Paper One: Decisionally Impaired Research Subjects Disorders and Research Promises-Commissioned Papers
The Nature of Disorders that Affect Decisionmaking Ability
Any disorder that alters mentation may adversely affect decisionmaking ability. When such a disorder is present in an early or mild phase, the resulting impairment may not rise to the level at which a potential research subject would be considered unable to consent to research participation, although extra care in the informed consent process may be required. More advanced or severe forms of disorder, however, may render the subject incapable of independent choice. Thus, identification of a potential subject as suffering from a disorder that may impair mentation does not obviate the need for an individualized assessment of the person's decisionmaking abilities. A relatively small body of research has documented the effects of various disorders on decisionmaking capacity per se, but this is supplemented in many cases by data on cognitive functioning in general and by a good deal of clinical experience with these populations.
Dementia
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, a progressive disorder whose cause is presently unknown, the incidence of which increases with age, from 2 to 4 percent in the population over 65 years old to 20 percent or more in persons over 85 years old.1 Dementias may also be caused by vascular infarcts of the brain, head trauma, HIV infection, and other neurological conditions, such as Parkinson's disease and Huntington's disease.
Study of decisionmaking impairment in persons with dementia has focused on Alzheimer's disease. Even patients with mild Alzheimer's dementia may evidence deficits in understanding relevant information and reasoning sufficient to call their capacities into question, although the choices they make about treatment and research may not differ at this point from non-impaired populations. As dementia progresses to the moderate stage, however, the range and magnitude of deficits
expands, and many more persons fail even the simplest tests of decisionmaking capacity.2 The co-occurrence of other disorders, such as delirium or depression, may exacerbate the impact of dementia on the ability to make decisions.
Delirium
Like dementia, delirium involves alterations in cognition, but usually evolves over hours to days. Disturbances of consciousness and attention are prominent. Delirium is most often caused by systemic medical conditions, side effects of medications, intoxication with or withdrawal from psychoactive agents, or toxins.3 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, the treatments being administered. 4 In contrast, other work suggests that serious medical illness that does not directly impair brain function, even when it results in hospitalization, is not likely, by itself, to result in limitations on decisionmaking abilities.5
Schizophrenia
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, have 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.6 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 understanding, appreciation, and reasoning. 7 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.8 Lack of insight into the presence of illness and need for treatment is common among persons with schizophrenia;9 this may make it especially difficult for them to anticipate consequences of their decisions related to the risk of future relapse.
Depression
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.10 Cognitive impairments may exist in information processing11 and reasoning,12 among other functions. It has also been suggested that decreased motivation to protect their interests may reduce depressed patients' abilities to make decisions,13 and alter the nature of those decisions.14 Less clear is the extent to which these consequences of depression impede decision making. One study suggested that hospitalized depressed patients may manifest problems roughly half as often as patients with schizophrenia, that is, in about one quarter of cases.15 But it is likely that the degree of impairment relates to the intensity of depressive symptoms, and thus will vary across populations.
Other Disorders
Although less subject to formal study in the context of consent to treatment or research, there is good reason to believe that other conditions may also predispose to impaired decisional functions. Mental retardation, affecting as it does a range of cognitive abilities, is more likely to impair capacities 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 notorious for making 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 probably have some of the same consequences for decision making. Substance use disorders, including use of alcohol and illegal drugs, result in states of intoxication and withdrawal that resemble delirium in their effects on attention, cognition, and other mental functions.
This list, while highlighting the major conditions that impact decisionmaking ability, is by no means exhaustive.
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The Promise of Research with Disorders that Cause Decisional Impairments
Psychiatric, neurological, and other disorders that may render persons decisionally impaired account for enormous morbidity, with associated human and economic costs. Of the ten leading causes of disability in the world, according to a recent World Health Organization report, five were psychiatric conditions: unipolar depression, alcohol use, bipolar affective disorder, schizophrenia, and obsessive-compulsive disorder.16 It has been estimated that direct and indirect costs of mental illness and substance abuse in the United States totaled more than $313 billion in 1990.17 Alzheimer's disease now afflicts approximately 4 million people in this country and, with the number of persons over 65 years of age expected to double by the year 2030, the resulting morbidity will grow proportionately.
Given the scope of these disorders, when treatments can be identified that mitigate their impact, the benefits are substantial. Since 1970, the cumulative savings to the U.S. economy from the introduction of lithium as a treatment for bipolar disorder is estimated at $145 billion. 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 have yielded savings of $1.4 billion per year since 1990.18 Thus, every incentive exists to improve our understanding of disorders affecting brain function and to develop more effective treatments for them.
Research on these conditions falls into two broad categories: studies aimed at elucidating the underlying pathophysiologic bases of the disorders; and studies intended to develop or 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), fast magnetic resonance imaging (fMRI), single photon emission computer tomography (SPECT), and related devices facilitate identification of the anatomic location of brain areas involved in cognitive and affective functions.19 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.20
Medications are the mainstay of treatment for severe psychiatric and neurologic disorders?lthough behavioral interventions can be useful adjuncts and thus are the primary focus of treatment-oriented research. Development of new medications is being facilitated 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 still on the drawing boards include
insertion of new genes to correct identified defects underlying brain disorders ("gene therapy"), and use of immunologic therapies, like the recent successful inoculation of rats against the psychostimulant effects of cocaine.21
Some basic research (e.g., on brain receptor mechanisms) can be performed with animal subjects rather than with humans. But when disease processes themselves are under study, the absence of animal models for most psychiatric and neurologic syndromes means that research on both underlying mechanisms of disease and on promising treatments must involve human subjects. Moreover, unless research is to be limited to the mildest forms of the disorders hich may differ substantively from more chronic or severe forms; persons whose decisionmaking capacities may be impaired are likely to be involved. From this reality flows the central dilemma of designing
appropriate protections in research on decisionally impaired populations: protection of subjects from harm must be balanced against the potential for benefit to subjects themselves, and to other persons with their disorders, that may arise from research participation.
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Footnotes