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Capacity to consent to research among patients with bipolar disorder
Journal of Affective Disorders 80 (2004) 115 – 123 www.elsevier.com/locate/jad
Special Article
Capacity to consent to research among patients with bipolar disorder Sahana Misra a,c,*, Linda Ganzini a,b,c a
Department of Psychiatry, Oregon Health & Sciences University, Portland, OR, USA Department of Medicine, Oregon Health & Sciences University, Portland, OR, USA c Mental Health Division, Portland Veterans Affairs Medical Center (P3MHDC), 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA b
Received 17 December 2002; accepted 15 April 2003
Abstract Experts have debated the influence of mental illness on decision-making capacity. This paper reviews concepts of decisionmaking capacity and existing research on the influence of mental illness on capacity to consent to research. We propose how bipolar disorder, especially mania, may have an effect on consent capacity. The current conceptualization of capacity utilizes legal standards of ‘choice’, ‘understanding’, ‘appreciation’ and ‘rational reasoning’, as well as voluntarism, or the assurance that the patient is free to agree or to decline to participate in research. Studies of patients with schizophrenia suggest impaired cognition influences ‘understanding’ and is more important than severity of psychosis in affecting decision-making abilities. There are no studies of sources and extent of impairment to consent to research among manic patients. Mania may influence a patient’s understanding of the research protocol, but also alter the patient’s views, values and level of insight, thus impairing decision-making abilities at the ‘appreciation’ standard even when the patient understands the relevant information. Mania may impact freedom to decide, yet paradoxically, manic patients may be less influenced by others and less vulnerable to coercion, undue influence and undue incentives compared to patients without mental illness. We suggest that in patients with mood disorders, the legal standard of appreciation be thoroughly probed during the consent procedure. Studies of the effect of mania and depression on consent capacity and voluntarism are needed in order to develop processes that increase safeguards in the informed consent process. Published by Elsevier B.V. Keywords: Research; Decision-making capacity; Bipolar disorder
1. Introduction In recent years, experts have debated the need for greater protection of mentally ill subjects who partic* Corresponding author. Tel.: +1-503-220-8262x51177; fax: +1-503-220-3499. E-mail address: [email protected] (S. Misra). 0165-0327/$ - see front matter. Published by Elsevier B.V. doi:10.1016/S0165-0327(03)00109-5
ipate in research. In the United States, this expert debate, coupled with legal cases and public controversy, led to the National Bioethics Advisory Commission’s (NBAC) examination of research involving the mentally ill. A 1998 NBAC report specifically focused on potential impairments in decision-making capacity as a result of mental disorders, including bipolar disorder. NBAC concluded that the US regu-
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lations protecting mentally ill patients were not adequate and proposed 21 recommendations regarding research design and risk level, informed consent, surrogate decision-making, and education of researchers about informed consent and decision-making capacity (NBAC, 1998). Although the recommendations were not adopted, the debate heightened awareness of the potential influence of mental illness on decisionmaking capacity. NBAC’s concerns about mentally ill patients’ ability to make decisions have been voiced by others. Symptoms often seen in mental illnesses, such as attentional and memory deficits, poor judgment and insight, ambivalence, psychosis, severe depression, and impulsivity, might influence patients’ abilities to participate adequately in an informed consent discussion (Parker, 2002; Roberts, 1998; Elliott, 1997). Even in cases where patients can give informed consent, the ethics of placebo controlled studies and other ‘high risk’ types of protocols, including those of unproven treatments or with ‘wash out’ periods, have been challenged, especially in situations where there are known effective treatments (Roberts et al., 2001). Studies suggest that patients who otherwise demonstrate adequate decision-making capacity may not understand some important goals of research. Patients may be particularly susceptible to ‘therapeutic misconception’ wherein their decision to participate in a study is driven by hopes that decisions about their treatment will be determined by their clinical need, rather than recognizing that the true purpose of the research study is to obtain information that may contribute to future advances in the field under study (Benson et al., 1988). Patients’ motivations to participate in research have also been questioned. As ‘vulnerable patients’ their voluntariness may be compromised: they may be at risk for coercion from researchers, medical providers or family and may be subject to undue influence through many incentives. Although concern has been raised about the ability of patients with bipolar disorder to participate in research, little is written about how bipolar disorder impacts decision-making capacity. This paper discusses the unique aspects of bipolar disorder that may impact decision-making capacity for research studies, including: (1) arguments for research about bipolar disorder, (2) concepts of ‘decision-making
capacity’ and ‘voluntarism’, (3) hallmark studies of consent capacity in mentally ill research subjects, (4) the effects of mood disorders on decision-making and voluntarism, and (5) applications relevant to researchers. Reflecting terms used in existent literature, the terms ‘capacity’ and ‘competency’ will be used interchangeably.
2. Arguments for research about bipolar disorder There are convincing and cogent arguments for including patients with bipolar disorder in research. The prevalence of bipolar disorder in the general population has been reported between 0.4 and 1.6%, and 10 –15% of all patients with bipolar disorder die by suicide (APA, 1994). Significant advances have been made in the treatment of bipolar disorder. It has been estimated that there has been $140 billion savings to the US economy as a result of the introduction of lithium for the treatment of bipolar disorder (NBAC, 1998). Research thus far has not shown any other medication to clearly surpass lithium in relapse prevention. All currently available treatments for bipolar disorder have significant adverse effects. Relapse rates for bipolar patients on maintenance treatment range from 37% at 1 year to 87% at 5 years (Gitlin et al., 1995). Continued research on treatments for bipolar disorder is needed, and, in order to develop treatments for mania, research designs must include manic patients. New pharmacological treatments cannot be assessed without clinical trials, optimally either placebo-controlled trials or head to head medication comparisons. (Quitkin, 1999). Yet concerns about mentally ill patients’ vulnerability and potential impairment in decision-making capacity pose challenges for institutional review boards. Such was the case recently at our institution where an industry sponsored placebo-controlled drug trial for treatment of mania was declined, in part due to concerns about consent capacity in manic subjects.
