The ethics of research on deep brain stimulation for depression: decisional capacity and therapeutic misconception

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: Brain Stimulation in Neurology and Psychiatry

The ethics of research on deep brain stimulation fordepression: decisional capacity and therapeuticmisconception

Carl Erik Fisher,1 Laura B. Dunn,2 Paul P. Christopher,3 Paul E. Holtzheimer,4 Yan Leykin,2

Helen S. Mayberg,5 Sarah H. Lisanby,6 and Paul S. Appelbaum1

1Department of Psychiatry, College of Physicians & Surgeons, Columbia University and New York State Psychiatric Institute,New York, New York. 2Department of Psychiatry, University of California, San Francisco, San Francisco, California.3Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts. 4Department ofPsychiatry, Dartmouth Medical School, Hanover, New Hampshire. 5Department of Psychiatry and Behavioral Sciences, EmoryUniversity School of Medicine, Atlanta, Georgia. 6Department of Psychiatry, Duke University School of Medicine, Durham,North Carolina

Address for correspondence: Paul S. Appelbaum, MD, New York State Psychiatric Institute, 1051 Riverside Drive, Unit 122,New York, NY 10032. [email protected]

Research on deep brain stimulation (DBS) for treatment-resistant depression appears promising, but concerns havebeen raised about the decisional capacity of severely depressed patients and their potential misconceptions about theresearch. We assessed 31 DBS research participants with the MacArthur Competence Assessment Tool for ClinicalResearch (MacCAT-CR), a well-validated capacity measure, and with a scale to measure therapeutic misconception,which occurs when subjects do not recognize key differences between treatment and clinical research. Correlationswith baseline depressive symptoms were explored. Subjects’ performance on the MacCAT-CR was excellent, buttherapeutic misconception was still apparent. A trend toward significance was found in the correlation betweenbaseline depression ratings and total therapeutic misconception score. Responses to open-ended prompts revealedboth reassuring and concerning statements related to expectations of risk, benefit, and individualization. Evenseverely depressed patients did not manifest impairments in their capacity to consent to DBS research. Therapeuticmisconception, however, remained prevalent.

Keywords: research ethics; deep brain stimulation; decisional capacity; therapeutic misconception

Introduction

Nearly one in six Americans will experience majordepression in their lifetimes.1 Yet, despite 50 yearsof evolving pharmacologic treatments, up to half ofdepressed patients fail to achieve remission after twoadequate antidepressant trials,2 and rates of remis-sion decline in subsequent trials.3 Patients with suchtreatment-resistant depression (TRD) face higherrates of disability,4 social impairment,5 medical co-morbidity,6 and mortality.5,7

Deep brain stimulation (DBS)—an effective in-tervention for severe treatment-refractory Parkin-son’s disease, essential tremor, and primarydystonia8—has recently emerged as a promising

therapy for TRD.9–12 DBS involves stereotactic im-plantation of electrodes to stimulate specific brainregions, powered by a pulse generator implantedalong the chest wall. Results from a growing num-ber of small trials suggest DBS can be effective notonly in reducing depressive symptoms but in im-proving physical health and social functioning inpatients with TRD.9–13

Given the risks associated with DBS, includinghemorrhage and infection, and the limited thera-peutic options available to eligible subjects, severalethical issues regarding trial design and protectionof human subjects have been raised.14–18 These in-clude the worry that TRD may itself impair sub-jects’ capacity to make informed decisions regarding

doi: 10.1111/j.1749-6632.2012.06596.xAnn. N.Y. Acad. Sci. xxxx (2012) 1–11 c© 2012 New York Academy of Sciences. 1

Ethics of DBS for depression research Fisher et al.

enrollment in DBS research, and concerns that sub-jects may hold therapeutic misconceptions aboutparticipating in DBS research,19–21 i.e., by failingto recognize adequately the key differences betweentreatment and clinical research.22 Additional con-cerns are that subjects may underestimate the likeli-hood of risk associated with a DBS trial or have un-realistic expectations of personally benefitting fromthe study.18 These concerns are based in part onmedia portrayals of DBS studies, which tend toexaggerate the therapeutic effects while downplay-ing risks.21,23 Indeed, even when used for standard,approved indications (e.g., movement disorders),physicians have struggled to establish realistic ex-pectations for patients undergoing DBS.24

