The FDA Alert on Serotonin Syndrome With Combined Use of SSRIs or SNRIs and Triptans: An Analysis of the 29 Case Reports

Randolph W. Evans, MD

Abstract

Background: On July 19, 2006, the US Food and Drug Administration (FDA) issued an alert, "Potentially Life-Threatening Serotonin Syndrome With Combined Use of SSRIs or SNRIs and Triptan Medications." However, the cases that were the basis for the alert were not made available. The FDA recommends that patients treated concomitantly with a triptan and a selective serotonin reuptake inhibitor (SSRI)/selective norepinephrine reuptake inhibitor (SNRI) be informed of the possibility of serotonin syndrome.
Methods: Following a Freedom of Information Act request, the FDA provided the 29 cases that they evaluated as the basis for the alert. I summarize the cases, rate the quality of the cases on the basis of the information provided, and then determine whether the cases fulfill the Sternbach and Hunter criteria for serotonin syndrome.
Results: Seven cases met the Sternbach criteria but did not meet the Hunter criteria. No cases met both criteria or just the Hunter criteria.
Conclusions: Triptans when administered with SSRIs or SNRIs might rarely precipitate serotonin syndrome. The data do not support prohibiting the use of triptans with SSRIs or SNRIs. With increased physician awareness of serotonin syndrome, it is possible that additional cases may be reported.

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List of Drug Names
SSRIs and a Combination Drug Containing an SSRI	SNRIs	Triptans
Celexa (citalopram) Fluvoxamine Lexapro (escitalopram) Paxil (paroxetine) Prozac (fluoxetine) Symbyax (olanzapine/fluoxetine) Zoloft (sertraline)	Cymbalta (duloxetine) Effexor (venlafaxine) Meridia (sibutramine)*	Amerge (naratriptan) Axert (almotriptan) Frova (frovatriptan) Imitrex (sumatriptan) Maxalt and Maxalt MLT (rizatriptan) Relpax (eletriptan) Zomig and Zomig ZMG (zolmitriptan)

Taken directly from: US Food and Drug Administration. FDA Public Health Advisory Combined Use of 5-Hydroxytryptamine Receptor Agonists (Triptans), Selective Serotonin Reuptake Inhibitors (SSRIs) or Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) May Result in Life-threatening Serotonin Syndrome. July 19, 2006, updated November 24, 2006. Available at: https://www.fda.gov/cder/drug/advisory/SSRI_SS200607.htm Accessed August 29, 2007.
*Sibutramine (Meridia), a drug approved for weight loss but not depression, is a SNRI and should therefore be used with caution with triptans and other serotonergic drugs. Sibutramine label
SSRIs = selective serotonin reuptake inhibitors; SNRIs = selective norepinephrine reuptake inhibitor

Manifestations of Severe Serotonin Syndrome and Related Clinical Conditions
Condition	MedicationHistory	Time Needed for Condition to Develop	Vital Signs	Pupils	Mucosa	Skin	Bowel Sounds	Neuromuscular Tone	Reflexes	Mental Status
Serotonin syndrome	Proserotonergic drug	< 12 hr	Hypertension, tachycardia, tachypnea, hyperthermia (> 41.1°C)	Mydriasis	Sialorrhea	Diaphoresis	Hyperactive	Increased, predominantly in lower extremities	Hyperreflexia, clonus (unless masked by increased muscle tone)	Agitation, coma
Anticholinergic "toxidrome"	Anticholinergic agent	<12 hr	Hypertension (mild), tachycardia, tachypnea, hyperthermia (typically 38.8°C or less)	Mydriasis	Dry	Erythema, hot, and dry to touch	Decreased or absent	Normal	Normal	Agitated delirium
Neuroleptic malignant syndrome	Dopamine antagonist	1-3 days	Hypertension, tachycardia, tachypnea, hyperthermia (> 41.1°C)	Normal	Sialorrhea	Pallor, diaphoresis	Normal or decreased	"Lead-pipe" rigidity, present in all muscle groups	Bradyreflexia	Stupor, alert mutism, coma
Malignant hyperthermia	Inhalational anesthesia	30 min to 24 hr after administration of inhalational anesthesia or succinylcholine	Hypertension, tachycardia, tachypnea, hyperthermia (can be as high as 46.0°C)	Normal	Normal	Mottled appearance, diaphoresis	Decreased	Rigor mortislike rigidity	Hyporeflexia	Agitation

From Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;35:1112-1120, with permission.

