Treatment Search Fatigue and Informed Consent

Mergenthaler and colleagues have provided important empirical data on recruitment and consent in human intracranial electrophysiology research. One phenomenon that is particularly important in this context is what we call treatment search fatigue. Patients who are eligible for experimental trials examining the effectiveness of novel electrophysiological interventions such as deep brain stimulation (DBS) for managing treatment-resistant conditions (e.g., movement and psychiatric disorders) generally have severe presentations of these conditions and have undergone numerous unsuccessful treatments. For example, in one trial of adaptive DBS for OCD, eligibility requires:

• at least 5-year history of treatment-resistant OCD “that causes substantial subjective distress and impairment in functioning,”

• Y-BOCS minimum score of 28 which indicates severe to extreme case of OCD,

• an adequate trial of at least three SSRIs,

• an adequate trial of clomipramine,

• an augmentation trial of one of the SSRIs or clomipramine with antipsychotic medication, and

• an adequate trial of cognitive behavioral therapy (CBT), in this case 25 hours of exposure and response prevention (National Institute of Neurological Disorders and Stroke 2019).

The experience of searching for years for a treatment that can effectively manage their severe symptoms, in addition to the experience of these symptoms themselves, can be very taxing on patients. Treatment search fatigue could potentially lead patients to be more willing to undertake the risks and burdens associated with trials of this or other novel interventions.

Treatment search fatigue raises concerns among researchers and other stakeholders, who often characterize patients as “desperate” to find an effective intervention. As Mergenthaler and colleagues report, “Respondents conducting experimental trials expressed that patients’ desperation in the absence of established treatment options for their conditions may adversely affect voluntariness when considering participation in a study considering potential risks” (Mergenthaler et al., 11). They report one co-investigator of an experimental trial as having said, “I think a lot of the patients that have this disorder, once they get to the DBS, they’re pretty severe, and they would come in the next day or the next week. I mean they would want to come in fast. I mean, those people that want to come are pretty desperate” (Mergenthaler et al., 29). While often mentioned as a potential concern in this type of research, there has been little detailed discussion about the implications of treatment search fatigue for informed consent and how it should be managed.

Treatment search fatigue certainly may impact a patient’s decision to participate in a trial of a novel electrophysiological intervention. However, it is important not to assume that treatment search fatigue diminishes decision-making capacity or undermines the voluntariness of the decision. The criteria generally used to determine whether a patient has decision-making capacity to give informed consent are: whether the patient can communicate a choice, understand relevant information such as what the intervention entails, appreciate how this information applies to their own situation including risks, burdens, and potential benefits, and reason about the treatment options such as by comparing options and providing justifications for their decision (Appelbaum, 2007; Appelbaum and Grisso 1988). When an individual has decision-making capacity for the particular decision at issue, it is also necessary for informed consent that they make the decision voluntarily, that is, without coercion or undue influence (Appelbaum 2009).

It is not immediately clear just how treatment search fatigue might interfere with fulfillment of these criteria. Treatment search fatigue seems unlikely to interfere with patients’ ability to communicate a choice or to understand information presented to them. Similarly, it is unlikely to impair their ability to reason about their options, as this criterion is usually taken to require only that patients draw rationally legitimate inferences from a consistent set of initial premises, not that these initial premises (such as acceptability of risks) be accepted by or convincing to others. While some neurological and psychiatric disorders can involve cognitive impairments that may impact communication, understanding, or reasoning, in such cases it is not treatment search fatigue but rather symptoms themselves that potentially undermine decision-making capacity.

So, if treatment search fatigue does sometimes threaten adequately informed consent, it is likely due to threatening the appreciation criterion of capacity and/or to threatening the voluntariness of the decision. Appreciation of the risks and burdens of participation requires grasping how these apply in one’s own case, as opposed to possessing only a general knowledge of them. This plausibly requires the exercise of attention, reflection, and imagination. These are finite capacities in any individual, and ones also likely to be drawn upon in patients’ appreciation of potential benefits. Treatment search fatigue could in principle impact appreciation by leading a patient to focus strongly on potential benefits and the hope such benefits justifiably occasion, to the exclusion or minimization of consideration of risks and burdens.

Mergenthaler et al., however, focus not on decision-making capacity but on the voluntariness of research participation. Even if patients meet all four conditions for decision-making capacity, a decision might still be (at least to some degree) non-voluntary due to the pressure of their difficult situation. This is what Mergenthaler et al. interpret some of their interviewees as suggesting, and also suggest themselves (Mergenthaler et al., 5). They stress the lack of other effective options available for patients’ conditions and the resultant strength and urgency with which patients therefore often seek relief.

This type of background “situational constraint” is not traditionally thought to threaten the voluntariness of decisions except in extreme cases (Appelbaum et al. 2009, 33), as the lack of an acceptable alternative alone does not imply coercion Wertheimer (2014 [1987], 230–231). This suggests that some of the researchers interviewed either i) see treatment search fatigue as potentially being an extreme situational constraint of the kind that can undermine voluntariness, or ii) depart to some extent from the traditional view of voluntariness. Either way, this issue demands further attention. Because researchers’ ethical views are likely to be responsive to relevant facts and distinctions that may not be obvious to outsiders, their views may contain important insights about the application of ethical concepts and principles (Lázaro-Muñoz et al. 2019). We therefore advocate further dialogue between researchers and neuroethicists to shed light on how exactly researchers see treatment search fatigue as threatening voluntariness.

Treatment search fatigue may also be relevant when patients lack sufficient capacity to provide informed consent for other reasons. In such cases, the ethical course of action is for researchers to consult with the patient’s legally authorized representative to evaluate whether the patient should participate in the study. This is complexified by the need to first determine who is the appropriate legally authorized representative to provide consent for research. There are no clear guidelines in the Common Rule, and state law often does not provide guidance on the issue either (Yarborough 2015). But assuming that the legally authorized representative is determined to be a caregiver, as is often the case, it then falls to the caregiver to employ substituted judgment to determine whether given the risks, burdens, and potential benefits to the patient and others, the patient would choose to participate in the study.

While this may seem like a straightforward approach, it is also important to consider that providing care for a patient with a severe treatment-resistant condition is itself often very taxing (Schrag et al. 2006). Caregivers are subject to the burden of treatment search fatigue and caregiving fatigue more generally. Caregivers inherently have an interest in reducing the burden of the condition on both the patient and themselves (Klein 2016). Of course, interests between two or more individuals are rarely (if ever) perfectly aligned, so this is not a reason to doubt the status of caregivers as appropriate surrogate decision makers. However, in research such as this that involves significantly greater than minimal risk, researchers should be cognizant of these interests (National Institute of Mental Health 2015).

While we have suggested respects in which treatment search fatigue might interfere with informed consent, we want to caution against assuming that treatment search fatigue is always or even often a threat to such consent. The internal, experiential nature of many of these symptoms and their effect on quality of life implies that it is patients who are best-positioned to judge their harmfulness and weigh such harmfulness accordingly in decision-making. What strikes another person as desperation sufficient to impair adequate appreciation, voluntariness, or other criteria might in fact be an accurate assessment of the intolerability of these symptoms, as experienced from the inside. This may increase patients’ willingness and even eagerness to undertake certain risks and burdens that strike others as unjustified, but based on their persistent symptom severity are to them worth taking on in light of the possibility that these symptoms could be relieved for themselves and/or others whom the research may someday benefit. Recognition of this decisional complexity will be an important area for further reflection as experimental trials of intracranial electrophysiology devices continue.