The Purpose of This Report

A wide variety of important research studies using human subjects1 has long played an essential and irreplaceable role in advancing biomedical and behavioral science, thus enhancing our ability to treat illness and better understand human behavior. In recent decades, however, researchers and commentators alike have become increasingly sensitive to the ethical issues associated with such research studies, especially as they concern the rights and welfare of subjects. As a result, government regulations,2 professional guidelines, and various institution-based mechanisms have been established in countries around the world to help ensure that such studies meet appropriate ethical standards for the protection of human subjects. The two most fundamental measures developed to meet this goal are an independent review of protocols by an institutional review board (IRB), and the informed consent of human subjects. The former is designed to ensure the moral acceptability of the ends of the research protocol by assessing its scientific validity and importance and the ethical acceptability of the means. The latter expresses respect for persons and their choices about research participation.

Mental disorders—which can be heartbreakingly burdensome for some and their families and frustrating for the professionals who treat them—have in recent years been the focus of research studies that have produced not only important and clinically relevant scientific findings but also a certain amount of public controversy, governmental sanctions, and even lawsuits (see the further discussion in Appendix I). Although existing federal regulations for research involving human subjects have provided special protections for certain populations that are regarded as particularly vulnerable,3 persons with mental disorders who may have impaired capacity4 to make decisions, and therefore to give voluntary informed consent, have not received any such special protections. While current U.S. regulations note the need to ensure the ethical treatment of human research subjects with mental disorders,5 they provide no specific guidance for IRBs and investigators regarding vulnerable subjects who are not already covered by a set of specific regulations.6 The National Bioethics Advisory Commission (NBAC) believes this state of affairs is not satisfactory.

It is useful to clarify at the outset the key characteristics of the current system of federal protections that apply to human subjects research. Two main categories of protections are provided.7 The first set of protections is provided in the Federal Policy for the Protection of Human Subjects, also known as the "Common Rule." The Common Rule is a set of regulations adopted independently by 17 federal agencies that support or conduct research with human subjects. The 17 agencies adopted regulations based on the language set forth in Subpart A, Part 46, Title 45 of the Code of Federal Regulations (CFR). Thus, the Common Rule is, for most intents and purposes, Subpart A of DHHS’s regulations. For simplicity’s sake, throughout this report wherever reference is made to a particular section of the Common Rule (e.g., the "General requirements for informed consent"), the appropriate title, part, and section of DHHS’s regulations is cited (in this example, 45 CFR 46.116). The reader should know, then, that wherever HHS’s Subpart A (45 CFR 46.101 through 45 CFR 46.124) is cited, those same regulations will in most, if not all, cases apply across the 17 signatory agencies.

The second category of federal protections that relates to human research subjects is the set of rules governing drug, device, and biologics research. These rules are administered by the U.S. Food and Drug Administration (FDA).8 Research that comes under FDA jurisdiction constitutes an important and growing portion of human subjects research. To the extent that FDA’s rules are different from the Common Rule and are relevant to the discussion, reference will be made to them.

Despite the existence of a federal policy for the protection of human subjects in research, some concerns have emerged about its adequacy. In 1995, for example, the Advisory Committee on Human Radiation Experiments (ACHRE), based on its own empirical studies, noted its concern about "serious deficiencies in some parts of the current system for the protection of the rights and interests of human subjects."9 As part of its work, ACHRE reviewed 125 research proposals involving human subjects in ionizing radiation studies that were approved and funded in fiscal years 1990 through 1993, and found that almost half of these studies involving greater than minimal risk raised "serious or moderate concerns" about risks to human subjects.10 Among the research protocols that concerned ACHRE were some involving persons at risk for impaired decisionmaking capacity. In particular, ACHRE expressed concern about studies on adults with questionable decisionmaking capacity, specifically research that offers no prospect of direct benefit to the subjects but that involves unpleasant procedures and exposes them to greater than minimal risk.11 In surveying hundreds of people who were ill but who retained decisionmaking capacity and were currently participating in clinical trials, ACHRE concluded that many of them were not aware of important and relevant elements of the research.12 Considering the special complexities of research involving persons whose decisional capacity may be affected by mental disorders, ACHRE’s concerns must not be overlooked.

The deliberations that produced NBAC’s report were not, however, stimulated by a perceived crisis in the participation of persons from this population in clinical studies, but instead by the recognition of considerable confusion about the principles and procedures that should govern such research. Although NBAC heard powerful testimony from members of the public and the professions about the conduct of such research, and about the strengths and weaknesses of the system of human subjects protection, it did not rely on this testimony as sufficient evidence of the need to "fix a broken system." NBAC was informed by this valuable input, and grateful for it, but its approach was a prospective and constructive one to close a perceived gap in human subjects protection.13

The confusion noted above has been evident in several legal cases and in widespread public discussion of the appropriate role of this population in research. One well-publicized case was the suicide, well after the completion of a research protocol, of a former subject in a "washout" study at the University of California at Los Angeles (UCLA).14 This particular case led to an investigation by the Office for Protection from Research Risks (OPRR).15 In addition, a number of organizations and government agencies, in both the United States16 and abroad,17 have recently offered recommendations regarding research on this population. Numerous scholarly papers have also appeared in the last several years addressing various aspects of the topic.18 In sum, a critical mass of concern has developed, affording NBAC the opportunity to review and consider these issues in the context of its responsibility to advise the President through the National Science and Technology Council.

Further, many new, potentially useful therapies for treating mental disorders will be developed over the next few years. The prospect of increasing numbers of research protocols, with the attendant potential increase in the number of persons with possibly impaired decisionmaking capacity recruited into these studies, makes it all the more important to clarify the ethical framework for such research.

It is generally agreed that those who lack the capacity to make an informed decision about participating in a research protocol may only be included under certain conditions—for example, when research cannot be conducted with subjects whose capacity to make decisions is not impaired, and the study entails a reasonable level of risk in light of its potential benefits and the protections involved. NBAC concluded, however, that additional guidance is required. In addition, it was mindful of concerns about the ability of IRBs at some large research centers to actually monitor, as necessary, approved research proposals.

The justification for this report, therefore, is the confluence of several considerations, including perceived gaps in the federal system for the protection of human subjects; historical and contemporary cases in which the protection of human subjects appears to have been inadequate; and the need to ensure that research designed to develop better treatments for mental disorders can proceed with full public confidence in its ethical framework. The continuing vitality of the research enterprise ultimately depends on the public’s trust that appropriate ethical constraints are in place and will be followed.

In this report, NBAC considers how ethically acceptable research can be conducted using human subjects who suffer from mental disorders that may affect their decisionmaking capacity; whether, in fact, additional protections are needed; and, if so, what they should be and how they should be implemented. In addition, this report provides an opportunity for investigators, IRB members, persons with mental disorders and their families, and the general public to become better informed about the goals of such research and appropriate protections for the human subjects involved.

Of the ten leading causes of disability in the world, according to a recent World Health Organization report, five are psychiatric conditions: unipolar depression, alcohol use, bipolar affective disorder, schizophrenia, and obsessive-compulsive disorder.19 It has been estimated that direct and indirect costs of mental illness and substance abuse in the United States totaled more than $313 billion dollars in 1990.20 Alzheimer’s disease now afflicts approximately 4 million people in this country, and, with the number of persons over 65 years of age predicted to double by the year 2030, the resulting morbidity can be expected to grow proportionately.