Summary of Cases Reported by US Food and Drug Administration (FDA) Alert: Potentially Life-Threatening Serotonin Syndrome (SS) With Combined Use of SSRIs or SNRIs and Triptan Medications: the 29 Cases
Case Number/ Medications	Case Summary	Quality of Case Information*/Meets Sternbach and Hunter Criteria
1. Sumatriptan tab sertraline	42 y.o. woman reported she received sumatriptan (Imitrex) tabs, sertraline (Zoloft), and pseudoephedrine (for sinusitis) and developed allergic reactions with flushing, hives, wheezing, closing sensation in throat, panic, chest pain, rapid pulse, arrhythmia, sensations of fainting and being on a roller coaster, feeling like death was imminent, diarrhea, uterine cramping with spotting, shivering, chattering jaw, and myoclonus. Treated in ED with diphenhydramine. Symptoms later off sumatriptan. Psychiatrist diagnosed panic disorder. Allergist diagnosed possible conversion hysteria. Primary physician diagnosed psychophysiologic reaction.	++ No No
2. Sumatriptan tab and sc fluoxetine lithium	39 y.o. woman on fluoxetine (Prozac; dose not specified) taking Imitrex tab and sc frequently. Physician-husband described patient as becoming "manic" (spending hours cleaning the car) and reported hallucinations. If not manic, she would have bouts of trembling, sweatiness, and weakness. Lithium did not help mania. Symptoms resolved off medications. Physician reported that the symptoms she suffered were similar to that of Imitrex with fenfluramine.	++ Yes No
3. Sumatriptan (unknown formulation) Unspecified SSRI	A nurse reported to a sales representative that a patient received Imitrex and an unspecified SSRI and developed SS. Age and sex not provided.	+ No No
4. Sumatriptan tab paroxetine	Physician told sales representative that a patient (unspecified sex and age) developed medically serious SS. No details provided. Imitrex and paroxetine (Paxil) continued. Symptoms resolved.	+ No No
5. sumatriptan tab venlafaxine fluoxetine buspirone	43 y.o. man reported that after increasing his venlafaxine (Effexor XR) dose to 300 mg daily, he began to experience dizziness and confusion until he reduced the dose to 150 mg daily. Taking hydrocodone with acetaminophen following knee surgery made him confused. He started retaking old prescriptions for buspirone (BuSpar) and Prozac. The patient stated he would like to receive a letter from Wyeth stating that side effects of Effexor and effects of interactions with other medications could have led to his "not being able to pull it together in court."	+ No No
6. Sumatriptan tab fluoxetine	38 y.o. man with increase in slurred speech, diaphoresis, increased confusion, and worsening gait. Patient received dose of Imitrex while on Prozac. Possible SS.	+ Yes No
7. Zolmitriptan tab sertraline	51 y.o. man admitted with agitation, afebrile, tachycardic, leukocytosis, flushed, and diaphoretic. Patient was diagnosed as having SS as he was taking sertraline (50 mg daily) and recently restarted zolmitriptan (Zomig) (5 mg). These were both discontinued and patient's symptoms slowly began to subside.	++ No No
8. Naratriptan Methysergide Venlafaxine oxycodone tramadol	57 y.o. woman hospitalized with hallucinations, delirium, agitation, sweating, tremor, and shivering	++ Yes No
9. Naratriptan venlafaxine	Age unknown female on Effexor XR 150 mg. On naratriptan (Amerge) 1 mg half twice daily starting prior to menses. According to the patient, she experienced SS during the third day on Amerge when she developed agitation, tachycardia, hypertension, and ataxia. Treated in the ED with 1 mg of lorazepam. She discontinued the drugs. Two days later, she developed neutropenia, mononucleosis, joint pain, and stiffness. The physician stated, "Not clear if drug related or viral."	++ No No
