Thirteen RCTs were included in the review (n=4,098). Three trials were placebo-controlled, five were active controlled and five had both placebo and active control. Twelve trials were included in the meta-analysis. Overall methodological quality was considered to be good. Publication bias was considered to be minor.
There were no statistically significant differences between reboxetine and placebo for remission rate or response rate. The latter result followed exclusion of one statistically outlying in-patient trial, which demonstrated that trial setting was likely to be an effect modifier. Heterogeneity was I2=49% (remission) and 42% (response rate).
Reboxetine was associated with a lower remission rate (OR 0.80, 95% CI 0.67 to 0.96, I2=4.6%; eight trials) and a lower response rate (OR 0.80, 95% CI 0.67 to 0.95, I2=0%; eight trials) compared to SSRIs overall. Similar trends were noted in comparisons with individual SSRIs and with trials that compared reboxetine with both placebo and SSRIs.
Reboxetine was associated with a higher rate of patients with at least one adverse event (OR 2.14, 95% CI 1.59 to 2.88, I2=44%; eight trials) and a higher withdrawal rate due to adverse events (OR 2.21, 95% CI 1.45 to 3.37, I2=38.4%; eight trials) compared to placebo. There were no statistically significant differences in adverse event rate between reboxetine and SSRIs (overall and individually), but a gender effect was noted in the comparison with fluoxetine. Withdrawal rates were significantly higher with reboxetine compared with fluoxetine (OR 1.79, 95% CI 1.06 to 3.05, I2=19.3%; four trials).
For remission and response outcomes, inclusion of unpublished data substantially reversed the reported superiority of reboxetine over placebo and over SSRIs in published trials. Published data was reported to over-estimate the benefits of reboxetine compared to placebo by 99% to 115% and when compared to SSRIs by 19% to 23%. For adverse events and withdrawals due to adverse events, inclusion of unpublished data similarly reversed the direction of effect, which meant that reboxetine was less favourable than placebo and fluoxetine.