Suicidal Patients Often Excluded From Antidepressant Trials

Batya Swift Yasgur, MA, LSW

February 21, 2020

Clinical trials of antidepressants that inform US Food and Drug Administration (FDA) approval decisions often exclude suicidal patients, leaving clinicians uncertain of the efficacy of these drugs in this patient population, new research shows.

Investigators found that of 36 publications reporting on drug approvals between 1991 and 2000, 26 did not mention patients with suicidality, 9 excluded them, and only 1 study included this patient population.

In addition, 28 publications reporting on trials leading to the approval of antidepressants between 2000 and 2013 excluded individuals with suicidality.

"Clinicians should be deeply concerned about this reality and support the importance of research that yields truly generalizable knowledge," lead investigator Ana S. Iltis, PhD, director of the Center for Bioethics, Health and Society and professor of philosophy at Wake Forest University, Winston-Salem, North Carolina, told Medscape Medical News.

"Clinicians who treat depressed patients with suicidal ideation or a prior suicide attempt should ideally favor antidepressant approaches that have documented efficacy for suicidal ideation and behavior," she added.

The study was published online February 4 in the Journal of Clinical Psychiatry.

Potential Harm

Clinical trials of antidepressants in individuals with major depressive disorder (MDD) often exclude individuals with a range of characteristics, including suicidality, thereby "masking information about the applicability of results to the target population" — a situation that the authors describe as a "health inequity."

Exclusion or underrepresentation of suicidal patients in clinical trials means research results may not apply to this population; moreover, assuming they do also carries the potential for harm, the investigators note.

The aim of the study was to document the exclusion of suicidal patients in antidepressant trials used to secure FDA approval, describe barriers to inclusion, and identify possible solutions to overcoming such barriers. 

The investigators obtained inclusion and exclusion criteria for the efficacy trials for depression or MDD for 14 antidepressants approved between 1991 and 2013: sertraline, paroxetine, venlafaxine, nefazodone, mirtazapine, venlafaxine ER, citalopram, escitalopram, duloxetine, desvenlafaxine, trazodone, vilazodone, levomilnacipran, and vortioxetine.

Using data from the FDA as well as a search of PubMed for publications of clinical trials involving each medication, they derived a final list of publications that reflected, "an informed guess based on all publicly available information."

Publications from two time periods were divided into four categories, based on the inclusion or exclusion of suicidality in the reported study design.

Table. Trials of Drugs Approved From 1991 to 2000 (n = 36)

Presence/Absence of Suicidality

Number of Publications

No mention of suicidality in the inclusion or exclusion criteria

26

Persons with suicidality excluded, but no reported instrument (eg, HDRS17, MADRS) used to assess suicidality

7

Persons with suicidality excluded, and ≥ 1 instrument (eg, HDRS17, MADRS) used to assess suicidality

2

Persons with suicidality explicitly included

1

 

Table 2. Trials of Drugs Approved From 2000 to 2013 (n = 28)

Presence/Absence of Suicidality

Number of Publications

No mention of suicidality in the inclusion or exclusion criteria

4

Persons with suicidality excluded, but no reported instrument (eg, HDRS17, MADRS) used to assess suicidality

12

Persons with suicidality excluded, and ≥ 1 instrument (eg, HDRS17, MADRS) used to assess suicidality

12

Persons with suicidality explicitly included

0

HDRS17 = 17-item Hamilton Depression Rating Scale
MADRS = Montgomery-Asberg Depression Rating Scale

 

"More stringent criteria for assessing and excluding based on suicidality very likely applied for drugs approved post-2000," the authors write.

The investigators outlined four barriers affecting inclusion of individuals with suicidality in research, suggesting potential means to overcome them:

Barrier (Belief That Including Individuals with Suicidality Could…)

Approaches for Overcoming Barrier

Be too risky for the participant

  • Evaluate risks/benefits, based on evidence

  • Plan/implement measure to address risks

Participants might lack decisional capacity

  • Use validated instruments to assess decisional capacity

  • Use tested measures to foster decisional capacity

Inclusion would be too burdensome (increased cost, potential participant nonadherence, increased liability)

  • Treat informed consent like other ethical requirements for research

  • Utilize methods to promote adherence

  • Employ measures to reduce liability

Statistical considerations (introducing variables that might compromise results; no incentive to undertake additional costs/burdens)

  • Design inclusive studies

  • Measure variability

  • Incentivize inclusion

 

The authors note that the draft FDA guidance issued in 2018 states that "patients with a history of suicidal ideation and behavior need not be systematically excluded from trials…Sponsors should provide the rationale for restrictive inclusion and exclusion criteria."

However, "whether such guidance will significantly increase the generalizability of findings to persons with suicidal ideation and behavior remains to be seen," the investigators note.

The researchers suggest that a sponsor might define a target population in "unrealistically narrow ways" because "FDA approval permits it, and off-label prescribing of approved drugs expands the pool of patients taking a drug without the burden of costly research."

An Issue of Justice

Commenting on the study for Medscape Medical News, Dominic Sisti, PhD, director of the Scattergood Program for Applied Ethics in Behavioral Health Care at the University of Pennsylvania in Philadelphia, called the exclusion of individuals with suicidality from antidepressant research "an issue of justice."

"Individuals with serious, even terminal medical conditions are not excluded from potentially beneficial research without a specific reason [and] when mental illness is correctly understood as equivalent to medical illness, the default exclusion of suicidal people in antidepressant research appears to be arbitrary and unjustified."

Sisti, who was not involved with the study, added that many researchers "may be unaware that the FDA has stated that suicidal ideation or behavior need not be exclusion criteria in psychiatric research."

Also commenting on the study for Medscape Medical News, Mark Zimmerman, MD, professor of psychiatry and human behavior, Warren Alpert Medical School of Brown University, Providence, Rhode Island, said the "data was of no surprise, since it's been reported and replicated before."

Zimmerman's group has extensively researched this issue and found that "the inclusion and exclusion criteria, including suicidal ideation [in antidepressant efficacy trials], have gotten narrower, not broader, making these trials even less generalizable than they had previously been," he said.

However, "what was interesting and, I thought, new was the discussion of the ethical principles, particularly the whole issue of generalizability and ethical conduct of research, and how you balance those competing needs," said Zimmerman, who is also the director of outpatient psychiatry and the partial hospital program at Rhode Island Hospital and was not involved with this current study.

Lead investigator Iltis noted, "At a minimum, clinicians can insist on greater transparency and clarity regarding research populations so that they can readily determine to whom the findings apply."

The study was completed without grant support. Iltis has disclosed no relevant financial relationships. The other authors' disclosures are listed on the original paper. Sisti and Zimmerman have disclosed no relevant financial relationships.

J Clin Psychiatry. Published online February 4, 2020. Abstract

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