10. Rizatriptan sertraline	55 y.o. woman on sertraline (Zoloft) for migraine prevention. Took rizatriptan (Maxalt) for migraine with sensory aura but persistent headache. The next day, headache less intense. Took Zoloft, went back to bed, and was unable to speak. Paramedics found blood pressure of 216/160 mm Hg and her arms were moving uncontrollably. At the hospital, her temperature was 104°F ; she was diaphoretic, unconscious, and thrashing so much that she was paralyzed and intubated. A CT and MRI of the brain were normal. An EEG showed no seizure activity. A lumbar puncture produced normal CSF. West Nile and herpes cultures were negative. She was discharged at the end of the week in good health.	+++ Yes No
11. Rizatriptan paroxetine	20 y.o. woman on Maxalt10 mg 3-4 daily for 5 weeks for migraine. Started Paxil 10 mg daily 4 weeks after starting Maxalt. Six days later, increased Paxil to 20 mg daily. Later that day, took Maxalt. Five hours later, developed burning sensation over back and body, nausea, dry mouth, flushing, and generalized weakness. Increased deep tendon reflexes and bilateral ankle clonus on exam. Maxalt and Paxil were discontinued. The symptoms resolved over 24 hr.	+++ No No
12. Sumatriptan paroxetine	Patient ( sex and age not specified) on Imitrex (formulation not provided) and developed bilateral retinal detachments	+ No No
13. Sumatriptan tab buspirone venlafaxine	43 y.o man on Imitrex 100 mg daily. Switched from Prozac 20 mg 3 times daily to Effexor XR 225 mg daily; after 1 week, dose increased to 300 mg daily. The next day, he reported lightheadedness, dizziness, lack of balance, flushing associated with an increase in blood pressure, a sense of invulnerability, an unusual dream, and mental confusion.	+ No No
14. Sumatriptan tab venlafaxine	65 y.o. woman on Effexor (dose unknown). At an unknown time after starting Imitrex 50 mg, the patient experienced chills, shivering, lethargy, and seizure and was hospitalized. Physician suspected SS.	+ No No
15. Sumatriptan sc paroxetine	65 y.o. woman's dose of paroxetine was increased from 40 mg to 60 mg daily. She was hospitalized with joint pain, swelling of the face, hands and feet, and difficulty breathing. She was given 2 sumatriptan sc injections for migraine. At some point that day, she developed lightheadedness, muscle pain, confusion, dizziness, difficult urination, sweating, feeling hot, and restlessness. The next day, the symptoms were resolved and she was discharged. Treatment with sumatriptan was continued and the action with paroxetine was unknown.	++ No No
16. Sumatriptan tab unspecified SSRI	Patient ( sex and age not specified) on an unspecified SSRI started Imitrex 100 mg. After an unspecified period of time, the patient experienced SS according to a report by a physician via a sales representative.	+ No No
17. Sumatriptan tab fluoxetine	34 y.o. woman on fluoxetine 20 mg daily. Several hours following administration of sumatriptan 100 mg and a second dose of sumatriptan 50 mg and fluoxetine, she experienced tightness of the chest and palpitations. Treatment with sumatriptan and fluoxetine was continued. The events were reported as resolved.	++ No No
18. Rizatriptan citalopram	37 y.o. woman on citalopram 20 mg daily for 4 months. Took rizatriptan 10 mg. Had symptoms of palpitation, tachycardia, tremor, "close syncope," vomiting, diarrhea, and hyperthermia. The patient was not hospitalized. Rizatriptan discontinued. Had been treated before without any adverse reactions.	++ Yes No
19. Sumatriptan sc paroxetine	33 y.o. woman began paroxetine 20 mg and injected sumatriptan 6 mg sc. She subsequently developed tremor, myoclonus, headache, and severe hypertension (but not hyperthermia) requiring 2 hospitalizations and prolonged treatment with lorazepam. The events resolved slowly over a 4-week period.	++ No No
20. Sumatriptan tab paroxetine	Patient ( sex and age unspecified) on Imitrex tablets. At an unspecified time, the patient started Paxil at an unspecified dose. Afterward, he experienced SS. Both Paxil and Imitrex were continued. The symptoms resolved.	+ No No
21. Zolmitriptan (unknown formulation) venlafaxine meperidine	45 y.o. woman received Zomig daily (dose and formulation unknown) in addition to Effexor, clonazepam, and meperidine (Demerol). She experienced fever, headache, palpitation, neck tightness, photophobia, and SS. The patient recovered without sequelae.	+ No No
