Background: Deep brain stimulation (DBS) has emerged in recent years as a novel therapy in the treatment of refractory psychiatric disease, including major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). Standardized outcome scales were crucial in establishing that DBS was an effective therapy for movement disorders. Objective: In order to better characterize the evidence supporting DBS for various psychiatric diseases, we performed a pooled analysis of those studies which incorporated specific standardized rating scales. Methods: A Medline search was conducted to identify all studies reporting DBS for MDD, OCD, and TS. The search yielded a total of 49 articles, of which 24 were included: 4 related to MDD (n = 48), 10 to OCD (n = 64), and 10 to TS (n = 46). Results: A meta-analysis of DBS for MDD, OCD, and TS in studies employing disease-specific standardized outcome scales showed that the outcome scales all improved in a statistically significant fashion for these psychiatric diseases. Our pooled analysis suggests that DBS for TS has the highest efficacy amongst the psychiatric diseases currently being treated with DBS, followed by OCD and MDD. Conclusion: DBS for psychiatric diseases remains investigational; however, even when studies failing to incorporate standardized outcome scales are excluded, there is statistically significant evidence that DBS can improve symptoms in MDD, OCD, and TS. Standardized disease-specific outcome scales facilitate pooled analysis and should be a required metric in future studies of DBS for psychiatric disease.

Deep brain stimulation (DBS) is emerging as a novel therapy for psychiatric conditions such as major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). A number of pilot studies in recent years [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24] have begun to show the efficacy of DBS as a therapeutic modality in the treatment of medically refractory patients with these psychiatric disorders. DBS has evolved from a history of ablative brain surgeries for psychiatric disease; however, it is more favorable than brain lesioning due to its adjustability and reversibility. The assessment of treatment efficacy in psychiatric disorders has been greatly aided by the development of disease-specific outcome scales. Despite the steady stream of DBS clinical studies for refractory MDD, OCD, and TS, the standardized outcome studies have not consistently been applied, which raises the question of whether DBS is truly efficacious. In order to statistically quantify the current efficacy for DBS in psychiatric disorders using the best evidence available, we reviewed the DBS psychosurgery literature and subjected it to a pooled analysis through a sieve focused on standardized outcome studies.

A Medline search was conducted to identify all studies reporting DBS for MDD, OCD, and TS. Studies were included if they included a standardized outcome scale [the Hamilton Depression Rating Scale (HDRS) for MDD, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) for OCD, and the Yale Global Tic Severity Scale (YGTSS) for TS] and also had reported preoperative and postoperative scores for each individual patient using the disease-specific standardized rating scale. While some studies used a combination of rating scales to report patient outcome following DBS intervention, we chose to focus on the scales that were prevalent and uniformly present in the literature being analyzed. We also excluded studies that had preoperative and postoperative scores but did not have the most prevalent scale of interest for a particular disease. In the studies found, HDRS was used predominantly for reports involving MDD (although in several versions, HDRS-17, 24, and 28), and Y-BOCS and YGTSS were the most widely validated outcome scales for OCD and TS, respectively. Furthermore, we chose to look at the absolute difference in score reduction on these standardized scales due to inconsistency in follow-up endpoints for the included studies.

Due to the investigational nature of studies involving DBS in the treatment of psychiatric disorders, we did not exclude studies from our analysis even if they comprised single case reports as long as they met the aforementioned criteria. Studies were excluded from our analysis if they failed to include one of the selected standardized outcome scales for each respective disease, used DBS to treat two comorbid conditions (i.e. Parkinson's disease and OCD), were review articles, had overlapping patient populations, or used DBS following a radiosurgical ablation procedure (anterior capsulotomy, limbic leucotomy, subcaudate tractotomy, etc.). The search yielded a total of 49 articles; 10 articles related to MDD, 22 to OCD, and 17 to TS. Of the articles retrieved, there were a total of 24 included in the analysis, 4 relating to MDD (n = 48) [1, 2, 3, 4], 10 to OCD (n = 64) [5, 6, 7, 8, 9, 10, 11, 12, 13, 14], and 10 to TS (n = 46) [15, 16, 17, 18, 19, 20, 21, 22, 23, 24].

