Brain Topogr DOI 10.1007/s10548-013-0315-9
ORIGINAL PAPER
Neuromodulation for Treatment Resistant Depression: State of the Art and Recommendations for Clinical and Scientific Conduct Thomas E. Schlaepfer • Bettina H. Bewernick
Received: 25 February 2013 / Accepted: 29 August 2013 Ó Springer Science+Business Media New York 2013
Abstract Research of Deep Brain Stimulation as a putative treatment for resistant psychiatric disorders might very well lead to the most significant development in clinical psychiatry of the last 40 years—possibly offering a rise of hope for patients to whom medicine had hitherto little to offer. Furthermore, translational research on neuromodulation will allow us to glean something about the underlying cause of patient’s illnesses before figuring out a treatment that addresses the source of the problem. Major depression offers perhaps the best example of the rapid progress being made in understanding the biology of mental illness. Studies on the underlying neurobiology of major depression have typically focused on the description of biological differences between patients and healthy subjects such as alterations of monoaminergic or endocrine systems. Psychotropic drugs work by altering neurochemistry to a large extent in widespread regions of the brain, many of which may be unrelated to depression. We believe that more focused, targeted treatment approaches that modulate specific networks in the brain will prove a more effective approach to help treatment-resistant patients. In other words, whereas existing depression treatments approach this disease as a general brain dysfunction, a
This is one of several papers published together in Brain Topography on the ‘‘Special Topic: Clinical and Ethical Implications of Neuromodulation Techniques’’. T. E. Schlaepfer (&) B. H. Bewernick Department of Psychiatry and Psychotherapy, University Hospital, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany e-mail:
[email protected] T. E. Schlaepfer Departments of Psychiatry and Mental Health, The Johns Hopkins University, Baltimore, MD, USA
more complete and appropriate treatment will arise from thinking of depression as a dysfunction of specific brain networks that mediate mood and reward signals (Berton and Nestler, Nat Rev Neurosci 7 (2):137–151, 2006; Krishnan and Nestler, Nature 455(7215):894–902, 2008). A better understanding of defined dysfunctions in these networks will invariably lead to a better understanding of patients afflicted with depression and perhaps contribute to a de-stigmatization of psychiatric patients and the medical specialty treating them. Keywords Major depression Deep brain stimulation Neuromodulation Nucleus accumbens Medial forebrain bundle Subgenual cingulate gyrus Anterior limb of internal capsule
Introduction References to disease states, which we might today classify as major depression, can be found in ancient texts like the Old Testament, Egyptian papyri and the Indian Ramayana (Davison 2006). Hippocrates (460–377 BC) was probably first in stating that Melancholia might be related to a dysfunction of the brain (Davison 2006), but did not offer a biological treatment (Millon 2004). In the 17th century, electric shocks were applied for epilepsy and ‘‘hysteria’’ without scientific hypotheses (Millon 2004) and electroconvulsive therapy was introduced in 1937 by Cerletti and Bini who treated psychotic subjects (Shorter and Healy 2007). Not until after 1950, technical development made it possible to chronically stimulate human brains through implanted electrodes (Hariz et al. 2010). Robert Heath described the concept of electrical selfstimulation, patients stimulated at the ‘‘septal area’’ (close
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to the nucleus accumbens) described this stimulation as ‘‘pleasant’’ or ‘‘euphoric’’ (Heath 1972); the manipulation of emotions was suggested by Robert Heath in the late 70s who posited this treatment for intractable psychiatric illnesses (Hariz et al. 2010). The misguided dream of unlimited control of brain processes using electric currents was expressed in 1965 (Delgado 1965), this author believed that autonomic and somatic functions, behavior, emotional and mental reactions could be manipulated by electrical stimulation of specific brain areas. This enthusiasm is still shared by some of today0 s researchers who believe that the possibility to manipulate human brain function ‘‘might well shape history as powerfully as the development of metallurgy in the Iron Age, mechanization in the Industrial Revolution or genetics in the second half of the twentieth century.’’ (Farah et al. 2004). In spite of these dreams and many available treatment options (pharmacotherapy, psychotherapy, electroconvulsive therapy) and new interventions in research (e.g. vagus nerve stimulation, magnetic seizure therapy), a third of patients suffering from depression can be classified as treatment-resistant (Rush et al. 2006) with little hope of recovery, highly stigmatized and poor quality of life. For these patients, deep brain stimulation is currently under research. Already in the 70s, Latinen pointed out some ethical problems of early brain stimulation research and the experimental nature of the treatment (Hariz et al. 2010). Today, possible benefits and dangers of brain stimulation in psychiatry and how society should control its use (e.g. neuroenhancement) are in a desperately warranted debate. This review aims to cover the state of the art of deep brain stimulation in depression; practical aspects of research,
Fig. 1 Figure showing approximate location of the currently used Deep Brain Stimulation targets for treatment refractory major depression
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scientific standards as well as ethical issues are discussed Fig. 1.
