Potential Surgical Targets For Deep Brain Stimulation In Treatment-Resistant Depression

Jason S. Hauptman, MD; Antonio A. F. DeSalles, MD, PhD; Randall Espinoza, MD, MPH; Mark Sedrak, MD; Warren Ishida, MD


Neurosurg Focus. 2008;25(1):E3 

In This Article

Abstract and Introduction


Object: The goal of this study was to evaluate the definition of treatment-resistant depression (TRD), review the literature regarding deep brain stimulation (DBS) for TRD, and identify potential anatomical and functional targets for future widespread clinical application.
Methods: A comprehensive literature review was performed to determine the current status of DBS for TRD, with an emphasis on the scientific support for various implantation sites.
Results: The definition of TRD is presented, as is its management scheme. The rationale behind using DBS for depression is reviewed. Five potential targets have been identified in the literature: ventral striatum/nucleus accumbens, subgenual cingulate cortex (area 25), inferior thalamic peduncle, rostral cingulate cortex (area 24a), and lateral habenula. Deep brain stimulation electrodes thus far have been implanted and activated in only the first 3 of these structures in humans. These targets have proven to be safe and effective, albeit in a small number of cases.
Conclusions: Surgical intervention for TRD in the form of DBS is emerging as a viable treatment alternative to existing modalities. Although the studies reported thus far have small sample sizes, the results appear to be promising. Various surgical targets, such as the subgenual cingulate cortex, inferior thalamic peduncle, and nucleus accumbens, have been shown to be safe and to lead to beneficial effects with various stimulation parameters. Further studies with larger patient groups are required to adequately assess the safety and efficacy of these targets, as well as the optimal stimulation parameters and long-term effects.


Major depressive disorder is a significant health problem affecting ∼ 18 million people in the US alone, with a 17.1% lifetime risk of the disease.[28] The disorder is the most disabling condition for females; two-thirds of all depressed patients are female. Overall, it is the second most disabling condition in more technologically advanced countries and the fourth most disabling condition worldwide.[28,35] Furthermore, MDD is associated with increases in both medical and psychiatric morbidity and mortality rates (consider, for example, pain, myocardial infarction, or suicide).[4,17,22,56,73] For this reason, depression carries a significant cost to healthcare delivery and utilization. For patients, the disease can significantly affect quality of life and workplace productivity.

Major depressive disorder is primarily characterized by anhedonia or sadness of mood. It usually disrupts the patient's life at both home and work and is characterized by several concomitant psychological and neurovegetative symptoms such as suicidal ideation, impaired attention and concentration, sleep disturbances, changes in appetite and sexual desire, and psychomotor agitation, or retardation.[2] It is critical to note that MDD has the potential to be both chronic and recurrent. Approximately 25–40% of patients experience a recurrence after the index episode, and 60% experience a recurrence within 5 years. Thirty percent of patients with just 1 episode of depression experience chronic depression, defined as continuous depression for > 1 year.[27,46,65] Although more than half of all depressed patients respond to any 1 antidepressant, only two-thirds of this group experience complete remission. Among the remaining patients are those who experience only a partial response and continue to have residual symptoms, do not respond at all, or do not tolerate pharmacotherapy. Factors predictive of resistance to pharmacotherapy include a family history of depression, Axis I comorbidities (for example, substance abuse, anxiety disorders, or cognitive disorders), medical comorbidities, extremes in age at onset, the delay from diagnosis to treatment, chronicity of depressive episode, and Axis II comorbidities (personality disorders).[15,27,46,55,65]

Treatment-resistant depression is defined as “the lack of a clinical response after adequate pharmacotherapy has been attempted.”[15,55] The practical application of this definition has led to disagreement among psychiatrists, specifically with regard to definitions of adequate duration and magnitude of response and adequacy of treatments.[21,36] Furthermore, pseudoresistance—due to misdiagnosis of the primary disorder, inadequate dosing, early discontinuation of medication, poor medication adherence, or atypical pharmacokinetics—may result in apparent treatment failure.[51] One classification scheme, developed by Thase and Rush and utilized by clinicians, identifies criteria with which to judge resistance to therapy (Fig. 1).[52,62,65]

Figure 1.

Table showing the Thase and Rush classification scheme of TRD.

Therapy for TRD is centered around several principles: 1) ensuring proper diagnosis and treatment, 2) ensuring that any pharmacological trial is of adequate dosage and duration (and that the patient is adhering to the therapy), 3) maximizing medical therapy in cases of a partial response (increasing dosage and/or duration), and 4) optimizing the side effect/symptom profile for medical treatment to improve drug tolerance.[27,44,46,51] In addition to medication (including augmentation/adjunctive drugs), combination therapy including psychotherapy has been shown to be beneficial.[41] When these treatment modalities fail, somatic therapies can be used.[12,18]

Somatic therapy for depression includes several modalities: 1) ECT, 2) VNS, 3) TMS, 4) ablation of deep brain targets, and 5) DBS. Electroconvulsive therapy has a long history of use in TRD and has been shown to have a 50-60% rate of efficacy. Disadvantages to ECT include acute rapid relapse, greater acute efficacy compared with long-term relief, acute and chronic cognitive side effects (memory disturbance), and lack of appeal to patients.[18,50] Vagus nerve stimulation has no acute efficacy in the treatment of TRD but may have a role in the treatment of chronic depression.[9,54] Concerns regarding VNS include its high cost, lack of Medicare or commercial coverage, and inadequacy in treating acute depression. Transcranial magnetic stimulation, which has not been approved by the Food and Drug Administration for the treatment of depression, has demonstrated only modest results.[47] Stereotactic limbic leukotomy, anterior cingulotomy, anterior capsulotomy, and subcaudate tractotomy have been used in the treatment of intractable neuropsychiatric disease. A 2002 review of stereotactic limbic leukotomy revealed that the procedure has the potential of improving symptoms in 36-50% of patients with intractable affective and obsessive-compulsive disorders, although side effects such as apathy, urinary incontinence, and memory impairment were reported.[43] Stereotactic subcaudate tractotomy has also been successful, with a reduction in the suicide rate and improvement in global functioning among patients with uncontrollable affective disorders.[6,20,29] Approximately 38-61% of patients with TRD who undergo stereotactic anterior cingulotomy or anterior capsulotomy have shown clinical improvement.[11,29,63,64] The main disadvantage to ablative therapies is their irreversibility; however, DBS has the advantage of being both reversible and modulatory. Deep brain stimulation has shown promise in the treatment of TRD in some small series and case reports.[23,24,32,40,59,64,67,69] As an established treatment for pain and movement disorders, the procedure may be more acceptable to patients who are considering a somatic treatment modality. Early reports show good results in the acute phases of therapy, which is an advantage over VNS. In this paper, initial data regarding DBS for the treatment of TRD will be reviewed, with an emphasis on the different putative surgical targets.


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