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Reanalysis shows low efficacy, increased harms of paroxetine, imipramine for adolescent depression

Reanalysis of a randomized controlled trial examining the efficacy and safety of imipramine and paroxetine compared with placebo among adolescents with unipolar major depression found little efficacy and increased harms, contrary to originally published results.

“In 2013, in the face of the selective reporting of outcomes of randomized controlled trials, an international group of researchers called on funders and investigators of abandoned (unpublished) or misreported trials to publish undisclosed outcomes or correct misleading publications. This initiative was called ‘restoring invisible and abandoned trials’ (RIAT),” Joanna LeNoury, PhD, of Bangor University in Wales, United Kingdom, and colleagues wrote. “The researchers identified many trials requiring restoration and emailed the funders, asking them to signal their intention to publish the unpublished trials or publish corrected versions of misreported trials. If funders and investigators failed to undertake to correct a trial that had been identified as unpublished or misreported, independent groups were encouraged to publish an accurate representation of the clinical trial based on the relevant regulatory information.”

Under RIAT, LeNoury and colleagues conducted a reanalysis of study 329, a multicenter 8-week double-blind randomized controlled trial examining the efficacy and safety of imipramine and paroxetine compared with placebo in the treatment of adolescents with unipolar major depression. Adolescents with major depression (n = 275) were randomly assigned to 8 weeks of paroxetine (20 mg to 40 mg), imipramine (200 mg to 300 mg) or placebo.

Change in total Hamilton depression scale (HAM-D) from baseline to 8 weeks was the primary efficacy outcome of study 329. Secondary outcomes included changes from baseline to endpoint in depression items in Kiddie-Sads-Present and Lifetime Version (K-SADS-L), clinical global impression, autonomous functioning checklist, self-perception profile and sickness impact scale.

LeNoury and colleagues found that paroxetine and imipramine did not have statistically or clinically difference efficacy compared with placebo regarding any primary or secondary outcomes.

HAM-D scores decreased by 10.7 (95% CI, 9.1-12.3), 9 (95% CI, 7.4-10.5), and 9.1 (95% CI, 7.5-10.7) points for paroxetine, imipramine and placebo groups, respectively.

Researchers found a clinically significant increase in harms, including suicidal ideation and behavior in the paroxetine group and cardiovascular events in the imipramine group.

“Contrary to the original report by Keller and colleagues, our reanalysis of Study 329 showed no advantage of paroxetine or imipramine over placebo in adolescents with symptoms of depression on any of the pre-specified variables. The extent of the clinically significant increases in adverse events in the paroxetine and imipramine arms, including serious, severe, and suicide related adverse events, became apparent only when the data were made available for reanalysis,” the researchers wrote.

In response to the discrepancies highlighted by this reanalysis, David Henry, MB ChB, MRCP, FRCP, of the University of Toronto, and Tiffany Fitzpatrick, of the Ontario Strategy for Patient-Oriented Research Support Unit, discussed the benefits of revisiting dormant clinical trials in an accompanying editorial.

“Despite the importance of reproducibility in research, clinical trials are rarely subject to independent reanalysis,” Henry and Fitzpatrick wrote. “To enable reactivation of important clinical trials we will need to review some policies and procedures. Trial consent processes should routinely request permission to link the data to study long term outcomes. Stored data from participants should always include linkable fields, particularly health insurance numbers. Data management and retention policies should be reviewed to enable preservation of the data needed to enable long term follow-up of important clinical outcomes.

“Most clinical trials are extremely expensive, and we believe that the pay-off from a systematic effort to reactivate selected clinical trials will be high and will further justify the original huge investments of time and money.” – by Amanda Oldt

Disclosure: LeNoury reports no relevant financial disclosures. Henry and Fitzpatrick report authors work with the Ontario SPOR SUPPORT Unit, funded by the Canadian Institutes for Health Research and the Ontario Ministries of Health and Long-Term Care and Research and Innovation. Please see the full study for a list of all authors’ relevant financial disclosures.