To date, despite substantial discussion of theseethical issues in the literature, there has been limitedempirical investigation. Prior studies on decisionalcapacity to enroll in clinical research have consis-tently found that patients with depression have littleif any impairment,25,26 even when compared withhealthy controls.27 In the first empirical examina-tion of these issues in DBS research subjects, weexplored risk and benefit perceptions and the pres-ence of therapeutic misconception among depressedpatients after an informed consent discussion forparticipation in trials of DBS for TRD.28 On thewhole, these patients offered accurate appraisals ofthe trials’ risks and benefits, were able to distinguishamong a variety of procedural risks, and expressedreasonable hopes for personal benefit. However,nearly two-thirds of subjects (64.5%) displayed ev-idence of therapeutic misconception regarding theDBS trial; that is, they incorrectly answered at leastone question related to the study’s purpose, like-lihood of personal benefit, or individualization oftreatment. This finding is consistent with the preva-lence of therapeutic misconception identified in avariety of clinical research settings.29–33 Thematicanalyses suggested that research subjects made theirdecisions to enroll in the trials based on a numberof complex, yet sometimes idiosyncratic consider-ations.34 There was no clear evidence from eitherthe quantitative or qualitative data to suggest thatthese depressed subjects lacked adequate capacity toconsent to these DBS trials.

In the present analysis of data from this sample ofpotential participants in DBS research for TRD, weexamined consent-related abilities, as measured by awell-validated research capacity assessment tool, in-

cluding whether performance on this measure wasassociated with depression severity. We also moreclosely examined the types of therapeutic miscon-ceptions held by these patients and determined thecorrelations among therapeutic misconception, de-pression severity, and estimation of risks associatedwith the DBS trial. In addition, we conducted anexploratory investigation of subjects’ perceptionsof risks, benefits, degree of study individualization,and their motivations for participation, based on re-sponses to open-ended prompts, to identify illustra-tive themes underlying apparent misconceptions.

Methods

ParticipantsParticipants were recruited from two separate DBSfor TRD studies (both of which targeted the subcal-losal cingulate gyrus or Cg25) at two urban medicalschools. Site A conducted a nonprofit, foundation-funded study,11 and Site B was part of an industry-sponsored pivotal trial (from which the data havenot yet been published). Key inclusion criteria atSite A were 18–70 years old, a diagnosis of majordepressive disorder (MDD) or bipolar II disorder,current major depressive episode of greater than 12months duration, nonresponse to more than fouradequate antidepressant treatments, and either life-time failure of electroconvulsive therapy (ECT) orinability to receive ECT. Key exclusion criteria wereclinically significant medical or psychiatric comor-bidities, recent substance use disorder, and unten-able suicide risk (i.e., active suicidal ideation withplan or intent, or recent suicide attempts). At Site B,key inclusion and exclusion criteria were similar toSite A’s, except the age range was limited to 21–70years old, the diagnosis was restricted to MDD, andnonresponse to a psychotherapy of known efficacywas required.

Individuals who passed an initial screening andwho had undergone consent procedures for theDBS study, including a presurgical observation pe-riod to ensure that they continued to meet severitycriteria based on the Hamilton Depression RatingScale (HDRS-17),35 were asked to participate in thisancillary study of ethical issues in DBS research.(At Site A, the HDRS-17 score inclusion criterionrequired an average preoperative score of 20 orgreater, averaged over screening and weekly presur-gical evaluations, and a final preoperative HDRS-17score no more than 30% lower than the baseline

2 Ann. N.Y. Acad. Sci. xxxx (2012) 1–11 c© 2012 New York Academy of Sciences.

Fisher et al. Ethics of DBS for depression research

screening HDRS score. HDRS-17 scores were notinclusion criteria at Site B.) Consent was obtainedby a study psychiatrist at Site A and by a research co-ordinator or study psychiatrist at Site B. The clinicalstudy itself consisted of DBS surgery followed by asham (stimulation off) control period (Site A: onemonth of sham; Site B: six months of either shamor stimulation). All subjects received diagnostic andfollow-up studies (e.g., MRI and neuropsycholog-ical testing), but Site A included several additionalresearch-related procedures (e.g., positron emissiontomography (PET), endocrine function testing, andelectroencephalography (EEG)).

Our optional, ancillary study was approved by in-stitutional review boards at the participating insti-tutions, and all subjects provided written informedconsent.