Targets and Efficacy Data Subgenual Cingulate White Matter (Brodman area Cg25) In a model posited by Mayberg (1997), the rostral cingulate cortex plays a dominant role in regulating a corticolimbic network. It has been demonstrated that depression is associated with increased activity in the subgenual cingulate cortex (covering Cg25, cg24, BA10) and remission was associated with a reduction of hypermetabolism in this region (Fily et al. 2011). Dysfunctional connections from the cingulate cortex to the dorsal (including the dorsolateral prefrontal cortex, inferior parietal cortex and striatum) and ventral parts (hypothalamic–pituitary–adrenal axis, insula, subgenual cingulate and brainstem) of the emotion regulation circuit in depression are involved in depression. It was hypothesized that DBS to the cingulate cortex would lead to antidepressant effects by modulating the depression network through a reduction of Cg25 activity (Mayberg 1997). Anterior Limb of the Capsula Interna (ALIC) The cortico-striato-thalamo-cortical network is associated with Parkinson’s disease and has a role in obsessive– compulsive disorder (OCD)(Bourne et al. 2012). Observations from historical lesion studies (e.g., anterior capsulotomy) and antidepressant effects that were seen in
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OCD patients who were stimulated in the anterior limb of the interior capsule/the ventral striatum (Greenberg et al. 2008), lead to a study in which this structure was stimulated in treatment-resistant depression (Malone et al. 2009). Targets Belonging to the Reward System (Nucleus Accumbens and Medial Forebrain Bundle)
recently shown that activation and modulation of afferent fiber tracts are a plausible mechanism of action in DBS (Gradinaru et al. 2009). Thus, excitatory modulation and not inactivation of the MFB would be postulated as the antidepressant mechanism of action (Coenen 2010; Schlaepfer et al. 2012b).
Nucleus Accumbens (NAcc)
Efficacy and Safety
The nucleus accumbens (NAcc) is another structure that has been identified as a key center of the depression network (Berton and Nestler 2006). Specifically, the NAcc is thought to act as the motivation gateway between systems involved in emotion and motor control (Schlaepfer et al. 2008). Anhedonia, a symptom which has been correlated with NAcc dysfunction (Tremblay et al. 2005) is a core symptoms in depression (Rush and Weissenburger 1994; Argyropoulos and Nutt 1997). Converging evidence from animal, pharmacological and neuroimaging studies point toward NAcc dysfunction in depression and DBS of the NAcc leads to increases of all monoaminergic neurotransmitters in the prefrontal cortex (van Dijk et al. 2012); this led to the hypothesis that DBS to the NAcc would lead to antidepressant effects by modulating the depression network (Schlaepfer et al. 2008).
For all three main targets (Cg25, ALIC, NAcc), acute and long-term antidepressant effects have been published (Bewernick et al. 2012, 2010; Holtzheimer et al. 2012; Kennedy et al. 2011; Lozano et al. 2008; Malone et al. 2009; Puigdemont et al. 2011). In two studies, patients have been followed for up to 6 years (Bewernick et al. 2012; Kennedy et al. 2011). Sample sizes of these studies are small (\30) and sham control is not included in all studies. Thus efficacy data are still on a pilot level.
