Electrodes in the brain—Ethical criteria for research and treatment with deep brain stimulation for neuropsychiatric disorders

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Electrodes in the braindEthical criteria for research and treatment with deep brain stimulation for neuropsychiatric disorders Matthis Synofzika, Thomas E. Schlaepferb,c a

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Department for Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tu¨bingen, Germany b Department of Psychiatry and Psychotherapy, University Hospital, Bonn, Germany c Departments of Psychiatry and Mental Health, The Johns Hopkins University, Baltimore, Maryland

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Background Deep brain stimulation (DBS) has been used for neuropsychiatric disorders in clinical and research settings for almost 50 years now. Recent evidence demonstrates some efficacy in treating obsessivecompulsive disorder and major depression in patients refractory to other treatment modalities beyond single case reports. This has led to a considerable surge of clinical and commercial interest in DBS for psychiatric indications. Because of the high vulnerability of psychiatric patients, the lack of extensive short- and long-term data about effectiveness and adverse effects and the haunting history of psychosurgery, this new field in psychiatry raises important and specific ethical issues that have only rarely been systematically addressed so far. Objective and Methods We here review an evidence-based systematic ethical analysis of psychiatric DBS using the criteria of beneficence, nonmaleficence, and autonomy.

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Conclusions These criteria can easily be applied to research and future clinical application of DBS in neuropsychiatric disorders. This will prepare the ground for ethically justified, empirically comprehensive DBS in this highly vulnerable population and allow stringent future societal discussions about its legitimation. Ó 2010 Elsevier Inc. All rights reserved. Keywords

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deep brain stimulation; neuroethics; major depression

Dr. Schlaepfer received limited support for an Investigator Initiated Study on DBS in resistant major depression from Medtronic Inc., a manufacturer of DBS equipment between 2004 and 2007. Correspondence: Thomas E. Schlaepfer, MD, Department of Psychiatry / University Hospital, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.

E-mail address: [email protected] Submitted July 27, 2009; revised January 12, 2010. Accepted for publication January 14, 2010.

1935-861X/10/$ -see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.brs.2010.01.006

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1. When does a patient truly benefit from DBS?

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To provide a benefit to a patient, DBS first of all has to prove to be effective and, preferably, to be more effective than both nonsurgical measures and ablative surgery. Recent studies in obsessive-compulsive disorder (OCD) or major depressive disorder (MDD) have demonstrated first evidence of DBS effectiveness at least in some patients.6-824,25 Given the fact that patients studied were selected on basis of their high treatment-refractoriness to pharmacotherapy and psychotherapy, these findings are significant. However, the ability to adequately determine true therapeutic effects from these data is limited by small sample sizes (,70 patients total) and the uncontrolled nature of most study designs. Furthermore, these data indicate that, 50-75% of OCD2,25 and 25-50% of MDD patients6-8,24 fail to show long-term response to DBStreatment, individual prognostic predictors for lasting treatment effects remain unclear. In the face of this considerable percentage of DBS nonresponders, who continue hsving severe psychiatric disease despite undergoing a treatment with serious potential side effects, one has to be keep in mind that some patients, even with severe and chronic forms of the disorder, might finally respond after years of creative pharmacological and behavioral treatment.26 Moreover, effectiveness of DBS is not yet shown to be clearly superior to ablative surgery in case of OCD (e.g., gamma-knife capsulotomy).2 Taking these factors into account, a highly differentiated evaluation specific to every individual patient’s situation needs to strictly ensure that DBS is likely to be superior to non-DBS measures before offering DBS to the patient. Contrary to the currently prevailing perspective,15 however, treatment refractoriness per se does not necessarily have to be a mandatory criterion in the future: DBS might prove to be so superior in OCD and MDD that especially patients who have not been on medication for a longer time and whose social and physical life is not yet devastated by disease might benefit more from DBS and thus present the best candidates for DBS. This scenario seems provocative at first glance, but parallels a lesson recently learned in DBS for Parkinson’s disease27-29 and primary dystonia.30 Correspondingly, several studies are underway assessing benefits of DBS in early stages of Parkinson’s diseases in comparably young Parkinson patients (ClinicalTrials.gov Identifier: NCT00354133 [Kiel, Germany], and NCT00282152 [Vanderbilt, TN]). Currently, however, double-blind and controlled studies are clearly required to further corroborate the recent open label findings. To provide an actual benefit to the very individual patient, DBS not only has to be effective, that is, improve scores in OCD or MDD rating scales, but also has to

