The use of pharmacological preventative strategies for tension-type headache remains controversial as there has not been consistent evidence supporting the use of antidepressants as prophylactic agents, even as some guidelines (such as the European Federation of Neurological Societies) recommend amitriptyline as a first-line treatment and mirtazapine and venlafaxine as second-line. An update to an original 2005 review in the Cochrane Library on the use of selective serotonin re-update inhibitors (SSRIs) for preventing migraine and tension-type headache focuses on the use of both SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) for tension-type headache.

Since the publication of the initial review, two new studies have been published to bring the total number of studies to eight involving 412 adults. No ongoing studies were identified in clinical trial registries. Most of the studies had small sample sizes, were limited to 2–4 months, and had an unclear or high risk of bias. The studies collected compared citalopram, fluoxetine, sertraline, paroxetine, fluvoxamine, amitriptyline, mianserin, desipramine, and venlafaxine to placebo but no studies compared SSRIs or SNRIs with a drug treatment other than antidepressants or with a non-pharmacological treatment (behavioral or physical therapy). In addition, there were no head-to-head comparisons of two different SSRIs or SNRIs. Overall, these antidpressents were no better than placebo in reducing number of days with tension-type headaches and there was no difference in minor side effects compared to placebo.

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Based on these results, the authors do not recommend additional randomized controlled trials (RCTs) comparing a SSRI or SNRI vs. non-pharmacological drug. They do, however, recommend research to explore the safety and efficacy of medications from different classes, like mirtazapine, for depressed patients with tension-type headache.

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