Selective serotonin reuptake inhibitors (SSRIs) and serotonin‐norepinephrine reuptake inhibitors (SNRIs) for the prevention of migraine in adults



This is an updated version of the original Cochrane review published in 2005 on selective serotonin reuptake 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 reuptake 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.

Search methods

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.

Selection criteria

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.

Data collection and analysis

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.

Main results

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; I2 = 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).

Authors' conclusions

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.


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


Plain language summary

Selective serotonin reuptake inhibitors (SSRIs) and serotonin‐norepinephrine reuptake inhibitors (SNRIs) for preventing migraine

Migraine is a common condition that can significantly impair people's quality of life. Individuals who experience frequent or severe migraine may benefit from preventive medications taken prior to an attack and before the pain starts. Studies have suggested the potential role of neurotransmitters in the genesis of headache. Accordingly, drugs that inhibit the passage of neurotransmitters in brain cells and, therefore, increase their levels, have been examined for their potential benefit in preventing migraine. Two classes of inhibitors, the selective serotonin reuptake inhibitors (SSRIs) and serotonin‐norepinephrine reuptake inhibitors (SNRIs), typically used to treat depression, are evaluated in this review.

This is an update of a previous review that included studies on migraine and tension‐type headache. This original review has been split in two separate reviews: this update addresses only studies on migraine, while a second focuses on tension‐type headache. In November 2014, we identified three new studies. Eight studies were already included in the previous version of the review. Overall, we analysed a total of 585 participants. All the studies had a small number of participants and were conducted over a period of two to three months. Only a few were of high quality.

The results suggest that SSRIs and SNRIs are no better than placebo (sugar pill) for reducing the number of migraine attacks. There were no differences in minor side effects between participants treated with SSRIs or SNRIs versus those treated with placebo. SSRIs and SNRIs seem not to offer advantages when compared to other active treatments, specifically the tricyclic antidepressant amitriptyline. The participants treated with SSRIs or SNRIs suffered fewer minor side effects than those who took amitriptyline, however the number of people who stopped taking one drug or the other due to side effects was approximately equal. These results are based on short‐term trials (no more than three months), which are not properly sized and feature serious methodological deficiencies. We did not find studies comparing SSRIs or SNRIs with pharmacological treatments other than antidepressants (e.g. antiepileptics and anti‐hypertensives).


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

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Since the last version of this review, we included three new relevant studies, which have provided little new evidence on the effectiveness of selective serotonin reuptake inhibitors (SSRIs) and serotonin‐norepinephrine reuptake inhibitors (SNRIs) in patients with migraine. SSRIs or SNRIs are no more effective than placebo and are likely to be less effective than amitriptyline in preventing migraine. Fluoxetine was the most studied SSRI, while venlafaxine was the only SNRI under investigation.

The usefulness of SSRIs or SNRIs for preventing migraine is obscure and the best guess is that these drugs are unlikely to be effective for the majority of patients. When compared to placebo or amitriptyline, SSRIs and SNRIs did not show any superiority on relevant outcomes (migraine frequency, intensity, duration). There was some evidence that SSRIs are better tolerated than amitriptyline and venlafaxine. The issue of long‐term treatment (more than three months) with respect to efficacy and tolerability should still be addressed because in real‐life conditions, patients with chronic migraine receive treatment for more than a few weeks.

No conclusion can be drawn on the use of antidepressants with respect to other prophylactic pharmacological treatments, such as antihypertensives (e.g. angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists, beta‐blockers, calcium channel antagonists) or antiepileptics.

Implications for research 

Overall, the standards in terms of design and reporting of randomised clinical trials still need to be improved. For example, open designs are not acceptable in this context. Migraine frequency should be the primary outcome measure in any new trial. Migraine is a recurrent condition that persists over long periods of time/whole parts of the lifespan, therefore longer follow‐up is needed and harder outcomes that relate to real‐life should be assessed (e.g. migraine frequency, acute medication use, days off work, and quality of life) (Tfelt‐Hansen 2012). This will also avoid the use of non‐validated indexes, discouraging multiple comparisons at different time points, with the warning that multiple data testing easily results in misleading statistically significant findings that appear by chance (Moja 2005; Thornley 1998). Standardised collection of outcomes as suggested by the COMET (Core Outcome Measures in Effectiveness Trials) Initiative, which is engaged in developing, applying, and promoting core outcomes sets (COS), using rigorous consensus methods, for effectiveness trials (Williamson 2012) could be helpful. The sample size should be carefully estimated on the basis of the available evidence and the expected effect, in order to protect the study against random error.

During the current update, we noticed a clear reduction in the number of publications testing SSRIs and SNRIs in the prophylaxis of migraine. For several clinically relevant outcomes, we reported a low level of evidence. This indicates that "further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate" (Guyatt 2008). Under this assumption, amitriptyline could still be suggested as a reference comparator to be used in clinical trials comparing antidepressants for prevention of migraine. The limited number of studies on SNRIs retrieved by this review may suggest that further exploration of the role of these drugs, such as duloxetine, is needed in migraine prevention. However, overall, we think that the value of new studies comparing different antidepressants in this setting is questionable. A randomised controlled trial comparing a SSRI or a SNRI versus another drug or another non‐pharmacological intervention is not a priority in the migraine research pipeline and might not exert a significant impact on the overall evidence. Other preventive strategies are likely to be the target of future research. In the field of antidepressants, exploring the efficacy and safety SSRIs or SNRIs in depressed patients with migraine might be of greater interest, as optimal treatments and the role of weak antidepressants are still debatable.

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