Will deep-brain stimulation be as successful in major depression as it has been in Parkinson’s disease?

Keywords::

• deep-brain stimulation
• major depression
• mental disorders
• nucleus accumbens
• subcallosal cingulate gyrus

The introduction of deep-brain stimulation (DBS) by Benabid in the mid-1980s marked the beginning of a whole new era of therapy for movement disorders [1]. Owing to its high evidence-based efficacy, this procedure has, in the meantime, been applied to more than 50,000 patients with Parkinson’s disease worldwide. Despite many years of experience, the precise mode of action of DBS remains unclear. The DBS procedure involves the implantation of quadripolar electrodes that continuously emit short, high-frequency, low-voltage electrical pulses to the ambient neural tissue of subcortical brain regions after they have been connected to an implanted impulse generator. For a long time, the electrode tip was believed to induce a reversible functional lesion in the surrounding tissue, owing to effects of DBS in some diseases that are remarkably similar to lesioning. The simplified mechanism that was proposed to underlie this effect was a functional neuronal blockade. However, the currently favored explanation of DBS efficacy is a stimulation-induced modulation of impaired network activity [2].

The knowledge and success gained through the application of DBS in Parkinson’s disease has been leveraged for the treatment of non-motor disorders, including chronic pain states, epilepsy and even psychiatric diseases [3]. Considering the nonresponse rate of approximately 10% for prevalent psychopharmacological, psychotherapeutical strategies and electroconvulsive therapy, it is perhaps obvious that DBS should, in the case of therapy resistance, also be considered as a treatment for the most frequent psychiatric disease – monopolar depression. Although the exact pathophysiology underpinning major depression is still unknown, approved models of depressive disorders describe complex dysregulations in widely distributed forebrain and limbic networks [4]. These models form the rationale upon which the application of DBS for this disease pattern is based.

The first results of using DBS to treat severe treatment-refractory depressive disorders (TRDs) were acquired by Helen Mayberg and her colleagues in 2005 [5].

Mayberg’s rationale for choosing the subcallosal cingulate gyrus (SCG; Brodmann area 25) as the target structure for DBS in major depression was based on several human imaging studies, post-mortem explorations [6] and earlier approaches incorporating neurosurgical lesioning procedures [7]. The most convincing data concerning the selection of the SCG were the results of PET analysis, which were mainly gained from Mayberg’s own preliminary work [8]. Depression was, in particular, found to be associated with increased activity in the SCG, and effective interventions, including pharmacotherapy, transcranial magnetic stimulation and electroconvulsive therapy, were shown to ameliorate the clinical features of depression, in addition to reducing hyperactivity of the SCG.

Applying DBS to the SCG, Mayberg et al. achieved a remission of previously TRD symptomatology in four out of six treated patients. Patients showed an average reduction of 71% in their scores on the Hamilton Rating Scale for Depression (HAM-D) [5]. 3 years later, the same study group presented results based on a larger sample of 20 patients with TRD who also underwent DBS of the SCG [9]. 1 month after surgery, 35% of patients were characterized as responders (defined as a reduction in the HAM-D score of at least 50%) and 10% were in remission (HAM-D score <7). After 6 months of DBS, 60% of the patients were characterized as responders and 35% were in remission. Benefits were maintained 12 months after surgery, and adverse effects proved trivial and transient. In both studies, the antidepressant effects of DBS were associated with changes in the metabolic activity of cortical and limbic circuits implicated in the pathogenesis of depression. These effects can be seen as a verification of the underlying hypothesis.