3. Decision-making capacity and voluntarism Ethical participation in research studies requires consenting subjects who exhibit adequate decisionmaking abilities and freely agree to participate. The
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current conceptualization of decision-making abilities utilizes legal standards of competency which include: (1) communicating a stable ‘choice’ about research participation, (2) ‘understanding’ relevant information about the research study, (3) ‘appreciating’ the situation, risks and benefits of research participation, and (4) use of ‘rational reasoning’, or a logical chain of thoughts, demonstrating that an individual weighs the risks and benefits of participation in the process of eventually arriving at a final decision (Appelbaum and Grisso, 1988). Decisional-making abilities, as defined by the legal standards, can be viewed on a continuum with the ‘choice’ standard being the least stringent in that it assesses a less demanding level of decisionmaking ability which is the ability to simply state a choice. The ‘understanding’, ‘appreciation’, and ‘rational reasons’ legal standards are considered more stringent legal standards in that they make more demands from the patient to explore reasons behind a choice. These standards evaluate one’s ability to comprehend the information being presented, to recall the details of the information, to demonstrate insight into one’s situation, and to communicate to others how the information would affect one personally. With decisions of increased risk and/or decreased benefit, it is prudent that the more stringent legal standards for decision-making abilities be met. In research participation, particularly in medication trials where risks may outweigh any direct individual benefit for the subject, it is important that all of the legal standards are met. Several points about decision-making capacity should be underscored. First, decision-making capacity for research is not generalizable but should be viewed as ‘situation specific’. An individual who is not able to show decision-making capacity for one protocol, such as a placebo-controlled trial of medication, may be able to demonstrate adequate decision-making capacity for another that is of less complicated design or with fewer risks, such as a survey. Second, the presence of a psychiatric diagnosis or cognitive impairment does not equate with a lack of decision-making capacity. As we shall review, many subjects with schizophrenia and dementia have been shown to exhibit adequate decisionmaking capacity. Finally, there are some situations in which decision-making capacity fluctuates during the course of an illness. This is most apparent in
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delirium and can be accounted for by fluctuations in cognitive functioning. What remains unanswered is if alterations in mood, as seen in bipolar illness, are associated with fluctuations in decision-making capacity. The most common approach to the assessment of subjects’ capacities to participate is the judgment of referring clinicians and/or researchers. Studies have shown low rates of agreement between ‘expert’ physicians assessing capacities of ‘vulnerable’ populations. Kim and colleagues utilized expert judgment to assess competency of the subjects with mild Alzheimer’s disease. Three ‘experts’ (from geriatric psychiatry and emergency psychiatry) listened to audiotapes of a subgroup of Alzheimer’s disease subjects’ interviews, made overall competency judgments, and agreed in 75% of cases (Kim et al., 2001). Marson and colleagues also evaluated agreement among experts. Five physicians from the specialties of geriatric psychiatry, geriatric medicine and neurology known to have extensive clinical experience in both capacity assessment and dementia, viewed videotaped interviews of subjects with mild Alzheimer’s disease and non-ill elderly controls and made judgments about the subjects’ decision-making capacities. Physician agreement about capacity was 98% in the non-ill control subjects and 56% in the subjects with mild Alzheimer’s disease (Marson et al., 1997). Agreement improved to 76% when physicians applied the legal standards for decision-making capacity in their assessment (Marson et al., 2000). Difficulties in the assessment of decision-making capacity for research participation include both the lack of an established and consistently used gold-standard method for assessment and a lack of formal training for researchers in this area. Voluntarism is another essential component of decision-making capacity to consent to research and assures that a subject is free to agree or decline to participate in research. Mentally ill populations may be vulnerable to coercion by persons viewed to be in positions of authority such as physicians or family members. Lack of readily available mental health resources may result in self-imposed or family-imposed pressure to participate in research as a way to receive treatment of any kind. The manner in which monetary reimbursement may serve as an undue influence on subjects’ decisions for research participation
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versus providing appropriate compensation for subjects’ time and effort is not well researched (NBAC, 1998; NCPHS, 1978). The legal standards for assessment of decisionmaking abilities, although requiring voluntarism, do not explicitly define it or provide guidelines for its assessment. Roberts recently presented an overview on voluntarism and suggested a framework for its assessment. As with decision-making capacity, the capacity for voluntarism is situation-specific, and cannot be generalizable to all decisions. The suggested framework for the assessment of ‘capacity for voluntarism’ includes evaluating the roles of developmental factors (such as cognition, emotional maturity and moral character); mental and/or physical illness (such as ambivalence, negative thoughts, pain and fatigue); psychological issues and cultural and religious values; and, external features and pressures (Roberts, 2002). Researchers must at a minimum assure that subjects are not coerced to participate or unduly influenced by monetary reimbursement. As with the legal standards, decisions that carry more risk and/or less benefits necessitate more extensive inquiries by researchers into factors that impact voluntarism, such as ambivalence and the role of external motivators such as payment for research participation and the influences of others.
4. Studies of consent capacity in mentally ill research subjects Several studies on capacity to consent to psychiatric treatment and psychiatric research among patients with depression, dementia and schizophrenia have been published. These address whether mentally ill patients can give consent, whether their decision making capacity is more impaired than medically ill patients, and the effect of educational interventions on mentally ill patients. Appelbaum and Grisso’s landmark study, the MacArthur Treatment Competence Study, assessed psychiatric, medical, and non-ill subjects’ abilities to consent to psychiatric and medical treatments. Participants’ abilities to meet the four legal standards of competency were assessed using an early version of the MacArthur Competency Assessment Tool (MacCAT), designed by the investigators. Cognitive functioning
was also assessed. The subjects with schizophrenia more often exhibited deficits in decision-making capacity compared to other subjects, with the most difficulty occurring in the area of ‘understanding’ (Appelbaum and Grisso, 1995). The influence of educational interventions or ‘enhanced informed consent’ on decision-making capacity has been examined. Carpenter and colleagues, using the research version of the MacArthur competency tool (MacCAT-CR), assessed decision making capacity, symptom severity, and cognition in patients with schizophrenia and non-ill patients. The schizophrenic group performed more poorly on the MacCAT-CR than the non-ill group and their performance was correlated to severity of cognitive deficits but not to severity of psychotic symptoms. A subset of patients with schizophrenia received an educational intervention which consisted of reviewing the protocol, having questions answered, and working on a computerized interactive program designed to teach basic research concepts such as placebo, drug withdrawal, protocol and random assignment. The MacCAT-CR was readministered after the educational intervention. The ‘understanding’ scores of this subset of subjects with schizophrenia improved equaling the non-ill group, indicating that many patients with schizophrenia could exhibit improvement in decisional capacity abilities if educational efforts were utilized in the informed consent process (Carpenter et al., 2000). Dunn and colleagues demonstrated the beneficial effect of enhanced informed consent by randomizing middle age and elderly patients with psychotic disorders and similar aged non-ill controls to ‘regular’ or ‘enhanced’ consent procedures using an actual protocol. The enhanced consent procedure consisted of a slide show presenting the consent form verbatim. At various points, key aspects were summarized and subjects were asked if they had any questions. Although the non-ill group demonstrated better understanding than the patient group, subjects in the enhanced consent procedure arm of the study performed better than subjects in the regular consent procedure arm. Most importantly, the patient group in the enhanced consent procedure arm performed just as well as the normal comparison group in the routine consent procedure arm of the study (Dunn et al., 2002).