The scope of these disorders is so large that when treatments can be identified that can mitigate their impact, the human, social, and economic benefits are enormous. For example, since 1970, the cumulative savings to the U.S. economy from the introduction of lithium as a treatment for bipolar disorder are estimated at $145 billion. Furthermore, no dollar figure can be put on the benefits to patients and families spared the anguish of manic and depressive episodes, which often tear apart the fabric of family life and social relationships. Similarly, the introduction of clozapine for treatment of schizophrenia has been estimated to yield savings of $1.4 billion per year since 1990.21 Thus, in addition to compassion, there are economic incentives to improve our understanding of disorders affecting brain function and to develop more effective treatments.

Most research on these conditions falls into two broad categories: studies aimed at elucidating the underlying pathophysiologic basis of the disorders, and studies intended to test new treatments for them. Among the most powerful approaches to examining basic aspects of brain function and dysfunction are new techniques that allow imaging of the working brain. Positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single photon emission computer tomography (SPECT), and related procedures help identify the anatomic location of brain areas involved in cognitive and affective functions.22 Comparisons of normal and afflicted populations permit localization of regions affected by the disease process. These techniques also allow monitoring of the effects of treatment regimens at the level of the brain.23

Currently, pharmaceuticals are a primary focus of treatment-oriented research, and the development of new medications is being facilitated, for example, by studies of brain neurotransmitter receptors, which allow new molecules to be created that have the desired therapeutic effects with minimal side effects. More innovative approaches that are still in early and speculative development include insertion of new genes to correct identified defects underlying brain disorders (gene therapy), and the use of immunologic therapies, like the recent successful inoculation of rats against the psycho-stimulant effects of cocaine.24 Recently, there have been important developments in applying genetic technologies to the study of mental disorders and mental illness.25 The study of mental disorders and genetics has already been the subject of some ethical discussion.26

Some basic research (e.g., on brain receptor mechanisms) can be conducted with animals rather than with humans. But when disease processes themselves are under study, the absence of animal models for most psychiatric and many neurologic syndromes means that research on both the underlying dynamics of disease and promising treatments must, at some stage, involve human subjects. Moreover, unless research is to be limited to the mildest forms of the disorders, some persons whose decisionmaking capacity may be impaired are likely to be required in important protocols. From this reality flows the central problem of designing appropriate protections for persons with mental disorders who participate in such research protocols, while providing the opportunity to obtain the potential for benefit that may arise from their participation and, to some more limited extent, the potential benefit for other persons with the same disorder.

Persons with mental disorders are not, of course, unique in being at risk for loss of decisionmaking capacity. Accident and trauma victims, highly medicated patients, and many people who are severely ill may be significantly impaired in making autonomous and self-protective decisions. Indeed, a comprehensive list of individuals whose decision making might be compromised includes, in addition to persons with certain mental disorders, children, comatose patients, critically ill patients, institutionalized individuals, prisoners, people lacking certain language skills, and others.27 NBAC recognizes that many of the issues and concerns raised in this report (and, indeed, many of its recommended protections) could be applied to all persons with questionable or diminished capacity. NBAC principally focused its attention on those who may be primarily considered for research protocols because it is their particular mental disorder that is being studied. NBAC recognizes that it is difficult to consistently fit diseases or conditions within particular linguistic categories, particularly in areas such as psychiatry and neurology in which the boundaries of investigation are moving faster than the development of new labels. This difficulty has been noted by the American Psychiatric Association in its Diagnostic and Statistical Manual of Mental Disorders:

Although this volume is titled the Diagnostic and Statistical Manual of Mental Disorders, the term mental disorder unfortunately implies a distinction between "mental" disorders and "physical" disorders that is a reductionistic anachronism of mind/body dualism. A compelling literature documents that there is much "physical" in "mental" disorders and much "mental" in "physical" disorders. The problem raised by the term "mental" disorders has been much clearer than its solution, and, unfortunately, the term persists in the title of DSM-IV because we have not found an appropriate substitute.

Moreover, although this manual provides a classification of mental disorders, it must be admitted that no definition adequately specifies precise boundaries for the concept of "mental disorder." The concept of mental disorder, like many other concepts in medicine and science, lacks a consistent operational definition that covers all situations.28

Others also have recognized that there is no widely held definition of mental disorders, including, for example, the World Health Organization in its International Classification of Disease,29 and more recently the Nuffield Council on Bioethics;30 and yet the term is still considered to be useful since, at the core, certain conditions are widely accepted as mental disorders that may affect decisionmaking capacity. Although this report focuses principally on research involving persons with mental disorders, NBAC recognizes and encourages its use by others seeking guidance for conducting research on other persons whose decisionmaking capacity may be impaired.

NBAC was mindful of the concerns that could arise from a focus on individuals who are members of a group (i.e., persons with certain mental disorders) rather than on persons who share a common functional characteristic (i.e., questionable decisionmaking capacity). This focus could raise the specter of equating mental disorders with incapacity and thus potentially stigmatize these individuals. NBAC shares this concern and recognizes that not all persons with mental disorders have impaired decisionmaking capacity. Furthermore, such impairments do not necessarily compromise decision making about research participation. The intent is not to label persons but rather to describe and explain a set of appropriate concerns regarding research involving certain persons and to propose ways both to ensure adequate subject protection and promote important research. The recommended measures to protect these individuals are designed for those who are vulnerable when they are vulnerable to intended or unintended coercion and exploitation. These measures can only be successful when they do not, as a consequence, discriminate against those persons who may have a mental disorder, but who do not now, and who may never, have decisional impairment that would limit their ability to decide whether or not to participate in research.

To assume that a diagnosis of a mental disorder implies that a person is incapable of deciding whether to participate in a research protocol is prejudicial and incorrect. Such a diagnosis is simply one among many factors that may trigger an assessment of decisionmaking capacity. This assessment could conclude that a particular person with such a disorder either lacks or retains the capacity to make an informed decision about participating in research. Although persons with mental disorders are not necessarily decisionally impaired, much less decisionally incapable, any evidence that places a person’s decisionmaking ability into question should trigger a clinical assessment. Any disorder that alters mentation may adversely affect decisionmaking ability; but when such a disorder is present in an early or mild phase the resulting impairment may not affect a research subject’s consent to participate, even though it may necessitate extra care in the informed consent process. More advanced or severe forms of a disorder, however, may render the subject incapable of a valid, informed consent.

Clearly, special difficulties arise in designing ethically acceptable research protocols that involve human subjects with mental disorders whose decisionmaking capacity, and therefore their ability to give informed consent, may be impaired. Such mental conditions can complicate efforts to respect the rights of human subjects involved in a research project, especially when the research design is such that the subjects themselves will receive no direct medical benefits.31 Problems in determining the presence or absence of appropriate decisionmaking capacity, however, represent only one difficulty in conducting ethically acceptable research involving persons with mental disorders.

Many of the conditions underlying impaired decision making manifest themselves in behaviors that may make prospective subjects difficult to understand and may cause discomfort in others. As a result, persons with these disorders have often been stigmatized, and efforts to improve their medical treatment frequently have been marginalized. Moreover, those who are hospitalized in psychiatric units are especially vulnerable by virtue of the unique dynamics of that environment.32 As is the case for other potential research participants, confusion about the goals of a study can easily occur when the physician caring for the patient is also a researcher who may wish to enlist the patient in a research protocol. Finally, because mechanisms for funding appropriate treatment of these diseases are often seriously wanting, this population may be especially vulnerable as its members often do not have adequate access, for financial and other reasons, to health care outside the research context.33 Nevertheless, the etiology and treatment of these disorders badly need much further study, since currently there are too few satisfactory treatments.

