If a medication for major depression has a dangerous adverse interaction with a different medication that’s being studied in a clinical trial, will it be discovered by researchers and reported in the literature? Not likely, if no one enrolled in the study has major depression.

“We need to make sure that the people we study are like the people we treat,” says Keith Humphreys, PhD, a professor of psychiatry and behavioral sciences at Stanford University. “The healthcare system takes care of many people with psychiatric disorders all over the system, not just in psychiatry.”

Previous research has shown that women and older people are often disproportionately excluded from research. “We wanted to see if the same was true of people with mental illness. It’s an important question to ask because people with mental illness are just as likely, or even more likely, as the general population to have serious medical problems,” says Humphreys.

The researchers found that half of 400 highly cited randomized trials across 20 common chronic disorders reported possible or definite psychiatric exclusion criteria.1 Negative attitudes about people with mental illness are one likely reason, researchers found. Another is that researchers make blanket assumptions about lack capacity to give consent.

“The problem is that research then doesn’t generalize as well to people with psychiatric problems as it does to the rest of the population,” says Humphreys, the study’s lead author.

When enrolling patients with psychiatric disorders in research, it’s ethically important to “balance research opportunities with research protection,” says Cynthia M.A. Geppert, MD, MPH, chief ethics consultant at New Mexico Veterans Affairs Health Care System in Albuquerque.

“In areas where psychiatric patients may have vulnerabilities such as impairments in executive functioning, efforts should be made to minimize risks and maximize the benefits of participation,” Geppert says.

Previous research indicates that patients with serious mental illness want the opportunity to express their altruism and autonomy through research participation.2 “These patients should be not prevented from enrolling in research based on misconceptions about capacity,” says Geppert.

The presumption that many psychiatric patients are incapable of providing informed consent for research is still prevalent. “This is despite empirical work demonstrating that the majority of patients are able to provide informed consent for research participation,” Geppert says. For the small number of psychiatric patients who lack the capacity to consent, she suggests that proxy decision-making can safeguard patients’ welfare while permitting participation.

Marilyn A. Fisher, MD, MSBioethics, associate professor at the Center for Biomedical Ethics Education & Research at Albany (NY) Medical College, says, “Because patients who are decisionally incapacitated may seem to be convenient, gullible, and exploitable research participants, they have the right to be afforded extra protections from the dangers of participating in research.” The following are two primary ethical concerns:

People with psychiatric conditions are particularly vulnerable to coercion.

Coercion may cause an institutionalized person to consent to participate in a research study for reasons other than wanting to contribute to scientific knowledge to help others, due to fear of retribution, says Fisher.

“In order to minimize effects of coercion, the potential study subject should clearly understand that participation will not be rewarded and non-participation will not be punished,” says Fisher.

Barton W. Palmer, PhD, professor of psychiatry at University of California, San Diego, notes that a cornerstone of ethical research is that it be voluntary. This means participants cannot be coerced or unduly influenced.

“This can raise complex issues when the investigator also wears the hat of clinical provider, and is recruiting his or her own clinical patients into a protocol,” says Palmer. While this is not necessarily unethical, the potential for undue influence needs to be carefully considered, he says.

People with psychiatric conditions may have a permanent, or fluctuating, lack of capacity.

“The informed consent process should be carried out in a way that is understandable to the potential research subject, and at a time when he or she has the most capacity for understanding the information discussed,” Fisher says.

Upon diagnosis of a psychiatric illness, during a period of lucidity, advance directives can be sought for eventual participation in the research study, suggests Fisher. “The patient should have the opportunity to contemplate the study over a period of time, to ask questions about the study, and to discuss it with his or her support people,” says Fisher.

To declare all patients who are decisionally incapacitated ineligible to participate in clinical trials violates the ethical principle of justice, says Fisher. “This is because other diseases are having active research performed in hopes of finding their cures, so cures should also be actively being sought for psychiatric disease,” she says.

Certain psychiatric disorders are associated with greater risk of impaired decisional capacity. However, says Palmer, “a large body of research has shown that there is considerable within-group heterogeneity — such that it would be inappropriate to equate a psychiatric diagnosis with impaired capacity.”

Another challenge is that the participant has be be able to follow the study processes — taking medications as scheduled, avoiding anything contraindicated, completing visits and procedures as scheduled especially for safety assessment — throughout the entire study.

Moreover, it is not a person’s general decisional capacity that is at issue — rather, the capacity to make a very specific decision. “A person may retain capacity to make a decision about a straightforward protocol with a good risk/benefit ratio, but have questionable capacity to decide in regard to a more procedurally complex protocol, or one in which the risk/benefit considerations are more complicated,” says Palmer. Therefore, capacity must be evaluated on a situation-specific basis, he says.

“It is important to consider that the comprehension of a potential participant is influenced not only by his or her decisional capacity, but also by the quality of the consent process,” adds Palmer.

Except perhaps with very high-functioning individuals, it is generally inappropriate to simply have the person read and sign the consent form. “Rather, consent should be conducted as an interactive process,” says Palmer. This includes checking of participant comprehension with open-ended questions, provision of corrective feedback, and further assessment of comprehension.

“When decisional capacity is in question, formal assessment with an established tool should be considered,” Palmer adds.

REFERENCES

  1. Humphreys K, Blodgett JC, Roberts LW. The exclusion of people with psychiatric disorders from medical research. J Psychiatr Res 2015; 70:28-32.
  2. Roberts LW, Warner TD, Brody JL. Perspectives of patients with schizophrenia and psychiatrists regarding ethically important aspects of research participation. Am J Psychiatry 2000; 157(1):67-74.