Following identification, each disorder was looked at separately and subjected to a pooled analysis, with studies with ≤5 patients lumped together to allow for proper pooling of data. Specifically, since we chose to use the most widely prevalent scale in the studies being examined, the plots resulting from the pooled analysis are representative of a single scale (i.e. the plot for MDD shows the effects of DBS on MDD in the context of the HDRS, which was consistently present across the included studies). If studies had multiple endpoints (i.e. 3 months, 6 months, etc.), we chose to use the longest follow-up available to include in the pooled analysis, as the length of each study was not uniform.

A total of 24 papers met the criteria necessary for inclusion and were included in our pooled analysis: 4 for MDD, 10 for OCD, and 10 for TS. The studies included are shown in tables 1, 2, 3. The articles by Mayberg et al. [25] and Hamani et al. [26] were excluded solely because of an overlap in patient population with Lozano et al. [1]. Tables 4 and 5, for MDD and OCD, respectively, show the number of patients achieving response and remission by criteria specific to each included study. A similar table for TS was not created because the definition of what constituted response and remission was unclear across the studies included in our analysis.

Table 1

Characteristics of studies for MDD

Characteristics of studies for MDD
Characteristics of studies for MDD

Table 2

Characteristics of studies for OCD

Characteristics of studies for OCD
Characteristics of studies for OCD

Table 3

Characteristics of studies for TS

Characteristics of studies for TS
Characteristics of studies for TS

Table 4

Responses to DBS in MDD

Responses to DBS in MDD
Responses to DBS in MDD

Table 5

Responses to DBS in OCD

Responses to DBS in OCD
Responses to DBS in OCD

Figures 1, 2, 3 show the results of the pooled analysis for each particular disorder, plotted as the standardized mean difference, which is the absolute difference in score change with treatment divided by the standard deviation. The plots also show that a response (i.e. reduction of the standardized rating scale) is positive even though scores actually decrease (thereby producing clinical improvement). Studies with >5 patients were listed separately, while studies with <5 patients were lumped together in order to facilitate the pooled analysis. The lines represent confidence intervals (CIs) for each of the studies. While it is evident that some individual studies crossed zero (statistically insignificant effect of DBS) for each of the disorders, the pooled analysis yielded a clinically detectable difference of DBS on disease severity for each of the disorders individually. A test for heterogeneity was run for each disorder, and was found to be statistically insignificant in the case of MDD (p = 0.34) and TS (p = 0.22), and significant in the case of OCD (p < 0.0001). The test for heterogeneity was necessary in order to preserve statistical rigor for the pooled analysis for each particular disease. In the case of OCD, the statistically significant p value indicates that studies included may have had differences in study design which need to be accounted for when performing a pooled analysis and this is accomplished through the use of the random effects model, which widens the CI as is evident on the forest plot for OCD (fig. 2).

Fig. 1

DBS in MDD. This plot shows the effect of DBS on refractory MDD. As is evident, all studies tended to cluster within the same region, and the test for heterogeneity was insignificant (p = 0.34), allowing for the fixed effects model to be used. The average improvement in score reduction was 2.47 standard deviations (95% CI 1.899-3.037).

Fig. 1

DBS in MDD. This plot shows the effect of DBS on refractory MDD. As is evident, all studies tended to cluster within the same region, and the test for heterogeneity was insignificant (p = 0.34), allowing for the fixed effects model to be used. The average improvement in score reduction was 2.47 standard deviations (95% CI 1.899-3.037).

Close modal
Fig. 2

DBS in OCD. This plot shows the effect of DBS on refractory OCD. Unlike DBS for MDD and TS, the test for heterogeneity was significant (p < 0.0001), necessitating the use of the random effects model. While intrinsically widening the CI, the improvement in score reduction remained statistically significant. The average improvement in score reduction was 2.77 standard deviations (95% CI 0.641-4.896).

Fig. 2

DBS in OCD. This plot shows the effect of DBS on refractory OCD. Unlike DBS for MDD and TS, the test for heterogeneity was significant (p < 0.0001), necessitating the use of the random effects model. While intrinsically widening the CI, the improvement in score reduction remained statistically significant. The average improvement in score reduction was 2.77 standard deviations (95% CI 0.641-4.896).