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High-frequency electrical deep brain stimulation (DBS) of specific brain circuits has gained increasing acceptance in treatment of several neurologic disorders because of its high effectiveness anddcompared with classical ablative neurosurgical interventionsdits less invasive, largely reversible, and adjustable features.1 First evidence for efficacy has also been shown in studies of treatment-refractory psychiatric diseases, such as obsessive-compulsive disorder2-5 and major depression6-8 and, in fact, psychiatric DBS is already moving from experimental to clinical use. This is evidenced by the growing number of worldwide DBS implantations in neuropsychiatric cases, the increasing amount of publications presenting outcome data9 and the fact that two large pivotal trials of DBS for major depression have been launched recently.10,11 But at what point should we recommend DBS to individual patients with severe depression or obsessivecompulsive disorder? And, in turn, when should we discourage operation? Given the quickly increasing interest in DBS research for neuropsychiatric disorders, investigators, investigational review boards, psychiatrists, patients and caregivers are obviously in the need of clear criteria that can easily be applied to both research and clinical decision making. Although some ethical concerns of DBS for psychiatric indications have been addressed already,12-19 no systematic, criteria-oriented ethical analysis is available, helping in both directly analyzing empirical evidence and guiding clinical decision making. We state, in this report, ethical criteria, which are not only widely shared in western culture, but can also be easily applied to empirical research on, and clinical application of DBS in psychiatry.

turn, there is an ethical obligation to refrain from DBS when harms outweigh benefits or when it does not correspond to his or her true value choices.

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Setting the stage

Ethical criteria for neuropsychiatric DBSd Stepping beyond common ethical references

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Many current ethical perspectives draw on references to early psychosurgery17,20 or the risk to alter a patient’s personality15,21 to delineate negative ethical criteria for psychiatric DBS. However, these references are of rather limited value for establishing positive ethical criteria that can be systematically applied in current research and clinical DBS to perform evidence-based ethical decision-making processes.22 At first sight, there is no need for specific ethical criteria for DBS in psychiatric disorders, but the same criteria as for DBS in movement disorders or as for any other biomedical intervention can be applied: DBS has to (1) benefit the patient (principle of beneficence), (2) do no harm to the patient (principle of nonmaleficence), and (3) reflect his preferences and overall will (principle of respect for autonomy).23 Consequently, there might even be an ethical obligation to perform DBS in a psychiatric patient when benefits outweigh harms and under the prerequisite that it corresponds to his or her true value choices. In

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ARTICLE IN PRESS Electrodes in the brain Table 1 Factors contributing to psychosocial misadjustment after ‘‘successful’’ DBS in a chronic disease, exemplarily demonstrated for Parkinson patients with stimulation of the subthalamic nucleus Experiences of psychosocial maladjustment after ‘‘successful’’ DBS

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 Loss of an aim in life after being less challenged in fighting the chronic disease  Negative retrospective perspective on the disaster the disease has caused in their lives  Persistent negative anticipation of future problems  Marital problems, for example, - The spouse is forced to switch from the role of a caregiver to the role of an equal partner - The spouse overburdens the patient who is still not able to run his or her own life to the same extent as before the illness  Inability to reintegrate into work life, for example, - By insisting on the sick role - By prioritizing leisure and artistic activities  Incorporation of an alien implanted device into the body image

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Factors contributing to psychosocial misadjustment after ‘‘successful’’ DBS in a chronic disease, exemplarily demonstrated for Parkinson patients with stimulation of the subthalamic nucles.

- Postoperative complications such as pneumonia, pulmonary embolism or hepatopathy with a 30-day mortality rate of 0.4 %.37

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demonstrate that these abstract improvements indeed are associated with an actual improvement of the very individual patient abilities to achieve personally valuable goals, that is, goals that are valuable in light of his or her very individual psychosocial situation and on the basis of his or her very individual evaluative concept of a good life. In other words, statistically significant efficacy is only a necessary, but not a sufficient condition, for true effectiveness and might, in certain cases, present an invalid surrogate parameter for the patient’s true well-being. This ethically highly important difference, which applies to many medical fields,31 has been overlooked for a long time in DBS for movement disorders. Both research and clinical practice have focused initially on motor outcome only, but have neglected quality of life independent of motor function and, in particular, normative and psychosocial factors that are easily missed with quantitative outcome parameters (e.g., with movement scores or quality of life scores).32,33 Even if it was convincingly demonstrated, that motor, behavioral, and disease-related quality of life variables improve after DBS surgery (as it has already been shown by RCTs for Parkinson’s disease34 or primary dystonia35), these measures might still present invalid surrogate parameter for true benefits of DBS. As shown by a recent open interview study, many Parkinson patients are not happier with their lives, go through tormented periods in their marriages, or fail to resume professional activity after surgery, despite (or probably even because of) clear improvement in various of these outcome variables after DBS implantation.32 Because the contributory factors to these psychosocial misadjustments do not seem to be specific to Parkinson’s disease (Table 1), but can be expected after rapid symptom modification in any chronic life-determining disease, the exact same problems could be expected after DBS in OCD or MDD. Therefore, clinical studies should not only ask whether DBS is effective, that is, demonstrate improvement on OCD or depression scores, but whether it indeed allows the very individual patient to live a more satisfying life, including psychosocial dimensions. Therefore, quantitative measures have to cover also variables like reintegration in social and work environments and psychosocial and global quality of life. Moreover, they have to be complemented with qualitative measures, in particular as changes in disease severity, comorbidities, and psychosocial life situations are harder to capture in psychiatric disease than in movement disorders.