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Wirshing and colleagues assessed comprehension of relevant information in research protocols and the effect of educational interventions among outpatient and inpatient subjects with schizophrenia who were enrolled in clinical research studies. Patients interested in participating reviewed the consent form for an actual randomized clinical trial protocol with a study coordinator. The investigators administered a questionnaire and then determined if the subjects met the legal standards of competency. When an item was incorrectly answered, the corresponding part of the consent form was reviewed and the subject was retested. This process continued until all the items were answered correctly. Over half of the patients required a second trial and over one-third required three or more trials to answer 100% of the items correctly (Wirshing et al., 1998). The investigators did not report which legal standards of competency subjects had the most difficulty with or showed the most improvement in; however, the majority of questions seemed to assess level of understanding. Finally, Stiles and colleagues examined different methodologies used in efforts to improve understanding of the consent form for a hypothetical research study among patients with schizophrenia and depression, as well as non-ill controls. One method of presentation of the study involved an iterative process utilizing a research assistant who presented the consent form in full and tested understanding with recall and recognition tests. If questions were incorrectly answered on the recognition test, subjects were given feedback, certain sections of the consent form pertaining to the missed questions were reread, and the entire recognition test was repeated. This process occurred for up to two trials. The other method involved the presence of a facilitator who reviewed the consent form once with subjects but stopped at several points to ask the subjects what main points were just discussed and if they had any questions. After this review, the recall and recognition tests were administered once. The mean understanding scores did not significantly differ between the depression group and the non-ill group; however, were lower for the schizophrenia group. In addition, the method of iterative feedback was associated with higher understanding scores in all three subject groups than the method utilizing a facilitator (Stiles et al., 2001).
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Studies of dementia patients have shown that even mild cognitive impairment can impact decision-making abilities. Marson et al. in a study comparing normal controls with mildly and moderately impaired patients with Alzheimer’s disease reported that all subjects performed without significant differences on the least stringent legal standard of ‘choice’. Control subjects performed better than the dementia groups on all other standards. The mildly impaired group showed difficulty in ‘understanding’ and ‘rational reasons’ yet performed better than the moderately impaired group who had difficulty in ‘appreciation’, ‘rational reasons’ and ‘understanding’. Performance of the dementia groups on the ‘understanding’ competency level was best predicted by measures of conceptualization and confrontation naming which authors attributed to deficits in conceptualization, semantic memory and verbal recall. Performance of the dementia groups on the ‘appreciation’ and ‘rational reasoning’ levels were best predicted by measures of word fluency which authors attributed to frontal lobe executive dysfunction (Marson et al., 1995, 1996). In summary, studies of patients with schizophrenia suggest impaired cognition has a more important impact than severity of psychosis on capacity by impairing patients’ abilities to understand the information. Similarly, studies of patients with dementia suggest that difficulties with memory and executive functioning predict impairments in decision-making abilities. Educational interventions improved decision-making abilities in patients with depression, schizophrenia and non-ill control groups as well as in subjects with mild cognitive deficits (Kim et al., 2002).
5. The effect of mood disorders on decision-making The above-mentioned studies have focused on the association between cognitive deficits and decisionmaking abilities, particularly at the level of ‘understanding’. Cognitive impairment can be seen in diseased mood states such as severe depression, especially in the elderly (pseudodementia). Although cognitive impairment can develop during severe episodes of mania or depression, it is not recognized as a substantial aspect of bipolar disorder. Mania or de-
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pression, however, may alter insight into one’s current situation and the ability to foresee one’s future, thus impacting decision-making capacity at the level of ‘appreciation’ rather than at the level of ‘understanding’. For example, Appelbaum and colleagues, assessed the capacity of 26 moderately depressed unipolar outpatients to consent to research. More than 90% of subjects received full credit on capacity measures of the MacCAT-CR and there was no association between level of depression and performance. Some subjects, however, believed their assignment to a treatment group was based on their own clinical condition (Appelbaum et al., 1999). This finding may represent impairment at the level of appreciation. Patients with mania may be devoid of significant cognitive impairment and may demonstrate comprehension of a research protocol pertaining to treatment for mania, thereby meeting the ‘understanding’ standard of capacity; however, if they lack insight into their illness and current circumstances (i.e., do not believe they are manic), they will have trouble applying the risks and benefits of the protocol information to their own particular situation by overestimating a good outcome or denying risks. By this definition, they would not meet the ‘appreciation’ standard of capacity. Increased educational efforts during the informed consent process may not have any impact on one’s level of appreciation especially as the informed consent process may not involve a discussion of each individual’s own unique set of circumstances. Currently there is no published literature assessing the effect of mania specifically on ‘appreciation’ or on decision-making abilities for research. There are some studies that have examined depressed and manic subjects’ views and values on treatment issues. Arguments have been made for including evaluation of views and values of a patient in the decisional capacity assessment, particularly if those views and values are influenced by a diseased mood state (Elliott, 1997). Values are conceptualized to reflect a person’s whole-life experience and are thought to be stable and relatively steadfast. Changes in views or values, if occurring in the context of a diseased mood state such as mania, may result in inauthentic decision-making, specifically at the level of ‘appreciation’, that is not