22. Sumatriptan sc sertraline lithium methysergide^[18]	44 y.o. woman on the medications listed for 3 months, administered 6 mg of sumatriptan sc. One hour later, she developed weakness, severe incoordination, and abnormal jerking movements. On examination, she was dysarthric, excited, hypomanic, shivering, with dilated pupils with weakness of all limbs more pronounced on the right. She had frequent myoclonic jerking in all limbs with hemiballistic movements in the right upper extremity. She was diffusely hyperreflexic with plantar flexors. She had ataxia of limb and gait. Serum electrolytes, ECG, and MRI of the brain were normal. All symptoms resolved within 24 hr except for hyperreflexia, which resolved within 48 hr. She was discharged on methysergide and sertraline for migraine prevention. In the month following, she had 5 similar but less severe transient episodes in close temporal proximity to the symptomatic use of sumatriptan for migraine. When sertraline was discontinued, sumatriptan was effective without adverse events.	+++ Yes No
23. Sumatriptan sc Sertraline^[18]	48 y.o. woman on sertraline 100 mg daily and propranolol for migraine and depression. Ten minutes after administering sumatriptan sc for the first time, she became anxious, agitated, disoriented, and diffusely weak. She could not walk without assistance. In the ED, pulse was 120 with normal blood pressure and temperature. She was anxious and easily excitable with weakness, incoordination, and hyperreflexia in all 4 limbs. ECG and EEG were normal. Improvement in her mental status, speech, and motor control began within 3 hr of symptom onset and complete recovery within 24 hr. Sertraline was discontinued. When sumatriptan was combined with nortriptyline, she had no similar events.	+++ Yes No
24. Sumatriptan sc Metoclopramide^[18]	44 y.o. woman took ibuprofen and sumatriptan 6 mg sc for menstrual migraine. When the headache recurred the next day, she took sumatriptan 6 mg. Now 24 hours later, she had myoclonic jerking worse with movement with anxiety, hyperreflexia, and incoordination, which all resolved within 24 hr. An EEG after the myoclonus resolved was normal. She had 2 prior similar episodes associated with the use of metoclopramide and naproxen for migraine.	+++ No No
25. Zolmitriptan tab paroxetine^[19]	25 y.o. woman with migraine and depression on paroxetine 2/day and indoramin 2/day. She took zolmitriptan 1 pill (dose not specified) for the first time and was pain-free in 1 hr. The next afternoon, she had a migraine and took 1 zolmitriptan and 1 paroxetine together. During the night, she developed diffuse sweating, hypertonia, and myoclonus of the forelimbs, which disappeared in the morning. She stopped indoramin but took another pill of paroxetine 2 days after the prior dose. She was hospitalized after she developed the same symptoms and tachycardia, hyperreflexia, diarrhea, and agitation. She returned to normal in 3 days.	+++ Yes No
26. Zolmitriptan tab Viloxazine^[19]	43 y.o. woman on viloxazine [a bicyclic antidepressant] for depression. She had been taking zolmitriptan 1 per migraine without side effects for about 6 months. She then treated a migraine with 3 zolmitriptan (dose not specified) in 6 hr. She presented the following morning with asthenia, abdominal pain, nausea, diarrhea, and diffuse sweat alternating with diffuse heat. She had no myoclonus. All symptoms disappeared in 1 hr.	++ No No