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2. Potential harms of DBS

DBS to different targets is associated with severe short-term and long-term risks on both biologic and psychosocial levels. Adverse short-term effects related to surgery and implantation encompass: - Severe perioperative complications such as intracerebral hemorrhages, seizures, infections, or hemiparesis (incidence 0.2-2%36; Figure 1).

Adverse short-term effects related to the stimulation comprise: -

Mood elevation/ hypomania2,5,25,38 Sadness, anxiety, panic2,39 Aggression40 Distracting epigastric or gustatory sensations25 Decreased alertness or cognitive dulling25

Adverse long-term effects related to the stimulation comprise: - Worsening of apathy41 - Depression42 - Cognitive impairments, for example, in verbal fluency, color naming, selective attention, and verbal memory43 - Sudden symptom reoccurrence and aggravation in case of battery depletion (occurring as a function of programmed stimulation parameters, usually after 5-13 months in the case of higher stimulation current amplitudes such as those required for OCD) or of accidental deactivation, risking, for example, depressive exacerbations.25 - Long-term neuroplastic changes. Even though DBS effects are generally considered to be ‘‘reversible,’’9 prolonged stimulation leads to changes in the neural network that endure well beyond the cessation of stimulation, for example, by exerting long-term effects on synaptic plasticity.44,45 Evidence so far indicates that these changes seem to be associated with persistent benefit rather than persistent harm in psychiatric patients,24 yet this might

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Adverse short- and long-term effects on a psychosocial level might be comprise of:

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- Psychosocial misadjustment even and especially in case of an effective treatment response32 - Suicidality,46-48 in particular in patients who have an elevated risk of depression and suicidal behavior, for example, OCD patients.49 - Harmful psychological consequences of nonresponsiveness to DBS, for example, severe disappointment and renewed desperation2: This risk is particularly high in severely disabling, potentially fatal conditions such as psychiatric diseases in which patients might see the treatment as ‘‘the last rope’’ and it might make patients even more susceptible to suicide. - Psychosocial irreversibility of the procedure. Even though active DBS can be easily discontinued, for example, in case of failing efficacy, alternative future treatment options or changed patient preferences, the patients’ psychological states might not simply fully reverse to a pre-DBS baseline condition after longer periods of treatment. In case of effective DBS, patients will go through completely new experiences and will change their ways of living, whereas in case of nonefficacy, severe despair will be added to their life. Thus, the assumption that DBS effects are fully reversible, which is commonly taken as one of the strongest ethical arguments in support of psychiatric DBS,15,17might be both inaccurate and even potentially dangerous.

separately. A location-specific efficacy-harm ratio might be of particular importance in psychiatric DBS assessments, as often several very different anatomic targets (e.g., nucleus accumbens, habenula, inferior thalamic peduncle, internal capsule, Brodmann area 25) are proposed for the same condition (depression) and as it is probable that different targets will have different efficacy-harm ratios. Because it is unlikely that stimulation of one brain area will be sufficient for all types of one psychiatric disease (e.g., depression), an individual symptom-specific approach will be the future of psychiatric DBS which selects the target site depending on the individual’s symptom profile.50 DBS broadly defined is a very imprecise category for discussing risk/benefit, a fact that has to be kept in mind in societal discussions about psychiatric DBS or in future scientific comparisons of DBS with other different treatment modalities (e.g., DBS versus ECT or TMS for depression). However, under the assumption that DBS would be an efficacious treatment, one might do harm to patients not only by performing DBS, but also by not performing it. The chronic and partly even progressive course of treatmentrefractory OCD or MDD implies an constant increase in psychological suffering, work disintegration, social withdrawal, and partnership and family relation problems. Thus, also not performing DBS in psychiatric patients might 1 day posit specific, well-reasoned ethical justifications. Moreover, all pharmacological treatments are associated with significant adverse effects, for example, agitation, sexual side effects, sedation, sleep disturbances, and night sweats in the case of depression treatment, often leading to noncompliance.51 The same is less recognized but nevertheless the case for psychotherapy.52 These adverse effects have to be counterbalanced against those of DBS, in particular as none of these adverse events has been reported in DBS depression treatment so far.6-8,24,50

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potentially be conversed in cases in which patients experience harmful effects of DBS.