reflective of one’s true self. Clinicians recognize this therapeutically by often advising manic or depressed patients to defer important life decisions until they are stabilized. Several studies have examined how depression and mania impact treatment decisions. Ganzini and colleagues evaluated the effect of depression on the views of elderly patients pertaining to life-sustaining treatment. Elderly, depressed patients were interviewed at admission and discharge of their psychiatric hospitalization and asked about preferences for lifesustaining treatment. In the majority of patients, improvement in depressive symptoms did not result in a change in desired preferences. However, a subgroup of severely depressed patients was found to have more hopelessness and negativism when predicting benefits of treatment options and was therefore inclined to refuse life sustaining treatments. With treatment of their mood disorder and improvement of their symptoms, their understanding of the elements of treatment did not improve. They were, however, less affected by hopelessness and underestimates of benefits for themselves and became more likely to accept previously shunned treatments (Ganzini et al., 1994). This finding suggests that the depressive symptoms of hopelessness and negativism, when severe, significantly impacted the subjects’ insight or appreciation into their current situations and altered their treatment decisions. Another example of how changes in views or values may result in inauthentic decision-making at the level of ‘appreciation’ was shown in Schwartz and colleagues’ study assessing views of psychiatrically hospitalized patients who required involuntary medication, a subgroup of whom were patients with manic symptomatology. Symptom severity was rated in these subjects first at the point when they were given involuntary medication and then again at their discharge. Also at the time of discharge, the subjects were asked to rate statements that assessed their views on their illness, their need for hospitalization, their need for medication, their view on being involuntarily medicated and general questions about the value of psychiatric care for the mentally ill population. At time of discharge, 81% felt that in retrospect it was necessary for them to have received involuntary medication and acknowledged that they had an illness that required treatment. In addition, they felt that they
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should be treated against their will again in the future if necessary. The remaining 19% who did not feel it was right to be medicated against their will, showed less improvement in symptoms particularly with continued increased grandiosity and denial ‘of psychotic proportions’ into their illness and 86% of these patients had the diagnosis of bipolar disorder. Of the subjects who approved being medicated involuntarily, only 24% had bipolar disorder. Both groups responded positively to general statements that psychiatric care was helpful and that certain mentally ill patients may not recognize their own symptoms (Schwartz et al., 1988). Decisions and attitudes about treatment changed in the subgroup of subjects who demonstrated the most clinical improvement, including improved insight. The manic symptoms of increased grandiosity and extreme denial of illness, significantly hampered the subjects’ appreciation into their current situations, which in turn affected their treatment preferences. Other studies have also suggested that suggest that medication noncompliance is associated with grandiosity and that medication noncompliant patients are more likely to have bipolar disorder than schizophrenia (Marder et al., 1984; Zito et al., 1985). These studies support the argument that the diseased mood states of depression and mania may alter one’s views and values and impair decisionmaking abilities at the ‘appreciation’ standard. Whether this impacts decisions to participate in research is unknown.
6. The effect of mood disorders on voluntarism The assessment of individuals’ motivations to participate in research may reveal the extent to which patients are truly free or not free to decline participation and are vulnerable to influence, inducements and coercion. Studies have examined patients’ motivations towards both research and treatment with the goal of understanding not only if patients have decisionmaking capacity, but also how patients’ motivations impact their decisions. Wirshing and colleagues asked patients with schizophrenia open-ended questions about motivations for participating in research. Sixty-five percent of the patients reported that they were participating for
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altruistic reasons or for either their own personal benefit and 35% reported that they were participating at the suggestion of others (Wirshing et al., 1998). Roberts and colleagues in a study of patients with schizophrenia reported that the subjects strongly supported research on schizophrenia and agreed that helping science and others were valid reasons to participate in research. Subjects, however were accepting of the influence of others on their decision to participate in research (Roberts et al., 2000). Both of these studies support concern that some patients with mental illness lack sufficient autonomy for the informed consent process and may rely more on the views of others, such as family and care providers, than researchers may realize. Paradoxically, manic patients may be less influenced by others and less vulnerable to influence, particularly if their insight or appreciation is influenced by grandiosity. It is also uncertain if mania and depression influences one’s motivations including altruism or influence of payment for participation.
7. Implications for researchers All subjects must demonstrate capacity to consent to research; meet some or all of the legal standards, depending on the burdens and benefits; and give consent voluntarily. The most common study procedure is that a single discussion occurs at the time a subject is presented the consent form. The particulars of the discussion are left to individual researchers. It is implied that the investigator will assess understanding, appreciation and rational manipulation of the information during this discussion and before the subject’s final choice about participation. ‘Enhanced’ informed consent procedures improved decision-making capacity in subjects with schizophrenia and mild dementia, particularly in the area of comprehension or ‘understanding’. Whether this is true or not for manic patients has not been tested. We suspect the results will not be as impressive as in schizophrenic patients since deficits may be more at the level of appreciation than understanding. We suggest that with mood disorders, appreciation be especially probed during the consent procedure. Currently available tools that formalize the questions needed to be asked to ascertain a subject’s appreci-
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ation, understanding, rational reasoning and choice for a protocol, such as the MacCAT-CR, would be useful for researchers to include in the informed consent process to ensure that an assessment of decision-making capacity was thorough. A weakness of these tools is that a final judgment on whether a subject has sufficient decision-making capacity cannot be ‘calculated’; however, research suggests that using tools provide researchers with additional information to make a final judgment about a subject’s capacity and result in improved agreement between researchers. More studies assessing decision-making abilities of mentally ill patients, including bipolar patients, to participate in research, particularly ‘high risk’ protocols, are needed to help institutional review boards make sound decisions about research practices based on empirical data. Continued research utilizing scales, such as the MacCAT-CR, in various mentally ill populations will help elucidate the degree of vulnerability in different populations. Studies utilizing hypothetical ‘high risk’ protocols can also provide some useful information with the caution that there is no information whether ‘appreciation’ differs between subjects considering hypothetical versus actual studies. The data these studies provide, however, may allow for the IRB approval of some higher risk studies. Longitudinal studies of patients with bipolar disorder are needed with individuals serving as their own controls in order to obtain optimal information on the effects that varying mood states (mania, depression, euthymia) on decision-making capacity, views and motivators. Enrollment of euthymic bipolar patients for future study when they are manic or depressed warrants investigation. Finally, issues of concordance among investigators testing bipolar patients’ consent capacity and the effects of enhanced informed consent procedures on manic subjects’ improvements in decision-making should be examined.
Acknowledgements Support was received from the Medical Research Foundation of Oregon (Dr. Misra) and the Department of Veterans Affairs Merit Review Program (Dr. Ganzini). The opinions expressed are those of the
authors, not the Department of Veterans Affairs of the U.S. government.
