Deep brain stimulation is beneficial for treatment-resistant depression: A systematic review and meta–analysis of clinical trials and long-term follow-ups

Deep brain stimulation is beneficial for treatment-resistant depression: A systematic review and meta–analysis of clinical trials and long-term follow-ups | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Deep brain stimulation is beneficial for treatment-resistant depression: A systematic review and meta–analysis of clinical trials and long-term follow-ups Ali Sepas, Hussein Alkafaji, Vedat Atici, Carsten R. Bjarkam, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7736553/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Most conventional treatments for MDD (major depressive disorder ) fail to demonstrate significant results, which highlights an urgent need for novel treatments. DBS (deep brain stimulation ) has shown great promise in several clinical trials. However, the efficacy of DBS, compared to conventional treatments for patients with TRD ( treatment − resistant depression ) , and the targets with highest efficiency for treatment of TRD remain understudied objectives. Methods A systematic search in PubMed, ProQuest Dissertations and Theses Global, Embase, PsycINFO, and Scopus accompanied by a hand search in journals and grey literature was conducted in (January 10th, 2025 ) . Any controlled trial with at least one group for comparison such as sham group was included. A random-effects meta-analysis was performed, quantitatively probing the efficacy of DBS vs sham/placebo for patients with TRD. A meta-analysis of response rate after long − term follow-up was also conducted. In addition, a meta-regression analysis was implemented to detect potentially moderating variables. Quality assessment was performed by utilizing the NOS (Newcastle Ottawa Scale ) and Jadad scale. Results 1744 records were identified and screened for relevance, among which 14 were included in the quantitative analysis. Meta-analysis of the included studies revealed a medium-large effect size (SMD (standardized mean difference) Hedge’s g = -0.51) in favor of active stimulation compared to sham. In the sensitivity analysis the effect size was statistically insignificant only when randomized controlled trials were included. The effect size and pooled response rate after long-term follow-up was = -1.12 and 56.14%, respectively. Conclusion The results indicate that DBS is potentially favorable for TRD compared to sham, as DBS exhibited greater efficacy compared to sham in both clinical trial and long-term follow-up phases. Further large-scale evidence-based studies, however, are required to substantially support these findings. Neurology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Introduction MDD ( major depressive disorder) is among the world’s leading non-fatal causes of disability, affecting hundreds of millions worldwide 1 . Additionally, depressive patients may experience associated issues such as eating disorders, poor sleep, suicidal ideation, as well as problems with work, education, and social relations 2 – 4 . A large Canadian study 5 included 568,242 patients and found the treatment costs of depressed individuals to be more than three times that of comparably ill, non-depressed patients. The significantly increased costs can be explained by non–adherence to treatment and, possibly, by a greater number of doctor’s visits by individuals in the depressed cohort 5 , 6 , which illuminates a need for better handling of patients with depression. The established treatment for MDD consists of psychotherapy and pharmacotherapy with antidepressants 6 , 7 . The medical treatment includes SSRIs (selective serotonin reuptake inhibitors), TCAs (tricyclic antidepressants), MAOIs (monoamine oxidase inhibitors), as well as various augmentation strategies, e.g., a TCA + Lithium 6 . While these strategies are valid for most clinically depressed patients, a large study (n = 3,671) found that only two-thirds of the patients with non-psychotic depression achieved remission following four consecutive stages of antidepressant treatment, each stage lasting approximately three months and consecutive stages being more aggressive than the preceding 8 . Additionally, patients who suffer from TRD (treatment-resistant depression ) are usually referred to as ECT (electroconvulsive therapy) 6 . However, meta-analyses of published studies indicate that nearly half of the patients with a history of medication failure in the current depressive episode do not achieve clinical response following ECT 9 , 10 . Furthermore, the relapse of depressive symptoms following ECT remains a significant challenge 11 , 12 , e.g. a recent study reported a relapse rate of 28.4% 13 . The failure of aggressive medical interventions for treating patients with severe TRD calls for novel approaches. One such approach is DBS (deep brain stimulation), which is a neurosurgical intervention that essentially functions as ‘a pacemaker for the brain’, delivering electrical impulses with the aim of disrupting pathological neural activity 14 . In 2005, Mayberg and colleagues published the first clinical trial testing the effect of DBS on patients with TRD through stimulation of the SCC (subcallosal cingulate gyrus) of the brain (Brodmann area 25) 15 . These were followed by additional studies, which expanded the DBS targets for depression to include the MFB (medial forebrain bundle), the internal capsule (IC), the Acb (nucleus accumbens), the ITP (inferior thalamic peduncle) and the caudate nucleus (Cn), among others 16 , 17 . The literature, however, remains undecided regarding the effects of DBS for treatment of TRD. Some studies report significant alleviation of depressive symptoms 