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Figure 1 Computed tomographic images displaying right frontal hemorrhage, presumably induced by disruption of an aberrant vein during DBS electrode insertion in the subthalamic nucleus, directly after incidence (A) and 10 days afterwards (B). Because of malignant edema, the skull calotte had to be removed (arrow in B). (r 5 right, l 5left; a 5 anterior; p 5 posterior.)

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For some biologic and psychosocial risks, it still remains unclear whether they result from brain stimulation per se, from a secondary reaction to the stimulation effects, or from the underlying irresistibly progressive disease in case of neurodegenerative disturbances. In addition, a final risk-(and benefit)-assessment cannot be performed for DBS in general, but needs to be specifically completed for each DBS location

3. Satisfying the psychiatric patient’s will Personal value preferences based on one’s very individual concept of a good life are of special importance for both,

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or in OCD,5 but which might even be more easily induced in psychiatric stimulation targets like the anterior limb of the internal capsule and the nucleus accumbens,61,62 might cause patients to want to stay on current parameter settings even when they lead to detrimental effects. Hypothetically, a patient might ask for an increase in stimulation amplitude to continuously boost his mood. For these reasons, decision-making in psychiatric DBS should be embedded in a deliberative, participative physician-patient relationship,63 in which the psychiatrist is explicitly asked to scrutinize the patient’s will, to give recommendations and to mentor his formation of will. Moreover, decisions about DBS, whether it may be DBS insertion or DBS parameter adjustment, issued by a multidisciplinary committee can question and overrule patients’ wishes for DBS if they do not appear to be adequate.

Implementing procedural safeguards

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Obviously, the specific challenges in assessing benefit, harm, and autonomy do not present a general argument to not perform DBS in psychiatric patients, yet they put emphasis on the need to carefully scrutinize DBS considerations, to study effects and adverse events with different outcome measures and methodologies and to openly report any kind of short- or long-term adverse events. In addition, like in other vulnerable populations (e.g., DBS in children with movement disorders or in Parkinson patients with beginning dementia), these difficulties require implementation of the following specific procedural safeguards (for other meaningful possible safeguards64,65). Multidisciplinary committee. Potential candidacy of a patient needs to be assessed by a multidisciplinary committee,66 including not only physicians directly caring for the patient, but also an independent psychiatrist. This allows bringing together patient specific disease variables, value choices, and scientific evidence in assessing potential benefit and harm for the individual patient in his specific psychosocial context and disease situation. The participation of an independent psychiatrist might not only offer a new, independent perspective on the case, but also ensures that recommendations do not primarily depend on research and financial interests that might certainly play a role in this early, innovative stage of researching DBS for psychiatric indications. Right of veto. If potential harms clearly outweigh potential benefits, DBS should not been offered, even if the patient would demand it (Figure 2). In this case, obligations based on beneficence overrule autonomy-based obligations. This right is certainly not specific to psychiatric DBS, yet it gains special importance in case of psychiatric patients as their demands might be determined by preferences and evaluation processes influenced by their respective psychiatric disease or comorbid personality disturbances.

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taking the decision to undergo a DBS procedure in the first place and determining adequacy of stimulation parameter adjustment in the further course of treatment. For example, evaluations of probability (does a 0.4-3.6% risk of severe perioperative complications seem to be a lot to me or rather negligible?), of benefit (is tremor improvement beneficial to me, and if yes, does it outweigh a more dysarthric speech?), and of relevance of neurological and psychosocial risks (can my partnership bear a sudden change in disease behavior? am I at risk to loose my aim of life when fighting the disease is no longer the main purpose in everyday life?) are clearly value choices that vary largely with the very individual’s life style, the psychosocial support system, and conscious value preferences. For instance in neurologic disorders, a college teacher with Parkinson’s disease who is mainly involved in teaching and lecturing might consider an even slightly dysarthric speech induced by DBS53 to be so disabling that he prefers an akinetic movement pattern, whereas a carpenter whose concept of a fulfilling life strongly depends on laborious handcraft might accept some DBS-induced dysarthria and slight cognitive disturbances for being able to move better (for other examples of even more extreme trade-offs in neurologic DBS15). Although comparable trade-offs between different capabilities are not yet known for psychiatric DBS, it is highly probable that they are necessitated here as well. The capacity for autonomous decision making and especially value choices might be associated with more and stronger confounds in psychiatric patients than in many patients who are having movement disorders: First, general treatment preferences are strongly influenced by affective components, for example, major depression,54-57 in both MDD and OCD patients (up to 80% of the OCD patients undergoing DBS have comorbid DSM IV major depression2,25). Second, desperation is high in chronic, treatmentrefractory and potentially deadly mental disorders, thus giving ground to hasty decisions in favor of DBS, which potentially undervalue the fact that (1) individual treatment-response to DBS is highly uncertain unclear, (2) some adverse effects might be deadly or lead to severe disability (e.g., in case of haemorrhage), and (3) long-term cognitive, emotional, and behavioral effects of psychiatric DBS are still largely unknown. The high desperation of treatment-resistant patients predisposes them, to severe disappointment in case of nonresponsiveness and to suicidal reactions.2 It thus complicates not only assessment of efficacy, but also patient management in demanding protocols and in the subsequent physician-patient-relationship. Third, because psychiatric side effects such as elevated mood or anxiety might more likely in psychiatric DBS, patients’ preferences for or against certain parameter settings might be directly influenced by the stimulation per se, but not reflect their general value perspective, unaffected by DBS treatment. For example, hypomania, which has been reported as a side effect of STN-stimulation in Parkinson’s disease58-60