27. Sumatriptan (formulation not specified) tramadol fluoxetine mirtazapine divalproex sodium^[20] sumatriptan nefazodone divalproex	43 y.o. woman on sumatriptan and tramadol for migraine and fluoxetine 60 mg/day and mirtazapine for major depression. She consumed a 1-week supply of these medications over 3 days and presented to the ED with sleeplessness, agitation, and rapid speech. She received activated charcoal and was treated for mania with divalproex sodium. By the next morning, she was confused, anxious, agitated, and flushed, with a heart rate of 124/minute. She had muscle stiffness, myoclonic jerking at rest, mydriasis, and a temperature of 37.8°C. She was treated with cyproheptadine 8 mg every 8 hr until her symptoms remitted 4 days later. When the racing thoughts recurred, the divalproex therapy was resumed and she was discharged. One year later, she took the prescribed dose of divalproex but took a 2-week supply of nefazodone and sumatriptan in less than 1 week. In the ED, she was manic and fully oriented with marked stiffness, fever (37.38°C), tachycardia, flushing, and mydriasis.	+++ Yes No +++ No No
28. Sumatriptan tab sertraline citalopram moclobemide^[21]	33 y.o. woman took overdose of unspecified number of tablets of sumatriptan, sertraline, citalopram, moclobemide, thioridazine, and alcohol. When the ambulance arrived 1-2 hr after ingestion of the tablets, she had vomited and was fatigued but able to speak. On arrival at the hospital, she was unconscious with blood pressure 135/60 mm Hg with mydriasis. Over the next few hours, she developed muscle rigidity, trismus, fever of 42°C, and deterioration of breathing that resulted in mechanical ventilation. Blood samples indicated rhabdomyolysis and disseminated intravascular coagulation. She was treated with dantrolene, benzodiazepines, and cyproheptadine. She recovered after 9 days.	+++ No No
29. Sumatriptan suppository paroxetine^[22]	65 y.o. woman on paroxetine 20 mg daily for 4 years. Several hours after receiving sumatriptan 25 mg suppository, she experienced tachycardia, agitation, hyperthermia, hypertension, and confusion. She was hospitalized and a diagnosis of SS was made. She made a full recovery within 48 hr.	+++ Yes No

*The quality of the cases was ranked on the basis of the clinical information provided using the following scale: poor + ++ +++ ++++ excellent
ED = emergency department; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor; tab = tablet; sc = subcutaneous; y.o.= year old; CT = computed tomographic scan; MRI = magnetic resonance imaging; EEG = electroencephalogram; CSF = cerebrospinal fluid; ECG = electrocardiogram

Summary of Cases Reported by US Food and Drug Administration (FDA) Alert: Potentially Life-Threatening Serotonin Syndrome (SS) With Combined Use of SSRIs or SNRIs and Triptan Medications: the 29 Cases
Case Number/ Medications	Case Summary	Quality of Case Information*/Meets Sternbach and Hunter Criteria
1. Sumatriptan tab sertraline	42 y.o. woman reported she received sumatriptan (Imitrex) tabs, sertraline (Zoloft), and pseudoephedrine (for sinusitis) and developed allergic reactions with flushing, hives, wheezing, closing sensation in throat, panic, chest pain, rapid pulse, arrhythmia, sensations of fainting and being on a roller coaster, feeling like death was imminent, diarrhea, uterine cramping with spotting, shivering, chattering jaw, and myoclonus. Treated in ED with diphenhydramine. Symptoms later off sumatriptan. Psychiatrist diagnosed panic disorder. Allergist diagnosed possible conversion hysteria. Primary physician diagnosed psychophysiologic reaction.	++ No No
2. Sumatriptan tab and sc fluoxetine lithium	39 y.o. woman on fluoxetine (Prozac; dose not specified) taking Imitrex tab and sc frequently. Physician-husband described patient as becoming "manic" (spending hours cleaning the car) and reported hallucinations. If not manic, she would have bouts of trembling, sweatiness, and weakness. Lithium did not help mania. Symptoms resolved off medications. Physician reported that the symptoms she suffered were similar to that of Imitrex with fenfluramine.	++ Yes No
3. Sumatriptan (unknown formulation) Unspecified SSRI	A nurse reported to a sales representative that a patient received Imitrex and an unspecified SSRI and developed SS. Age and sex not provided.	+ No No
4. Sumatriptan tab paroxetine	Physician told sales representative that a patient (unspecified sex and age) developed medically serious SS. No details provided. Imitrex and paroxetine (Paxil) continued. Symptoms resolved.	+ No No