18 . While others report no effect compared to sham 19 , hence necessitating an up-to-date review of the literature. This systematic review and meta-analysis reveal the first assessment of the efficacy of DBS for TRD. Our study also provides the first meta-analysis that reviews the findings of separate DBS treatment in RCTs (randomized controlled trials). Furthermore, we provide a meta-analysis of DBS treatment efficacy and the pooled response rate after long-term follow-up. As a secondary goal , our systematic review and meta-analysis also aim at detecting potential moderator variables that would influence the efficacy of DBS to lay the foundation for more specialized DBS treatment regimens for patients suffering from TRD. Methods Search Strategy A systematic search was conducted (January 10 th, 2025) in the following databases: PubMed, ProQuest Dissertations and Theses Global, Embase, PsycNet, and Scopus. An all-fields search was conducted in all databases except for ProQuest Dissertations and Theses Global and Scopus in where the search was conducted in all fields except for full text to limit the number of search outcomes to relevant hits only. An overview of the search terms can be seen in Table 1 . Table 1 A schematic illustration of the search string used for the systematic search. The full search string is presented in the supplementary materials. AND OR Psychiatric disorder Disease stage Intervention Comparison Depres* Major depression Depressive disorder Treatment resist* Failed treatment Unresponsive Unmanageable Refractory treat* Drug resist* Intractable DBS Deep brain stimulation Sham Compar* Placebo Set against Relation Additionally, to maximize the number of potentially eligible articles, a hand search was performed in the following journals: Jama Network, Brain Stimulation, Depression & Anxiety, Biological Psychiatry, Neuropsychopharmacology, and Journal of Psychiatry & Neuroscience with the search term: “Treatment-resistant Depression and Deep Brain Stimulation”. An additional search for ongoing trials in clinicaltrials.gov and a hand search in related articles such as citations from previously published systematic reviews and included studies were also conducted. The authors of the present manuscript also attempted to contact researchers identified in the literature search to obtain possible unpublished data, although no data was received. All identified articles were independently screened for inclusion by AS, HA and VA, and discrepancies were resolved internally with the senior authors CB and TM. Selection Criteria All potentially eligible articles were subjected to the following inclusion/exclusion criteria. Inclusion: Articles include patients with TRUD ( treatment-resistant unipolar depression as primary diagnosis), as defined by the authors of the included study Any form of a controlled trial with at least one comparison group such as sham, lithium treatment, another DBS target etc. Articles containing any form of DBS treatment for TRUD Only studies on humans, no age restriction Applied the proper instruments to measure depression, such as HAMD or any similar measurement tools Quantitative analysis of outcomes in the intervention and comparison group Articles from any country, articles in the English, Danish and Turkish languages were eligible Full text should be available for free online (including institutional access provided by the Aalborg University) Exclusion: Articles include patients with anxiety, schizophrenia, and other psychiatric disorders except for unipolar depression Animal models of DBS for TRD Case studies, reviews, books, newspaper articles, posters, and letters to editors Exclusively qualitative analysis of outcomes Articles that do not include DBS treatment Data Extraction All the included articles assessed depression severity using various versions of the HAMD ( Hamilton Depression Rating Scale) such as HAMD-17, HAMD-24, HAMD-29 or MADRS ( Montgomery-Åsberg Depression Rating Scale ) . HAMD or MADRS scores were extracted. Only data from patients with TRUD was extracted when possible. Authors were contacted if data from bipolar patients could not be separated. For each study, group means, and standard deviation (HAMD/MADRS score) were extracted, as well as publication year, national setting, sample size (number of patients included in the quantitative analysis), mean age of subjects at study entry, duration of active stimulation in the controlled trial phase, DBS target, and utilized depression scale. These were obtained from tables or calculated from individual data found in the published version of the studies included. For some studies, the tool WebPlotDigitizer was utilized to extract means and standard deviations from the graphs provided. Quality Assessment The methodological quality of each study was assessed using the JADAD scale for RCTs and the NOS (Newcastle-Ottawa scale) for non-RCTs (non-randomized controlled trials). Each scale returns a score, and based on this score, each article was given a ranking of either low, medium, or high quality. For RCTs, a maximum of five points was given in the following domains: randomization, blinding, and an account of outcomes in all patients. Studies were of high, moderate, or low quality if the score was ≥ 4, 2–3, or < 2, respectively. The NOS assigns a maximum of nine points, assessing the categories of comparability, selection, and outcome. Studies were judged to be of high, medium, or low methodological quality if the score was > 5, 3–5, or < 3 respectively. Statistical Analysis The SMD (standardized mean difference), Hedge’s g of each study was computed manually (accounting for paired and non-paired samples) based on the mean score and standard deviation of the depression scale