Close modal
Fig. 3

DBS in TS. This plot shows the effect of DBS on refractory TS. Like MDD, the studies tended to cluster in the same region, and the test for heterogeneity was insignificant (p = 0.22), allowing the fixed effects model to be used. The average improvement in score reduction was 2.796 standard deviations (95% CI 2.038-3.554), demonstrating the highest efficacy among the three disorders.

Fig. 3

DBS in TS. This plot shows the effect of DBS on refractory TS. Like MDD, the studies tended to cluster in the same region, and the test for heterogeneity was insignificant (p = 0.22), allowing the fixed effects model to be used. The average improvement in score reduction was 2.796 standard deviations (95% CI 2.038-3.554), demonstrating the highest efficacy among the three disorders.

Close modal

As is evident from the plots for MDD (fig. 1) and TS (fig. 3), the studies tended to cluster within the same region on the graph, indicating similar improvements across outcome scales. Specifically, because the test for heterogeneity of the MDD/TS studies was statistically insignificant, the fixed effects model could be used for interpretation of the pooled analysis. Our pooled analysis of DBS in these two disorders showed a positive effect of DBS in patients with medically refractory disease; for MDD, the average improvement in score reduction was 2.468 standard deviations (95% CI 1.899-3.037). For TS, the average improvement in patients that underwent DBS surgery was 2.796 standard deviations (95% CI 2.038-3.554), displaying the highest efficacy in score improvement across the three disorders. For OCD, the test for heterogeneity was statistically significant, necessitating the use of the random effects model which, as mentioned previously, intrinsically widens the CI. However, in spite of this, the 95% CI remained above zero, maintaining statistical significance. In the case of OCD, the average improvement in score reduction was 2.769 standard deviations (95% CI 0.641-4.896).

The pooled analysis plots show that all studies had clinically detectable and statistically significant reduction in disease-specific outcome scale scores when DBS was used in MDD, OCD, and TS. Although most of the DBS psychosurgery literature has focused on OCD, only 45% of published DBS-OCD studies were found to utilize the Y-BOCS rating scale. From the standpoint of the disease-specific standardized outcome scales used for inclusion in this study, the meta-analysis suggests that DBS for TS has the highest efficacy amongst the psychiatric diseases currently being treated with DBS. Despite the fact that MDD is the most prevalent of the psychiatric diseases currently targeted by DBS, only 20% of published DBS psychosurgery papers address this disease.

The goal of our pooled analysis was to elucidate whether a statistically significant therapeutic response was present for DBS in MDD, OCD, and TS when studies lacking the most common disease-specific standardized outcome scales were excluded. Furthermore, while data from the individual studies have been promising, there is no class I data supporting DBS as a treatment modality. Therefore, a secondary goal of our pooled analysis was to discern whether further studies are warranted involving larger patient populations. Review papers analyzing the DBS psychosurgery literature thus far have been hindered by the lack of statistical support that shows that DBS is an efficacious therapy for treatment-refractory patients and instead rely on superficial comparisons between studies. Our analysis, which focused on a single widely validated outcome scale, enabled the data to be subjected to a pooled analysis and yield a statistically quantifiable measure of benefit from DBS therapy.

Our search yielded a total of 49 articles, of which 24 were included in the analysis, 4 relating to MDD, 10 to OCD, and 10 to TS. For each particular disorder, we chose to use a single outcome scale that was the most prevalent across the DBS psychosurgery literature because of the variability of outcome measures and neuropsychological batteries used in the studies. Our meta-analysis, as illustrated via forest plots (fig. 1, 2, 3), shows a statistically significant benefit for DBS in MDD, OCD, and TS. While individual studies did cross zero (statistically insignificant effect of DBS), the pooled analysis of all included studies for each disorder shows a clinically meaningful benefit in these disorders. The efficacy of DBS is most pronounced in TS, followed by MDD and OCD, respectively. Our analysis was also able to demonstrate that for all three diseases, the score reductions with DBS were large enough in magnitude to meet stringent criteria for response, and in some cases, remission (tables 4, 5).

