A Stop Sign for SSRIs and SNRIs?

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, the authors of a new meta-analysis conclude.

The analysis, published in the Cochrane Database of Systematic Reviews (April 2015), is an updated version of the original Cochrane review published in 2005. Researchers sought 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 through a database search for randomized controlled trials.

Where the original review included eight studies on migraine, the authors now included 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 and/or reporting shortcomings: all studies were at unclear risk of selection and reporting bias, and follow-up rarely extended beyond three months. The lack of adequate power of most of the studies was a major concern, and few studies explored the effect of SSRIs or SNRIs on migraine frequency, the primary endpoint of the analysis.

The researchers found two of the studies had unclear reporting comparing SSRIs and SNRIs to placebo, suggesting a lack of evidence for a difference. Two more studies compared SSRIs or SNRIs versus amitriptyline and found no evidence for a difference in terms of migraine frequency 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 other reasons.

We spoke to lead author Rita Banzi, PhD, of the IRCCS Mario Negri Institute for Pharmacological Research, Milan.

What is the take away for neurologists?

Rita Banzi, PhD: By reading this review, neurologists should understand that the decision of prescribing SSRIs and SNRIs in patients with frequent migraine attacks is not supported by evidence.

One of the most relevant findings of this updated review is the paucity of new studies investigating the use of SSRIs and SNRIs as preventive drugs for migraine. We retrieved only three new studies that did not change the essence of our conclusions. The evidence supporting the use of these drugs was scarce in 2005 and not better in 2015. In the meantime, other interventions were tested and, even if we have only a few direct comparisons between different pharmacological strategies, we may reasonably speculate that SSRIs and SNRIs are not among the best options to prevent these conditions.

The same conclusions are valid for the use of SSRIs and SNRIs in the prevention of tension-type headache.

Taking the researcher perspective, I think that the book is closed. Other approaches and pharmacological targets appear to be more promising. From a clinician perspective, it might be of some interest to explore the effectiveness in depressed patients. However, I wonder if this is really an open question given the fact that the efficacy of SSRIs and SNRIs as antidepressant has been downsized in the past years.

Why do some physicians still prescribe SSRIs and SNRIs for migraine?

Dr. Banzi: Hard to say. Some SSRIs are blockbusters and their prescription has probably nothing to do with evidence. Clinical decisions should be based on evidence but are also driven by contextual factors and patients’ values. It is likely that some neurologists found that antidepressants are effective in some of their patients, and they decide to use SSRIs rather than amitriptyline (which may have a small effect in ameliorating migraine duration or the intake of analgesics) because of their alleged better tolerability.

Did any of the findings surprise you?

Dr. Banzi: We were disappointed by the poor quality of new trials. In fact, we registered the same deficiencies as 10 years ago, even if the methodology in the field has been improved and standardized (e.g., the IHS guidelines). For example, the choice of use of outcome of limited value for the patients rather than relevant outcomes, such as quality of life or disability, the short follow ups of trials, and the lack of information on the duration of the therapy. Moreover, we did not find studies on duloxetine that showed an effect on neuropathic pain.

What are some of the limitations of your analysis?

Dr. Banzi: We applied the Cochrane methodology for preparing this review, thus we are quite confident that the methods applied are robust and reliable. However, as with any systematic review, our analysis suffers of the limitations of the studies we included.

First, the data we pooled in the meta-analyses were few because the reporting of some studies was suboptimal and we could not retrieve all the data needed to fully assess results.

Second, the majority of the trials we included had shortcomings in methodology and a small sample size; so, we cannot exclude systematic and random errors. In other words, we found small or no differences between SSRIs and SNRIs and placebo, or other antidepressants, but we cannot firmly conclude that these differences are true, if they exist. They could have been produced by the play of chance and not the intervention.

Third, many of the included studies used placebo as control group and measured outcomes of limited value for patients. Thus, the generalizability and clinical impact of our results may be limited. For example, we cannot answer to a patient, or clinician, questioning if these drugs improve quality of life or tell if they are better than other preventive approaches—antiepilectics, antihypertensive, cognitive-behavioral strategies. n