in the intervention and comparison group post-treatment. Potential differences in sample sizes in the beginning and end of an intervention were accounted for through modified pooled standard deviation, where both sample sizes were included in addition to the sample size from the sham group, and the harmonic mean was used to account for changes in the intervention group. The effect sizes were synthesized by using the DerSimonian and Laird random effects model 20 in the statistics software R 21 . The random effects model was applied , since the studies were estimating related but different effect sizes due to variations in study design, surgical procedure, stimulation duration, depression rating scale, etc 22 . A two-way p-value of < 0.05 was considered significant. Statistical heterogeneity was assessed by I 2 , I 2 < 50% was considered low. For sensitivity analysis , different meta-analyses were conducted where: Only the results of RCTs for estimating the pooled effect size were included. Studies were excluded when the data from patients with unipolar and bipolar depression could not be separated. Studies were used when upfront randomization or blinded discontinuation were used. Only medium and high quality RCTs were included. Only medium and high quality non-RCTs were included. Meta-regression analysis was performed in R to identify potential moderator variables that might have influenced the effect sizes 21 . The included potential moderators were age, gender, stimulation length in the controlled trial phase, duration of the current depressive episode at the study entry , stimulation optimization duration, long-term follow-up duration, upfront randomization or blinded discontinuation. Effect sizes from two different DBS targets vs. sham in the studies by Raymaekers et al. (2017) 23 were considered separately in the meta-analysis. Publication Bias Funnel plots were used to evaluate bias and plot asymmetry. Additionally, Egger’s test was utilized to quantitatively assess the asymmetry in the funnel plot. Finally, the non-parametric trim-and-fill method 24 was applied to detect whether any studies should be imputed in calculating the pooled effect sizes, possibly adjusting these effects. Results The initial search returned 1864 results (1082 after removal of duplicates); these were all screened for relevance based on title and abstract. Following this selection, 245 articles remained. Articles were then filtered by full-text screening based on the previously described inclusion/exclusion criteria. A total of 11 articles remained, which were all quantitatively analyzed. A PRISMA flow diagram illustrating the search procedure can be seen in Fig. 1 . 189 unique patients were included in the meta-analysis ; the number of patients with unipolar depression was 187, and the number of patients with bipolar depression was 2. The average stimulation duration (trial phase) was 20.13 weeks. Some studies reported a follow-up extension period, where changes in pharmacotherapy were allowed concurrently with DBS or DBS parameters were adjusted to induce greater clinical efficacy. The mean age of subjects across all studies was 49.4 ± 9.9 years. All studies were blinded, and, among the included studies, 4/11 utilized a crossover design with patients functioning as their own controls. Eight of the studies included were RCTs (Table 2 ). Inclusion criteria and the definition of TRD differed from study to study. HAMD measures for inclusion ranged from ≥ 17 to ≥ 21 and MADRS from ≥ 21 to ≥ 26. Most studies defined TRD as a failure of four adequate antidepressant trials and ECT, analogous to stage V resistance described by Thase et al. in their seminal study of TRD 7 . All studies utilized a definition of TRD where at least two adequate antidepressant trials had failed to alleviate depressive symptoms. The definition of TRD in each study can be found in Supplementary Table S1. Table 2 Summary of study characteristics No. Author (Year) National setting Study design Sample size (female %) Mean/SD age at disease onset (years) Mean age at study entry (years) Stimulation target(s) Stimulation duration (Trial phase) (weeks) Optimization phase (weeks) Follow-up duration after trial phase (weeks) Depression scale Hedge’s g (g 0 = favors sham stimulation) Quality Assessment 1. Bergfeld et al. (2016) 18 The Netherlands RCT (crossover) 16 (NA) 37.8 ± (9.8) 53.1 ± 8.4 Ventral anterior limb of the IC (internal capsule) 6 52 - HAMD-17 -1.55 [-2.35; -0.90] High 2. Coenen et al. (2019) 42 Germany RCT (parallel) 16 (38) [1 BPIID] 28.5 ± 9.8 51.6 ± 10.2 Superolateral MFB (medial forebrain bundle) 8 NA 44 MADRS -0.65 [-1.59; 0.32] High 3. Dougherty et al., (2015) 19 USA RCT (parallel) 29 (45) - 47.7 ± 12.0 VC/VS (Ventral Capsule/Ventral Striatum) 16 4 88 MADRS 0.11 [-0.60; 0.82] High 4. Fenoy et al. (2018) 31 USA Controlled trial (single blinded) 6 (60) 15.2 ± 6.3 50.2 ± 10.2 Superolateral MFB 26 NA 52*** MADRS -0.30 [-1.39; 0.80] ** Low 5. Fenoy et al. (2022) 30 USA Controlled trial (single blinded) 4 (50) 22 ± 4.6 50.8 ± 3.5 Superolateral MFB 26 NA 600 (5 years) *** MADRS 0.94 [-0.48; 2.28] ** Low 6. Holtzheimer et al. (2012) 29 USA Controlled trial (single blinded) 10 (NA) 20.3 ± 5.6 40.0 ± 9.3 SCC 24 NA 144 (2 years) + HAMD-17 -1.64 [-2.80; -0.83] Medium 7. Holtzheimer et al. (2017) 36 USA RCT (parallel) 85 (NA) - 50.5 ± 9.7 SCC 26 10 144 (2 years)++ MADRS -0.17 [-0.63; 0.29] +++ High 8. Merkl et al. (2018) 29 Germany RCT (parallel) 8 (13) [1 BPID] 28.6 ± 9.7 48.3 ± 12.1 SCC 8 NA 144 (24 months) ****** HAMD-24 0.53 [-0.73; 1.75] High 9 Puigdemont et al. (2015) 32 Spain RCT (crossover) 5 (N/A) 23.2 ± 2.1 47.2 ± 13.0 SCC 13 NA NA HAMD-17 -0.53 [-1.76; 0.49] High 10. Ramasubbu et al. (2013) 41 Canada RCT (crossover) 4 (75) 50.2 ± 4.2 50.3 ± 3.6 SCC 12 12 26 HAMD-17 -0.49 [-1.88; 0.63] High 11. Raymaekers et al. (2017) 23 The Netherlands & Belgium RCT (crossover) Crossover 1 n = 6 Crossover 2 n = 5 (NA) 35.3 ± 8.8 50.0 ± 5.2 (at cross over 1) Ventral anterior limb of the IC & ITP (Inferior Thalamic Peduncle) 18 22 (5 months) 156 (3 years) HAMD-17 IC vs sham: -1,24 [-2.11; -0.34] ITP vs sham: -0,58 [-1.81; 0.42] IC vs ITP (g 0 = favors IT DBS): -0,21 [-1.42; 0.92] High BPID = Bipolar I Disorder, BPIID = Bipolar II Disorder, TRD = treatment-resistant depression, NA = not available, HAMD = Hamilton Depression Rating Scale, RCT: randomized controlled trial, MADRS: Montgomery-Åsberg Depression Rating Scale, SCC: Subcallosal cingulate gyrus, IC: internal capsule, MFB: medial forebrain bundle, * Data from the first year of the study was included, due to high dropout rate, **active outcome based on data from 26 weeks of stimulation. Although stimulation was continued for 52 weeks, patients were required to maintain the same medication for 6 months post-surgery,*** data from 1 year of follow-up included in subgroup meta analysis. ****active outcome = average of all active settings.***** Data from only 24 months was used for long-term follow-up analysis since data from all patients after 36 weeks (about 8 and a half months) were not available, ****** Data from only 24 weeks used for long-term follow-up analysis, data excluded from 28 weeks due to 50% drop out. + only 8 MDD patients remained after 2 years, not possible to separate BP from MDD patients for response rate analysis. ++ data from 2 years not included due to significant dropout rate in follow-up meta-analysis. For follow-up meta-analysis, data from n = 82 was included, Data from 26 weeks (n = 90) at baseline were included in a primary meta-analysis of controlled results compared to long-term active (n = 30) baseline sham. The meta-analysis of 11 included studies (189 patients) comparing DBS to sham treatment revealed that active DBS led to a greater reduction in depressive symptoms compared to sham, with Hedges’ g = − 0.51, 95% CI [–0.97; − 0.05], I² = 64%. The non-parametric trim-and-fill analysis did not adjust the effect size (Table 3 , Fig. 2 ., Fig. 4 (a)). Table 3 Summary of meta-analysis and sensitivity analysis (trial phase) Number of studies (subjects at baseline) Hedge’s g with 95% CI p-value Adjusted Hedge’s g with 95% CI Significant Moderators DBS vs sham 11 (189) -0.51 [-0.97; -0.05] < 0.05 No adjustments None DBS vs sham (only RCTs) 8 (169) -0.52 [-1.01, -0.04] < 0.05 -0.19 [-0.76, 0.39] None DBS vs sham (only medium to high quality non-RCTs) 1 (10) -1.64 [-2.80; -0.83] < 0.05 No adjustments None DBS vs sham (excluding studies with bipolar patients) 9 (165) -0.58 [-1.10; -0.06] 0.05 -0.80 [-1.62, 0.015] None DBS vs sham blinded discontinuation 5 (140) -0.65 [-1.30, 0.01] > 0.05 -0.14 [-0.93, 0.66] None DBS SCC vs sham 5 (112) -0.47 [-1.13, 0.19] > 0.05 No adjustments None DBS SCC vs sham (only RCTs) 4 (102) -0.18 [-0.56, 0.21] > 0.05 No adjustments None DBS SCC vs sham (excluding studies bipolar patients) 4 (104) -0.65 [-1.33, 0.04] > 0.05 -0.24 [-0.99, 0.51] None DBS IC vs sham 3 (51) -0.88 [-1.90, 0.14] > 0.05 -0.88 [-1.904, 0.14] None DBS MFB vs sham 3 (26) -0.12 [-0.97, 0.73] > 0.05 -0.12 [-0.97, 0.73] None DBS MFB vs sham (RCT) 1 (16) -0.65 [-1.60, 0.32] >0.05 No adjustments None DBS MFB vs sham (excluding bipolar patients) 2 (10) 0.25 [-0.96, 1.45] > 0.05 No adjustments None ITP DBS vs. sham 1(5) -0.58 [-1.70, 0.53] > 0.05 No adjustments None *Adjusted Hedge’s g values were calculated in STATA following the application of non-parametric trim-and-fill analysis for reducing publication bias by imputing more studies. After excluding non-RCTs, the analysis of eight studies (169 patients) resulted in an effect size of g = − 0.52, 95% CI [–1.01; − 0.04] (Table 3 ) , I² = 62%. Six studies utilized upfront randomization, and the combined pooled effect size was g = -0.35, 95% CI [-1.07, 0.36], I² = 59% (Table 3 ). In a separate comparison of internal capsule (IC) vs. inferior thalamic peduncle (ITP) DBS (5 patients), the effect size was g = − 0.21, 95% CI [–1.38; 0.96] (Table 3 ). Egger’s test indicated publication bias in the pooled analysis of all studies, that had a long-term follow-up phase ( p = 0.03). The overall pooled response rate was r = 0.56, 95% CI [0.36; 0.76], I² = 92% (Table 4 , Fig. 5 (a)). When non-RCTs were excluded, the response rate adjusted to r = 0.48, 95% CI [0.25; 0.70], I² = 91% (Table 4 , Fig. 6 ). Furthermore, upfront randomization vs. blinded discontinuation as a moderator was also significant in DBS vs sham (excluding studies with bipolar patients, response rate) (Table 4 ). Eight studies (166 patients) conducted open-label long-term follow-up, yielding a pooled effect size of g = − 1.12, 95% CI [–1.89; − 0.36], I² = 74% (Table 5 , Fig. 3 , Fig. 6 ). Table 4 Summary of response rate meta-analysis Number of studies (subjects) Hedge’s g with 95% CI p-value Adjusted Hedge’s g with 95% CI Significant Moderators DBS vs sham 8 (166) 0.56 [0.36; 0.76] < 0.01 0.29 [0.0184, 0.55] None DBS vs sham (only RCTs) 6 (146) 0.48 [0.25, 0.70] < 0.010.26 [-0.01, 0.53] None DBS vs sham (excluding studies with bipolar patients) 6 (142) 0.54 [0.30, 0.77] < 0.05 0.28 [-0.02, 0.58] Upfront randomization vs blinded discontinuation DBS vs sham (only medium to high quality non-RCTs) 1 (10) 0.92 [0.65, 0.99] < 0.01 No adjustments None DBS vs sham upfront randomization 4 (44) 0.81 [0.56, 1.06] < 0.01 No adjustments None DBS vs sham blinded discontinuation 4 (122) 0.37 [0.20, 0.54] < 0.01 0.31 [0.09, 0.52] None DBS SCC vs sham 4 (107) 0.50 [0.19, 0.82] 0.05 0.26 [-0.01, 0.53] None DBS SCC vs sham (excluding studies