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Special Article
Capacity to consent to research among patients with bipolar disorder Sahana Misra a,c,*, Linda Ganzini a,b,c a
Department of Psychiatry, Oregon Health & Sciences University, Portland, OR, USA Department of Medicine, Oregon Health & Sciences University, Portland, OR, USA c Mental Health Division, Portland Veterans Affairs Medical Center (P3MHDC), 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA b
Received 17 December 2002; accepted 15 April 2003
Abstract Experts have debated the influence of mental illness on decision-making capacity. This paper reviews concepts of decisionmaking capacity and existing research on the influence of mental illness on capacity to consent to research. We propose how bipolar disorder, especially mania, may have an effect on consent capacity. The current conceptualization of capacity utilizes legal standards of ‘choice’, ‘understanding’, ‘appreciation’ and ‘rational reasoning’, as well as voluntarism, or the assurance that the patient is free to agree or to decline to participate in research. Studies of patients with schizophrenia suggest impaired cognition influences ‘understanding’ and is more important than severity of psychosis in affecting decision-making abilities. There are no studies of sources and extent of impairment to consent to research among manic patients. Mania may influence a patient’s understanding of the research protocol, but also alter the patient’s views, values and level of insight, thus impairing decision-making abilities at the ‘appreciation’ standard even when the patient understands the relevant information. Mania may impact freedom to decide, yet paradoxically, manic patients may be less influenced by others and less vulnerable to coercion, undue influence and undue incentives compared to patients without mental illness. We suggest that in patients with mood disorders, the legal standard of appreciation be thoroughly probed during the consent procedure. Studies of the effect of mania and depression on consent capacity and voluntarism are needed in order to develop processes that increase safeguards in the informed consent process. Published by Elsevier B.V. Keywords: Research; Decision-making capacity; Bipolar disorder
1. Introduction In recent years, experts have debated the need for greater protection of mentally ill subjects who partic* Corresponding author. Tel.: +1-503-220-8262x51177; fax: +1-503-220-3499. E-mail address: [email protected] (S. Misra). 0165-0327/$ - see front matter. Published by Elsevier B.V. doi:10.1016/S0165-0327(03)00109-5
ipate in research. In the United States, this expert debate, coupled with legal cases and public controversy, led to the National Bioethics Advisory Commission’s (NBAC) examination of research involving the mentally ill. A 1998 NBAC report specifically focused on potential impairments in decision-making capacity as a result of mental disorders, including bipolar disorder. NBAC concluded that the US regu-
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lations protecting mentally ill patients were not adequate and proposed 21 recommendations regarding research design and risk level, informed consent, surrogate decision-making, and education of researchers about informed consent and decision-making capacity (NBAC, 1998). Although the recommendations were not adopted, the debate heightened awareness of the potential influence of mental illness on decisionmaking capacity. NBAC’s concerns about mentally ill patients’ ability to make decisions have been voiced by others. Symptoms often seen in mental illnesses, such as attentional and memory deficits, poor judgment and insight, ambivalence, psychosis, severe depression, and impulsivity, might influence patients’ abilities to participate adequately in an informed consent discussion (Parker, 2002; Roberts, 1998; Elliott, 1997). Even in cases where patients can give informed consent, the ethics of placebo controlled studies and other ‘high risk’ types of protocols, including those of unproven treatments or with ‘wash out’ periods, have been challenged, especially in situations where there are known effective treatments (Roberts et al., 2001). Studies suggest that patients who otherwise demonstrate adequate decision-making capacity may not understand some important goals of research. Patients may be particularly susceptible to ‘therapeutic misconception’ wherein their decision to participate in a study is driven by hopes that decisions about their treatment will be determined by their clinical need, rather than recognizing that the true purpose of the research study is to obtain information that may contribute to future advances in the field under study (Benson et al., 1988). Patients’ motivations to participate in research have also been questioned. As ‘vulnerable patients’ their voluntariness may be compromised: they may be at risk for coercion from researchers, medical providers or family and may be subject to undue influence through many incentives. Although concern has been raised about the ability of patients with bipolar disorder to participate in research, little is written about how bipolar disorder impacts decision-making capacity. This paper discusses the unique aspects of bipolar disorder that may impact decision-making capacity for research studies, including: (1) arguments for research about bipolar disorder, (2) concepts of ‘decision-making
capacity’ and ‘voluntarism’, (3) hallmark studies of consent capacity in mentally ill research subjects, (4) the effects of mood disorders on decision-making and voluntarism, and (5) applications relevant to researchers. Reflecting terms used in existent literature, the terms ‘capacity’ and ‘competency’ will be used interchangeably.
2. Arguments for research about bipolar disorder There are convincing and cogent arguments for including patients with bipolar disorder in research. The prevalence of bipolar disorder in the general population has been reported between 0.4 and 1.6%, and 10 –15% of all patients with bipolar disorder die by suicide (APA, 1994). Significant advances have been made in the treatment of bipolar disorder. It has been estimated that there has been $140 billion savings to the US economy as a result of the introduction of lithium for the treatment of bipolar disorder (NBAC, 1998). Research thus far has not shown any other medication to clearly surpass lithium in relapse prevention. All currently available treatments for bipolar disorder have significant adverse effects. Relapse rates for bipolar patients on maintenance treatment range from 37% at 1 year to 87% at 5 years (Gitlin et al., 1995). Continued research on treatments for bipolar disorder is needed, and, in order to develop treatments for mania, research designs must include manic patients. New pharmacological treatments cannot be assessed without clinical trials, optimally either placebo-controlled trials or head to head medication comparisons. (Quitkin, 1999). Yet concerns about mentally ill patients’ vulnerability and potential impairment in decision-making capacity pose challenges for institutional review boards. Such was the case recently at our institution where an industry sponsored placebo-controlled drug trial for treatment of mania was declined, in part due to concerns about consent capacity in manic subjects.
