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
- 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]])
- 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
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
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
Activated Charcoal (see Activated Charcoal, [[Activated Charcoal]])
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
- Mechanism of reversal of toxic effects of amitriptyline on cardiac Purkinje fibers by sodium bicarbonate. J Pharmacol Exp Ther. 1984;231:387-394
- 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
- Serotonin syndrome: a brief review. Can Med Assoc J. 2003;168:1439–42
- Cardiotoxicity and late onset seizures with citalopram overdose. J Emerg Med. 2003;25:163-166
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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
- Serotonin toxicity caused by an interaction between fentanyl and paroxetine. Can J Anaesth. 2008 Aug;55(8):521-5 [ MEDLINE]
- Linezolid and Serotonin Syndrome. Prim Care Companion J Clin Psychiatry. 2009; 11(6): 353–356
- The role of methylene blue in serotonin syndrome: a systematic review. Psychosomatics. 2010 May;51(3):194-200
- 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]