Abstract: A total of 115 randomised controlled trials (26,134 participants) were included. In 54 studies paroxetine was compared with older ADs, in 21 studies with another SSRI, and in 40 studies with a newer or non-conventional antidepressant other than SSRIs. For the primary outcome (patients who responded to treatment), paroxetine was more effective than reboxetine at increasing patients who responded early to treatment (Odds Ratio (OR): 0.66, 95% Confidence Interval (CI) 0.50 to 0.87, number needed to treat to provide benefit (NNTb) = 16, 95% CI 10 to 50, at one to four weeks, 3 RCTs, 1375 participants, moderate quality of evidence), and less effective than mirtazapine (OR: 2.39, 95% CI 1.42 to 4.02, NNTb = 8, 95% CI 5 to 14, at one to four weeks, 3 RCTs, 726 participants, moderate quality of evidence). Paroxetine was less effective than citalopram in improving response to treatment (OR: 1.54, 95% CI 1.04 to 2.28, NNTb = 9, 95% CI 5 to 102, at six to 12 weeks, 1 RCT, 406 participants, moderate quality of evidence). We found no clear evidence that paroxetine was more or less effective compared with other antidepressants at increasing response to treatment at acute (six to 12 weeks), early (one to four weeks), or longer term follow-up (four to six months). Paroxetine was associated with a lower rate of adverse events than amitriptyline, imipramine and older ADs as a class, but was less well tolerated than agomelatine and hypericum. Included studies were generally at unclear or high risk of bias due to poor reporting of allocation concealment and blinding of outcome assessment, and incomplete reporting of outcomes. Some possibly clinically meaningful differences between paroxetine and other ADs exist, but no definitive conclusions can be drawn from these findings. In terms of response, there was a moderate quality of evidence that citalopram was better than paroxetine in the acute phase (six to 12 weeks), although only one study contributed data. In terms of early response to treatment (one to four weeks) there was moderate quality of evidence that mirtazapine was better than paroxetine and that paroxetine was better than reboxetine. However there was no clear evidence that paroxetine was better or worse compared with other antidepressants at increasing response to treatment at any time point. Even if some differences were identified, the findings from this review are better thought as hypothesis forming rather than hypothesis testing and it would be reassuring to see the conclusions replicated in future trials. Finally, most of included studies were at unclear or high risk of bias, and were sponsored by the drug industry. The potential for overestimation of treatment effect due to sponsorship bias should be borne in mind.

Plain-language summary: This review of the research on the effect of an antidepressant drug called paroxetine was conducted to shed light on the field of drug treatment for depression. In September 2012 we searched, in a wide ranging way, for all the useful studies (randomised controlled trials) which had been completed which compared paroxetine with any other antidepressant in treating people with depression. One hundred and fifteen studies were included in this review, with a total of 26,134 people. We grouped the studies according to the types of drug they compared paroxetine against; we then analysed the combined findings of these groups of studies. For the primary outcome (number of people who responded to treatment) paroxetine was more effective than reboxetine, but less effective than mirtazapine (in the early phase: one to four weeks follow-up) and probably citalopram (at endpoint: six weeks follow-up). There was some evidence that paroxetine is less well tolerated than agomelatine and St John's Wort, as more patients allocated to paroxetine experienced at least some side effects (though this finding for St John's Wort was only based on one study). In conclusion, some possibly meaningful differences between paroxetine and other antidepressants exist, but no definitive concluions can be drawn due to the limited number of studies per comparison. In addition, most of included studies were sponsored by the drug industry, which means they might potentially have overestimated the effect of paroxetine. Therefore, the results of this review should be interpreted with caution.