3. Decision-making capacity and voluntarism Ethical participation in research studies requires consenting subjects who exhibit adequate decisionmaking abilities and freely agree to participate. The
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current conceptualization of decision-making abilities utilizes legal standards of competency which include: (1) communicating a stable ‘choice’ about research participation, (2) ‘understanding’ relevant information about the research study, (3) ‘appreciating’ the situation, risks and benefits of research participation, and (4) use of ‘rational reasoning’, or a logical chain of thoughts, demonstrating that an individual weighs the risks and benefits of participation in the process of eventually arriving at a final decision (Appelbaum and Grisso, 1988). Decisional-making abilities, as defined by the legal standards, can be viewed on a continuum with the ‘choice’ standard being the least stringent in that it assesses a less demanding level of decisionmaking ability which is the ability to simply state a choice. The ‘understanding’, ‘appreciation’, and ‘rational reasons’ legal standards are considered more stringent legal standards in that they make more demands from the patient to explore reasons behind a choice. These standards evaluate one’s ability to comprehend the information being presented, to recall the details of the information, to demonstrate insight into one’s situation, and to communicate to others how the information would affect one personally. With decisions of increased risk and/or decreased benefit, it is prudent that the more stringent legal standards for decision-making abilities be met. In research participation, particularly in medication trials where risks may outweigh any direct individual benefit for the subject, it is important that all of the legal standards are met. Several points about decision-making capacity should be underscored. First, decision-making capacity for research is not generalizable but should be viewed as ‘situation specific’. An individual who is not able to show decision-making capacity for one protocol, such as a placebo-controlled trial of medication, may be able to demonstrate adequate decision-making capacity for another that is of less complicated design or with fewer risks, such as a survey. Second, the presence of a psychiatric diagnosis or cognitive impairment does not equate with a lack of decision-making capacity. As we shall review, many subjects with schizophrenia and dementia have been shown to exhibit adequate decisionmaking capacity. Finally, there are some situations in which decision-making capacity fluctuates during the course of an illness. This is most apparent in
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delirium and can be accounted for by fluctuations in cognitive functioning. What remains unanswered is if alterations in mood, as seen in bipolar illness, are associated with fluctuations in decision-making capacity. The most common approach to the assessment of subjects’ capacities to participate is the judgment of referring clinicians and/or researchers. Studies have shown low rates of agreement between ‘expert’ physicians assessing capacities of ‘vulnerable’ populations. Kim and colleagues utilized expert judgment to assess competency of the subjects with mild Alzheimer’s disease. Three ‘experts’ (from geriatric psychiatry and emergency psychiatry) listened to audiotapes of a subgroup of Alzheimer’s disease subjects’ interviews, made overall competency judgments, and agreed in 75% of cases (Kim et al., 2001). Marson and colleagues also evaluated agreement among experts. Five physicians from the specialties of geriatric psychiatry, geriatric medicine and neurology known to have extensive clinical experience in both capacity assessment and dementia, viewed videotaped interviews of subjects with mild Alzheimer’s disease and non-ill elderly controls and made judgments about the subjects’ decision-making capacities. Physician agreement about capacity was 98% in the non-ill control subjects and 56% in the subjects with mild Alzheimer’s disease (Marson et al., 1997). Agreement improved to 76% when physicians applied the legal standards for decision-making capacity in their assessment (Marson et al., 2000). Difficulties in the assessment of decision-making capacity for research participation include both the lack of an established and consistently used gold-standard method for assessment and a lack of formal training for researchers in this area. Voluntarism is another essential component of decision-making capacity to consent to research and assures that a subject is free to agree or decline to participate in research. Mentally ill populations may be vulnerable to coercion by persons viewed to be in positions of authority such as physicians or family members. Lack of readily available mental health resources may result in self-imposed or family-imposed pressure to participate in research as a way to receive treatment of any kind. The manner in which monetary reimbursement may serve as an undue influence on subjects’ decisions for research participation
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versus providing appropriate compensation for subjects’ time and effort is not well researched (NBAC, 1998; NCPHS, 1978). The legal standards for assessment of decisionmaking abilities, although requiring voluntarism, do not explicitly define it or provide guidelines for its assessment. Roberts recently presented an overview on voluntarism and suggested a framework for its assessment. As with decision-making capacity, the capacity for voluntarism is situation-specific, and cannot be generalizable to all decisions. The suggested framework for the assessment of ‘capacity for voluntarism’ includes evaluating the roles of developmental factors (such as cognition, emotional maturity and moral character); mental and/or physical illness (such as ambivalence, negative thoughts, pain and fatigue); psychological issues and cultural and religious values; and, external features and pressures (Roberts, 2002). Researchers must at a minimum assure that subjects are not coerced to participate or unduly influenced by monetary reimbursement. As with the legal standards, decisions that carry more risk and/or less benefits necessitate more extensive inquiries by researchers into factors that impact voluntarism, such as ambivalence and the role of external motivators such as payment for research participation and the influences of others.
4. Studies of consent capacity in mentally ill research subjects Several studies on capacity to consent to psychiatric treatment and psychiatric research among patients with depression, dementia and schizophrenia have been published. These address whether mentally ill patients can give consent, whether their decision making capacity is more impaired than medically ill patients, and the effect of educational interventions on mentally ill patients. Appelbaum and Grisso’s landmark study, the MacArthur Treatment Competence Study, assessed psychiatric, medical, and non-ill subjects’ abilities to consent to psychiatric and medical treatments. Participants’ abilities to meet the four legal standards of competency were assessed using an early version of the MacArthur Competency Assessment Tool (MacCAT), designed by the investigators. Cognitive functioning
was also assessed. The subjects with schizophrenia more often exhibited deficits in decision-making capacity compared to other subjects, with the most difficulty occurring in the area of ‘understanding’ (Appelbaum and Grisso, 1995). The influence of educational interventions or ‘enhanced informed consent’ on decision-making capacity has been examined. Carpenter and colleagues, using the research version of the MacArthur competency tool (MacCAT-CR), assessed decision making capacity, symptom severity, and cognition in patients with schizophrenia and non-ill patients. The schizophrenic group performed more poorly on the MacCAT-CR than the non-ill group and their performance was correlated to severity of cognitive deficits but not to severity of psychotic symptoms. A subset of patients with schizophrenia received an educational intervention which consisted of reviewing the protocol, having questions answered, and working on a computerized interactive program designed to teach basic research concepts such as placebo, drug withdrawal, protocol and random assignment. The MacCAT-CR was readministered after the educational intervention. The ‘understanding’ scores of this subset of subjects with schizophrenia improved equaling the non-ill group, indicating that many patients with schizophrenia could exhibit improvement in decisional capacity abilities if educational efforts were utilized in the informed consent process (Carpenter et al., 2000). Dunn and colleagues demonstrated the beneficial effect of enhanced informed consent by randomizing middle age and elderly patients with psychotic disorders and similar aged non-ill controls to ‘regular’ or ‘enhanced’ consent procedures using an actual protocol. The enhanced consent procedure consisted of a slide show presenting the consent form verbatim. At various points, key aspects were summarized and subjects were asked if they had any questions. Although the non-ill group demonstrated better understanding than the patient group, subjects in the enhanced consent procedure arm of the study performed better than subjects in the regular consent procedure arm. Most importantly, the patient group in the enhanced consent procedure arm performed just as well as the normal comparison group in the routine consent procedure arm of the study (Dunn et al., 2002).
