Meta-analysis: Second generation antidepressants and headache

Background: To assess the risk of headache associated with commonly prescribed antidepressant medications and to examine the impact of medication class, pharmacodynamics and dosage on risk of headache.

Methods: We searched PubMed to identify all randomized, double-blind, placebo-controlled trials examining the efficacy of second generation antidepressant medications in the treatment of adults with depression, anxiety or obsessive-compulsive disorders. We used a fixed-effect meta-analysis to examine the pooled risk ratio of headache reported as a side-effect in adults treated with second generation antidepressants compared to placebo. We used stratified subgroup analysis and meta-regression to examine the effects of medication type, class, dosage, indication, and receptor affinity profile on the measured risk of headache.

Results: SSRIs were associated with a significantly increased risk of headache (RR = 1.06, 95%CI = 1.00-1.13, z = 2.0, p = 0.045) when compared to placebo. There was no significant difference (test for subgroup differences χ² = 2.2, df = 1, p = 0.14) in the risk of headache between SSRIs and SNRIs (RR = 0.97, 95%CI = 0.88-1.06, p = 0.63). There was no significant difference in the relative risk of headache with second generation antidepressants based on diagnostic indication, pharmacological properties and dosage of medications. The only antidepressants that were found to be significantly associated with increased risk of headache compared to placebo were bupropion (RR = 1.22, 95%CI = 1.06-1.41, z = 2.73, p = 0.006) and escitalopram (RR = 1.18, 95%CI = 1.01-1.37, z = 2.11, p = 0.04).

Limitations: The small number of studies that examined side effects within fixed-dose trials may have limited the power to examine the association between medication dosing and risk of headache. Additionally, reporting bias could potentially occur non-randomly across agents and therefore effect meta-analysis results.

Conclusions: Headaches reported after the initiation of second generation antidepressant medications are more likely to be coincidental than a treatment-emergent side effect of these medications.