bipolar patients) 3 (99) 0.56 [0.15, 0.96] 0.05 No adjustments None DBS MFB vs sham 2 (26) 0.79 [0.59, 1.00] p < 0.05 No adjustments None DBS MFB vs sham (RCT) 1 (16) 0.88 [0.64, 0.97] p < 0.05 No adjustments None DBS MFB vs sham (excluding bipolar patients) 1 (10) 0.66 [0.35, 0.88] p < 0.05 No adjustments None *Adjusted Hedge’s g values were calculated in STATA following the application of non-parametric trim-and-fill analysis for reducing publication bias by imputing more studies. Table 5 Summary of meta-analysis and sensitivity analysis (long term follow-up phase) Number of studies (subjects) Hedge’s g with 95% CI p-value Adjusted Hedge’s g with 95% CI Significant Moderators DBS vs sham 8 (166) -1.12 [-1.89; -0.36] < 0.05 − 0.59 [-1.64, 0.46] Age DBS vs sham (only RCTs) 6 (146) -0.80 [-1.29, -0.30] < 0.05 -0.41 [-0.98, 0.16] Upfront Randomization or Blinded discontinuation DBS vs sham (excluding studies with bipolar patients) 6 (142) -1.08 [-2.12; -0.04] < 0.05 No adjustments Age DBS vs sham (only medium to high quality non-RCTs) 1 (10) -1.64 [-2.8; -0.83] < 0.05 No adjustments None DBS vs sham upfront randomization 4 (44) -1.73 [-3.29, -0.18] < 0.05 No adjustments None DBS vs sham blinded discontinuation 4 (122) -0.49 [-0.86, -0.13] 0.05 -0.43 [-2.27, 1.40] None DBS SCC vs sham (only RCTs) 3 (97) -0.47 [-0.92, -0.01] 0.05 -1.63 [-3.95, 0.69] None DBS IC vs sham 2 (35) -0.73 [-1.61, 0.16] > 0.05 No adjustments None DBS MFB vs sham 2 (26) -1.09 [-2.52, 0.33] > 0.05 o adjustments Nne DBS MFB vs sham (RCT) 1 (16) -1.80 [-2.77, -0.81] 0.05 No adjustments None *Adjusted Hedge’s g values were calculated in STATA following the application of non-parametric trim-and-fill analysis for reducing publication bias by imputing more studies. Number of subjects in baseline is included. ILLUSTRATIONS 🡨 Favors ACTIVE Favors SHAM 🡪 (b) SCC DBS vs. sham (all studies included) 🡨 Favors ACTIVE Favors SHAM 🡪 (c) IC DBS vs. sham (all studies included) 🡨 Favors ACTIVE Favors SHAM 🡪 (d) MFB DBS vs. sham (all studies included) For the long-term follow-up, the exclusion of non-RCTs resulted in six studies, yielding g = − 0.80, 95% CI [–1.29; − 0.30], p < 0.05, I² = 42% (Table 5 ). The trim-and-fill analysis adjusted the effect size to g = − 0.41, 95% CI [–0.98; 0.16]. When studies involving bipolar patients were excluded, the meta-analysis of DBS vs. sham produced an effect size of g = -1.08, 95% CI [–2.12; − 0.04 ], p 0.05, I² = 58% (Table 5 , Fig. 3 , Fig. 6 (b)). Excluding non-RCTs in the analysis of SCC DBS vs. sham adjusted the result to g = − 0.18, 95% CI [–0.56; 0.21], I² = 47% (Table 5 ). For medial forebrain bundle (MFB) DBS vs. sham (26 patients), the effect size was g = − 0.12, 95% CI [–0.97; 0.73], I² = 43% (Table 5 , Fig. 3 , Fig. 6 (d)). Since all the RCTs were of high quality, no further sensitivity analysis was required. Accordingly, only high quality RCTs were included in the relevant analyses. Age was found to be a significant moderator in the analysis of DBS vs. sham (all studies included, long-term follow-up), and DBS vs. sham (excluding studies with bipolar patients, long-term follow-up). Upfront randomization vs. blinded discontinuation was a significant moderator in the analysis: DBS vs. sham (only RCTs, long-term follow-up) (Table 5 ). The most relevant funnel plots are presented in (Figs. 7 – 9 ). Discussion This paper analyzed the efficacy of DBS as a treatment for TRD 16 , 25 – 27 . Corroborating earlier reports, DBS significantly alleviated depressive symptoms in TRD patients. Meta-analysis yielded a medium-large 28 effect size comparing DBS to sham, with a Hedges’ g = − 0.51, 95% CI [–0.97; − 0.05]. Additionally, meta-analysis of DBS vs. sham (excluding non-RCTs) yielded a SMD of g = − 0.52, 95% CI [–1.01; − 0.04], which suggests that DBS represents a possible alternative when conventional treatment strategies fail. Analysis of the different targets showed that SCC as DBS target has greater efficacy than sham g = − 0.47, 95% CI [–1.13; 0.19]. Furthermore, the sensitivity analysis of SCC DBS vs sham (excluding non-RCTs) did not yield significant difference g = − 0.18, 95% CI [–0.56; 0.21]. Consequently, future RCTs with bigger sample sizes are required to assess whether SCC DBS outperforms sham surgery. Most of the RCTs had small sample sizes, resulting in wider confidence intervals and greater uncertainty in interpreting the results. Patient-specific stimulation design in RCTs, originally guided by MRI/CT scans 29 and now by diffusion tractography 30 , vary in both target location and stimulation settings (amplitude, pulse width, frequency) 31 , 32 . The chosen settings critically influence clinical outcomes, highlighting the need for individualized treatment protocols. Age was found to be a significant moderator in the analysis of DBS vs. sham (all studies included, long-term follow-up), and upfront randomization vs. blinded discontinuation as a moderator variable was also significant in DBS vs. sham (only RCTs, long-term follow-up). These findings suggest that age and stimulation strategy could play a role in how well patients respond to DBS over time. However, these findings are based on a few studies, and no moderator was consistently significant across all sensitivity analyses; consequently, current evidence remains too limited for firm conclusions. Prior meta-analyses have also assessed the efficacy of DBS in TRD. All have demonstrated significantly better results with active stimulation compared to sham 16 , 25 – 27 . A meta-analysis of Hitti and colleagues 16 yielded similar results to the current study. The authors found DBS to be better than sham overall in the trial phase. The differences can be attributed to the inclusion of the study by Fenoy et al. and