Supero-Lateral Branch of the Medial Forebrain Bundle (slMFB) The supero-lateral branch of the medial forebrain bundle (slMFB) has also been proposed as a target (Coenen et al. 2010). Early lesional interventions have been found to exert their effect by influencing two major pathways (SchoeneBake et al. 2010). These two affect-regulating fiber systems, the slMFB and the anterior thalamic radiation (ATR) are concerned with maintenance of emotional homeostasis. The slMFB is linked to reward seeking and appetitive motivation in general, whereas the ATR is probably more involved in negative feelings (e.g. sadness, separation-distress, psychic pain) (Coenen et al. 2012). Compared to neurological indications, higher stimulation intensities have been used in DBS for depression, the generated large electric fields thus stimulate structures beyond the intended target sites and in all cases the slMFB. Electric field simulation and probabilistic fiber tracking has demonstrated that the slMFB is anatomically and functionally connected with other DBS targets (Cg25, ALIC and NAcc) (Coenen 2010). This lead to the hypothesis that most likely these targets are clinically effective because of a stimulation in a network that to a larger proportion is realized through the MFB. A study using optogenetic neuromodulation together with DBS has
Acute Clinical Effects Immediate clinical effects after onset of stimulation include more spontaneous engagement in conversation, positive change in mood, increased alertness, relaxation, increased motivation, higher activity level and a sense of calmness (Bewernick et al. 2010; Holtzheimer et al. 2012; Mayberg et al. 2005). Acute side effects include tension, dizziness, and anxiety. Only some patients experienced acute effects, which do not seem predictive for long-term effects (Bewernick et al. 2010; Puigdemont 2011). Possibly, an initial acute stimulation effect during surgery diminishes after re-initiation of stimulation (Holtzheimer et al. 2012). In a recent pilot study of slMFB-DBS all seven patients showed strikingly similar intraoperative acute effects of increased appetitive motivation. Six of seven patients attained the response criterion; response was rapid, and mean MADRS of the whole sample was reduced by more than 50 % at day seven after onset of stimulation (Bewernick, et al. 2012; Coenen et al. 2013). Longer-Term Clinical Effects After one to 6 months of chronic DBS, antidepressant response has been demonstrated in six small studies at three different targets (Bewernick et al. 2010; Kennedy et al. 2011; Malone et al. 2009; Puigdemont 2011; Lozano et al. 2008, 2012). Amelioration of other clinical measures (e.g. Quality of Life, anxiety, general psychopathological burden) has been associated with antidepressant effects for all three major targets (Cg25, ALIC, NAcc). When
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comparing outcomes of DBS studies, different ways of analyzing results have an impact on efficacy because most dropouts are non-responders. Thus, intent-to-treat analysis (of all patients including dropouts up to the final endpoint, mostly in a carried forward manner) seems to be a more adequate, conservative method to reflect efficacy. Nonetheless, most authors report data analyzed as ‘‘per protocol/ as treated’’. In this way, dropouts and non-responders are not reflected in the data after their dropout, this leads to an artificially inflated efficacy. In addition, it is questionable whether a newly introduced time point ‘‘last observation’’ is of scientific value, as it mostly reflects scores of patients that are treated for a short time and others treated long-term (up to many years). Response rate was similar for all targets (Bewernick et al. 2010; Lozano et al. 2008; Malone et al. 2009; Puigdemont 2011). Twenty patients stimulated at Cg25 had a response rate of 55 % after 1 year, 45 % after 2 years, 60 % after 3 years and 55 % response at the last follow-up visit (up to 6 years) in an intent-to-treat analysis (Kennedy et al. 2011). Similarly, a study with eight patients stimulating Cg24/25, reported response rates of 87 % after 6 months and 62,5 % after 12 months (n = 8) (Puigdemont 2011). In a mixed sample with ten MDD patients and seven patients suffering from bipolar disorder (Holtzheimer et al. 2012) response rates for the patients still followed in the study (n = 12 after 2 years) were 36 % after 1 year (n = 14), and 92 % after 2 years (n = 12) in a per protocol analysis. In a multicenter open-label trial targeting subgenual cingulate (n = 21), 48 % of patients responded after 6 months, and 29 % after 12 months (Lozano et al. 2012). Seventeen patients were studied targeting the anterior limb of the internal capsule (ALIC). Response rates were 53 % after 12 months (n = 17) and 71 % at last follow-up (ranging from 14–67 months) (Malone et al. 2009). Eleven patients were stimulated at the NAcc, 50 % responded significantly during the first 6 months and remained stable during follow-up (up to 4 years), in an intent-to-treat analysis (Bewernick et al. 2012). Young, female patients with previous response to ECT and phases in remission after first onset of depression appear to show a more probable benefit from DBS (Bewernick et al. 2010; Puigdemont 2011) although small sample size limit the possibility to identify predictors of response. In addition, NAcc-DBS specifically influenced the symptoms of anhedonia and anxiety (Bewernick et al. 2010). Only recently, a hypothesis concerning exact electrode position has been assessed. In one study targeting Cg25/24, electrode position had an influence on antidepressant outcome (Puigdemont 2011); among responders most patients had electrodes placed in Cg24. Another study did not find a relationship between electrode location and clinical effect (Lozano et al. 2008).