Measures: decisional capacitySubjects were assessed with the MacArthur Com-petence Assessment Tool for Clinical Research(MacCAT-CR),36 a semistructured, open-ended in-terview instrument designed to aid in the assess-ment of capacity to consent to participate in clin-ical research. The MacCAT-CR was designed forprotocol-specific adaptation; therefore, relevant in-formation was selected by PSA, PEH, and LBD basedon each site’s trial specifics (versions used for thisstudy are available from the corresponding authoron request). As specified by the MacCAT-CR, the in-strument was administered after a full consent dis-cussion. Disclosures (briefer presentations of infor-mation relevant to specific sections of the MacCAT-CR) were read aloud, and a standard set of questionswas asked. The MacCAT-CR subscales explored thefollowing:

• Understanding: comprehending study details(e.g., purpose, duration, procedures, risks, andpotential benefits—including the possibility ofno benefit).

• Appreciation: applying the information to thesubject’s own situation (e.g., recognizing thatpersonal benefits are not the primary objec-tive of the study, acknowledging the possibilitythat being in study might not be personallybeneficial).

• Reasoning: comparing research participationwith other treatment options and describingthe potential consequences of participating ver-sus not participating.

Trained research staff administered the MacCAT-CR to study subjects; these interviews were video-taped and subsequently transcribed verbatim. Sub-jects were permitted up to three trials of the Un-derstanding subscale questions to achieve their bestpossible score (one more than recommended in theMacCAT-CR manual36) and one trial each of theAppreciation and Reasoning subscales. Althoughthe MacCAT-CR also assesses subjects’ abilities toevidence a choice, all subjects in this study wereable to indicate their choice and so those dataare not reported here. At Site A, the study psy-chiatrist (PEH) administered the MacCAT-CR. AtSite B, a trained staff member administered theMacCAT-CR.

Measures: therapeutic misconceptionBased on prior work by Appelbaum, Lidz, andothers on therapeutic misconception,32,37,38 eighttrue/false statements were used to evaluate beliefsregarding the likelihood of personal benefit fromthe study, the individualization of treatment, andthe purpose of the study. Each item was scored 0(correct) or 1 (incorrect), with higher scores indi-cating a greater degree of therapeutic misconcep-tion. Eight additional questions examined percep-tions about overall study risks, potential for per-sonal benefit, and altruistic motivations, all scoredon 5-point Likert-type scales (because certain studyprocedures—endocrine testing, PET, and EEG—were only conducted at Site A, the number of sub-jects differs for some of the risk ratings). In addi-tion, responses to open-ended items were elicited atbaseline and six months regarding subjects’ percep-tions of risks, benefits, and altruistic motivations(data from the six-month follow-up were incom-plete and hence are not reported here). The statisti-cal results of this portion of the study are describedin more detail elsewhere.28 In the present report, wetested for associations between therapeutic miscon-ception scores and baseline clinical variables, andwe further explored open-ended items to identifycommon themes.

Measures: perceptions of risksNine further questions examined perceptions aboutspecific study and procedural risks, each scored ona 4-point ordinal scale: minimal risk or less (risksinvolved in everyday activities), minor increase overminimal risk, moderate risk, or high risk.

Ann. N.Y. Acad. Sci. xxxx (2012) 1–11 c© 2012 New York Academy of Sciences. 3


Data analysisDescriptive statistics were used to characterize re-sponses. Pearson correlations were used to describerelationships between variables. Three investigators(CEF, LBD, PSA) reviewed responses to the open-ended prompts to identify common themes. As theseitems were designed to stimulate ideas for further re-search rather than to describe exhaustively the sub-jects’ perceptions and beliefs, we did not try to quan-tify the number of instances in which each themewas expressed. Therefore, these data provide a snap-shot, rather than an in-depth portrayal, of some ofthe thoughts of these participants as they were con-sidering enrollment.

Results

Thirty-one participants from both sites reached theconsent process for the DBS trials. At Site A, 24individuals passed the initial screening and reachedthe consent process; of these, three did not completethe full set of questionnaires, leaving 21 subjectswith usable data. At Site B, 10 participants reachedthe consent process for the DBS study, but one didnot complete the full set of questionnaires, leavingnine individuals with usable MacCAT-CR data. Notall subjects were administered every MacCAT-CRitem, leading to variable total responses to subscaleitems.