accounting for changes in sample sizes during the time course of some of the trials 30 . Furthermore, in studies where patients underwent sham stimulation before active stimulation, we used the difference between sham and corresponding active stimulation endpoints to account for possible insertional effects. Additionally, when calculating the effect sizes for individual studies, no considerations regarding paired or unpaired samples were made. The differing efficacies reported by literature may be attributed to multiple factors 16 . Firstly, the neurophysiological properties of depression vary from individual to individual, making it difficult to pinpoint which target(s) is ideal for DBS 33 . Current studies do not fully account for these neurobiological differences. Secondly, it is yet to be explored whether non-responders to DBS of one brain target region may benefit from stimulation of an alternative target 33 . However, the neurosurgical nature of DBS treatment limits these possibilities. Thirdly, differing efficacy may relate to the accuracy of measurement of treatment outcomes. As noted by Rabin et al. 34 , suboptimal measures of outcomes stand in the way of truly recognizing signs of effective treatment. While depression rating scales are generally acknowledged for assessing depression, they do present some inadequacies, especially when synthesizing data in meta-analyses 35 . For instance, multiple versions of the HAMD scale were used in the literature, despite all versions being tailored to different uses and including different domains of assessment. This may lead to overestimation of the importance of certain factors, depending on which scale is used. This, of course, extends to differences between HAMD and other rating scales, such as MADRS. A great advantage of DBS is that active/sham stimulation can be compared within the same patient. This reduces inter − subject variability and allows for greater statistical power with fewer participants. This advantage was reflected in the included trials that utilized crossover design. However, the two largest of the included trials both used a parallel design analysis 19 , 36 . Both studies reported substantially lower efficacy of active stimulation compared to sham. A possible explanation for this discrepancy, as noted in the study by Raymaekers et al. 23 , is that subjects were able to correctly “guess” whether stimulation was on or off, which suggests that adequate blinding was not achieved. Limitations and direction for future research Most studies utilized various versions of HAMD, which have been criticized for being flawed and incapable of depicting depression severity, as well as some of the main aspects of depression , e.g. feelings of worthlessness and anhedonia 37 . Furthermore, some evidence suggests that the total score of HAMD, which was utilized in the present study, does not adequately reflect depression severity 35 . However, a more recent critical review of various forms of HAMD validated the scale and reported it as being sensitive 35 . MADRS was utilized as well in some studies ; however , this scale has been criticized for being less sensitive in detecting treatment effects compared to HAMD 38 . Another limitation may be the lack of a coherent definition for TRD in scientific literature. Some studies resorted to defining TRD as the failure of response to multiple adequate trials of various antidepressants, while others utilized a staging approach such as the Thase-Rush five-stage classification. Nevertheless , further evidence is required to assess the efficacy of such staging models 39 . A consensus that seems to emerge is to define TRD as a failure of response to at least two adequate trials of antidepressants 26 , 40 . Future studies should consider utilizing large-scale double − blinded RCT designs and utilize a better definition of TRD, where consensus is emerging. Additionally, researchers should consider the most appropriate depression scale based on their approach for assessing treatment efficacy; for instance, if the goal is to assess the different severity levels of depression, then HAMD-17 can be utilized. Conversely, if treatment efficacy of DBS is compared to sham, then HAMD-6 may be better suited 35 . An optimal study design for future trials should consider methods of blinding patients, where patients are not able to “guess” whether DBS is on or off, as reported in the study by Raymaekers et al 23 . Future studies should compare DBS to a specific type of conventional treatment for TRD such as lithium or ECT. Advances in target-localization methodologies, from conventional anatomical MRI to individualized tractography, indicate that DBS efficacy in TRD is contingent upon both the selected anatomical target and the fiber bundle. Consequently, a singular “one-target-fits-all” is unlikely to optimize therapeutic outcomes across the heterogeneous TRD population. Future clinical trials should therefore consider personalized targets, rather than restricting DBS to a single region such as SCC, to enhance the efficacy and reproducibility of DBS interventions in TRD. Conclusion The results obtained indicate that DBS, when performed correctly at the correct target in the correctly identified patient , is potentially superior to sham. DBS indicated greater efficacy compared to sham in clinical trial phase and long-term follow-up phase. The pooled response rate after long-term follow-up was found to be 56%. Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Competing interests The authors declare that they have no competing interests Data sharing Upon request additional data is available Supplementary materials The following search string was used for pubmed: ("depres*"[All Fields] OR "Depressive disorder"[All Fields] OR "Major depression"[All Fields]) AND ("refractory treat*"[All Fields] OR "Failed treatment"[All Fields] OR "treatment resist*"[All Fields] OR "drug resist*"[All Fields] OR "Intractable"[All Fields] OR "Unmanageable"[All Fields] OR "Unresponsive"[All Fields]) AND ("DBS"[All Fields] OR "Deep Brain Stimulation"[All Fields]) AND ("Placebo"[All Fields] OR "compar*"[All Fields] OR "sham*"[All Fields] OR ("set"[All Fields] AND "against"[All Fields]) OR "Relation"[All Fields]) Similar search terms were utilized for the other databases. Funding No funding has been provided Author contributions Study design: All authors. Screening of literature: AS, HA and VA. Data extraction and statistical analysis: AS and HA. Manuscript first draft: AS and HA. Manuscript editing and reviewing: AS, HA, CB, and TM. All authors have read and approved the final revised version of this manuscript Acknowledgements The authors wish to thank Professor Helen S. Mayberg , Icahn School of Medicine at Mount Sinai, New York, for providing unpublished data regarding patients with treatment-resistant unipolar depression. Dr. Mohtadin Hashemi is acknowledged for giving feedback on the final draft of the paper. References James SL et al (2018) Global, regional, and national incidence, prevalence, and years lived with disability for 354 Diseases and Injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. 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J Psychiatry Neurosci 38:325–332 Coenen VA et al (2019) Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial. Neuropsychopharmacology 44:1224–1232 Holtzheimer PE et al (2012) Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry 69:150–158 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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16:38:28","extension":"png","order_by":75,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":44236,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-7736553/v1/5fbea9e8001a4f6d6c1ad87d.png"},{"id":92530839,"identity":"1a650227-5b33-404f-b1dc-0d00186edaa4","added_by":"auto","created_at":"2025-09-30 16:38:28","extension":"xml","order_by":76,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":168704,"visible":true,"origin":"","legend":"","description":"","filename":"rs77365530structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7736553/v1/891d496f0e29144b132ea270.xml"},{"id":92530841,"identity":"36e143fe-4d59-4272-8aef-2094acd80895","added_by":"auto","created_at":"2025-09-30 16:38:28","extension":"html","order_by":77,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":185995,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7736553/v1/dd30b441a8c208aa0a9c0760.html"},{"id":92532096,"identity":"5c3051a0-7152-4c03-b066-a68be471f02f","added_by":"auto","created_at":"2025-09-30 16:46:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":72645,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7736553/v1/4f25dccf2597303ab7dde8ef.png"},{"id":92532078,"identity":"10b0ad74-e9af-4baf-80e5-477e0470e4f7","added_by":"auto","created_at":"2025-09-30 16:46:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":101479,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStimulation Targets and Meta-analytic Results: Trial Phase\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7736553/v1/28650e4a82516e4a78e9a9ae.png"},{"id":92530725,"identity":"58e09264-3777-440b-bcf8-09e2901d1649","added_by":"auto","created_at":"2025-09-30 16:38:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":95762,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStimulation Targets and Meta-analytic Results: Long-term Follow-up\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7736553/v1/e40bd03cfe8c202a1df10c92.png"},{"id":92532920,"identity":"da16249d-f66d-4a4a-b66f-5f33e2d2def3","added_by":"auto","created_at":"2025-09-30 16:54:24","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":296671,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plots comparing the effect of active DBS to sham (trial phase).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7736553/v1/edc831635784ae47fd853e48.png"},{"id":92530732,"identity":"2f0ad774-16ea-43af-a137-81686fd02996","added_by":"auto","created_at":"2025-09-30 16:38:23","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":625285,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plots of response rate\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7736553/v1/6f84479de758b6b40c673281.png"},{"id":92530724,"identity":"5c7f9761-198a-4a68-9b83-fcd9e3f4dc38","added_by":"auto","created_at":"2025-09-30 16:38:23","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":265751,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plots comparing the effect of active DBS to sham (long term follow-up phase)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7736553/v1/38117804310144fa85162af7.png"},{"id":92530735,"identity":"326e644c-cbc3-4bf4-95e5-09b7d4274386","added_by":"auto","created_at":"2025-09-30 16:38:23","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":93395,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plots of DBS vs. sham (trial phase)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-7736553/v1/0d906209fb720c3294123e73.png"},{"id":92530812,"identity":"1120ee85-318c-45ad-8ba5-61ca8f6c96e0","added_by":"auto","created_at":"2025-09-30 16:38:27","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":92673,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plots of response rate\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-7736553/v1/b8886b4011df0e8ea29dc0eb.png"},{"id":92530788,"identity":"61911e94-6b52-4334-94cb-9193fc1998ea","added_by":"auto","created_at":"2025-09-30 16:38:26","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":102384,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plots of active DBS vs. sham (long-term follow-up phase)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-7736553/v1/d90bc0ad1f36bb0c7517a2c5.png"},{"id":92532923,"identity":"16fed83e-00c9-4c9b-ab0a-4f9672b0ede2","added_by":"auto","created_at":"2025-09-30 16:54:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3044530,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7736553/v1/959c5330-7abf-4fa4-8cc5-2a432edf4d80.