stored vesicles
  • Lithium (see Lithium, [[Lithium]])
    • Pharmacology: direct 5HT receptor stimulation
  • L-Tryptophan (see L-Tryptophan, [[L-Tryptophan]])
    • Pharmacology: increased availability of serotonin precursor
  • Lysergic Acid Diethylamide (LSD) (see Lysergic Acid Diethylamide, [[Lysergic Acid Diethylamide]])
    • Pharmacology: 5HT receptor stimulation
  • Mescaline-Containing Cacti (see Mescaline, [[Mescaline]])
    • Pharmacology: 5HT receptor stimulation
    • Agents
      • Peyote
  • Methamphetamine (see Methamphetamine, [[Methamphetamine]])
    • Pharmacology: indirect neurotransmitter which moves into cytoplasmic vesicles in presynaptic adrenergic neurons –> displaces epinephrine, norepinephrine, dopamine, and serotonin into the cytosol
  • Methylphenidate (Ritalin) (see Methylphenidate, [[Methylphenidate]])
    • Pharmacology: xxx
  • Mirtazapine (Remeron, Avanza, Axit, Mirtaz, Mirtazon, Zispin) (see Mirtazapine, [[Mirtazapine]])
    • Pharmacology: tetracyclic alpha-2 adrenergic heteroreceptor blocker that increases norepinephrine and serotonin release in addition to blocking serotonin receptors
  • Nefazodone (see Nefazodone, [[Nefazodone]])
    • Pharmacology: decreases serotonin reuptake
  • Reserpine (see Reserpine, [[Reserpine]])
    • Pharmacology: increases serotonin release from stored vesicles
  • S-Adenosyl Methionine (see S-Adenosyl Methionine, [[S-Adenosyl Methionine]])
  • St John’s Wort (Hypericum Species) (see St John’s Wort, [[St Johns Wort]])
    • Pharmacology: decreases serotonin reuptake and degradation
  • Trazodone (Desyrel) (see Trazodone, [[Trazodone]])
    • Pharmacology: tetracyclic that blocks serotonin reuptake and has an antagonistic effect at the serotonin 5-HT2 receptor

Serotonin Physiology

  • Serotonin (5-hydroxytryptamine, 5HT) is a central and peripheral nervous system neurotransmitter
    • Serotonin is synthesized from L-tryptophan in the brainstem raphe nucleus and is stored in presynaptic vesicles -> released by neuronal activation
  • Serotonin Metabolism
    • Excess serotonin is taken back up into presynaptic vesicles by active transport or locally metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid
    • Systemic serotonin is metabolized via hepatic mixed function oxidases
      • Inhibition of particular mixed function oxidases by medications or other substances (grapefruit, etc) -> decreased serotonin metabolism -> increased drug effect
  • Serotonin Receceptors: there are 7 distinct 5HT receptors (with further specific subtypes), producing a wide variety of physiologic effects
    • Most central nervous system 5HT receptors are located in the brainstem raphe nuclei
    • The physiologic manifestations of serotonin syndrome are largely due to stimulation of 5HT1a and 5HT2 receptors
  • Serotonergic Projections to Thalamus and Cortex
    • Sleep-Wake Cycles
    • Mood
    • Thermoregulation
    • Appetite
    • Pain Perception
    • Sexual Function
  • Serotonin Projections to Brainstem and Medulla
    • Muscle Tone

Sternbach Criteria for Serotonin Syndrome (1991)