Medical science has recently made great strides in understanding the underlying biological and chemical processes that are associated with some of the mental disorders that affect millions of Americans. Moreover, the future research agenda in this area looks very promising. As a result, as already noted, issues regarding the appropriate design of research protocols involving persons with disorders that may affect decisionmaking capacity are likely to become even more prominent in the near future. The great needs of this population represent a significant opportunity for the pharmaceutical industry to develop effective new medications; and for medical research centers, and all those dedicated to helping those with these disorders, to expand both their understanding of the origins of these disorders and their capacity to develop better treatments. In the United States the increasingly important interactions among private industry, government, academia, and other research institutions present a favorable atmosphere for scientific development, but they also present a challenge to create a regulatory framework that can protect individuals while allowing appropriate research and product development to flourish.34

In addition, because access to health care for patients with mental disorders is limited, the "benefits" of being a research subject may easily be exaggerated when in fact clinical studies are not only uncertain in their potential benefits, but may actually be designed to investigate issues that do not relate directly to the subject’s current therapeutic needs. Further, the patient’s understandable interest in access to promising experimental drugs or devices should not distract from the need to ensure that physicians are aware of therapies that have already been recognized as safe and effective and that should be incorporated into the treatment of their patients. The combination of these and other factors again calls attention to the need to consider more specific guidance about the appropriate ethical constraints in research protocols involving persons with mental disorders who may have decisionmaking impairments.

For a variety of reasons, previous efforts to establish specific protections for such subjects have largely failed, although some researchers and institutions have taken important and responsible initiatives. A recent report of the Department of Health and Human Services (DHHS) Office of the Inspector General describes such innovative practices,35 but the practices described focus on IRB review generally, not the review of protocols involving vulnerable populations. It seems that efforts to establish appropriate regulations have been hampered either by longstanding inimical social attitudes toward persons with mental disorders that may affect their decisionmaking capacity or by lack of consensus regarding how the appropriate protections should be structured. Nevertheless, society has an important and continuing obligation to address these issues more effectively for the sake of those who are directly affected by them.

Several tensions are inherent in current discourse on these issues. On the one hand, those who suffer from these disorders, and those who care about them, desperately want medical science to find ways to improve their conditions. On the other hand, there is disagreement about how this can be done without exploiting those with mental disorders who participate in research protocols, thus causing them still greater suffering.36 Despite these tensions, much can be done to reduce the apparent conflict between the need to continue promising lines of research and the ethical imperative to protect the dignity and well-being of research subjects.

A relatively small body of research has documented the effects of various disorders on decisionmaking capacity per se, supplemented by data on cognitive functioning in general and by clinical observation of these populations. The following are some of the disorders in which decisionmaking capacity may be affected, although this list is by no means exhaustive.

Dementias

Dementias are characterized by multiple cognitive deficits, most prominently impairment of memory. The best known of these conditions is dementia of the Alzheimer’s type, an irreversible progressive disorder that affects cognition (including but not limited to memory), behavior, and function. The cause of Alzheimer’s disease (AD) is presently unknown. The incidence of AD increases with age—from 2 to 4 percent in the population over 65 years old and to more than 20 percent in those over 85 years old.37 Dementias may also be caused by vascular infarcts of the brain, head trauma, HIV infection, and neurological conditions, such as Parkinson’s disease and Huntington’s disease.

The study of decisionmaking impairment in persons with dementia has focused primarily on AD. Even patients with mild forms of the disease may exhibit enough deficits in understanding relevant information and reasoning to call their capacities into question. The choices they make about treatment and research, however, may not differ from those of non-impaired populations. But as dementia progresses from the mild to the moderate stage, the range and magnitude of deficits expand, and individuals may fail even the simplest tests of decisionmaking capacity.38 The co-occurrence of other disorders such as delirium or depression may exacerbate the impact of dementia on the ability to make decisions.

Like dementia, delirium involves alterations in cognition, but usually evolves over hours or days. Disturbances of consciousness and attention are prominent. Delirium is often caused by systemic medical conditions, side effects of medications, or intoxication with or withdrawal from psychoactive agents or toxins.39 Studies demonstrating high rates of decisional impairment in severely ill hospitalized patients are probably detecting the effects of delirium secondary to the underlying conditions and, in some cases, to the treatments being administered.40 Other work suggests that serious medical illness does not directly impair brain function, even when it results in hospitalization, and is not likely, by itself, to result in limitations on decisionmaking abilities.41

Schizophrenia is a severe psychiatric disorder marked by delusions, hallucinations, disorganized speech or behavior, and diminished affect and initiative. A variety of cognitive dysfunctions, including several related to processing information, has been associated with the disorder. Its onset typically occurs in early adulthood and, although its course is variable, symptoms often wax and wane, with the result that functional impairment fluctuates over time.42 Many of its manifestations can be reduced with antipsychotic medication, but residual symptoms are frequent and relapse is not uncommon.

As many as one-half of acutely hospitalized patients with schizophrenia may have substantially impaired decisionmaking abilities, including difficulties in understanding, appreciation, and reasoning.43 Since many of these impairments appear to be related to active symptoms, the prevalence of reduced capacity is likely to be lower among outpatient groups.44 Lack of insight into the presence of illness and need for treatment is common among persons with schizophrenia.45 This may make it especially difficult for them to anticipate the consequences of their decisions on participation in research as they relate to the risk of future relapse.

Symptoms of major depression include: depressed mood; feelings of worthlessness; diminished interest and pleasure in most activities; changes in appetite, sleep patterns, and energy levels; and difficulties in concentration.46 Cognitive impairments may exist in information processing47 and reasoning,48 among other functions. Less clear is the extent to which these consequences of depression impede decision making. It has been suggested that decreased motivation to protect their interests may reduce depressed patients’ abilities to make decisions49 or to alter the nature of those decisions.50 One study suggested that hospitalized depressed patients may manifest decisionmaking problems roughly half as often as patients with schizophrenia—that is, in about one-quarter of cases.51 But it is likely that the degree of impairment relates to the intensity of depressive symptoms, and thus will vary across populations.

There is good reason to believe that the capacity of persons with other mental disorders to participate in research may, at some time, be impaired. Mental retardation, affecting as it does a range of cognitive abilities, is more likely to impair capacity as severity increases. Bipolar disorder results in alternating states of depression and mania, the latter comprising elevated mood, increased impulsivity, and reduced attention, among other features. Manic patients are known to make poor decisions about money and personal affairs, and it is probable that this deficit extends into research decision making for some subset of this group. Other psychotic disorders involve some of the symptoms seen in schizophrenia, including delusions and hallucinations, and may have some of the same consequences for decision making. Substance abuse disorders, for example, including use of alcohol and illegal drugs, result in states of intoxication and withdrawal that resemble delirium in their effects on attention, cognition, other mental functions, and, consequently, decision making. There also can be some decisional impairments associated with drug abuse and addiction outside the circumstances of intoxication and certain forms of withdrawal. However, it is important to emphasize that the diagnosis of substance abuse disorders does not imply that decisionmaking capacity is necessarily impaired.

The purpose of medical research is to understand, prevent, and treat disease, and our society is deeply committed to continuing these efforts. At the same time, in the pursuit of clinically relevant knowledge, there is often no substitute for a human subject, and this is certainly true of the study of illnesses like depression or delusional states that manifest themselves partly by altering human subjectivity or by impairing cognitive functioning.