5. sumatriptan tab venlafaxine fluoxetine buspirone	43 y.o. man reported that after increasing his venlafaxine (Effexor XR) dose to 300 mg daily, he began to experience dizziness and confusion until he reduced the dose to 150 mg daily. Taking hydrocodone with acetaminophen following knee surgery made him confused. He started retaking old prescriptions for buspirone (BuSpar) and Prozac. The patient stated he would like to receive a letter from Wyeth stating that side effects of Effexor and effects of interactions with other medications could have led to his "not being able to pull it together in court."	+ No No
6. Sumatriptan tab fluoxetine	38 y.o. man with increase in slurred speech, diaphoresis, increased confusion, and worsening gait. Patient received dose of Imitrex while on Prozac. Possible SS.	+ Yes No
7. Zolmitriptan tab sertraline	51 y.o. man admitted with agitation, afebrile, tachycardic, leukocytosis, flushed, and diaphoretic. Patient was diagnosed as having SS as he was taking sertraline (50 mg daily) and recently restarted zolmitriptan (Zomig) (5 mg). These were both discontinued and patient's symptoms slowly began to subside.	++ No No
8. Naratriptan Methysergide Venlafaxine oxycodone tramadol	57 y.o. woman hospitalized with hallucinations, delirium, agitation, sweating, tremor, and shivering	++ Yes No
9. Naratriptan venlafaxine	Age unknown female on Effexor XR 150 mg. On naratriptan (Amerge) 1 mg half twice daily starting prior to menses. According to the patient, she experienced SS during the third day on Amerge when she developed agitation, tachycardia, hypertension, and ataxia. Treated in the ED with 1 mg of lorazepam. She discontinued the drugs. Two days later, she developed neutropenia, mononucleosis, joint pain, and stiffness. The physician stated, "Not clear if drug related or viral."	++ No No
10. Rizatriptan sertraline	55 y.o. woman on sertraline (Zoloft) for migraine prevention. Took rizatriptan (Maxalt) for migraine with sensory aura but persistent headache. The next day, headache less intense. Took Zoloft, went back to bed, and was unable to speak. Paramedics found blood pressure of 216/160 mm Hg and her arms were moving uncontrollably. At the hospital, her temperature was 104°F ; she was diaphoretic, unconscious, and thrashing so much that she was paralyzed and intubated. A CT and MRI of the brain were normal. An EEG showed no seizure activity. A lumbar puncture produced normal CSF. West Nile and herpes cultures were negative. She was discharged at the end of the week in good health.	+++ Yes No
11. Rizatriptan paroxetine	20 y.o. woman on Maxalt10 mg 3-4 daily for 5 weeks for migraine. Started Paxil 10 mg daily 4 weeks after starting Maxalt. Six days later, increased Paxil to 20 mg daily. Later that day, took Maxalt. Five hours later, developed burning sensation over back and body, nausea, dry mouth, flushing, and generalized weakness. Increased deep tendon reflexes and bilateral ankle clonus on exam. Maxalt and Paxil were discontinued. The symptoms resolved over 24 hr.	+++ No No
12. Sumatriptan paroxetine	Patient ( sex and age not specified) on Imitrex (formulation not provided) and developed bilateral retinal detachments	+ No No
13. Sumatriptan tab buspirone venlafaxine	43 y.o man on Imitrex 100 mg daily. Switched from Prozac 20 mg 3 times daily to Effexor XR 225 mg daily; after 1 week, dose increased to 300 mg daily. The next day, he reported lightheadedness, dizziness, lack of balance, flushing associated with an increase in blood pressure, a sense of invulnerability, an unusual dream, and mental confusion.	+ No No
14. Sumatriptan tab venlafaxine	65 y.o. woman on Effexor (dose unknown). At an unknown time after starting Imitrex 50 mg, the patient experienced chills, shivering, lethargy, and seizure and was hospitalized. Physician suspected SS.	+ No No