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Side Effects Side effects are related to surgical procedure (e.g. intracranial bleeding, infection of DBS device), malfunctioning of DBS device (e.g. lead dislocation, disruption of contacts) or to stimulation (e.g. erythema, increase in anxiety, agitation, elevation of mood). Problems related to surgery occurred rarely and side effects due to stimulation were transient or could be counteracted by a change in stimulation settings. Nonetheless, careful assessment of patients is needed after parameters have been changed. Suicidal ideation occurred for all three targets, and suicide was reported to be attempted or committed (Bewernick et al. 2010; Holtzheimer et al. 2012; Kennedy et al. 2011; Lozano et al. 2012).
Discussion After a decade of deep brain stimulation against depression, we are still away from realizing the dream of control over dysfunctional emotions. However, first studies have found encouraging antidepressant effects. Adverse Events Hemorrhage and Infection Wound infection after surgery or battery exchange, lead migration and device-related infections are important complications in DBS studies. Lead migration (2.5 % of patients), erosion and infection (4.5–8.9 % of patients) have been reported (Doshi 2011; Fily et al. 2011). So far, there is only one report of hemorrhage in DBS studies for depression (Bewernick, et al. 2012), but statistically, DBS surgery has a substantial of 0.9 % to cause hemorrhage (Zrinzo et al. 2012). This should be considered in risk– benefit analysis, especially if conventional treatment methods have not sufficiently been tried. Suicide Up to 15 % of patients suffering from treatment-resistant depression commit suicide (Wulsin et al. 1999; Isometsa et al. 1994). This risk is 4–5 times higher in severe depression compared to moderate or mild depression (Holtzheimer et al. 2012). The aggravation of symptoms due to battery depletion, unattended stimulation stop or during the blinding phase has been described (Bewernick et al. 2012; Holtzheimer et al. 2012; Lozano et al. 2008). In spite of regular careful visits, suicides and suicide attempts have been reported
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(Bewernick et al. 2010; Holtzheimer et al. 2012; Kennedy et al. 2011; Lozano et al. 2012). Thus, careful patient tracking is needed during follow-up, especially before optimal stimulation parameters have been established and during sham stimulation.
has to be discussed with the patient. There is no evidence on cognitive enhancement beyond normal function in DBS-TRD studies.
Ethical Issues and Scientific Standards
Research on DBS allows—in addition to possibly explore new treatment avenues—a unique possibility to explore brain circuits in humans; i.e., we were able to obtain basic neurophysiological data on human reward and memory processing (Cohen et al. 2009, 2009, 2009; Axmacher et al. 2010). In order to maximize scientific outcome, all indices including neuroimaging, electrophysiology, standardized cognitive functioning, data on quality of life, personality changes, life events should be monitored and all results published in addition to specific depression ratings. All study protocols should include at least a follow-up phase of 5 years in order to evaluate sustained efficacy and a pre-implantation baseline of 3 months to control for symptom fluctuation. Obtaining sham-controlled outcomes is germane; due to severe symptom worsening reported in sham controlled studies, it may be advisable to start with a stimulation period (staggered onset design (Goodman et al. 2010)) and a rescue criterion must be defined a priori.
