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Savvy Psychopharmacology

How to prevent serotonin syndrome from drug-drug interactions

Vol. 10, No. 03 / March 2011

Practice Points

Know which drugs are associated with serotonin syndrome.

• Understand the types of drug interactions that may precipitate serotonin syndrome and use drug information resources such as Micromedex, Lexicomp, Physicians’ Desk Reference, AHFS Drug Information, and Facts and Comparisons.

Know what prescription medications your patient is receiving from other providers as well as any over-the-counter and illicit drugs they may be using.

Ms. B, age 22, is brought to the emergency department (ED) by her roommate for evaluation of confusion. Ms. B has a history of migraines and major depressive disorder and has been taking fluoxetine, 40 mg/d, for 1 year. A week ago, she started amitriptyline, 50 mg/d, when her migraines became more frequent. According to her roommate, Ms. B experienced a migraine early in the morning and had taken 2 doses of sumatriptan, 50 mg. She later complained of nausea and vomiting, and when her roommate returned from work that evening Ms. B was disoriented and her leg muscles would not stop twitching.

In the ED, Ms. B is diaphoretic and increasingly agitated. Blood alcohol and urine drug screens are negative. Blood glucose is 95 mg/dL. Complete blood count, basic metabolic panel, liver function, and kidney function tests are within normal limits. Her physical examination reveals a blood pressure of 130/85 mm Hg, heart rate of 130 beats per minute, respiratory rate of 21 breaths per minute, and body temperature of 38.6°C (101. 4°F). Myoclonus and hyperreflexia affect her lower extremities. Ms. B is admitted with a preliminary diagnosis of serotonin (5-HT) syndrome.

Serotonin syndrome: What is it?

Serotonin syndrome is a rare but potentially serious adverse event resulting from excess serotonergic activity at central and peripheral 5-HT2A and 5-HT1A receptors. Serotonin syndrome toxicity ranges from relatively mild to severe, and may be lethal. Symptoms develop rapidly—within hours—and may include altered mental status, clonus, tremor, hyperthermia, diaphoresis, tachycardia, mydriasis, and akathisia ( Table 1 ). 1-3 Fortunately, if recognized promptly and offending agents are discontinued, serotonin syndrome often resolves within a couple of days.

The differential diagnosis includes neuroleptic malignant syndrome (NMS), anticholinergic toxicity, and malignant hyperthermia. 1 Differentiating serotonin syndrome from NMS can be difficult. NMS results from dopamine blockade; however, many NMS symptoms are similar to those experienced with serotonin syndrome. Obtaining a history of recent medication and/or illicit drug use, conducting a physical exam, and evaluating the patient’s clinical course help clarify a likely diagnosis. NMS generally has a slower onset—within days—and patients demonstrate neuromuscular rigidity and bradykinesia rather than the neuromuscular hyperreactivity (myoclonus, hyperreflexia) seen with serotonin syndrome.

Table 1

Characteristics of serotonin syndrome*

Recent addition or dose increase of a serotonergic agent

Tremor plus hyperreflexia

Muscle rigidity plus fever plus clonus

Spontaneous clonus

Ocular clonus plus agitation or diaphoresis

Inducible clonus plus agitation or diaphoresis

*A combination of these characteristics may indicate serotonin syndrome

Source: References 1-3

Interactions that increase risk

A drug interaction is a pharmacologic or clinical response to a combination of medications that differs from the agents’ known effects if given on their own. In the context of serotonin syndrome, the serotonergic activity of a drug can be increased as a result of a pharmacokinetic (PK) interaction, a pharmacodynamic (PD) interaction, or a combination of both.

PK interactions may result from the coadministration of a drug that alters absorption, distribution, metabolism, or elimination parameters of \>1 other drugs. Serotonergic antidepressants usually are metabolized by cytochrome P450 (CYP450) enzymes. Any drug that inhibits a CYP450 enzyme responsible for biotransformation of 1 of these antidepressants may increase exposure to the antidepressant and raise the risk of serotonin syndrome. CYP450 inhibitors include prescription medications as well as seemingly benign over-the-counter (OTC) drugs.

PD interactions may result from an additive or synergistic pharmacologic effect caused by coadministration of 2 agents that produce the same or similar end result. In Ms. B’s case, agents inhibiting 5-HT reuptake (fluoxetine and amitriptyline) were combined with a direct 5-HT agonist (sumatriptan). The resulting potentiation of 5-HT via 2 distinct mechanisms increased Ms. B’s risk of serotonin syndrome. Similarly, simultaneous use of 2 agents potentiating 5-HT through identical mechanisms, such as combining 2 serotonin reuptake inhibitors, also may increase the risk of serotonin syndrome ( Table 2 ). 1

A combination of PK and PD interactions also may increase the risk of serotonin syndrome. For example, Ms. B is taking fluoxetine and amitriptyline for different therapeutic reasons. Both of these agents inhibit 5-HT reuptake, potentiating 5-HT. In addition, amitriptyline is a substrate for CYP2D6 and fluoxetine is a robust CYP2D6 inhibitor. The coadministration of fluoxetine with tricyclic antidepressants (TCAs) results in a 4- to 5-fold increase in TCA exposure, which may increase the risk of serotonin syndrome and other sequelae from TCA toxicity. 4,5