Protecting human subjects from harm in research is perfectly compatible with pursuing important research goals; one does not have to be compromised to accommodate the other. The improvement in the design of research protocols that has occurred over the last three decades stems, in part, from the impact of regulatory frameworks that were established to ensure that human subjects in biomedical and behavioral research protocols were treated with respect. Over time, researchers have both refined their understanding of what it means to respect human subjects involved in research protocols and improved their research designs to minimize risks.

If human beings must become research subjects in order for important questions to be answered, their respectful treatment begins with soundness in research design, which is the sine qua non for ethical research involving human subjects. It has long been recognized, for example, that unless the researcher is a competent investigator and the research design is sound, it is inappropriate to attempt to engage persons as research subjects, regardless of the level of risk.

Even with the best research designs, however, research protocols can rarely eliminate all risks. As long as research is conducted involving human beings, there is a possibility that subjects will be harmed. Anyone who serves as a subject in a research protocol therefore is engaged in a form of public service that may involve risk and for which there may be no direct or tangible personal reward.

The unavoidable element of risk has warranted protections for all research subjects, and clearly such protections must never be less stringent for research subjects whose ability to be fully informed and to freely consent is lacking, diminished, or doubtful than they are for others. This proposition is already well recognized in research with children. Finally, because freedom from all risk cannot be guaranteed, and because those who have specific impairments in their decisionmaking ability do not have the same opportunity to determine the extent of their research involvement as do others, care must be taken not to succumb to any temptations to target members of this population for research when their participation is unnecessary. In particular, this population should not be exploited, that is, it should never shoulder all the risks and burdens of a scientific project when the benefits are expected to flow primarily to other segments of the population. NBAC continues to take seriously the relevance of the principle of distributive justice described by the National Commission in the Belmont Report:

Justice is relevant to the selection of subjects of research at two levels: the social and the individual. Individual justice in the selection of subjects would require that researchers exhibit fairness: thus they should not offer potentially beneficial research only to some patients who are in their favor or select only "undesirable" persons for risky research. Social justice requires that distinction be drawn between classes of subjects that ought, and ought not, to participate in any particular kind of research, based on the ability of members of that class to bear the burdens and on the appropriateness of placing further burdens on already burdened persons.52

NBAC’s views about respect for persons, beneficence, and justice are squarely in the tradition established by the National Commission nearly 20 years ago. Yet the research environment has changed, including the way in which research is conducted, its funding sources, and, in many instances, its complexity.

To say that a person consents to participate in research presupposes that he or she has the capacity to consent. An analysis of informed consent by Faden and Beauchamp holds that judgments about competence to consent perform a gatekeeping function: "competence judgments function to distinguish persons from whom consent should be solicited from those from whom consent need not or should not be solicited."53 Every effort must be made to engage the prospective subject in the informed consent process as much as his or her ability to participate in that process permits. Thus, an individual who is able to understand the purpose, risks, and possible benefits of a study must be given all the information relevant to make an informed decision about research participation. There is also an obligation to help those with cognitive impairments understand the relevant information as much as possible. The National Commission described this obligation as part of the principle of respect for persons: "Respect for persons incorporates at least two ethical convictions; first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection."54

An ethically justifiable system of clinical research should take into account the wide variations in the conditions that may affect the decisionmaking capacity of potential human subjects. It is important to recognize that decisionmaking ability may be limited in diverse ways. Appreciating and recognizing this diversity will help in the design of ethically sensitive research protocols, recruitment procedures, and consent processes.

At least four types of limitations in decisionmaking ability should be considered when planning and conducting research with this population. First, some individuals might have fluctuating capacity, what is often called waxing and waning ability to make decisions, as in schizophrenia, bi-polar disorders, depressive disorders, and some dementias. Second, decisionmaking deficits can be predicted in some individuals due to the course of their disease or the nature of their treatment. Although these individuals may be decisionally capable in the early stages of the disease progression, such as in Alzheimer’s disease, they have prospective incapacity. Third, most persons with limited capacity are in some way still able to object or assent to research, as in the case of more advanced Alzheimer’s disease. Fourth, persons who have permanently lost the ability to make nearly any decision that involves any significant degree of reflection are decisionally incapable, as in the later stages of Alzheimer’s disease and profound dementia.

These four sorts of decisional limitations—fluctuating, prospective, limited, and complete—provide an initial framework both for the different ways the problem of decisionmaking capacity can manifest itself and for the design of appropriate protections.55 At the same time, some disorders entail limitations on decisionmaking ability that are subtle and hard to identify, and even individuals who fit within a particular diagnostic category may exhibit decisionmaking limitations in different ways.

The situation is further complicated by the fact that two or more of these four categories often apply to the same individual over the course of a disease. Thus someone in the early stages of Alzheimer’s disease may have prospective incapacity, then experience very subtle decisionmaking limitations or have fluctuating capacity, and, finally, progress to incapacity. It is therefore critical that researchers who work with this population be familiar with the ways that decisionmaking impairments manifest themselves, and that they design appropriate mechanisms to maximize the subject’s ability to decide whether to enter or continue in a study. In addition, circumstantial factors often affect decisionmaking capacity. All persons feel more empowered and in control in some social situations than in others. Similarly, some persons with mental disorders may be more or less capable of making their own decisions depending on circumstances. For example, some individuals may feel more empowered in dealing with certain health care professionals or family members, and less so in dealing with others; or they may more effectively express their wishes at home than in an institution, or the reverse. Such insights can be critical in helping the individual achieve as high a degree of self-determination as possible.

Finally, a basic difficulty is central to deliberations on research involving those who may be decisionally impaired: our society has not decided what degree of impairment counts as a lack of decisionmaking capacity. Although there are certain clear cases of those who are fully capable and those who are wholly incapable, persons with fluctuating or limited capacity present serious challenges to assessment. When can those whose capacity is uncertain over periods of time be deemed capable of decide about participating in research? In a society that treasures personal freedom and centers its political system on the integrity and value of each individual, this question goes to the very heart of our culture and must therefore be addressed with utmost caution.

Research involving persons with mental disorders must take into account other especially relevant issues, beyond those having to do with informed consent. Some of these include:

Limitations on drug development: Currently, illnesses associated with decisional impairments often involve testing at an earlier stage of drug development than is usually the case in pharmaceutical research, because animal models may not yield data that can be extrapolated to human diseases that cause psychological or cognitive symptoms.

Subjective experience of disorders: While all individuals experience their illnesses subjectively, the experiences of those with mental disorders pose additional challenges to research. In some instances, because of confusion or other manifestations of their disorder, they may perceive that they are at greater risk of harm than is actually the case. Their subjective perception is no less real, and therefore no less important, than the subjective perception of pain from physical injury, but it may require researchers to factor more individualized judgments into their projections of risk and benefit than may be the case for researchers in other fields.

Problems in mental health care: Mental health care has a checkered history characterized by periods of patient neglect, abuse, superstition, and stigmatization. Sadly, some of these historical trends can be found even in our own time and among relatively prosperous societies. The outward symptoms of some mental disorders and the fact that many stricken individuals are difficult to treat still make some people uncomfortable. In addition, some primary health care professionals are relatively unfamiliar with the symptoms of these illnesses or the best treatment for them. Some individuals in these groups are difficult to work with in the research setting. For these reasons and others, both clinical care and research in these diseases have often received lower priority than illnesses considered more "medical" in nature.