15. Sumatriptan sc paroxetine	65 y.o. woman's dose of paroxetine was increased from 40 mg to 60 mg daily. She was hospitalized with joint pain, swelling of the face, hands and feet, and difficulty breathing. She was given 2 sumatriptan sc injections for migraine. At some point that day, she developed lightheadedness, muscle pain, confusion, dizziness, difficult urination, sweating, feeling hot, and restlessness. The next day, the symptoms were resolved and she was discharged. Treatment with sumatriptan was continued and the action with paroxetine was unknown.	++ No No
16. Sumatriptan tab unspecified SSRI	Patient ( sex and age not specified) on an unspecified SSRI started Imitrex 100 mg. After an unspecified period of time, the patient experienced SS according to a report by a physician via a sales representative.	+ No No
17. Sumatriptan tab fluoxetine	34 y.o. woman on fluoxetine 20 mg daily. Several hours following administration of sumatriptan 100 mg and a second dose of sumatriptan 50 mg and fluoxetine, she experienced tightness of the chest and palpitations. Treatment with sumatriptan and fluoxetine was continued. The events were reported as resolved.	++ No No
18. Rizatriptan citalopram	37 y.o. woman on citalopram 20 mg daily for 4 months. Took rizatriptan 10 mg. Had symptoms of palpitation, tachycardia, tremor, "close syncope," vomiting, diarrhea, and hyperthermia. The patient was not hospitalized. Rizatriptan discontinued. Had been treated before without any adverse reactions.	++ Yes No
19. Sumatriptan sc paroxetine	33 y.o. woman began paroxetine 20 mg and injected sumatriptan 6 mg sc. She subsequently developed tremor, myoclonus, headache, and severe hypertension (but not hyperthermia) requiring 2 hospitalizations and prolonged treatment with lorazepam. The events resolved slowly over a 4-week period.	++ No No
20. Sumatriptan tab paroxetine	Patient ( sex and age unspecified) on Imitrex tablets. At an unspecified time, the patient started Paxil at an unspecified dose. Afterward, he experienced SS. Both Paxil and Imitrex were continued. The symptoms resolved.	+ No No
21. Zolmitriptan (unknown formulation) venlafaxine meperidine	45 y.o. woman received Zomig daily (dose and formulation unknown) in addition to Effexor, clonazepam, and meperidine (Demerol). She experienced fever, headache, palpitation, neck tightness, photophobia, and SS. The patient recovered without sequelae.	+ No No
22. Sumatriptan sc sertraline lithium methysergide^[18]	44 y.o. woman on the medications listed for 3 months, administered 6 mg of sumatriptan sc. One hour later, she developed weakness, severe incoordination, and abnormal jerking movements. On examination, she was dysarthric, excited, hypomanic, shivering, with dilated pupils with weakness of all limbs more pronounced on the right. She had frequent myoclonic jerking in all limbs with hemiballistic movements in the right upper extremity. She was diffusely hyperreflexic with plantar flexors. She had ataxia of limb and gait. Serum electrolytes, ECG, and MRI of the brain were normal. All symptoms resolved within 24 hr except for hyperreflexia, which resolved within 48 hr. She was discharged on methysergide and sertraline for migraine prevention. In the month following, she had 5 similar but less severe transient episodes in close temporal proximity to the symptomatic use of sumatriptan for migraine. When sertraline was discontinued, sumatriptan was effective without adverse events.	+++ Yes No
23. Sumatriptan sc Sertraline^[18]	48 y.o. woman on sertraline 100 mg daily and propranolol for migraine and depression. Ten minutes after administering sumatriptan sc for the first time, she became anxious, agitated, disoriented, and diffusely weak. She could not walk without assistance. In the ED, pulse was 120 with normal blood pressure and temperature. She was anxious and easily excitable with weakness, incoordination, and hyperreflexia in all 4 limbs. ECG and EEG were normal. Improvement in her mental status, speech, and motor control began within 3 hr of symptom onset and complete recovery within 24 hr. Sertraline was discontinued. When sumatriptan was combined with nortriptyline, she had no similar events.	+++ Yes No