Several ethical aspects have been raised regarding the application of DBS in psychiatric disorders differing from the application in neurological indications. Highest scientific standards have to be applied to minimize risks and maximize outcome for the patients in this young developing field of research. Patient Selection Careful patient selection is a crucial issue in DBS studies. Currently, only very treatment resistant patients, that have failed on conventional treatment options, should be selected for DBS (Schlaepfer et al. 2012a). Patients with psychiatric comorbidities should not be included at the current stage of research to minimize confounds. A careful, individualized risk–benefit analysis has to be performed. Patient0 s expectations have to be clarified along with a therapeutic goal. The patient has to be aware that magnetic resonance tomography may not be an option once implanted. Along with surgical risks (bleeding, wound infection etc.) possible influences on quality of life, social life, partnership and cognitive effects have to be discussed thoroughly. Therapeutic Effect Experience with neurological patients treated with DBS has shown that patient0 s motivation to obtain DBS can differ substantially from the clinician0 s agenda. Patients have a more global view on their life and thus values for example autonomy, the ability to drive a car, a reduction of medication doses, changes in partnership, the ability to partake in social life (e.g. meeting friends, hobbies) at least as much as changes in symptoms. Therefore, changes in currently used, symptom-oriented clinical scales reflect only a part of the patient0 s focus. Today, questionnaires reflecting patient0 s point of view are missing. Possibly, as patient0 s expectations are very individual, semi-structured interviews and qualitative ways of data analysis should be preferred. A critical aspect considering the assessment of therapeutic effect would be in the case of disagreement between the clinician0 s point of view and the patient0 s judgment. Who shall at the end decide whether DBS should be stopped? A clear criterion for ending the DBS treatment
Scientific Outcome and Study Design
Disciplined Data Reporting The well-known problem of publication bias with over reporting of positive results and underreporting of negative results is evident in DBS research: several single-case studies have been published only because of interesting secondary effects, whereas the primary outcome effects were not achieved (Schlaepfer and Fins 2010). Careful and comprehensive reporting—in particular in media targeted to a lay audience—is clearly warranted in order to safeguard DBS as a very promising development in psychiatry (Hariz and Hariz 2012). Patient Tracking Special care must be taken in phases of stimulation discontinuation and in case of battery depletion because symptom aggravation and suicidal ideation has been reported. To minimize risk of suicide, patients must be cared for by local outpatient programs (psychiatrist, psychosocial support). In order to help the patient to adapt to psychosocial changes or non-effect, psychotherapy should be mandatory. Involvement of Device Manufacturers Currently, two manufacturer sponsored pivotal randomized controlled trials for DBS in TRD are under way. Thus,
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industry has a major impact on which study center can take part of the study and how and what results will be communicated (Fins et al. 2011). To guarantee independent research, there is a need to create structures to finance randomized controlled trials independent from industry; funding agencies should create initiatives and consortia to financially support DBS studies to prevent premature commercialization or abandonment.
Challenges and Outlook After a decade of DBS for therapy resistant depression, all studies have shown substantial antidepressant effects. Nonetheless, substantial risks (e.g., hemorrhage, suicide) and high costs are associated with DBS. Experience from first preliminary studies has let to the proposal of new targets (e.g., sl-MFB) in a hypothesis-guided way awaiting scientific evaluation. Ongoing multi-center studies will hopefully allow to assess and quantify side effects (e.g., personality changes, cognitive changes, psychiatric and somatic effects, quality of life), answer the question of sham effects, find predictors of response and elucidate the modes of action of DBS. To really convince the field, double-blind assessments of therapeutic effects have to be conducted; despite the fact that blinding in the sham condition is not easy to maintain since patients often do not tolerate off phases leading to massive worsening of symptoms with increased risk for suicidal ideation (Schlaepfer et al. 2008). This problem could be circumvented with staggered-onset design protocols (Goodman et al. 2010), with a clear-cut rescue criterion for sham stimulation phases and weekly visits. Only experience with larger samples tracked over a long time will decide if DBS should be applied at an earlier stage of the disease [as in the early stim study for Parkinson’s disease (Schuepbach et al. 2013)]. To guarantee highest ethical standards, all further studies as well as single case studies should have an ethical approval, a substantial neurophysiological hypothesis, careful patient selection, a placebo controlled (blinded sham stimulation) design, secondary outcome measures (e.g., personality, cognition, quality of life), and careful side effect documentation (e.g., suicide, somatic effects). To optimize scientific outcome, add-on research (neuroimaging, neurophysiological methods) should be included in the study design. The occurrence of suicides demonstrates how important careful patient tracking throughout the study is, especially during sham phases and before optimal stimulation parameters are found. Regarding the application of DBS for other psychiatric indications (beside depression and OCD), risk–benefit as well as economic analyses have to be evaluated (Stephen et al. 2012).
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A compulsory registry prior to the study conduction will help transparency for researchers, patients and media. Governmental funding can influence to which degree future research will be determined by industry.
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