  • Accuracy of Criteria [MEDLINE]
    • Sensitivity 75%
    • Specificity 96%
  • Symptoms Coincide Temporally with Addition of Serotonergic Agent or with Increase in Dose of a Serotonergic Agent
  • At Least Three of the Following Clinical Findings
    • Agitation
    • Altered Mental Status: Delirium (see Delirium, [[Delirium]]), etc
    • Ataxia (see Ataxia, [[Ataxia]])
    • Diaphoresis (see Diaphoresis, [[Diaphoresis]])
    • Diarrhea (see Diarrhea, [[Diarrhea]])
    • Fever/Hyperthermia (see Fever, [[Fever]])
    • Hyperreflexia (see Hyperreflexia, [[Hyperreflexia]])
    • Myoclonus (see Myoclonus, [[Myoclonus]])
    • Shivering
    • Tremor (see Tremor, [[Tremor]])
  • A Neuroleptic Agent Has Not Been Recently Added or Increased in Dose
  • Other Etiologies Have Been Ruled Out
    • Infection
    • Intoxication
    • Metabolic Derangements
    • Substance Abuse
    • Withdrawal

Hunter Serotonin Toxicity Criteria (2003) [MEDLINE]

  • Accuracy of Criteria
    • Sensitivity 84%
    • Specificity 97%
  • Only the Following Variables are Predictive of Serotonin Syndrome
    • Agitation
    • Diaphoresis (see Diaphoresis, [[Diaphoresis]])
    • Hyperreflexia (see Hyperreflexia, [[Hyperreflexia]])
    • Inducible Myclonus (see Myoclonus, [[Myoclonus]])
    • Ocular Myoclonus (see Myoclonus, [[Myoclonus]])
    • Spontaneous Myoclonus (see Myoclonus, [[Myoclonus]])
    • Tremor (see Tremor, [[Tremor]])
  • Decision Rules: in the presence of a serotonergic agent
    • If (spontaneous clonus = yes), then serotonin toxicity = Yes
    • Else If (inducible clonus = yes) and [(agitation = yes) or (diaphoresis = yes)], then serotonin toxicity = Yes
    • Else If (ocular clonus = yes) and [(agitation = yes) or (diaphoresis = yes)], then serotonin toxicity = Yes
    • Else If (tremor = yes) and (hyperreflexia = yes), then serotonin toxicity = Yes
    • Else If (hypertonic = yes) and (temperature > 38 Degrees C) and [(ocular clonus = yes) or (inducible clonus = yes)], then serotonin toxicity = Yes
    • Else serotonin toxicity = No

Clinical Manifestations of Serotonin Syndrome

Cardiovascular Manifestations

  • Arrhythmias: have been reported with citalopram overdose
  • Hypertension (see Hypertension, [[Hypertension]])
  • Hypotension (see Hypotension, [[Hypotension]]): occurs more rarely than hypertension
  • Prolonged Q-T/QRS Prolongation (see Torsade, [[Torsade]]): dose-depedent Q-T prolongation has been reported with citalopram overdose
    • FDA Revised Citalopram Prescribing Information (8/11)
      • Citalopram dose should not exceed 40 mg/day
      • Citalopram is contraindicated with congenital prolonged Q-T
  • Sinus Tachycardia (see Sinus Tachycardia, [[Sinus Tachycardia]])

Dermatologic Manifestations

  • Diaphoresis (see Diaphoresis, [[Diaphoresis]]): due to autonomic system effects
  • Flushing (see Flushing, [[Flushing]])
  • Piloerection: due to autonomic system effects

Gastrointestinal Manifestations

  • Abdominal Cramping (see Abdominal Pain, [[Abdominal Pain]]): due to the high levels of serotonin in gastric and intestinal mucosal enterochromaffin cells
  • Diarrhea (see Diarrhea, [[Diarrhea]]): due to the high levels of serotonin in gastric and intestinal mucosal enterochromaffin cells
  • Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]]): SSRI’s moderately increase risk
  • Hyperactive Bowel Sounds
  • Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]]): due to the high levels of serotonin in gastric and intestinal mucosal enterochromaffin cells