Table 2

Drugs associated with serotonin syndrome

Drugs that increase 5-HT release

Amphetamine, cocaine, MDMA (ecstasy), mirtazapine, phentermine, reserpine

Drugs that inhibit 5-HT reuptake

Amitriptyline, amphetamine, bupropion, Citalopram, clomipramine, cocaine, desipramine, dextromethorphan, doxepin, duloxetine, escitalopram, fentanyl, fluoxetine, fluvoxamine, Hypericum perforatum (St. John’s wort), imipramine, MDMA, meperidine, nefazodone, nortriptyline, paroxetine, protriptyline, sertraline, tramadol, trazodone, venlafaxine

Drugs that decrease 5-HT metabolism

Isocarboxazid, linezolid, phenelzine, selegiline, tranylcypromine

Drugs that are direct 5-HT agonists

Almotriptan, buspirone, dihydroergotamine, eletriptan, frovatriptan, LSD, naratriptan, rizatriptan, sumatriptan, zolmitriptan


L-tryptophan, carbamazepine, carisoprodol, droperidol, levodopa, lithium, metoclopramide, pentazocine, phenylpropanolamine

5-HT: serotonin; LSD: lysergic acid; MDMA: methylenedioxymethamphetamine

Source: Reference 1

Preventing serotonin syndrome

The warnings highlighted in drug interaction references or pharmacy databases often mean that clinicians have to evaluate whether the risk of combining medications outweighs the therapeutic benefits. It is unknown why some patients tolerate multiple agents potentiating 5-HT, and practitioners cannot predict when and in whom serotonin syndrome may occur. However, the following strategies may help minimize these risks:

Know which drugs are associated with serotonin syndrome. Concomitant use of these drugs and agents that inhibit metabolism of these drugs increases risk.

Know which drugs your patient is taking. Patients may see several prescribers, which makes it essential to ask what they are receiving from other practitioners. Also inquire about OTC and illicit drug use.

Check for interactions. If you are unfamiliar with a new drug or drug-drug combination, check multiple resources for potential interactions. The potential severity of an interaction and the detail in which interactions are described—such as class effects vs documented cases or studies—differs among drug interaction resources, which means a potential interaction may be “flagged” in 1 source but not another. Electronic resources such as Micromedex and Lexicomp often have detailed literature summaries and citations so clinicians can review primary literature that lead to the categorization of an interaction. Using multiple sources is helpful when trying to translate warnings in the context of a clinical scenario.

Weigh the risks and benefits. Prescribers know that not all treatments are benign, but not treating a condition also may be detrimental. Identify potential alternative pharmacologic or nonpharmacologic treatments when possible. Discuss the risks and benefits of drug therapy with patients.

Counsel your patients. Although it is not possible to predict who may experience serotonin syndrome, educate patients on what symptoms to look for. Instruct them to call their prescriber or pharmacist if they show symptoms that may be consistent with serotonin syndrome.

Related Resource

• MedWatch: The FDA Safety Information and Adverse Event Reporting Program.

Drug Brand Names

  • Aripiprazole • Abilify
  • Almotriptan • Axert
  • Amitriptyline • Elavil
  • Bupropion • Wellbutrin, Zyban
  • Buspirone • BuSpar
  • Carbamazepine • Carbatrol, Equetro, others
  • Carisoprodol • Soma
  • Citalopram • Celexa
  • Desipramine • Norpramin
  • Dihydroergotamine • Migranal
  • Doxepin • Adapin, Silenor
  • Droperidol • Inapsine
  • Duloxetine • Cymbalta
  • Eletriptan • Relpax
  • Escitalopram • Lexapro
  • Fentanyl • Sublimaze, others
  • Fluoxetine • Prozac
  • Fluvoxamine • Luvox
  • Frovatriptan • Frova
  • Imipramine • Tofranil
  • Isocarboxazid • Marplan
  • Levodopa • Dopar, Larodopa, others
  • Linezolid • Zyvox
  • Lithium • Eskalith, Lithobid
  • Meperidine • Demerol
  • Metoclopramide • Reglan, Metozol
  • Mirtazapine • Remeron
  • Naratriptan • Amerge
  • Nefazodone • Serzone
  • Nortriptyline • Aventyl, Pamelor
  • Paroxetine • Paxil
  • Pentazocine • Talwin
  • Phenelzine • Nardil
  • Phentermine • Fastin, Adipex-P
  • Protriptyline • Vivactil
  • Reserpine • Serpasil
  • Rizatriptan • Maxalt
  • Selegiline • Carbex, Eldepryl, others
  • Sertraline • Zoloft
  • Sumatriptan • Imitrex, Alsuma
  • Tramadol • Ultram, Ultracet, others
  • Tranylcypromine • Parnate
  • Trazodone • Desyrel, Oleptro
  • Venlafaxine • Effexor
  • Zolmitriptan • Zomig


Dr. Jeffrey Bishop receives grant/research support from Ortho-McNeil-Janssen.

Dr. Danielle Bishop reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.


1. Beyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352:1112-1120.

2. Dunkley EJ, Isbister GK, Sibbritt D, et al. The TTunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96:635-642.

3. Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;148:705-713.

4. Preskorn SH, Beber JH, Faul JC, et al. Serious adverse effects of combining fluoxetine and tricyclic antidepressants. Am J Psychiatry. 1990;147-532.

5. Preskorn SH, Alderman J, Chung M, et al. Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J Clin Psychopharmacol. 1994;14:90-98.

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