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Figure 2 Decision-making algorithm to identify candidacy for psychiatric DBS based on a case-specific interpretation of the ethical principles beneficence, nonmaleficence and respect for autonomy and the best available empirical evidence on the effectiveness of the treatment options.

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Standardized, center-based protocols and follow-ups. Because of the lack of knowledge on short- and long-term risks, psychiatric DBS should currently only be offered in academic centers with extensive experience in treatment resistant disorders. Patients need to be enrolled in standardized reporting protocols (case registers) documenting meaningful effects beyond mere symptom scores and adverse events. Moreover, they should be guaranteed a particularly close, standardized, multidisciplinary follow-up that ensures monitoring long-term efficacy and potential side effects, to prevent battery depletion and to detect accidental deactivation. A close follow-up might allow, for example, to resolve stimulation-induced hypomania, one of the main psychiatric adverse events in OCD DBS that can easily be improved by parameter adjustment,5 or to detect suicidal ideation, a risk even in those psychiatric patients in whom DBS is effective.50 These demands might seem trivial at first glance because DBS for psychiatric disorders is currently available almost exclusively in academic medical centers that use established protocols. This is especially important because of the quick and ethically challenging broadening of DBS indications that is currently observed (e.g., obesity, dementia, schizophrenia, alcohol dependence). Also, for single case studies in patients who are unresponsive to standard therapy and who do not meet inclusion criteria of current study protocols, DBS should be restricted to centers that have extensive experience in diagnosing complex psychiatric diagnosis (or in detecting possible

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psychiatric comorbidities), which provide all alternative noninvasive treatment options on a high-quality level and have established standardized multidisciplinary follow-ups. Guideline development. To reduce incorrect individual assessments of the benefit-harm-ratio and to increase coherency and transparency of decision making, international guidelines for DBS need to be worked out by multidisciplinary expert committees.

Level of evidence for DBS efficacy and safety So far, most available data about psychiatric DBS has been uncontrolled, thus raising the question what level of evidence should be used to establish safety and efficacy. This complex question cannot be addressed here in full detail, but from an ethical perspective it seems obvious to ask for randomized controlled trials as only they can establish true efficacy and rule out possible confounding factors, previously described. It was well shown for DBS in Parkinson’s disease,34 primary dystonia,35 and even OCD5 that RCTs can indeed be justified and are feasible. It is more difficult to determine the ethically most appropriate control condition. Compared with placebo control, an active-controlled study design resorting to best medical treatment (i.e., pharmacotherapy and/or behavioral therapy) does not seem to suffice, as it could not convincingly rule out placebo responses to DBS insertion

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resistant to traditional methods, and maybe also in the future for those patients who show a significant, yet still insufficient effect to other treatments. There are no inherent ethical objections; the same ethical criteria that are already widely used to assess other biomedical interventions can be productively applied for analyzing DBS studies and for clinical decision making. These criteria, however, pose several specific challenges to psychiatric DBS, illustrating clearly that the time is not ripe yet for wide-spread clinical application in these indications, not only because of the current lack of scientific data, but also because of currently unmet ethical requirements. A particularly strict and highly careful weighing of potential benefits, the risk of serious adverse events and the patient’s preferences has to be performed for each patient individually. However, if we do our ethical homework conscientiously, confirm the favorable efficacy to side effect profile in larger and better controlled studies, learn from earlier mistakes in DBS for neurologic indications, and implement specific procedural safeguards, DBS has certainly the potential to become a promising and legitimate treatment approach in for some of the most disabling disorders known to humanity.