Furthermore, the adequacy of financial resources for treating many of these conditions continue to suffer compared to other diseases. Both public and private insurance policies often fail to provide adequate support for the kinds of intervention that may be required.56 This problem is further aggravated by the disadvantaged economic situation of many persons with mental disorders, since many may have trouble in completing education and training programs or in securing or retaining employment. As a result, they are often not well connected to social support networks. For all these reasons, there is a significant association between mental illness and poverty. According to a study published in 1992, 21 percent of adults with serious mental illness fall below the poverty threshold, compared with 9 percent of the general adult population.57 Many homeless Americans may suffer from a major mental illness.58 Moreover, the widespread lack of understanding of the nature and implications of these disorders itself serves, independently of financial issues, as a barrier to appropriate care. In any case, without adequate access to mental health services and other social supports, and without adequate financial resources, these individuals and their families may feel that their participation in a research protocol presents a rare opportunity for treatment. Even when they are not decisionally impaired, their hope can thus easily overwhelm their understanding of the various risks and the sometimes remote likelihood of direct benefit. Like any person who is ill, those who struggle with mental disorders that impair their decisionmaking abilities are vulnerable; and in some respects they may be more vulnerable. For example, having enrolled in a study that holds out the prospect of direct medical benefit, those struggling with psychiatric illness might feel more dependent on the research institution and study personnel, and fear being released from the study and losing their professional support.

In the blizzard of legal considerations and moral subtleties that swirl around the involvement of decisionally impaired persons in research, it is easy to lose sight of the critical role of informal caregivers, such as family and friends, in an individual’s decision to undergo treatment or participate in a research protocol. NBAC was moved by the testimony of those who, though often bearing witness to other matters, presented powerful stories of long-term commitment to loved ones struggling with the consequences of debilitating diseases. Their testimony raised two issues of particular relevance to NBAC’s deliberations: first, the persistent problem of providing ongoing care, given limited resources, to persons with mental disorders. As noted above, our health care system has familiar inadequacies in access to health care, especially in continuity of care, appropriate treatment of those with chronic disease, long-term care, and rehabilitation. Second, the more implicit problem of insufficient sharing of information about patients-subjects between physicians-researchers and caregivers. One particular example of this problem is the way in which information is shared with family members. Families frequently complain that some mental health professionals fail to include them as members of the team caring for the patient. In the words of NBAC Commissioner Patricia Backlar, "currently mental health providers rarely share relevant information with the informal caregiver, nor do they ask families for information germane to treatment or legal decisions."59 It is important to note, however, that the complex relationships that exist within families in which one member is identified as having a mental disorder are not always harmonious. As one public comment observed: "The innately complex nature of this field is illustrated by the fact that there may be varying alliances depending upon the individual situation of either patient with family, patient with professional, patient with scientist, or any other configuration of these groups."60

In fact, bioethical theory has rarely been sensitive to the underlying interpersonal support mechanisms of family and close friends that are often so important to those with long-term illnesses. Much theorizing has worked against recognizing and involving others in the process of conducting ethical research. To be sure, communication with informal caregivers raises important issues of individual autonomy and patient confidentiality. Within the autonomy-based framework of our society’s regulatory philosophy, there should also be a place for considering the important roles played by those who care for the potential subject.61 This can be done without undermining the critical role of self-determination in human subjects research. In this report, NBAC notes the important role of families and others in decision making about research participation, and recommends ways to recognize these roles.

Many research studies do not hold out the prospect of direct medical benefit to the human subjects involved. Such studies may be necessary, for example, to understand how a particular drug will function in human beings, or to study the subjects’ reactions to particular stimuli (e.g., modeling the dynamics of the disease). In these cases the hope is that the knowledge gained will eventually lead to better treatments. While the individual subject may garner certain indirect benefits—such as closer professional attention—such benefits are not produced by the medication, device, or mechanism being studied.

Other studies include drugs or procedures that have the potential of providing direct medical benefit to subjects. Even in these cases, however, it is not possible for researchers to know for certain whether an intervention would be better for the subject than doing nothing (which often occurs in a placebo control study), or whether the subject would benefit more from the currently available standard treatment. The nature of clinical research is that investigators cannot predict with certainty that a particular study will benefit a particular person, or even that it will benefit any subject. Indeed, if researchers were certain of the outcome, there would be no justification for doing the research in the first place. What is called "clinical equipoise" is commonly considered to be a prerequisite for ethically justified research, that is, the relevant medical and scientific community must be divided, on the basis of available evidence, about which medication or procedure is safer or more effective.62 Interest in access to potentially beneficial experimental treatment is not, of course, limited to persons with conditions that may be directly related to decisionmaking impairments. Anyone who suffers from a disease for which there is no adequate recognized treatment may wish to participate in a clinical trial. There is always the danger, therefore, that the desire for a treatment may overwhelm the ability to assess the likelihood of benefit or to balance the risks and potential benefits from the drug or device being studied. The situation is further complicated when the primary caregiver is also the researcher. This "therapeutic misconception"63 may be especially intense for those whose decision making is impaired. And patient-subjects who do not fully understand the differences between research and therapy may feel betrayed or abandoned when their study participation comes to an end.

There is considerable commentary on the ethical prerequisites for research involving human subjects, and much of it is represented in the Nuremberg Code and subsequent professional, national, and international codes and guidelines for research. The relevant considerations include whether the importance of the study is great enough to justify the potential harms to which human subjects are exposed, and whether there is any other reasonably effective way to obtain information that would reduce the level of risk to which the subjects are exposed. As well, there is a widely accepted view in the ethics of human subjects research, particularly since World War II, that some knowledge or potential benefit to others may have to be sacrificed if the costs to individual subjects are too great. Clearly, those who conduct research with human beings have a responsibility to design studies that are both scientifically and ethically sound. Nonetheless, in some contexts, scientific and ethical considerations are not always seen as jointly necessary features of high-quality research design. For example, textbooks on research methods and clinical trials rarely integrate ethical guidance with scientific guidance.64 On the other hand, many granting and regulatory groups are beginning to recognize that ethical research must meet the requirements of scientific validity and importance,65 and that scientific investigations using human subjects must be conducted according to ethical principles.

While all research should be expected to meet these requirements, studies that involve vulnerable persons would seem to warrant particular attention to these requirements. Deciding which design will best answer the research question, which design minimizes risks to the human subjects involved, what procedures will be used, and which subjects will be studied, are all questions that require both scientific and ethical justifications. Philosophers of science have long pointed out that even the selection of one hypothesis over another has moral implications, insofar as there are opportunity costs associated with this choice. Further, the decision to pursue some hypotheses, and the experimental design that accompanies that decision, can have direct moral consequences.

As part of its commitment to familiarize itself with research that has been conducted in this area, NBAC requested from investigators a number of relevant protocols and applicable consent forms. Its analysis, the details of which are described in the box below, identified several issues relating to study design, including recruitment and selection of subjects, and informed consent, that require further attention.

As has been the case for research with other populations, one of the controversial aspects of research involving persons with mental disorders concerns the ethical acceptability of the basic designs of some studies. There are, for example, significant concerns in some quarters about study designs that use drugs to stimulate behavioral or physiological manifestations of the disease under study. The term "challenge study" refers to a general category of psychological and pharmacological provocations.66 Miller and Rosenstein list among these provocations injection of intravenous amphetamine, inhalation of carbon dioxide, and presentation of a phobic stimulus. The principal scientific rationale for conducting psychiatric symptom-provoking studies is "to learn more about the underlying pathophysiological mechanisms responsible for the symptomatic expression of psychiatric illnesses."67 In these studies, the goal is to generate disease manifestations in a controlled setting so that they can be more fully understood and so that appropriate interventions can be designed, attempted, and evaluated.

