"Real-World" Patients Excluded from Most Antidepressant Trials

Study results published in the Journal of Psychiatric Practice suggest that more than 80% of patients with depression in the general population appear to not be eligible for clinical trials of antidepressant medications. The study investigators say their finding “means that more than 5 times the number of subjects would have to be screened to find a population that would meet the typical inclusion and exclusion criteria for an [antidepressant registration trial] ART, directly determining the screening effort required in terms of both resources and time.”

Sheldon H. Preskorn, MD, a professor in the Department of Psychiatry, and Matthew Macaluso, DO, Assistant Professor in the Department of Psychiatry, both of the University of Kansas School of Medicine-Wichita, along with Madhukar Trivedi, MD, Betty Jo Hay Distinguished Chair in Mental Health in the Department of Psychiatry at the University of Texas Southwestern Medical Center, conducted the study to investigate the effects of inclusion and exclusion criteria on study enrollment.

For the study, the team quantified the effects of the criteria used commonly in antidepressant registration trials (ARTs) by applying these criteria to more than 4,000 patients treated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, essentially using the STAR*D population as a surrogate for the general population of patients with major depressive disorder. STAR*D was chosen because it was the largest and longest study of depression treatment ever conducted and used minimal exclusion criteria to ensure that the “real world” population of patients with depression was represented.

“The effect of each criterion commonly used in ARTs was assessed in terms of the percentage of the STAR*D population that would have been excluded individually and collectively (ie, when all criteria were applied at once),” write the authors.

The researchers found that more than 82% of patients in the STAR*D study would not be eligible for enrollment in current ARTs. Among other findings:

• 14% of STAR*D patients would be excluded based on age alone, as most ARTs exclude patients older than aged 65
• 15% would be excluded because their depression was less severe than a commonly used cutoff point.
• More than 20% would be excluded from ARTs because of a “clinically significant or unstable general medical condition.
• 21% of women would be excluded because they were not using birth control to prevent pregnancy during the study.
• Using the even higher severity thresholds for enrollment used in more recent studies, more than 90% of STAR*D patients would be excluded from ARTs.

It is also important to note that whereas all STAR*D patients agreed to participated in the study, many patients with depression are unwilling to do.

Drs. Preskorn, Macaluso, and Trivedi hope their study findings will help drug developers understand how study criteria may affect ART enrollment and help in developing appropriate recruitment plans and timelines. “The timelines in most drug studies are unrealistically short and their recruitment plans are often woefully inadequate, resulting in studies that take longer than expected to complete and frequent budget overruns,” the wrote. They add that not considering the effort needed for ART recruitment could result in lost revenue, delays in bringing drugs to market, or an inability to develop effective medications.

Healthcare providers can look to the findings to help explain why ARTs tend to overestimate antidepressant treatment in “real world” patients with depression. “Obviously,” the researchers add, “the more patients who are excluded from the ARTs, the greater the chances that the results will not generalize to the routine clinical practice.”