References

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and DBS programming and would thus not allow to make a final decision about the quality of DBS. Although the well-documented low and poorly sustained placebo response rate in treatment-refractory psychiatric patients67-71 speaks against a major role of such placebo effects, there are at least two lines of argumentation why sham stimulation (e.g., 0.0 Volt or subthreshold stimulation) as a specific kind of an active placebo seems to serve as a better control condition. First, as there is no such thing as an inert operation in surgery, active placebos, or sham operations (comprising, inter alia surgery, electrode insertion, and parameter setting) are the only ways to control for the placebo effect; otherwise, control patients would be given nothing at all. If clinical trials would refrain from using active placebo, they might even lead to the approval and use of DBS treatments that appear superior in efficacy to standard treatments but may actually be no more effective than placebo (sham stimulation). This would confer an unjustified risk of harm for the patients treated with DBS and high intervention costs for the health care system. Second, because there is currently no alternative standard treatment of proven efficacy for the specific condition that is considered here, treatment-resistant MDD or OCD, patients in the placebo arm are not denied proven, effective treatment. After a limited, well-defined study period patients from the sham-stimulation arm should receive active stimulation. Such a trial design is almost ethically innocuous because patients are not asked to forego, but only to delay treatment of presumed benefit. However, sham-stimulation does not necessarily be performed in a double crossover design as this would mean that patients might experience major exacerbation of the underlying psychiatric disease. A recent study of DBS in major depression demonstrated that such a design might lead to ethically highly problematic consequences and, subsequently, its cessation.47 In this case, the chance of benefit equiponderates the non-trivial risk of harm of the surgery (Figure 1), which these patients have gone through. Moreover, it prevents exploitation of placebo-study arm for research purposes because patients’ participation confers presumed benefits not only to future patients and society from generating biomedical knowledge (beneficence in clinical research) but also to the individual patients themselves (beneficence in clinical medicine). The feasibility of DBS sham-stimulation has been demonstrated in a large scale study in dystonia patients,35 in a smaller study in OCD patients5 and was also exemplarily investigated in patients with depression using off-on-off-on trials of varying short periods as well as in a blinded discontinuation phase of 4 weeks.8,24

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Conclusion DBS might turn out to be a focused and efficacious treatment option for well-selected psychiatric patients

1. Perlmutter JS, Mink JW. Deep brain stimulation. Annu Rev Neurosci 2006;29:229-257. 2. Abelson JL, Curtis GC, Sagher O, et al. Deep brain stimulation for refractory obsessive-compulsive disorder. Biol Psychiatry 2005; 57(5):510-516. 3. Greenberg BD, Malone DA, Friehs GM, et al. Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 2006;31(11):2394. 4. Nuttin BJ, Gabriels LA, Cosyns PR, et al. Long-term electrical capsular stimulation in patients with obsessive-compulsive disorder. Neurosurgery 2003;52(6):1263-1272. discussion 1272–1274. 5. Mallet L, Polosan M, Jaafari N, et al. Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N Engl J Med 2008;359(20): 2121-2134. 6. Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry 2008;64(6):461-467. 7. Malone DA Jr., Dougherty DD, Rezai AR, et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry 2009;65:267-275. 8. Schlaepfer TE, Cohen MX, Frick C, et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 2008;33(2):368-377. 9. Goodman WK, Insel TR. Deep brain stimulation in psychiatry: concentrating on the road ahead. Biol Psychiatry 2009;65(4):263-266. 10. Advanced NeuromodulationSystems (ANS) Inc. BROADEN clinical study. A study of a non-pharmacological device for depression. 2007 [cited 2009 01/06]; Available from: http://www.broadenstudy. com/sb/index.html 11. Medtronic Inc. Medtronic to pursue major clinical trial of deep brain stimulation as depression treatment. 2006 [cited 2009 01/06]; Available from: http://findarticles.com/p/articles/mi_m0EIN/is_2006_ April_25/ai_n26838044?tag5content-inner;col1 12. Ford PJ. Neurosurgical implants: clinical protocol considerations. Camb Q Healthc Ethics 2007;16(3):308-311.