Major Depressive Disorder

Surprisingly, while MDD is far more prevalent in the population than either OCD or TS, there have been far fewer studies involving DBS for MDD than for either of the other diseases. While the first study of DBS in OCD was published in 1999, the first report by Mayberg et al. [25] for MDD did not surface until 2005. One explanation may be that during the late 1990s and early 2000s, several large-scale trials were underway investigating vagus nerve stimulation (VNS) as a modality for treatment-resistant MDD, precluding support for DBS, which thus far had been used primarily in movement disorders. While VNS gained Food and Drug Administration approval in 2005, the therapeutic benefit with VNS has been remarkably modest. In contrast to those patients included in the VNS MDD trials, the patient population in the DBS studies was significantly more treatment refractory (having undergone multiple medication trials, augmentation, ECT = Electroconvulsive Therapy, etc.) and was medically ill. Importantly, the magnitude of score reduction afforded by DBS for these patients enabled certain patients to even discontinue some of their antidepressant medications because of their robust response.

It is possible that the full benefit of DBS for MDD patients may not be captured by conventional rating scales for depression, which were designed primarily to assess the efficacy of pharmacotherapy, suggesting a floor effect for detecting clinical improvement [4]. It is also unlikely that one target will be optimal for all types of depression [27]. Future work should focus on the distinguishing characteristics of depression subtypes and identify the most effective target for stimulation, in addition to the design of scales that are more representative of the often dramatic clinical improvement seen in patients undergoing DBS for MDD.

Obsessive-Compulsive Disorder

OCD is characterized by obsessions, which are repetitive, intrusive thoughts and compulsions, which can be either mental or behavioral acts performed in an attempt to reduce anxiety. Antidepressant medications (selective serotonin reuptake inhibitors) are first-line therapy along with cognitive-behavioral therapy. Similar to MDD, augmentation strategies using medications from different classes are often attempted with limited success. Prior to DBS, stereotactic lesioning (through thermocoagulation or, more recently, the gamma knife) has been employed with success rates varying from 30 to 70% [28, 29, 30]. The minimally invasive nature of the gamma knife has made it an attractive option in recent years for treatment-refractory patients. However, in addition to being irreversible, lesion placement is not innocuous and patients may be at risk for radiation necrosis, seizures, and late cyst formation. Another key consideration is that the clinical benefit from lesion placement may not be apparent for several months. This is a less than attractive option for treatment-refractory OCD patients who are plagued by comorbid conditions such as major depression, social phobia, substance abuse disorder, and specific phobia [31], and significantly, patients with refractory disease are at high risk for suicide. In contrast, the effects of DBS are generally apparent during a much shorter time frame, with alleviation of depressive symptoms preceding the decrease in obsessions and compulsions [31].

Anecdotal reports that subthalamic nucleus DBS stimulation ameliorated obsessive-compulsive traits and decreased Y-BOCS scores in Parkinson's disease patients was the driving force behind investigations into DBS for OCD. The initial study by Nuttin et al. [32] explored the stereotactic placement of electrodes in the location normally targeted by anterior capsulotomy, resulting in an amelioration of OCD symptoms. This pioneering work prompted other observational studies of DBS in OCD, culminating in a limited humanitarian device exemption approval for severely refractory patients. Results of these studies have been promising, with a number of patients achieving a clinically significant reduction in Y-BOCS scores (>35%), in addition to achieving remission from their disease (Y-BOCS <16; table 5). In spite of a statistically significant p value for the test for heterogeneity, our pooled analysis demonstrates that DBS for OCD is an effective treatment option.

Tourette's Syndrome

TS usually manifests in early childhood, and it is estimated that almost 40% of patients have resolution of symptoms by adulthood. This makes DBS for this disorder controversial, even in severely refractory cases, until the age of 21 years has been reached. However, while many tics are simple motor (twitching involving the face, head, and upper body) and vocal (grunting, sniffing, and barking), the spectrum can include severe motor tics that result in joint dislocations, fractures, and cause issues with respiration and swallowing [33]. In the latter case, the refractory and dangerous nature of these entities warrants vigorous treatment with neuroleptics, which have been found to be the most efficacious.