Hematologic Manifestations

Neurologic Manifestations

  • Altered Mental Status: due to serotonergic projections to thalamus and cortex
  • Ataxia/Discoordination (see Ataxia, [[Ataxia]]): due to serotonergic projections to thalamus and cortex
  • Memory Loss: due to serotonergic projections to thalamus and cortex
  • Mydriasis (see Mydriasis, [[Mydriasis]]): due to autonomic system effects
  • Myoclonus (see Myoclonus, [[Myoclonus]]): due to serotonergic projections to brainstem and medulla
    • Spontaneous or inducible
    • May be ocular
  • Seizures (see Seizures, [[Seizures]])
  • Shivering/Shaking: due to serotonergic projections to thalamus and cortex
  • Tremor (see Tremor, [[Tremor]]): due to serotonergic projections to brainstem and medulla
  • Hyperreflexia (see Hyperreflexia, [[Hyperreflexia]]): due to serotonergic projections to brainstem and medulla
  • Muscular Rigidity: due to autonomic system effects
    • May mask clonus

Other Manifestations

  • Fever (see Fever, [[Fever]]): due to serotonergic projections to thalamus and cortex and autonomic system effects

Treatment

Supportive Care

  • Mechanical Ventilation: if required

Withdraw Serotonergic Agents

  • xxx

Activated Charcoal (see Activated Charcoal, [[Activated Charcoal]])

  • Indications
    • SSRI Overdose

Sodium Bicarbonate (see Sodium Bicarbonate, [[Sodium Bicarbonate]])

  • Rationale: not fully understood, and is, in part, an extrapolation from its use in TCA overdosage
    • In animal models, citalopram inhibits sodium/calcium cardiac channels and impairs cardiac conduction
    • Alkalinization may accelerate the recovery of sodium channels and alter the rate of drug unbinding
  • Indications
    • Citalopram Overdose: possible utility in other SSRI overdoses

References

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  • Citalopram overdose-review of cases treated in Swedish hospitals. J Toxicol Clin Toxicol. 1997;35:237-240
  • Citalopram in the treatment of depression and other potential uses in psychiatry. Pharmacotherapy. 1999;19:675-689
  • Speculations on difference between tricyclic and selective serotonin reuptake inhibitor antidepressants on their cardiac effects. Is there any? Curr Med Chem. 1999;6:469-480
  • An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypotheses. 2000;55:218–24
  • QTc interval prolongation associated with citalopram overdose: a case report and literature review. Clin Neuropharmacol. 2001;24:158-162
  • Serotonin syndrome and atypical antipsychotics. Am J Psychiatry. 2002;159:672-3
  • Serotonin syndrome after small doses of citalopram or sertraline. J Clin Psychopharmacol. 2002;20:713–4
  • Olanzapine and serotonin toxicity. Psychiatry Clin Neurosci. 2003;57:241–2
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  • Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004;42:277-285
  • Reversal of citalopram-induced junctional bradycardia with intravenous sodium bicarbonate. Pharmacotherapy. 2005;25:119-12
  • Possible serotonin syndrome with citalopram following cross-titration of clozapine to ziprasidone. Gen Hosp Psychiatry. 2005;27:223–4
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  • The serotonin syndrome. NEJM 2005;352:1112
  • 5-Hydroxytryptamine 1A receptors in the paraventricular nucleus of the hypothalamus mediate oxytocin and adrenocorticotropin hormone release and some behavioral components of the serotonin syndrome. J Pharmacol Exp Ther. 2005;313:1324–30
  • Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists. Pharmacotherapy 2006;26:1784
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  • Linezolid and Serotonin Syndrome. Prim Care Companion J Clin Psychiatry. 2009; 11(6): 353–356
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  • Serotonin syndrome precipitated by fentanyl during procedural sedation. J Emerg Med. 2010 May;38(4):477-80 [ MEDLINE]
  • Serotonin Syndrome in the Setting of Lamotrigine, Aripiprazole, and Cocaine Use. Case Rep Med. 2015;2015:769531. doi: 10.1155/2015/769531. Epub 2015 Aug 2 [MEDLINE]