Demographic and clinical characteristics of par-ticipants are presented in Table 1. Participantsranged from 27 to 63 years old (mean 43.3, SD =9.1), the majority (60.7%) were women, and 42.9%reported never having been married. The samplehad an average of 16.7 (SD = 3.0) years of school-ing; 89.3% of participants had at least some collegeeducation. Site differences were observed in partici-pants’ marital status (chi-square = 9.78, P = 0.04).Clinically, participants reported a mean of 6.4 de-pressive episodes, with a mean age of first-episodeonset of 21 years. The mean HDRS-17 score was 23(SD = 3.5, range: 17–30).

Research consent capacityFigure 1 presents data from the MacCAT-CR assess-ment. The vast majority of subjects performed verywell on the measures of all three abilities related tocapacity to decide. On the final trial of the Under-standing scale, 18 of 28 subjects scored perfectly, andout of a possible range of 0–38, all but one subjectscored 33 or greater. On the Appreciation scale, all

Table 1. Demographic and clinical characteristics of par-ticipants (N = 31)

Site A (N = 21) Site B (N = 10)

Characteristic Mean (SD) Mean (SD)

Age 42.7 (9.6) 44.4 (8.0)

Years of education 16.8 (3.4) 16.6 (1.5)

Age of depression onset 21.0 (10.5) 20.1 (4.0)

Number of depressive

episodes

7.11 (9.0) 4.3 (3.2)

Number of

hospitalizations

4.9 (5.3) 1.3 (0.5)

Number of suicide

attempts

1.68 (2.9) 1.29 (2.2)

HDRS-17 baseline

score

24.0 (3.4) 20.3 (2.3)

Number of hypomanic

episodes

4.53 (11.6) N/A

N (%) N (%)

Gender (% female) 13 (61.9%) 4 (57.1%)

% never married* 8 (38.1%) 4 (57.1%)

% at least some college

education

18 (85.7%) 7 (100%)

% family history of

bipolar disorder

42.1% N/A

*Chi-square = 9.78, P = 0.04.

but two subjects scored perfectly, and on the Rea-soning scale, all but four subjects scored perfectly.No subject scored lower than 4 (out of 6) on theAppreciation scale or 6 (out of 8) on the Reasoningscale. Regarding the individual items asked as part ofthese subscales, only two items had more than twosubjects who did not achieve a perfect score: purposeof special procedures (missed by 5) and major risks(missed by 7).

Correlations with depression scoresCorrelations with baseline depression scores arepresented in Table 2. A trend toward significancewas found in the negative correlation (Pearson’sr = –0.322, P = 0.082) between baseline HDRS-17scores and the overall measure of therapeutic mis-conception. No significant correlations were foundbetween baseline depression scores and individ-ual therapeutic misconception items; that is, itemsregarding the purpose of the study, the potentialfor personal benefit, the individualization of treat-ment, or altruistic motivations. In contrast, subjects’



Figure 1. MacCAT-CR scores.

ratings of the risk of two of the procedures (MRI andEEG) were significantly negatively correlated withbaseline depression ratings (r = –0.376, P < 0.05and r = –0.570, P < 0.05, respectively). The absenceof substantial variation in MacCAT-CR scores pre-cludes meaningful exploration of their relationshipwith depressive symptoms.

Common themes and illustrative statementsAs an exploratory aim in this study, we augmentedthe rating-scale items with open-ended questionsdesigned to elicit subjects’ perceptions of study pur-pose, risks, benefits, as well as to explore their moti-vations for participation. Table 3 displays examplesof identified themes.

Discussion

This study examined the capacity of severely de-pressed outpatients to consent to DBS research,

evaluated the associations between depressionseverity and therapeutic misconception, and inves-tigated misconceptions regarding this novel treat-ment modality. Even in a highly selected TRD sam-ple, subjects showed very good performance acrossall domains of decisional capacity. On a scale mea-suring therapeutic misconception, however, somesubjects tended to view the study’s purpose as di-rected specifically at helping the subjects involved,rather than exploring the efficacy of an experimentalintervention; to underrate the risks of the neurosur-gical intervention; and to overrate the likelihood ofpersonal benefit and degree of individualization oftheir care in the study. Therapeutic misconceptionscores suggested that subjects who were more de-pressed might have had fewer misconceptions aboutthe nature of the research study, a potential relation-ship warranting further exploration in larger andmore heterogeneous samples.