Based on the model proposing that depression results from deficits in brain reward processing, the collaborative group of Schlaepfer and Sturm adopted a different therapeutic approach [10]. As the key structure of the reward system, these researchers selected the nucleus accumbens (NAC) as the target for DBS in severely depressive patients. After commencing stimulation, the first three patients spontaneously showed positive effects. Within a week, HAM-D scores decreased by an average of 42%. Upon discontinuing stimulation under double-blind conditions, two of the three patients deteriorated to such an extent that the ‘off-condition’ had to be terminated. The correlation between stimulation and depression (HAM-D score) proved significant (r = –0.54; p < 0.01), demonstrating the efficacy of stimulation in the NAC. PET further illustrated that DBS of the NAC modulates activity in fronto–striatal networks [10]. This group recently published more extensive data on their first ten patients treated in this way, but without sham control. Five of the ten patients showed a significant reduction in HAM-D scores of 50%, and five patients were nonresponders. An anti-anxiety effect was observed (measured using the Hamilton Anxiety Scale) in the entire group over the 1-year observation period [11]. Remarkably, PET data also revealed that DBS of the NAC led to decreased metabolism in the SCG, indicating a shared therapeutic mechanism in the DBS approaches of Schlaepfer and Mayberg.

The group led by Malone and Dougherty reported the results of an open and prospectively designed trial in which DBS was applied to the region of the ventral internal capsule and the ventral striatum in 15 TRD patients [12]. This selected region shows overlap with that targeted by the collaboration group of Schlaepfer and Sturm; the NAC is a central part of the ventral striatum, and stimulation that primarily aims at the NAC can, depending on the path of access and adjustment of stimulation parameters, also include the frontal limb of the internal capsule. As a justification for the selected target point, Malone et al. refer to the first successful DBS treatments of patients with obsessive compulsive disorder that targeted this very region [13]. Both disorders are considered to be based on overlapping dysregulations of neural systems, and the application of DBS was found to improve not only obsessive compulsive disorder symptoms, but also depressive symptoms, an effect that the present authors have also observed in their own studies [14]. Along with lesioning studies targeting the same cortico–basal circuitry, these observations in obsessive compulsive disorder caused Malone et al. to explore the ventral internal capsule and the ventral striatum as a DBS target in the treatment of major depression. Over the first 6 months of observation, the group of 15 patients with TRD showed a 42% reduction in HAM-D scores. The final assessment (6 months to 4 years) revealed that almost 50% of all patients had responded and 40% were in remission [13]. The study by Malone et al. was the first multicenter trial of this particular DBS application field, and should, therefore, be noted as having demonstrated a supraregional generalizability of the observed effects.

In addition to the three above-mentioned studies, some case reports have also demonstrated a significant abatement of depressive pathology in TRD patients using DBS. These cases were based on stimulation of the inferior thalamic peduncle and the lateral habenula as target structures [15,16].

The efficacy of DBS of the lateral habenula is likely to be the subject of increasing exploration owing to the existence of a solid hypothesis that is also based on data from animal experiments [17].

As a potentially new therapeutic option that may prove particularly beneficial for serious, chronic and therapy-resistant depressive disorders, the DBS approach clearly represents a very young field of research and is still under development. Nonetheless, initial results appear very promising, indicating that DBS may constitute an effective treatment option for depressive patients that are otherwise treatment-resistant. Its pioneering stage explains why this field of research, which is highly relevant with regard to both basic sciences and clinical issues, proves so interesting and attractive and generates such a high response among the interested public. Hardly any other development within current medicine has so frequently and so constantly been accompanied by sensation-stirring messages, not only in the medical press, but also in the general media. However, this can also give rise to expectations that can not be fulfilled. The importance of gaining more insight into the effects of DBS on major depression based on multicenter trials with high ethical requirements and excellent methodological designs thus becomes apparent [18]. It is only then that the question formulated in the title of this article may plausibly be addressed; a question that can scarcely be answered based on the published data of 50 patients worldwide.

Acknowledgements

The authors thank Joachim Klosterkötter, Head of the Department of Psychiatry and Psychotherapy and Dean of the Medical Faculty of the University of Cologne, and Dipl.-Psych. Theo OJ Gründler from the Max Planck Research Group ‘Cognitive Neurology’ at the Max Planck Institute for Neurological Research in Cologne for their valuable support in compiling this article.

In order to assure a stylistic faultless English the manuscript was edited by native speakers.

Financial & competing interests disclosure

Jens Kuhn received financial assistance from AstraZeneca for traveling to congresses and received honoraria from Lundbeck for lecturing at conferences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.