In contrast to the MDD and OCD studies, the TS studies did not have widely accepted parameters for response and remission, which is important for a benchmark to assess whether a therapy is effective. According to our analysis, the effect of DBS was most pronounced in TS patients, and it is likely that a number of them achieved remission (though a definition for this was not given in the literature included). The fact that DBS was the most effective in TS compared with MDD and OCD may stem from experience of targeting nuclei such as the globus pallidus internus for movement disorders, since TS can be categorized as a movement disorder with psychiatric manifestations.

Interestingly, our analysis seems to imply that MDD, OCD, and TS exist on a spectrum of psychiatric disease, evidenced by the use of depression scales in the evaluation of DBS treatment for both OCD and TS. This fact is also supported by the use of OCD and MDD rating scales in TS, and it is well known that OCD patients commonly suffer from depression, and TS patients often suffer from MDD, OCD, as well as attention deficit-hyperactivity disorder. Together with the results of our pooled analysis and extensive experience in the neurosurgical literature with the treatment of movement disorders, this solidifies previous theories of the basal ganglia as important circuitry in movement as well as the processing of emotional information.

Methodological Limitations

Our meta-analysis was subject to several limitations secondary to the intrinsic nature of the studies themselves, including the number and variability of secondary outcome scales used, the total length of follow-up, the anatomic substrate targeted, as well as stimulation parameters. Importantly, while all of the patients across the studies were deemed ‘medically refractory' to pharmacologic treatment and/or other modes of treatment and thus qualified for surgery, it is important to note that the precise definition of refractory was not uniform. Unfortunately, the investigational nature of the included studies makes it difficult to control for such differences, which is why we focused our analysis on a single scale for each disorder which was quantifiable and could be reflected in a statistical model. In the case of MDD, while the HDRS is a widely validated tool used in research assessing depressive symptoms, other scales exist which have similar sensitivities for detection of the severity of depressive symptoms, including the Montgomery-Asberg Depression Rating Scale and the Beck Depression Inventory; however, their absence in some of the studies precluded them from being used for a pooled analysis.

In the case of OCD, the test for heterogeneity was statistically significant, predicating the use of a random effects model to account for the differences present across the included studies. This raises a caveat in interpreting the positive effects of DBS in treating this disorder, as the lower end of the CI was 0.6 standard deviations in score reduction, which does not translate to a meaningful improvement in patients with medically refractory disease. We were also limited by the data available in that from a statistical standpoint, group means and standardized deviations (which was what was used to run the pooled analysis) are not generally sensitive for detecting differences. Ideally, if scores were reported as individual preoperative baseline scores and postoperative scores, each patient would serve as their own control. However, many of the studies included had individual preoperative baseline scores for patients and only reported postoperative scores as a group, potentially confounding the results of our pooled analysis. While 49 articles were found that related DBS to the treatment of MDD, OCD, and TS, 20 (41%) were excluded, primarily due to a lack of preoperative baseline scores and postoperative scores for patients, among other reasons (as outlined in the exclusion criteria in the Methods section). This may introduce some degree of selection bias into our analysis in that the effects of DBS on these psychiatric conditions may be accentuated by the selective loss of studies which had no clinically significant difference following DBS treatment.

DBS is a novel therapy for the treatment of psychiatric disease. While the studies that have emerged are primarily pilot in nature, the use of DBS for MDD, OCD, and TS disorders appears to confer statistically significant benefit. Future work should focus on the generation of more objective rating scales which can capture the full spectrum of benefit from DBS and also the creation of tools that would identify the patients most likely to benefit from such an intervention. As the evidence mounts that DBS at various targets in the brain is effective for psychiatric diseases such as MDD, TS, and OCD, future studies are needed to compare targets for safety and efficacy. Finally, given the subjectivity inherent in detecting improvement in psychiatric symptoms as opposed to movement disorders, we recommend that future studies of DBS for psychiatric disease employ standardized outcome scales to improve the quality of outcome assessment.

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