Evidence-Based Reviews

Serotonin syndrome: How to avoid, identify, & treat dangerous drug interactions

Current Psychiatry. 2003 May;2(5):14-24

References

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Table 2

Serotonergic agents and their actions

Actions	Agents
Inhibit serotonin reuptake	Fluoxetine, sertraline, citalopram, escitalopram, paroxetine, clomipramine, venlafaxine, fluvoxamine, tramadol, trazodone, nefazodone, tricyclic antidepressants, amphetamine, cocaine, dextromethorphan, meperidine, St. John’s wort
Increases serotonin synthesis	Tryptophan
Inhibit serotonin metabolism	Phenelzine, tranylcypromine, isocarboxazid, selegiline (deprenyl), linezolid, moclobemide
Increase serotonin release	MDMA (“Ecstasy”), amphetamine, cocaine, fenfluramine
Increase serotonin activity	Lithium, ECT
Serotonin receptor agonists	Buspirone, sumatriptan and other “triptans” used for migraine

Atypical antipsychotics. Original diagnostic criteria for serotonin syndrome excluded the addition of, or increase in, an antipsychotic prior to the syndrome’s onset.¹ However, serotonin syndrome has been reported with combinations of risperidone with paroxetine,¹⁹ olanzapine with mirtazapine and tramadol,²⁰ and olanzapine with lithium and citalopram.²¹ The 5HT2 antagonist effect of these atypical antipsychotics may have led indirectly to overactivation of 5HT1a receptors and serotonin syndrome. In each case, neuroleptic malignant syndrome was ruled out.

Table 3

Signs and symptoms that differentiate 5 hyperthermic states

Hyperthermic state	Symptoms/signs	Lab findings	Cause
Serotonin syndrome	Typically rapid onset with hyperreflexia, tremors, myoclonus, diaphoresis, confusion, agitation, or shivering; muscular rigidity not invariably present	Nonspecific	Increased serotonergic tone
Neuroleptic malignant syndrome	Variable rapidity of onset; severe muscular rigidity, diaphoresis, delirium, fluctuating blood pressure, tachycardia, extrapyramidal symptoms	Elevated CPK, leukocytosis	Blockade of dopamine receptors or abrupt withdrawal of a dopamine agonist
Lethal catatonia	Muscular rigidity, diaphoresis, delirium, alternating extreme excitement and stupor, tremors, hypertension	Nonspecific	Evidence of pre-existing psychosis (bipolar disorder, schizophrenia)
Anticholinergic toxicity	Hot, dry skin, pupillary dilatation, tachycardia, constipation, urinary retention, confusion, hallucinations, muscular relaxation	Nonspecific	Agents that block central and peripheral muscarinic cholinergic receptors
Malignant hyperthermia	Rapid onset, severe muscular rigidity, ischemia, hypotension	Elevated CPK, potassium, magnesium; DIC; acidosis; rhabdomyolysis	Inherited disorder with onset after exposure to anesthetic agents that block the neuromuscular junction
CPK: creatine phosphokinase
DIC: disseminated intravascular coagulation

Tramadol is an analgesic with opioid and serotonin-reuptake inhibiting properties that is metabolized by the cytochrome P (CYP)-450 isoenzyme 2D6. Serotonin syndrome has been reported from interactions between tramadol and sertraline²² and fluoxetine.²³ Possible causes include SSRI inhibition of CYP 2D6 metabolism of tramadol, tramadol abuse,²³ and multiple coadministered medications.²²

Sumatriptan is one of the selective 5HT1D agonists used in treating migraine. Gardner and Lynd²⁴ concluded that most patients tolerate sumatriptan with SSRIs or lithium. They felt they could not ensure the safety of sumatriptan with MAOIs, however, because sumatriptan elimination depends on hepatic MAO activity.

Among the 5HT1D agonists, using sumatriptan, zolmitriptan, rizatriptan, or almotriptan with an MAOI or within 2 weeks of discontinuing an MAOI is contraindicated. Naratriptan and frovatriptan appear less likely to interact with MAOIs, based on FDA-approved labeling.

MDMA. 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) is widely used as a recreational drug, especially at crowded dances (“raves”) and with other drugs.²⁵ This illicit amphetamine derivative stimulates the release of serotonin and inhibits its reuptake.

Kaskey reported the rapid onset of serotonin syndrome when a patient taking lithium and phenelzine ingested MDMA.²⁶ Signs and symptoms of serotonin syndrome also may develop when MDMA is used alone, facilitated by the high ambient temperatures on crowded dance floors and the dancers’ relative dehydration.

Fatalities have been blamed on complications including disseminated intravascular coagulation, rhabdomyolysis, and acute hepatic, renal, or cardiac failure.²⁵ Cases are difficult to interpret because of uncertainty about whether the victim ingested MDMA or another agent or combination.

St. John’s wort (Hypericum perforatum) contains numerous constituents, including hypericin and hyperforin, which have been found to inhibit the synaptic uptake of monoamines, including serotonin.²⁷ Which constituents are responsible for its clinical effect is unclear. Adverse effects from monotherapy include GI symptoms, confusion, dry mouth, dizziness, headache, fatigue, allergic skin reactions, photosensitivity, and urinary frequency.²⁷

Several cases of purported serotonin syndrome have been associated with St. John’s wort alone²⁸ or in combination with SSRIs, nefazodone, or fenfluramine.^29,30 GI symptoms and anxiety were the primary complaints and resolved without complications (adjunctive cyproheptadine was prescribed in two cases, though it is not clear that this agent contributed to resolution).

MISCELLANEOUS COMBINATIONS

Antiretroviral therapy. Five cases of serotonin syndrome were reported in HIV-infected patients taking fluoxetine with antiretroviral therapy.³¹ In particular, the use or addition of ritonavir—a potent CYP 2D6 inhibitor—was implicated, though saquinavir, efavirenz, or grapefruit juice (all primarily CYP 3A4 inhibitors) were also used, suggesting that pharmacokinetic interactions increased serotonergic stimulation. All five patients were taking multiple additional medications and had complex medical and/or psychiatric histories. Reducing SSRI dosages by one-half when used with ritonavir has been recommended to minimize adverse effects from a pharmacokinetic interaction.

Erythromycin was reported to induce serotonin syndrome in a 12-year-old boy when added to ongoing treatment with sertraline, an effect believed to be secondary to CYP 3A4 inhibition of sertraline metabolism.³²

Mirtazapine was reported to induce serotonin syndrome in an elderly man 8 days after it was added to a regimen he had been taking for several years to treat chronic obstructive pulmonary disease.³³ Serotonin syndrome also developed in a 12-year-old boy with Ewing’s sarcoma when the 5HT3 antagonist ondansetron was added to mirtazapine and morphine³⁴ and in an 11-year-old girl with acute lymphoblastic leukemia when ondansetron was added to fentanyl. Interestingly, another report³⁵ suggested using mirtazapine to treat serotonin syndrome caused by serotonergic antagonist effects.