Unique Ethical Issues with Research on Difficult-to-Treat Depression
Researchers face some unique ethical challenges with study protocols regarding treatment-resistant depression. “The field has largely been driven by the commonly held assumption that we can actually cure everybody if we just persist long enough,” says Augustus John Rush, MD, adjunct professor of psychiatry and behavioral sciences at Duke University School of Medicine.
Most patients with depression do improve, thanks to proper condition management. However, other patients do not return to normal function, and some may not be able to reach and sustain a depressive-free, symptom-free state. “Evidence-based medicine relies entirely on randomized, controlled trials. These are highly exclusive, aiming for high internal validity but relatively poor external generalizability,” Rush argues.
Many prospective participants with depression cannot participate in clinical trials because they do not meet the inclusion criteria.1 “This means that we are often shooting from the hip without strong evidence as to what to do since these people are excluded from the randomized, controlled trials,” Rush says.
Rush was part of a consensus group that proposed the term “difficult-to-treat” depression, and offered recommendations for how it should be identified, assessed, and managed.2 The group identified the challenges, obstacles, and opportunities in addressing the needs of those with difficult-to-treat depression. Their report focused on three important issues for clinical researchers:
• How to define this group of patients, which is heterogenous. “It might be difficult to define people with difficult-to-treat depression with enough specificity to define a clinical population for regulatory trial purposes,” Rush explains.
• How to acquire and interpret clinically meaningful outcome metrics. Traditional outcome metrics reflect short-term symptomatic changes.
“Those metrics don’t necessarily apply to difficult-to-treat depression, since trials will likely be of longer duration,” Rush explains.
Instead, researchers can consider longer-term outcome metrics. For example, one metric to consider would be: “Of the last six months, what proportion of the time was the patient symptom-free, only suffering mild symptoms (or moderate symptoms) or severe symptoms?”
• How to design clinical trials to promote generalizability. “A more careful, diligent evaluation will promote trial design with a focus on real-world patients who are often left out of participation in trials,” Rush says.
IRBs should realize trials must include patients who are quite ill to find out how to help this specific group. “IRBs are often so focused on internal validity that they require a curating of the sample so as to be less and less representative of real-world problems,” Rush notes.
Historically, patients with suicidal ideation are not allowed to participate in clinical trials.3 “Great effort has to be made to get them through IRBs, which are guarding the institution’s reputation often at the cost of diverting research efforts,” Rush reports.
The fact remains researchers simply cannot study treatments for suicidal patients unless they observe suicidal patients. “If suicidal patients are included in clinical trials, some of those people will, in fact, attempt suicide,” Rush says.
This may make IRBs reluctant to approve a study protocol that includes suicidal patients.
“The issue is not whether suicidal patients are at risk for committing suicide, but rather whether the treatment study puts them at greater risk than ordinarily encountered,” Rush says.
- Zimmerman M, Balling C, Chelminski I, Dalrymple K. Have treatment studies of depression become even less generalizable? Applying the inclusion and exclusion criteria in placebo-controlled antidepressant efficacy trials published over 20 years to a clinical sample. Psychother Psychosom 2019;88:165-170.
- Rush AJ, Sackeim HA, Conway CR, et al. Clinical research challenges posed by difficult-to-treat depression. Psychol Med 2022 Jan 7:1-14.
- Ballard ED, Snider SL, Nugent AC, et al. Active suicidal ideation during clinical antidepressant trials. Psychiatry Res 2017;257:303-308.
Researchers should focus on these three areas: How to define this group of patients, which is heterogenous; how to acquire and interpret clinically meaningful outcome metrics; and how to design clinical trials to promote generalizability.
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