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Wirshing and colleagues assessed comprehension of relevant information in research protocols and the effect of educational interventions among outpatient and inpatient subjects with schizophrenia who were enrolled in clinical research studies. Patients interested in participating reviewed the consent form for an actual randomized clinical trial protocol with a study coordinator. The investigators administered a questionnaire and then determined if the subjects met the legal standards of competency. When an item was incorrectly answered, the corresponding part of the consent form was reviewed and the subject was retested. This process continued until all the items were answered correctly. Over half of the patients required a second trial and over one-third required three or more trials to answer 100% of the items correctly (Wirshing et al., 1998). The investigators did not report which legal standards of competency subjects had the most difficulty with or showed the most improvement in; however, the majority of questions seemed to assess level of understanding. Finally, Stiles and colleagues examined different methodologies used in efforts to improve understanding of the consent form for a hypothetical research study among patients with schizophrenia and depression, as well as non-ill controls. One method of presentation of the study involved an iterative process utilizing a research assistant who presented the consent form in full and tested understanding with recall and recognition tests. If questions were incorrectly answered on the recognition test, subjects were given feedback, certain sections of the consent form pertaining to the missed questions were reread, and the entire recognition test was repeated. This process occurred for up to two trials. The other method involved the presence of a facilitator who reviewed the consent form once with subjects but stopped at several points to ask the subjects what main points were just discussed and if they had any questions. After this review, the recall and recognition tests were administered once. The mean understanding scores did not significantly differ between the depression group and the non-ill group; however, were lower for the schizophrenia group. In addition, the method of iterative feedback was associated with higher understanding scores in all three subject groups than the method utilizing a facilitator (Stiles et al., 2001).
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Studies of dementia patients have shown that even mild cognitive impairment can impact decision-making abilities. Marson et al. in a study comparing normal controls with mildly and moderately impaired patients with Alzheimer’s disease reported that all subjects performed without significant differences on the least stringent legal standard of ‘choice’. Control subjects performed better than the dementia groups on all other standards. The mildly impaired group showed difficulty in ‘understanding’ and ‘rational reasons’ yet performed better than the moderately impaired group who had difficulty in ‘appreciation’, ‘rational reasons’ and ‘understanding’. Performance of the dementia groups on the ‘understanding’ competency level was best predicted by measures of conceptualization and confrontation naming which authors attributed to deficits in conceptualization, semantic memory and verbal recall. Performance of the dementia groups on the ‘appreciation’ and ‘rational reasoning’ levels were best predicted by measures of word fluency which authors attributed to frontal lobe executive dysfunction (Marson et al., 1995, 1996). In summary, studies of patients with schizophrenia suggest impaired cognition has a more important impact than severity of psychosis on capacity by impairing patients’ abilities to understand the information. Similarly, studies of patients with dementia suggest that difficulties with memory and executive functioning predict impairments in decision-making abilities. Educational interventions improved decision-making abilities in patients with depression, schizophrenia and non-ill control groups as well as in subjects with mild cognitive deficits (Kim et al., 2002).
5. The effect of mood disorders on decision-making The above-mentioned studies have focused on the association between cognitive deficits and decisionmaking abilities, particularly at the level of ‘understanding’. Cognitive impairment can be seen in diseased mood states such as severe depression, especially in the elderly (pseudodementia). Although cognitive impairment can develop during severe episodes of mania or depression, it is not recognized as a substantial aspect of bipolar disorder. Mania or de-
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pression, however, may alter insight into one’s current situation and the ability to foresee one’s future, thus impacting decision-making capacity at the level of ‘appreciation’ rather than at the level of ‘understanding’. For example, Appelbaum and colleagues, assessed the capacity of 26 moderately depressed unipolar outpatients to consent to research. More than 90% of subjects received full credit on capacity measures of the MacCAT-CR and there was no association between level of depression and performance. Some subjects, however, believed their assignment to a treatment group was based on their own clinical condition (Appelbaum et al., 1999). This finding may represent impairment at the level of appreciation. Patients with mania may be devoid of significant cognitive impairment and may demonstrate comprehension of a research protocol pertaining to treatment for mania, thereby meeting the ‘understanding’ standard of capacity; however, if they lack insight into their illness and current circumstances (i.e., do not believe they are manic), they will have trouble applying the risks and benefits of the protocol information to their own particular situation by overestimating a good outcome or denying risks. By this definition, they would not meet the ‘appreciation’ standard of capacity. Increased educational efforts during the informed consent process may not have any impact on one’s level of appreciation especially as the informed consent process may not involve a discussion of each individual’s own unique set of circumstances. Currently there is no published literature assessing the effect of mania specifically on ‘appreciation’ or on decision-making abilities for research. There are some studies that have examined depressed and manic subjects’ views and values on treatment issues. Arguments have been made for including evaluation of views and values of a patient in the decisional capacity assessment, particularly if those views and values are influenced by a diseased mood state (Elliott, 1997). Values are conceptualized to reflect a person’s whole-life experience and are thought to be stable and relatively steadfast. Changes in views or values, if occurring in the context of a diseased mood state such as mania, may result in inauthentic decision-making, specifically at the level of ‘appreciation’, that is not