Challenge studies raise several ethical issues, and NBAC heard testimony on this subject by members of the public, scientists, and others on several occasions. Two concerns emerged from the public testimony and the literature. The first concern is whether it is possible to obtain informed consent to participate in a study designed to provoke symptoms. The second concern is whether the relationship between risks and potential benefits can ever justify enrolling individuals in such studies when the protocols include intentionally inducing what would otherwise be considered harmful.

Another study design that has generated a good deal of concern and debate is a "washout" study, which deprives the patient of medication prescribed for therapeutic purposes. Sometimes also called a "drug holiday," such a protocol often seeks to return the individual to a medication-free "baseline" state so that behavior can be assessed or new drugs introduced without the confounding factor of other substances already in the person’s system. In other protocols of this type a beneficial drug may be withdrawn for purposes of determining, for example, the appropriate duration of the drug therapy. Of particular concern are washout studies in which medication is suddenly or very rapidly withdrawn, principally because of the risks of harm this would entail. Often the washout and challenge approaches are combined in a single study.

Finally, the use of placebo controls also raises ethical concerns.68 Usually conducted in a "blinded" fashion so that neither the subject nor the investigator knows which agent is active and which is placebo, ethical placebo studies require that subjects understand that they will not necessarily receive the experimental intervention. As in the other study designs mentioned, there will be special ethical concerns for persons whose decisionmaking capacity is fluctuating or absent at the time of study enrollment, since the idea of a study in which some persons will receive an active drug, and others will receive a non-active pill, may not be a familiar one. Moreover, as noted above, the tendency to construe all "medical" interventions as having the potential to provide direct medical benefits may especially affect persons whose cognitive processes are impaired and who are particularly dependent upon physicians and medical institutions.

Since ethical guidelines and regulations are designed for use by IRBs, it is not surprising that, when reviewed in detail, they tend to concentrate on the requirement that there be scientific merit in the proposals.69 As noted previously, however, both scientific merit and ethical acceptability are jointly necessary for conducting human subject research. Washout studies, challenge studies, and placebo-controlled studies with subjects who are the focus of this report require special attention to appropriate ethical constraints, both from IRB members and from researchers who work with persons with mental disorders.

The investigator is the key player in our research system with respect to the protection of human subjects. Indeed, unless individual clinical investigators understand their ethical responsibilities, no regulatory system will function properly. Many of the central issues addressed in this report—standards for decisionmaking capacity, assessment of risk of harms and potential benefits, techniques for improving informed consent, and recognition of the involvement of family members and friends—turn on the integrity, compassion, and professionalism of the researcher as well as on his or her ability to conduct high-quality science. No matter how many regulations are put in place or guidelines are written, and no matter how intense the scrutiny by IRBs or other authorities, there can be no substitute for the ongoing commitment by researchers and the institutions in which they work to ethically appropriate behavior throughout the research process. This is true not only during protocol planning and development, but also throughout the trials themselves.

There is no "right" to conduct research with human subjects. It is a privilege conferred by society on researchers who are prepared to undergo rigorous scrutiny of their proposed studies. Nevertheless, researchers are under enormous pressure to find treatments for diseases that cause much suffering; thus, there can be a tendency for besieged researchers to view human participation in research as an obligation to society. This thinking is not simply misguided, but morally untenable and dangerous.

Researchers should be in the habit of asking the following questions: Does the scientific importance of my work justify asking people to participate as subjects in my research protocol? Should this person be recruited into my study? Are the risks and potential benefits of study participation acceptable for this potential subject? Does this person have the capacity to decide about participation in this study? Does he or she understand the nature of the research? Is his or her agreement to participate informed and voluntary? Is he or she unusually vulnerable to the therapeutic misconception? The ethically responsible researcher is expected to carry the dual burden to advance knowledge that can improve the human condition and, at the same time, to recognize the absolute imperative to treat human research subjects with the utmost care and respect.

Many of those who oppose additional special protections stress that the research environment is, in fact, often more beneficial than the usual clinical setting for persons who are ill. Research subjects might not only be receiving "cutting edge" treatment as well as standard therapy, but their conditions will probably be monitored more carefully than is usually the case. Furthermore, many research participants could not otherwise afford the highly specialized attention available in many protocols.

While there is some truth to these claims, prospective involvement in a study should not be presented or perceived simply as a substitute for health care or as a source of better health care. Further, using the research system as a supplement to a health care system that may not be accessible to many cannot be the principal justification for enrolling human subjects in research protocols. The context of research and health care must not be confused, if for no other reason than that the primary goal of the former is to expand medical knowledge and improve future treatment for particular disorders, and the primary goal of the latter is to provide immediate medical assistance.

Although many have accepted the wisdom of Henry Beecher’s observation more than three decades ago that in addition to informed consent, "there is the more reliable safeguard provided by the presence of an intelligent, informed, conscientious, compassionate, responsible investigator",70 it would be unfair and unrealistic to expect individual clinicians and researchers, who often face multiple conflicts of interest, to both recognize and resolve by themselves the complex moral problems arising from the use of human subjects in research trials. It is not adequate to focus these ethical responsibilities only on the individual investigator who, in fact, functions within a much broader research and clinical environment.

The responsibility for ensuring that the rights and welfare of human subjects are protected, therefore, also falls on the investigator’s research community, department, or institution. Specific responsibilities include, but are not limited to, educating investigators about the ethics of research and the protection of human subjects, and monitoring, as appropriate, investigators’ behavior in relation to the human subjects in their ongoing research. IRBs, for example, as they are presently constituted, do not discharge all of their responsibilities simply by approving an investigator’s research protocol. As we will discuss more fully below, IRBs also have considerable authority to monitor the research itself.

Three analytical chapters follow this introductory chapter. Chapter 2 focuses on informed consent and decisionmaking capacity. Chapter 3 addresses the issues of advance planning, surrogate decision making, and assent or objection. Chapter 4 presents an analysis of the assessment of risks and potential benefits. The final chapter presents NBAC’s recommendations for research involving persons with mental disorders that may affect their decisionmaking capacity. In making its recommendations, NBAC is acutely aware of the already considerable burdens placed upon dedicated clinical scientists and research centers. Some of the recommendations will undoubtedly require a greater investment of resources to enhance the protection of human research subjects. These new investments will be required to strengthen IRBs at the local level, federal offices charged with ensuring compliance with federal regulations regarding human subjects protections, and the National Institutes of Health (NIH) and other relevant federal research agencies. If important research that will benefit society is to flourish, it can only do so in an environment that strictly adheres to the values and rights that are so central to our society. NBAC believes that, in the long term, such investments will result in increased public support for biomedical research and improved therapies for individuals with mental disorders.

1 In this report, the National Bioethics Advisory Commission (NBAC) refers to persons on whom research interventions are performed (including participants who serve as members of a "control group" in clinical studies) as "human subjects," consistent with the language in current federal regulations. See 45 CFR 46.102(f) (1998) (defining human subject as "a living individual about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information"). Since the report also concerns itself with individuals who might be or may become prospective research subjects, we will generally refer to "persons" when discussing these individuals.