Table 2. Correlations of therapeutic misconception scaleand risk ratings with baseline HDRS-17 scores

Correlation

Scale (Pearson’s r) N

Therapeutic misconception

total score

–0.322∗ 30

Risk ratings

MRI –0.376∗∗ 29

Neuropsychological

testing

–0.273 29

Implantation surgery –0.194 29

Endocrine testing� –0.014 20

PET scan� –0.369 20

EEG� –0.570∗∗ 20

∗P = 0.082.∗∗P < 0.05.�These procedures were only conducted at Site A.

Concerns about the capacity of depressed patientsto consent to research are not new.20 Repeatedly,though, studies have failed to find substantial im-pairments in the decisional capacity of people withpsychiatric disorders to consent to research,25,39 in-cluding studies that evaluated severely depressed in-patients and those requiring electroconvulsive ther-apy.26,27 Although the MacCAT-CR is individualizedfor each investigation, which limits the validity ofquantitative comparisons across studies, it is notablethat participants in this study, representing a sub-set of extremely depressed individuals, performedextraordinarily well on all MacCAT-CR capacitymeasures. Indeed, most subjects achieved perfect ornear-perfect scores. In part, this may be due to theintensity and quality of the informational processto which prospective DBS subjects were exposed. Itbears noting, however, that seven subjects did notscore perfectly on the “major risks” item of the un-derstanding subscale, suggesting that this sectioncould benefit from greater emphasis during consentdiscussions. That said, taken together, these find-ings suggest that the persistence and prevalence ofconcerns about the capacity of depressed patients toconsent to research may be disproportionate to thereal risks, as long as adequate safeguards and suffi-cient information are present. Given the consistencyof these findings, the research community shouldconsider whether most individuals with psychiatricdisorders are actually as vulnerable to decisional im-

pairments as they are commonly portrayed,20 or ifsuch concerns might instead be a reflection of thewidespread stigma and prejudice against psychiatricdisorders.

This study further demonstrates that, when askedto elaborate on rating-scale responses regardingstudy purpose, risks, and benefits, participants gen-erally evidenced a grasp of the purpose of the studyas testing a new therapeutic modality for its safetyand efficacy; that there were risks to surgery, partic-ularly brain surgery; and that personal benefit wasnot guaranteed. There were clearly varying levels ofsophistication in these responses from this highlyselected group of participants who may not be rep-resentative of the level of research sophistication ofmost depressed individuals.

Participants expressed an interesting range of re-sponses when asked to reflect on their ratings oftheir level of altruism. Some clearly endorsed thedesire to help themselves first, with altruism beingonly a secondary consideration. Others more di-rectly stated that they wanted other people not tosuffer as they had, or that they wanted to contributeor give meaning to their suffering. These sorts of re-sponses do not seem distinctly different from thoseseen in patients with other serious illnesses—for ex-ample, advanced cancer patients who volunteer forearly-phase clinical trials.30

Nevertheless, this study also reinforces the mes-sage that even decisionally capable subjects may haveproblematic—even mistaken—beliefs about clini-cal research. The degree of therapeutic misconcep-tion found in these subjects (64.5%) is compara-ble with findings from similar studies conductedin psychiatric and nonpsychiatric populations, sug-gesting that this population is not uniquely sus-ceptible to therapeutic misconception.32,33,37,38 Asnoted elsewhere, educational approaches focused onthe differences between research and treatment—including the use of educators not directly involvedin the study—may help subjects avoid therapeu-tic misconception and better understand the natureof the clinical trial in which they are enrolled.37

However, social forces relevant to DBS may presentadditional challenges. The extensive media cov-erage of DBS for TRD, ranging from unrealisticexpectations about the brain’s newfound “happyswitch”40 to alarmism about “psychosurgery re-dux,”41 highlights the ways in which distorted viewsof the procedure may enter the public imagination.



Table 3. Examples of responses to open-ended items

Question domain (Prompt) Examples of responses (Site A or B subject)

Purpose of study (“What

would you say is the main

purpose of this research

project? That is, why are

the researchers doing it?”)

Safety/efficacy/mechanism investigation

- “To test the safety, efficacy, and mechanism of action of DBS” (A)

- “Study [the] efficacy and safety for TRD” (A)

- “Find out if [the] device works or not, safe or not” (A)

- “To test the implant’s efficacy” (A)

- “To investigate the efficacy of DBS of Cg25 in severe TRD and improve

understanding of neural networks, depression, etc.” (A)

- “To learn more about whether DBS is an effective treatment for depression, and if

so, to investigate the mechanism by which DBS affects depression” (B)

- “To determine [the] safety and effectiveness of DBS” (B)

- “DBS has not been FDA approved. . .still [a] study question on why/how DBS

works for depression” (B)

Possible misunderstanding of purpose of investigating DBS as depression “cure”

- “To find out if DBS is a cure for depression” (A)

Benefits (“How likely do you

think it is that you

personally will benefit

from being in this study?

