Triptans, SSRIs and serotonin syndrome

In 2006, the U.S. Food and Drug Administration (FDA) a warning regarding a potential life-threatening risk of serotonin syndrome when triptans are used in combination with a selective serotonin reuptake inhibitor (SSRI) or a selective serotonin/norepinephrine reuptake inhibitor (SNRI) (1). These are two classes of specific antidepressants. This warning was based on 29 case reports. Additionally, 11 further case reports of patients with serotonin syndrome who were on SSRI monotherapy and one case report involving combinations of serotonergic agents were published (2-9). These case reports were purely observational and lacked controls to establish a causal relationship. A causal relationship between combination therapy and the potential occurrence of serotonin syndrome cannot be established based on the available data. Of the 29 cases on which the FDA based its warning, only ten actually met the diagnostic criteria for serotonin syndrome. However, none of the patients met the criteria for serotonin toxicity. Based on this data, Evans et al. (2010, 5) concluded that there are no adequate data to determine a potential risk of serotonin syndrome from combining a triptan with an SSRI/SNRI or with triptan monotherapy. The current data do not justify limiting the use of a triptan with an SSRI or an SNRI, or even with triptan monotherapy. Nevertheless, physicians should generally be vigilant for potential symptoms of serotonin syndrome with regard to the seriousness of this complication (5).

A recent study investigated the combined use of triptans and SSRIs or SNRIs (6). US data for the period 2007–2008 and 2003–2004 were compared. In 2007–2008, an average of 5,256,958 patients were prescribed a triptan annually. In 2003–2004, an average of 3,874,367 patients received a triptan, representing an increase of 35.7%. An average of 68,603,600 patients received a prescription for an SSRI or SNRI in 2007–2008, compared to an average of 50,402,149 patients in 2003–2004, representing an increase of 36.1%. On average, 1,319,763 patients received a triptan in combination with an SSRI or an SNRI between 2007 and 2008. In 2003 and 2004, an average of 694,276 patients received such prescriptions. This represents an increase of 90.1%.

Experts have criticized the FDA's decision to issue a warning regarding the combined use of a triptan and an SSRI or SNRI (2-9). As outlined above, this criticism is based on a very small case series of 29 patients, of whom only 10 met the criteria for serotonin syndrome and in none of whom the criteria for serotonin intoxication could be validated. The currently published data on the combined use of triptans and SSRIs or SNRIs indicate that physicians consider the risk of serotonin syndrome from combining a triptan with an antidepressant to be negligible in practice. To date, there are no reliable figures on the potential development of serotonin syndrome due to the combined use of triptans and SSRIs or SNRIs.

It can be concluded that a potential risk of serotonin syndrome when triptans are used in combination with a selective serotonin reuptake inhibitor (SSRI) or a selective serotonin/norepinephrine reuptake inhibitor (SNRI) cannot be scientifically proven or quantified. Based on our own experience with triptan use over more than 20 years, we have not observed a single case of serotonin syndrome when triptans or antidepressants were used together. The same applies to the use of a triptan as monotherapy.

1. FDA