2 In the United States, federal regulations protecting human subjects first became effective on May 30, 1974. First issued in 1966 by the Department of Health, Education and Welfare (DHEW), the National Institutes of Health (NIH) Policies for the Protection of Human Subjects were codified at 45 CFR 46 (1974). The regulations established the Institutional Review Board (IRB) as one mechanism through which human subjects would be protected. Currently, the federal human research subjects protections only apply in: (1) research supported by one of the federal agencies subscribing to the Common Rule; (2) research conducted at an institution or by an individual investigator at an institution that has executed an assurance with the federal government in which the institution agrees that its human subjects research will be conducted in compliance with the regulations, regardless of funding source; or (3) research on an investigational new drug, device, or biologic subject to FDA rules.

3 Department of Health and Human Services (DHHS) regulations govern research involving fetuses, pregnant women, human in vitro fertilization (45 CFR 46, Subpt. B (1998)) and prisoners (45 CFR 46, Subpt. C (1998)); both DHHS and the Department of Education (ED) have regulations governing research involving children (45 CFR 46, Subpt. D.; 34 CFR 97, Subpt. D (1998)). Other potentially vulnerable subjects whose decisionmaking capacity may be compromised by such factors as trauma (e.g., head injury) or physical illness (e.g., cancer or sepsis) will not be considered directly in this report.

4 Throughout this report the term "capacity" is used rather than the term "competence" (although the two are often used interchangeably by others), because the latter often refers to a legal determination made by a court, and the former refers to a clinical judgment. See Jessica Wilen Berg and Paul S. Appelbaum, "Subjects’ capacity to consent to neurobiological Research," in Harold A. Pincus, Jeffery A. Lieberman and Sandy Ferris, eds., Ethics in Psychiatric Research A Resource Manual for Human Subjects Protection (Washington, D.C.: American Psychiatric Association, 1998): 81–106.

5 See for example 45 CFR 46.111(b) (1998), which notes the need to consider additional protections where "some or all of the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons."

6 Alison Wichman, "Protecting Vulnerable Research Subjects: Practical Realities of Institutional Review Board Review and Approval," Journal of Health Care Law and Policy 1, no. 1 (1998): 88–104, 92–93.

7 NBAC notes the existence of other federal laws that might bear on issues discussed in this report, but due to their apparent limited scope (e.g., 10 U.S.C. § 980 (1997) (restricting the circumstances in which the Department of Defense may use subjects in research), and because we believe the recommendations stated herein should apply generally, we do not discuss all relevant existing rules.

8 See 21 CFR 50 (1998) (informed consent requirements), 21 CFR 56 (1998) (Institutional Review Boards), 21 CFR 812 (1998) (Investigational Device Exemption), and 21 CFR 312 (1998) (Investigational Drug Exemption).

9 Advisory Committee on Human Radiation Experiments (ACHRE), Final Report (New York: Oxford University Press, 1995), 510.

10 Ibid., 456. These concerns related principally to the quality and content of consent forms, but also included other issues such as the level of risk, scientific merit, and recruitment strategies.

11 Ibid.

12 Ibid., 459–81.

13 James F. Childress, "The National Bioethics Advisory Commission: Bridging the Gaps in Human Subjects Research Protection," Journal of Health Care Law and Policy 1, no. 1 (1998): 105–22.

14 "Washout" studies are protocols that seek to return the individual to a medication-free "baseline" state so that behavior can be assessed or new drugs introduced without the confounding factor of other substances already in the person’s system.

15 Office for Protection from Research Risks (OPRR), Evaluation of Human Subject Protections in Schizophrenia Research Conducted by the University of California, Los Angeles (1994).

16 Expert Panel Report to the National Institutes of Health, Research Involving Individuals with Questionable Capacity to Consent: Ethical Issues and Practical Considerations for Institutional Review Boards (February 27, 1998); Office of the Maryland Attorney General, Final Report of the Attorney General’s Research Working Group (June 12, 1998); State of New York Department of Health Advisory Work Group on Human Subject Research Involving Protected Classes, Recommendations on the Oversight of Human Subject Research Involving Protected Classes, (New York: May 1998).

17 Council of Europe, Convention on Human Rights and Biomedicine (November 1996); The Law Commission, Mental Incapacity: Item 9 of the Fourth Programme of Law Reform: Mentally Incapacitated Adults (London: House of Commons, 1995); Council for International Organizations of Medical Sciences (CIOMS), International Ethical Guidelines for Biomedical Research Involving Human Subjects (Geneva: 1993); Medical Research Council of Canada, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada, Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (Ottawa: 1998).

18 Jay Katz, "Human Experimentation and Human Rights," St. Louis Law Journal 38 (1993): 7–54; Daniel C. Marson et al., "Assessing the Competency of Patients with Alzheimer’s Disease under Different Legal Standards," Archives of Neurology 52 (1995): 949–54; Barbara Stanley et al., "The Elderly Patient and Informed Consent," Journal of the American Medical Association 252 (1984): 1302–1306; Evan G. DeRenzo, "The Ethics of Involving Psychiatrically Impaired Persons in Research," IRB 16, no. 6 (1994): 7–11; John C. Fletcher and Alison Wichman, "A New Consent Policy for Research with Impaired Human Subjects," Psychopharmacology Bulletin 23 (1987): 382–85; Joseph M. Berg, Harry Karlinsky, and Frederick H. Lowy, eds. Alzheimer’s Disease Research: Ethical and Legal Issues (Toronto: Carswell, 1991); Edward W. Keyserlingk et al., "Proposed Guidelines for the Participation of Persons with Dementia as Research Subjects," Perspectives in Biology and Medicine 38 (1995): 319–62; Adil E. Shamoo and Timothy J. Keay, "Ethical Concerns About Relapse Studies," Cambridge Quarterly of Healthcare Ethics 5 (1996): 373–86; Paul S. Appelbaum and Thomas Grisso, "Capacities of Hospitalized, Medically Ill Patients to Consent to Treatment," Psychosomatics 38 (1997): 119–25; Richard J. Bonnie, "Research with Cognitively Impaired Subjects," Archives of General Psychiatry 54 (1997): 105–111; Jonathan D. Moreno, "Regulation of Research on the Decisionally Impaired: History and Gaps in the Current Regulatory System," Journal of Health Care Law & Policy 1(1) (1998): 1–21.

19 World Health Organization, The Global Burden of Disease (Cambridge: Harvard University Press, 1997).

20 National Institutes of Health, Disease-specific Estimates of Direct and Indirect Costs of Illness and NIH Support (update report to Congress, April 1997).

21 Herbert Y. Meltzer et al., "Cost Effectiveness of Clozapine in Neuroleptic-resistant Schizophrenia," American Journal of Psychiatry 150 (1993): 1630–38.

22 Nancy C. Andreasen, Daniel S. O’Leary, and Stephan Arndt, "Neuroimaging and Clinical Neuroscience: Basic Issues and Principles," American Psychiatric Press Review of Psychiatry 12, eds. John M. Oldham, Michelle B. Riba, and Allan Tasman (Washington, DC: American Psychiatric Press, 1993).

23 Lewis R. Baxter et al., "Caudate Glucose Metabolic Rate Changes with Both Drug and Behavior Therapy for Obsessive-compulsive Disorder," Archives of General Psychiatry 49 (1992): 681–89.