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ARTICLE IN PRESS 8

DP

RO

OF

38. Funkiewiez A, Ardouin C, Krack P, et al. Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson’s disease. Mov Disord 2003;18(5):524-530. 39. Shapira NA, Okun MS, Wint D, et al. Panic and fear induced by deep brain stimulation. J Neurol Neurosurg Psychiatry 2006;77(3):410-412. 40. Piasecki SD, Jefferson JW. Psychiatric complications of deep brain stimulation for Parkinson’s disease. J Clin Psychiatry 2004;65(6): 845-849. 41. Drapier D, Drapier S, Sauleau P, et al. Does subthalamic nucleus stimulation induce apathy in Parkinson’s disease? J Neurol 2006;253(8): 1083-1091. 42. Richard IH. Depression and apathy in Parkinson’s disease. Curr Neurol Neurosci Rep 2007;7(4):295-301. 43. Smeding HM, Speelman JD, Koning-Haanstra M, et al. Neuropsychological effects of bilateral STN stimulation in Parkinson disease: a controlled study. Neurology 2006;66(12):1830-1836. 44. Haber SN. The primate basal ganglia: parallel and integrative networks. J Chem Neuroanat 2003;26(4):317-330. 45. Carmichael ST, Price JL. Connectional networks within the orbital and medial prefrontal cortex of macaque monkeys. J Comp Neurol 1996; 371(2):179-207. 46. Appleby BS, Duggan PS, Regenberg A, Rabins PV. Psychiatric and neuropsychiatric adverse events associated with deep brain stimulation: a meta-analysis of ten years’ experience. Mov Disord 2007;22(12): 1722-1728. 47. Kapoor S. Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N Engl J Med 2009;360(9):931-932.. author reply 932. 48. Soulas T, Gurruchaga JM, Palfi S, Cesaro P, Nguyen JP, Fenelon G. Attempted and completed suicides after subthalamic nucleus stimulation for Parkinson’s disease. J Neurol Neurosurg Psychiatry 2008; 79(8):952-954. 49. Torres AR, Prince MJ, Bebbington PE, et al. Obsessive-compulsive disorder: prevalence, comorbidity, impact, and help-seeking in the British National Psychiatric Morbidity Survey of 2000. Am J Psychiatry 2006;163(11):1978-1985. 50. Bewernick BH, Hurlemann R, Matusch A, et al. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in extremely treatment-resistant depression. Biol Psychiatry 2010;67: 110-116. 51. Keller MB, Hirschfeld RM, Demyttenaere K, Baldwin DS. Optimizing outcomes in depression: focus on antidepressant compliance. Int Clin Psychopharmacol 2002;17(6):265-271. 52. Nutt DJ, Sharpe M. Uncritical positive regard? Issues in the efficacy and safety of psychotherapy. J Psychopharmacol 2008;22(1):3-6. 53. Kenney C, Simpson R, Hunter C, Ondo W, Almaguer M, Davidson A, et al. Short-term and long-term safety of deep brain stimulation in the treatment of movement disorders. J Neurosurg 2007;106(4):621-625. 54. Elliott C. Caring about risks. Are severely depressed patients competent to consent to research? Arch Gen Psychiatry 1997;54(2):113-116. 55. Bursztajn HJ, Harding HP Jr., Gutheil TG, Brodsky A. Beyond cognition: the role of disordered affective states in impairing competence to consent to treatment. Bull Am Acad Psychiatry Law 1991;19(4):383-388. 56. Grimes AL, McCullough LB, Kunik ME, Molinari V, Workman RH Jr. Informed consent and neuroanatomic correlates of intentionality and voluntariness among psychiatric patients. Psychiatr Serv 2000; 51(12):1561-1567. 57. Rudnick A. Depression and competence to refuse psychiatric treatment. J Med Ethics 2002;28(3):151-155. 58. Herzog J, Reiff J, Krack P, et al. Manic episode with psychotic symptoms induced by subthalamic nucleus stimulation in a patient with Parkinson’s disease. Mov Disord 2003;18(11):1382-1384. 59. Mandat TS, Hurwitz T, Honey CR. Hypomania as an adverse effect of subthalamic nucleus stimulation: report of two cases. Acta Neurochir (Wien) 2006;148(8):895-897.. discussion 898. 60. Raucher-Chene D, Charrel CL, de Maindreville AD, Limosin F. Manic episode with psychotic symptoms in a patient with Parkinson’s disease

