SSRIs, Triptans and Serotonin Syndrome:
What is the Risk of Serotonin Syndrome in Migraine?

The serotonin syndrome (SS) is an acute, sometimes serious and potentially fatal adverse drug reaction. It is due to medications that increase serotonergic activity throughout the body and nervous system. Serotonin syndrome, by definition, is a group of symptoms presenting as mental changes, autonomic nervous system malfunction, and neuromuscular complaints. Patients may present with confusion, agitation, diarrhea, sweating, shivering, hypertension, fever, increased white blood cell count, incoordination, marked increase in reflexes, muscle jerks, tremor, extreme stiffness, seizures and even coma. The severity of changes ranges from mild to fatal.

The most common drugs associated with serotonin syndrome involve three different classes of medication:
• Selective serotonin reuptake inhibitors (SSRIs)
• Monoamine oxidase inhibitors (MAOIs)
• Tricyclic antidepressants (TCAs)

The most common of these are the selective SSRIs, which are used for the treatment of a wide range of behavioral disorders including depression and panic disorders, among others (see Table 1). Combinations of medications are associated with increased risk of SS such as MAOIs given in combination with: meperidine (Demerol®), tryptophan, dextromethorphan (an ingredient in many over-the-counter products), tricyclic antidepressants, or an SSRI antidepressants.

SSRIs work on the serotonin system. Serotonin is a neurotransmitter available in the brain, spinal cord and peripheral nervous system. It causes blood vessels to constrict and also reduces the release of selected neurotransmitters, such as dopamine. SSRIs also inhibit the reuptake of serotonin once it has been released from the nerve terminals, and this is where their name comes from—selective serotonin reuptake inhibitors. As a result, SSRIs prolong the biological effects of serotonin in the nervous system. Prolonged exposure to serotonin may result in clinical symptoms referred to as SS. These symptoms are listed in Table 2. In very rare instances, SS can cause severe illness or death; however, the majority of symptoms associated with SS are mild in nature and resolve with time.

Triptans and ergotamines work on the serotonin system of the brain. Triptans are used for the acute treatment of migraine and include sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, and frovatriptan. Ergotamines are much less commonly used and current use consists mainly of dihydroergotamine. To date, there are no reported cases in the literature of migraine medications alone causing SS.

How Common is Serotonin Syndrome?

SSRIs rarely cause SS when patients are taking only a single medication. Serotonin syndrome among patients taking SSRIs in single drug therapy has been estimated in the range of 0.5 to 0.9 cases per 1000 patient-months of treatment. In some cases, patients may have more than one illness and therefore, patients may take more than one medication. An increased concern exists when two or more medications act on the serotonin system—might be the case with some migraine medications and SSRIs given to treat another medical condition such as depression. As a result, the SSRI and the migraine medication, such as a triptan, increase the amount of circulating serotonin in the body, and this is when the patient may experience signs or symptoms consistent with SS. In reviewing the patient database from a large medical insurance company (in 2001) it was found that just over 20% of migraineurs had both a prescription for a triptan and an SSRI. When applied to the insured population in the US, it is estimated that this may represent nearly 200,000 Americans for the year 2001.

In July of 2006, the Food and Drug Administration raised concerns that the combination of SSRIs and triptans used for migraine may increase the risk of SS based on 27 separate reported cases submitted to them between 1998-2002. It is estimated that during this reporting period almost one million relevant patient-month exposures to the combination of triptans and SSRIs occurred. Based on multiple assumptions it is estimated that the annual onset of new cases of SS to be <0.03% of those patients taking both SSRIs and triptans, and the annual incidence of life-threatening events (2 of the 27 FDA reports) to be <0.002 % of those similarly exposed.

What can trigger Serotonin Syndrome?

Serotonin syndrome is generally caused by one of four different possibilities:
1. Increase in serotonin production
2. Decrease serotonin breakdown (metabolism) (e.g., MAOIs)
3. Increase serotonin release (e.g., triptans)
4. Inhibition of serotonin removal (eg, SSRIs);

Another consideration that might increase the risk of experiencing SS depends on the half life of the medication. The half life is a measure of how long the medication is available in the body. For example, SSRIs have a long half-life and MAOIs have an irreversible effect. Taking these two medications together may be more likely to increase the risk of developing SS. Triptans and ergotamines generally have a short half life ranging from 2 to 13 hours (frovatriptan is the exception and has a longer half life). Most triptans do not stay in the circulation for very long. Because of this short half life, the risk of serotonin syndrome may be minimal or even nonexistent when used alone.

One of the more challenging aspects of predicting which patients are at risk of developing serotonin syndrome is to identify if patients are taking other medications that prolong serotonin including over the counter agents and supplements. Sometimes patients take these over-the-counter agents and they are not aware that they have an effect on the serotonin system of the brain.

If you think you have symptoms of Serotonin Syndrome, what should you do?

If you think you may have any of these symptoms that could be associated with the combination of medications you are taking, such as SSRIs or other agents including over-the-counter supplements, you should contact your physician. Keep a diary that details the medications and supplements taken, doses taken, and symptoms noted. Your physician may be able to adjust your medication or change your treatment plan in order to reduce the risk of having SS.

The editors of this newsletter suggest that if you use only a triptan as prescribed for the acute treatment of migraine, your risk of SS is minimal. If you take a triptan and are also taking another medication, your risk is also extremely low for developing SS. If you are taking three different medications (including over-the-counter supplements), of which one is for migraine, it is appropriate for you to discuss with your physician the risks that might be associated with taking multiple medications.