Please explain your

rating.”)

Pessimistic about personal benefit due to prior experience

- “I am skeptical about positive impact because of [my] poor responses to other

treatments, including meds, therapy, ECT, and other adjunctive treatments” (A)

Realistic estimation of uncertainty of personal benefit

- “It’s in the middle—not for sure” (A)

- “Nothing to inform decision except very limited study” (A)

- “The device is a great unknown” (A)

- “There does not exist enough data to make any meaningful estimation of the

benefits I may experience” (B)

Quantified chances

- “50–75% prior results” (A)

- “I feel there is a 40–50% chance of improvement” (B)

Hesitant to be hopeful

- “Don’t want to be completely hopeless. Don’t want to be overly hopeful” (A)

- “I’m neutral—but I’m also not getting my hopes up that I will be ‘cured’” (A)

Hopeful/optimistic

- “I’m optimistic due to previous studies” (A)

- “I’m very hopeful this study will help lift my depression” (A)

Misestimation/overestimation of potential personal benefit

- “I’ve been told that they have had good results so far so I have reason to believe I

will benefit as well” (B)

Risks (“How risky do you

believe this study is to you,

personally? Please explain

your rating.”)

Awareness of risks; realistic estimates of risks/unknowns; acceptable level of risk for

potential benefit

- “Surgery is a possible risk” (A)

- “The unknown of the long-term effects—could backfire” (A)

- “Brain surgery—[it’s] realistic to believe in at least moderate risk” (A)

- “It’s risky and invasive—but I’m okay with the risks associated” (A)

- “Some risk but acceptable amount” (A)

- “I see a lot of complications regarding DBS on the consent form” (B)

- “Many risks in pamphlet” (B)

- “There are risks during brain surgery” (B)

- “There are guidelines and boundaries, but can still be considered experimental,

which carries many risks” (B)



Table 3. Continued.

Question domain (prompt) Examples of responses (Site A or B subject)

Risks in context of prior data/other surgeries/neurosurgery/experience of

surgeons

- “They’ve done this in Parkinson’s disease and I don’t think there have been a

lot of problems” (A)

- “I’m hoping and according to data that it will go smoothly” (A)

- “I understand there are risks involved with brain surgery and any surgery for

that matter but that these risks are fairly low” (A)

- “Given what I have been told and read it is relatively less risky than other

neurosurgery but it is still brain surgery and that feels scary to me.” (A)

- “I’ve been told the surgeons here have performed the procedure hundreds of

times with very few people having side effects” (B)

Risks in relation to living with depression/risk of suicide

- “Worst thing is more impairment, more depression” (A)

- “Alternative (suicide) is a bigger risk” (B)

Possible underestimation or discounting of personal risk

- “I am healthy & do fine with surgery” (A)

- “Optimism. Serious effects. Some chance. . .not worried about it” (A)

- “Only know what I’ve read and what people tell me. I don’t think I

personally have any particular risk” (A)

Overestimation of personal risk

- “I feel I have ‘bad luck’ period” (A)

Altruism (“To what degree was

the desire to help others in the

future a motivation for your

participating in this study?”)

Kinship

- “I’m concerned for my kids” (A)

- “I don’t want my (child) and others to have the frustration I have

experienced” (A)

Helping prevent suffering of others/feeling that one is contributing/bringing

meaning to one’s suffering

- “I don’t want anyone to suffer as long as I have” (A)

- “Very, very willing to help find cure for this illness” (A)

- “Like to help prevent others from suffering” (A)

- “My lifelong struggle with depression will not have been my pain only” (A)

- “Participating. . .helps me feel like I’m contributing something in this

world” (B)

General statements about helping others or advancing depression treatment

- “If it doesn’t help me, maybe it will help others and future developments in

treating TRD” (A)

- “I believe that even if I am not helped by the study it may provide valuable

information in future advances in TRD and DBS” (A)

Explicit statements of personal concern being primary, and altruism secondary

- “I will be glad if my participation helps others but I have chosen to

participate purely for selfish reasons (i.e., hoping it helps me)” (A)