CO

RR

EC

TE

13. Fins JJ. A leg to stand on: Sir William Osler and Wilder Penfield’s ‘‘neuroethics’’. Am J Bioeth 2008;8(1):37-46. 14. Kubu CS, Ford PJ. Ethics in the clinical application of neural implants. Camb Q Healthc Ethics 2007;16(3):317-321. 15. Glannon W. Stimulating brains, altering minds. J Med Ethics 2009; 35(5):289-292. 16. Farris SM, Gianola FJ. Ethical issues surrounding deep brain stimulation in Parkinson’s disease. JAAPA 2009;22(2):57-58. 17. Kringelbach ML, Aziz TZ. Deep brain stimulation: avoiding the errors of psychosurgery. Jama 2009;301(16):1705-1707. 18. Farris S, Ford P, DeMarco J, Giroux ML. Deep brain stimulation and the ethics of protection and caring for the patient with Parkinson’s dementia. Mov Disord 2008;23(14):1973-1976. 19. Schiff ND, Giacino JT, Fins JJ. Deep brain stimulation, neuroethics, and the minimally conscious state: moving beyond proof of principle. Arch Neurol 2009;66(6):697-702. 20. Miller G. Neuropsychiatry: rewiring faulty circuits in the brain. Science 2009;323(5921):1554-1556. 21. Hildt E. Electrodes in the brain: some anthropological and ethical aspects of deep brain stimulation. Int Rev Information Ethics 2006; 5(9):33-39. 22. Synofzik M, Schlaepfer TE. Stimulating personality: ethical criteria for deep brain stimulation in psychiatric patients and for enhancement purposes. Biotechnol J 2008;3(12):1511-1520. 23. Beauchamp T, Childress J. Principles of biomedical ethics. 6th ed. New York: Oxford University Press; 2008. 24. Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005;45(5):651-660. 25. Greenberg BD, Malone DA, Friehs GM, et al. Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 2006;31(11):2384-2393. 26. Schlaepfer TE, Lieb K. Deep brain stimulation for treatment of refractory depression. Lancet 2005;366(9495):1420-1422. 27. Mesnage V, Houeto JL, Welter ML, et al. Parkinson’s disease: neurosurgery at an earlier stage? J Neurol Neurosurg Psychiatry 2002;73(6): 778-779. 28. Welter ML, Houeto JL, Tezenas du Montcel S, et al. Clinical predictive factors of subthalamic stimulation in Parkinson’s disease. Brain 2002;125(Pt 3):575-583. 29. Schupbach WM, Maltete D, Houeto JL, et al. Neurosurgery at an earlier stage of Parkinson disease: a randomized, controlled trial. Neurology 2007;68(4):267-271. 30. Isaias IU, Alterman RL, Tagliati M. Outcome predictors of pallidal stimulation in patients with primary dystonia: the role of disease duration. Brain 2008;131(Pt 7):1895-1902. 31. Synofzik M. [Effective, indicated - and yet without benefit? The goals of dementia drug treatment and the well-being of the patient.]. Z Gerontol Geriatr 2006;39(4):301-307. 32. Schupbach M, Gargiulo M, Welter ML, et al. Neurosurgery in Parkinson disease: a distressed mind in a repaired body? Neurology 2006; 66(12):1811-1816. 33. Agid Y, Schupbach M, Gargiulo M, Mallet L, et al. Neurosurgery in Parkinson’s disease: the doctor is happy, the patient less so? J Neural Transm Suppl 2006;(70):409-414. 34. Deuschl G, Schade-Brittinger C, Krack P, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006; 355(9):896-908. 35. Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006; 355(19):1978-1990. 36. Videnovic A, Metman LV. Deep brain stimulation for Parkinson’s disease: prevalence of adverse events and need for standardized reporting. Mov Disord 2008;23(3):343-349. 37. Voges J, Hilker R, Botzel K, et al. Thirty days complication rate following surgery performed for deep-brain-stimulation. Mov Disord 2007;22(10):1486-1489.

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ARTICLE IN PRESS Electrodes in the brain

OF

RO DP

65.

TE

64.

EC

63.

RR

62.

66. Ford PJ, Kubu CS. Stimulating debate: ethics in a multidisciplinary functional neurosurgery committee. J Med Ethics 2006;32(2):106-109. 67. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 2003;53(8):649-659. 68. Kennedy SH, Lam RW. Enhancing outcomes in the management of treatment resistant depression: a focus on atypical antipsychotics. Bipolar Disord 2003;5(Suppl 2):36-47. 69. Keller MB, Lavori PW, Mueller TI, et al. Time to recovery, chronicity, and levels of psychopathology in major depression: a 5-year prospective follow-up of 431 subjects. Arch Gen Psychiatry 1992;49(10):809-816. 70. Sackeim HA, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 2001;25(5):713-728. 71. Thase ME, Rush AJ. When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 1997; 58(Suppl. 13):23-29.

CO

61.

treated by subthalamic nucleus stimulation: improvement on switching the target. J Neurol Sci 2008;273(1-2):116-117. Okun MS, Mann G, Foote KD, et al. Deep brain stimulation in the internal capsule and nucleus accumbens region: responses observed during active and sham programming. J Neurol Neurosurg Psychiatry 2007;78(3):310-314. Okun MS, Bowers D, Springer U, et al. What’s in a ‘‘smile?’’ Intra-operative observations of contralateral smiles induced by deep brain stimulation. Neurocase 2004;10(4):271-279. Emanuel EJ, Emanuel LL. Four models of the physician-patient relationship. JAMA 1992;267(16):2221-2226. Nuttin B, Gybels J, Cosyns P, et al. Deep brain stimulation for psychiatric disorders. Neurosurgery 2002;51(2):519. Fins JJ, Rezai AR, Greenberg BD. Psychosurgery: avoiding an ethical redux while advancing a therapeutic future. Neurosurgery 2006;59(4): 713-716.

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