reflective of one’s true self. Clinicians recognize this therapeutically by often advising manic or depressed patients to defer important life decisions until they are stabilized. Several studies have examined how depression and mania impact treatment decisions. Ganzini and colleagues evaluated the effect of depression on the views of elderly patients pertaining to life-sustaining treatment. Elderly, depressed patients were interviewed at admission and discharge of their psychiatric hospitalization and asked about preferences for lifesustaining treatment. In the majority of patients, improvement in depressive symptoms did not result in a change in desired preferences. However, a subgroup of severely depressed patients was found to have more hopelessness and negativism when predicting benefits of treatment options and was therefore inclined to refuse life sustaining treatments. With treatment of their mood disorder and improvement of their symptoms, their understanding of the elements of treatment did not improve. They were, however, less affected by hopelessness and underestimates of benefits for themselves and became more likely to accept previously shunned treatments (Ganzini et al., 1994). This finding suggests that the depressive symptoms of hopelessness and negativism, when severe, significantly impacted the subjects’ insight or appreciation into their current situations and altered their treatment decisions. Another example of how changes in views or values may result in inauthentic decision-making at the level of ‘appreciation’ was shown in Schwartz and colleagues’ study assessing views of psychiatrically hospitalized patients who required involuntary medication, a subgroup of whom were patients with manic symptomatology. Symptom severity was rated in these subjects first at the point when they were given involuntary medication and then again at their discharge. Also at the time of discharge, the subjects were asked to rate statements that assessed their views on their illness, their need for hospitalization, their need for medication, their view on being involuntarily medicated and general questions about the value of psychiatric care for the mentally ill population. At time of discharge, 81% felt that in retrospect it was necessary for them to have received involuntary medication and acknowledged that they had an illness that required treatment. In addition, they felt that they
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should be treated against their will again in the future if necessary. The remaining 19% who did not feel it was right to be medicated against their will, showed less improvement in symptoms particularly with continued increased grandiosity and denial ‘of psychotic proportions’ into their illness and 86% of these patients had the diagnosis of bipolar disorder. Of the subjects who approved being medicated involuntarily, only 24% had bipolar disorder. Both groups responded positively to general statements that psychiatric care was helpful and that certain mentally ill patients may not recognize their own symptoms (Schwartz et al., 1988). Decisions and attitudes about treatment changed in the subgroup of subjects who demonstrated the most clinical improvement, including improved insight. The manic symptoms of increased grandiosity and extreme denial of illness, significantly hampered the subjects’ appreciation into their current situations, which in turn affected their treatment preferences. Other studies have also suggested that suggest that medication noncompliance is associated with grandiosity and that medication noncompliant patients are more likely to have bipolar disorder than schizophrenia (Marder et al., 1984; Zito et al., 1985). These studies support the argument that the diseased mood states of depression and mania may alter one’s views and values and impair decisionmaking abilities at the ‘appreciation’ standard. Whether this impacts decisions to participate in research is unknown.
6. The effect of mood disorders on voluntarism The assessment of individuals’ motivations to participate in research may reveal the extent to which patients are truly free or not free to decline participation and are vulnerable to influence, inducements and coercion. Studies have examined patients’ motivations towards both research and treatment with the goal of understanding not only if patients have decisionmaking capacity, but also how patients’ motivations impact their decisions. Wirshing and colleagues asked patients with schizophrenia open-ended questions about motivations for participating in research. Sixty-five percent of the patients reported that they were participating for
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altruistic reasons or for either their own personal benefit and 35% reported that they were participating at the suggestion of others (Wirshing et al., 1998). Roberts and colleagues in a study of patients with schizophrenia reported that the subjects strongly supported research on schizophrenia and agreed that helping science and others were valid reasons to participate in research. Subjects, however were accepting of the influence of others on their decision to participate in research (Roberts et al., 2000). Both of these studies support concern that some patients with mental illness lack sufficient autonomy for the informed consent process and may rely more on the views of others, such as family and care providers, than researchers may realize. Paradoxically, manic patients may be less influenced by others and less vulnerable to influence, particularly if their insight or appreciation is influenced by grandiosity. It is also uncertain if mania and depression influences one’s motivations including altruism or influence of payment for participation.
7. Implications for researchers All subjects must demonstrate capacity to consent to research; meet some or all of the legal standards, depending on the burdens and benefits; and give consent voluntarily. The most common study procedure is that a single discussion occurs at the time a subject is presented the consent form. The particulars of the discussion are left to individual researchers. It is implied that the investigator will assess understanding, appreciation and rational manipulation of the information during this discussion and before the subject’s final choice about participation. ‘Enhanced’ informed consent procedures improved decision-making capacity in subjects with schizophrenia and mild dementia, particularly in the area of comprehension or ‘understanding’. Whether this is true or not for manic patients has not been tested. We suspect the results will not be as impressive as in schizophrenic patients since deficits may be more at the level of appreciation than understanding. We suggest that with mood disorders, appreciation be especially probed during the consent procedure. Currently available tools that formalize the questions needed to be asked to ascertain a subject’s appreci-
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ation, understanding, rational reasoning and choice for a protocol, such as the MacCAT-CR, would be useful for researchers to include in the informed consent process to ensure that an assessment of decision-making capacity was thorough. A weakness of these tools is that a final judgment on whether a subject has sufficient decision-making capacity cannot be ‘calculated’; however, research suggests that using tools provide researchers with additional information to make a final judgment about a subject’s capacity and result in improved agreement between researchers. More studies assessing decision-making abilities of mentally ill patients, including bipolar patients, to participate in research, particularly ‘high risk’ protocols, are needed to help institutional review boards make sound decisions about research practices based on empirical data. Continued research utilizing scales, such as the MacCAT-CR, in various mentally ill populations will help elucidate the degree of vulnerability in different populations. Studies utilizing hypothetical ‘high risk’ protocols can also provide some useful information with the caution that there is no information whether ‘appreciation’ differs between subjects considering hypothetical versus actual studies. The data these studies provide, however, may allow for the IRB approval of some higher risk studies. Longitudinal studies of patients with bipolar disorder are needed with individuals serving as their own controls in order to obtain optimal information on the effects that varying mood states (mania, depression, euthymia) on decision-making capacity, views and motivators. Enrollment of euthymic bipolar patients for future study when they are manic or depressed warrants investigation. Finally, issues of concordance among investigators testing bipolar patients’ consent capacity and the effects of enhanced informed consent procedures on manic subjects’ improvements in decision-making should be examined.
Acknowledgements Support was received from the Medical Research Foundation of Oregon (Dr. Misra) and the Department of Veterans Affairs Merit Review Program (Dr. Ganzini). The opinions expressed are those of the
authors, not the Department of Veterans Affairs of the U.S. government.
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