- “I would certainly like to help the future sufferers of depression—but my

first priority has to be myself” (B)

- “I am desperate at the moment, that is my concern. Helping others is

secondary. I’m not proud of this, but it is true” (B)



Extra vigilance and effort on the part of the scientificcommunity to promote public understanding arethus required to combat broader misunderstand-ings about this novel intervention, as well as to fos-ter better understanding of the purpose and lim-itations of clinical research. The fact that subjectsin this study exhibited very good performance onmeasures of decisional capacity but still showed ev-idence of common misconceptions indicates thatrefinements and elaborations of the consent processalone may not be sufficient to remedy these misun-derstandings and counteract the forces that oper-ate at broader levels to drive overall public under-standing.

It is interesting that there was a trend towarda negative correlation between baseline depressionratings and total therapeutic misconception score,i.e., subjects who were more depressed demon-strated fewer misconceptions about the nature of theresearch study. They also showed lower levels of con-cern about the low-risk aspects of the study (MRIscans and neuropsychological testing). These find-ings might be a reflection of depressive realism,42 theidea that depressed individuals make more accuratejudgments than their nondepressed counterparts.On the other hand, more recent studies of this phe-nomenon have called the idea of depressive realisminto question, suggesting that clinically depressedindividuals make negatively distorted judgments.43

Particularly given the limitations of this study notedsubsequently, further work on this question is war-ranted.

Among this study’s limitations is that this sam-ple comprised a small, prescreened, well-educatedsubset of subjects with TRD. Subjects also had tobe highly motivated to participate in the study’s de-manding procedures—in some cases, they wouldhave to move to a new city to participate. More-over, our subjects’ desire to be in a study of DBSfor TRD may have influenced their responses, i.e.,they may have been concerned that admitting tothe “wrong” motivations would compromise theirability to remain in the study (although we foundmultiple instances of subjects providing frank as-sessments of their motivations and desperation). Inaddition, the validity of our findings may be lim-ited by the absence of validated measures for severalof the concepts that we sought to assess, includingdesperation and altruism. Similarly, the scale used tomeasure therapeutic misconception, although the-

oretically grounded and based on those used in pre-vious studies, had not been validated. Finally, therewas no control group, making it difficult to know theextent to which other variables may have accountedfor our findings.

Further studies are needed to examine decisionalcapacity and therapeutic misconception across abroader sample of participants with TRD. There isalso a need for further methodological refinementand validation of tools to assess influences on de-cision making. It might be most useful to compareTRD subjects with those with other serious illnessesconsidering early phase or invasive research in aneffort to identify which, if any, of the phenomenawe explored are specific to DBS for TRD research.This is particularly important at a time when mul-tiple brain-based interventions—for example, genetherapy trials that include sham surgery—are beingmounted for a variety of neurological and neurode-generative disorders.

Acknowledgments

This work was supported, in part, by the Green-wall Foundation (Drs. Dunn, Appelbaum, andHoltzheimer), and NIMH-sponsored Career Devel-opment Awards MH66062 (Dr. Dunn), MH077869(Dr. Holtzheimer), and MH091501 (Dr. Leykin).DBS studies at Emory were funded by grants fromthe Woodruff Fund, Stanley Medical Research In-stitute, the Dana Foundation, and Emory Health-care (Dr. Mayberg), and performed under FDA IDE:G060028 and Clinicaltrials.gov ID#: NCT00367003(Dr. Mayberg). The DBS research devices were do-nated by St. Jude Medical, Inc. DBS studies atColumbia were funded by St. Jude Medical, Inc.

Conflicts of interest

H. Mayberg consults and receives licensing fees forintellectual property related to deep brain stimu-lation for depression from St. Jude Medical, Inc. P.Holtzheimer serves as a consultant for St. Jude Med-ical, Inc. In this role he assists in the design and con-duct of their clinical trials in depression. S. Lisanbyhas received research grants on DBS to her institu-tion (Columbia and Duke University) from ANS/St.Jude Medical, Inc. S. Lisanby has received researchgrants to her institution on technologies not relatedto the topic of this manuscript from Brainsway andNeosync. She has received equipment support to herinstitution on technologies not related to the topic



of this manuscript from Magstim and Magventures.The other authors report no conflicts.

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The ethics of research on deep brain stimulation for depression: decisional capacity and therapeutic misconception

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