24. Sumatriptan sc Metoclopramide^[18]	44 y.o. woman took ibuprofen and sumatriptan 6 mg sc for menstrual migraine. When the headache recurred the next day, she took sumatriptan 6 mg. Now 24 hours later, she had myoclonic jerking worse with movement with anxiety, hyperreflexia, and incoordination, which all resolved within 24 hr. An EEG after the myoclonus resolved was normal. She had 2 prior similar episodes associated with the use of metoclopramide and naproxen for migraine.	+++ No No
25. Zolmitriptan tab paroxetine^[19]	25 y.o. woman with migraine and depression on paroxetine 2/day and indoramin 2/day. She took zolmitriptan 1 pill (dose not specified) for the first time and was pain-free in 1 hr. The next afternoon, she had a migraine and took 1 zolmitriptan and 1 paroxetine together. During the night, she developed diffuse sweating, hypertonia, and myoclonus of the forelimbs, which disappeared in the morning. She stopped indoramin but took another pill of paroxetine 2 days after the prior dose. She was hospitalized after she developed the same symptoms and tachycardia, hyperreflexia, diarrhea, and agitation. She returned to normal in 3 days.	+++ Yes No
26. Zolmitriptan tab Viloxazine^[19]	43 y.o. woman on viloxazine [a bicyclic antidepressant] for depression. She had been taking zolmitriptan 1 per migraine without side effects for about 6 months. She then treated a migraine with 3 zolmitriptan (dose not specified) in 6 hr. She presented the following morning with asthenia, abdominal pain, nausea, diarrhea, and diffuse sweat alternating with diffuse heat. She had no myoclonus. All symptoms disappeared in 1 hr.	++ No No
27. Sumatriptan (formulation not specified) tramadol fluoxetine mirtazapine divalproex sodium^[20] sumatriptan nefazodone divalproex	43 y.o. woman on sumatriptan and tramadol for migraine and fluoxetine 60 mg/day and mirtazapine for major depression. She consumed a 1-week supply of these medications over 3 days and presented to the ED with sleeplessness, agitation, and rapid speech. She received activated charcoal and was treated for mania with divalproex sodium. By the next morning, she was confused, anxious, agitated, and flushed, with a heart rate of 124/minute. She had muscle stiffness, myoclonic jerking at rest, mydriasis, and a temperature of 37.8°C. She was treated with cyproheptadine 8 mg every 8 hr until her symptoms remitted 4 days later. When the racing thoughts recurred, the divalproex therapy was resumed and she was discharged. One year later, she took the prescribed dose of divalproex but took a 2-week supply of nefazodone and sumatriptan in less than 1 week. In the ED, she was manic and fully oriented with marked stiffness, fever (37.38°C), tachycardia, flushing, and mydriasis.	+++ Yes No +++ No No
28. Sumatriptan tab sertraline citalopram moclobemide^[21]	33 y.o. woman took overdose of unspecified number of tablets of sumatriptan, sertraline, citalopram, moclobemide, thioridazine, and alcohol. When the ambulance arrived 1-2 hr after ingestion of the tablets, she had vomited and was fatigued but able to speak. On arrival at the hospital, she was unconscious with blood pressure 135/60 mm Hg with mydriasis. Over the next few hours, she developed muscle rigidity, trismus, fever of 42°C, and deterioration of breathing that resulted in mechanical ventilation. Blood samples indicated rhabdomyolysis and disseminated intravascular coagulation. She was treated with dantrolene, benzodiazepines, and cyproheptadine. She recovered after 9 days.	+++ No No
29. Sumatriptan suppository paroxetine^[22]	65 y.o. woman on paroxetine 20 mg daily for 4 years. Several hours after receiving sumatriptan 25 mg suppository, she experienced tachycardia, agitation, hyperthermia, hypertension, and confusion. She was hospitalized and a diagnosis of SS was made. She made a full recovery within 48 hr.	+++ Yes No

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The FDA Alert on Serotonin Syndrome With Combined Use of SSRIs or SNRIs and Triptans: An Analysis of the 29 Case Reports

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