Rita Banzi, Cristina Cusi, Concetta Randazzo, Roberto Sterzi, Dario Tedesco, Lorenzo Moja

This is an updated version of the original Cochrane review published in 2005 on selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headache. The original review has been split in two parts and this review now only regards migraine prevention. Another updated review is under development to cover tension-type headache.Migraine is a common disorder. The chronic forms are associated with disability and have a high economic impact. In view of discoveries about the role of serotonin and other neurotransmitters in pain mechanisms, selective serotonin re-uptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been evaluated for the prevention of migraine. To determine the efficacy and tolerability of SSRIs and SNRIs compared to placebo and other active interventions in the prevention of episodic and chronic migraine in adults. For the original review, we searched MEDLINE (1966 to January 2004), EMBASE (1994 to May 2003), the Cochrane Central Register of Controlled Trials (CENTRAL 2003, Issue 4), and Headache Quarterly (1990 to 2003). For this update, we applied a revised search strategy to reflect the broader type of intervention (SSRIs and SNRIs). We searched CENTRAL (2014, Issue 10), MEDLINE (1946 to November 2014), EMBASE (1980 to November 2014), and PsycINFO (1987 to November 2014). We also checked the reference lists of retrieved articles and searched trial registries for ongoing trials. We included randomised controlled trials comparing SSRIs or SNRIs with any type of control intervention in participants 18 years and older of either sex with migraine. Two authors independently extracted data (migraine frequency, index, intensity, and duration; use of symptomatic/analgesic medication; days off work; quality of life; mood improvement; cost-effectiveness; and adverse events) and assessed the risk of bias of trials. The primary outcome of this updated review is migraine frequency. The original review included eight studies on migraine. Overall, we now include 11 studies on five SSRIs and one SNRI with a total of 585 participants. Six studies were placebo-controlled, four compared a SSRI or SNRI to amitriptyline, and one was a head-to-head comparison (escitalopram versus venlafaxine). Most studies had methodological or reporting shortcomings (or both): all studies were at unclear risk of selection and reporting bias. Follow-up rarely extended beyond three months. The lack of adequate power of most of the studies is also a major concern.Few studies explored the effect of SSRIs or SNRIs on migraine frequency, the primary endpoint. Two studies with unclear reporting compared SSRIs and SNRIs to placebo, suggesting a lack of evidence for a difference. Two studies compared SSRIs or SNRIs versus amitriptyline and found no evidence for a difference in terms of migraine frequency (standardised mean difference (SMD) 0.04, 95% confidence interval (CI) -0.72 to 0.80; I(2) = 72%), or other secondary outcomes such as migraine intensity and duration.SSRIs or SNRIs were generally more tolerable than tricyclics. However, the two groups did not differ in terms of the number of participants who withdrew due to adverse advents or for other reasons (one study, odds ratio (OR) 0.39, 95% CI 0.10 to 1.50 and OR 0.42, 95% CI 0.13 to 1.34).We did not find studies comparing SSRIs or SNRIs with pharmacological treatments other than antidepressants (e.g. antiepileptics and anti-hypertensives). Since the last version of this review, the new included studies have not added high quality evidence to support the use of SSRIs or venlafaxine as preventive drugs for migraine. There is no evidence to consider SSRIs or venlafaxine as more effective than placebo or amitriptyline in reducing migraine frequency, intensity, and duration over two to three months of treatment. No reliable information is available at longer-term follow-up. Our conclusion is that the use of SSRIs and SNRIs for migraine prophylaxis is not supported by evidence.