24 M. Rocio A. Carrera et al., "Suppression of Psychoactive Effects of Cocaine by Active Immunization," Nature 378 (1995): 727–30.

25 Rogaeva Ekaterina et al., "Evidence for an Alzheimer Disease Susceptibility Locus on Chromosome 12 and for Further Locus Heterogeneity," The Journal of the American Medical Association 280 (1998): 614–618. See also, the recent Request for Applications (RFA) issued by the U.S. National Institute of Mental Health, NIH Guide to Grants and Contracts, "Molecular Genetics of Schizophrenia and Depression," RFA-MH-99-005, released November 18, 1998.

26 The Nuffield Council on Bioethics, Mental Disorders and Genetics: The Ethical Context (London: 1998).

27 Wichman, "Protecting Vulnerable Research Subjects," 104.

28 American Psychiatric Association (APA), Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (Washington, D.C.: American Psychiatric Association, 1994), xxi.

29 World Health Organization (WHO), The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines (Geneva: WHO, 1992), 5.

30 The Nuffield Council, supra, 10–12.

31 For example, some drug research is intended only to determine at what dosage the medication under study will cause a person to become ill or how rapidly the drug is excreted from the body.

32 This concern was described by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission) in its report, Research Involving Those Institutionalized as Mentally Infirm (Washington, D.C.: Department of Health, Education and Welfare, 1978).

33 The barriers to appropriate care can be due to financial or other factors (e.g., lack of knowledge or of qualified providers, denial, etc.). These barriers may be particularly acute if the initial onset of the disorder occurs before an individual is attached to some social support mechanism.

34 Another complicating factor in efforts to protect human research subjects is the unclear boundary between research and what is often called "innovative treatment." The latter category is intended to suggest that medical intervention is not undertaken as part of a scientific study but is rather an attempt to treat an individual patient who has not responded to standard therapy. For example, a patient whose physician recommends an "off-label" trial of a medication approved for a different use is not, with respect to federal regulation, a research subject unless the physician is engaged in the systematic collection of data about a specific use of the drug. In this kind of clinical situation, certain existing regulatory requirements for ethically sound research, such as prior review of the procedure by an Institutional Review Board, do not apply. Nevertheless, the usual requirement that the treating physician obtain informed consent for any intended treatment does apply, and the patient, or the patient’s legally authorized representative, should be informed about, and consent to, the innovative procedure.

35 Department of Health and Human Services, Office of the Inspector General, Institutional Review Boards: Promising Approaches (Washington, D.C.: DHHS, 1998).

36 Ethics in Neurobiological Research with Human Subjects, ed. Adil E. Shamoo (Amsterdam: Gordon and Breach, 1997).

37 APA, DSM-IV, 137.

38 Marson et al., "Assessing the Competency," 949–54; Stanley et al., "The Elderly Patient," 1302–1306.

39 APA, DSM-IV, 126.

40 Lewis M. Cohen, Jack D. McCue, and Gerald M. Green, "Do Clinical and Formal Assessment of the Capacity of Patients in the Intensive Care Unit to Make Decisions Agree?" Archives of Internal Medicine 153 (1993): 2481–85.

41 Appelbaum and Grisso, "Capacities," 119–25.

42 APA, DSM-IV, 282–83.

43 Thomas Grisso and Paul S. Appelbaum, "The MacArthur Treatment Competence Study III: Abilities of Patients to Consent to Psychiatric and Medical Treatments," Law and Human Behavior 19 (1995): 149–74.

44 Barry Rosenfeld, Eric Turkheimer, and William Gardner, "Decision Making in a Schizophrenic Population," Law and Human Behavior 16 (1992): 651–62.

45 Xavier F. Amador et al., "Awareness of Illness in Schizophrenia," Schizophrenia Bulletin 17 (1991): 113–32.

46 APA, DSM-IV, 345.

47 Shirley Hartlarge et al., "Automatic and Effortful Processing in Depression," Psychological Bulletin 113 (1993): 247–78.

48 Jane E. Baker and Shelley Channon, "Reasoning in Depression: Impairment on a Concept Discrimination Learning Task," Cognition and Emotion 9 (1995): 579–97.

49 Carl Elliott, "Caring About Risks: Are Severely Depressed Patients Competent to Consent to Research?" Archives of General Psychiatry 54 (1997): 113–16.

50 Melinda A. Lee and Linda Ganzini, "Depression in the Elderly: Effect on Patient Attitudes toward Life-sustaining Therapy," Journal of the American Geriatric Society 40 (1992): 983–88.

51 Thomas Grisso and Paul S. Appelbaum, "The MacArthur Treatment."

52 National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Biomedical and Behavioral Research (Washington, D.C.: U.S. Government Printing Office, 1979), 7.

53 Ruth R. Faden and Tom L. Beauchamp, A History and Theory of Informed Consent (New York: Oxford University Press, 1986), 288.

54 National Commission, Belmont Report, 4.

55 These categories do not apply to children, whose decisional limitations are developmentally appropriate and are not a result or symptom of an illness.

56 Thomas Szasz, "Parity for Mental Illness, Disparity for the Mental Patient," The Lancet 352 (1998): 1213–15.

57 Peggy R. Barker et al., "Serious Mental Illness and Disability in the Adult Household Population: United States, 1989," in Advance data from vital and health statistics of the National Center for Health Statistics, no. 218, eds. Ronald W. Manderscheid and Mary Anne Sonnenschein (Washington, D.C.: HHS, 1992).

58 Rael Jean Isaac and Virginia C. Armat, Madness in the Streets: How Psychiatry and the Law Abandoned the Mentally Ill (New York: Free Press, 1990).

59 Patricia Backlar, "Ethics in Community Mental Health Care: Confidentiality and Common sense," Community Mental Health Journal 32 (1996): 513–18.

60 Herbert Pardes, public comments in a letter to NBAC, Columbia University, July 31, 1998.

61 Julia Twigg and Karl Atkin, Carers Perceived: Policy and Practice in Informal Care (Buckingham: Open University Press, 1994).

62 Benjamin Freedman, "Equipoise and the Ethics of Clinical Research," New England Journal of Medicine 317 (1987): 141–145.

63 Paul S. Appelbaum et al., "False Hopes and Best Data: Consent to Research and the Therapeutic Misconception," Hastings Center Report 17, no. 2 (1987): 20–24.

64 Heather J. Sutherland, Eric M. Meslin, and James E. Till, "What’s Missing from Current Clinical Trials Guidelines? A Framework for Integrating Science, Ethics, and Community Context," Journal of Clinical Ethics 5 (1994): 297–303.

65 Benjamin Freedman, "Scientific Value and Validity as Ethical Requirements for Research: A Proposed Explication," IRB 9, no. 6 (1987): 7–10.

66 Franklin G. Miller and Donald L. Rosenstein, "Psychiatric Symptom-Provoking Studies: An Ethical Appraisal," Biological Psychiatry 42 (1997): 403–409.

67 Ibid., 403.

68 Donald Addington, "The Use of Placebos in Clinical Trials for Acute Schizophrenia," Canadian Journal of Psychiatry 40 (1995): 171–76; Kenneth J. Rothman and Karin B. Michels, "The Continuing Unethical Use of Placebo Controls," New England Journal of Medicine 331 (1994): 394–98.

69 Sutherland, Meslin, and Till, "Integrating Science, Ethics, and Community Context," 297.

70 Henry K. Beecher, "Ethics and Clinical Research," New England Journal of Medicine 274 (1966): 1354–60, 1360.

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