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eDeep brain stimulation is beneficial for treatment-resistant depression: A systematic review and meta–analysis of clinical trials and long-term follow-ups\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMDD \u003csup\u003e(\u003c/sup\u003emajor depressive disorder) is among the world\u0026rsquo;s leading non-fatal causes of disability, affecting hundreds of millions worldwide\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Additionally, depressive patients may experience associated issues such as eating disorders, poor sleep, suicidal ideation, as well as problems with work, education, and social relations\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. A large Canadian study\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e included 568,242 patients and found the treatment costs of depressed individuals to be more than three times that of comparably ill, non-depressed patients. The significantly increased costs can be explained by non\u0026ndash;adherence to treatment and, possibly, by a greater number of doctor\u0026rsquo;s visits by individuals in the depressed cohort\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003c/sup\u003e which illuminates a need for better handling of patients with depression.\u003c/p\u003e\u003cp\u003eThe established treatment for MDD consists of psychotherapy and pharmacotherapy with antidepressants\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The medical treatment includes SSRIs (selective serotonin reuptake inhibitors), TCAs (tricyclic antidepressants), MAOIs (monoamine oxidase inhibitors), as well as various augmentation strategies, e.g., a TCA\u0026thinsp;+\u0026thinsp;Lithium\u003csup\u003e6\u003c/sup\u003e. While these strategies are valid for most clinically depressed patients, a large study (n\u0026thinsp;=\u0026thinsp;3,671) found that only two-thirds of the patients with non-psychotic depression achieved remission following four consecutive stages of antidepressant treatment, each stage lasting approximately three months and consecutive stages being more aggressive than the preceding\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Additionally, patients who suffer from TRD (treatment-resistant depression\u003csup\u003e)\u003c/sup\u003e are usually referred to as ECT (electroconvulsive therapy)\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. However, meta-analyses of published studies indicate that nearly half of the patients with a history of medication failure in the current depressive episode do not achieve clinical response following ECT\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Furthermore, the relapse of depressive symptoms following ECT remains a significant challenge\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003c/sup\u003e e.g. a recent study reported a relapse rate of 28.4%\u003csup\u003e13\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe failure of aggressive medical interventions for treating patients with severe TRD calls for novel approaches. One such approach is DBS (deep brain stimulation), which is a neurosurgical intervention that essentially functions as \u0026lsquo;a pacemaker for the brain\u0026rsquo;, delivering electrical impulses with the aim of disrupting pathological neural activity\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. In 2005, Mayberg and colleagues published the first clinical trial testing the effect of DBS on patients with TRD through stimulation of the SCC (subcallosal cingulate gyrus) of the brain (Brodmann area 25)\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThese were followed by additional studies, which expanded the DBS targets for depression to include the MFB (medial forebrain bundle), the internal capsule (IC), the Acb (nucleus accumbens), the ITP (inferior thalamic peduncle) and the caudate nucleus (Cn),\u003c/p\u003e\u003cp\u003eamong others\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. The literature, however, remains undecided regarding the effects of DBS for treatment of TRD. Some studies report significant alleviation of depressive symptoms\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. While others report no effect compared to sham\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003c/sup\u003e hence necessitating an up-to-date review of the literature.\u003c/p\u003e\u003cp\u003eThis systematic review and meta-analysis reveal the first assessment of the efficacy of DBS for TRD. Our study also provides the first meta-analysis that reviews the findings of separate DBS treatment in RCTs (randomized controlled trials). Furthermore, we provide a meta-analysis of DBS treatment efficacy and the pooled response rate after long-term follow-up. As a secondary goal\u003csup\u003e,\u003c/sup\u003e our systematic review and meta-analysis also aim at detecting potential moderator variables that would influence the efficacy of DBS to lay the foundation for more specialized DBS treatment regimens for patients suffering from TRD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eSearch Strategy\u003c/h2\u003e\u003cp\u003eA systematic search was conducted (January 10\u003csup\u003eth,\u003c/sup\u003e 2025) in the following databases: PubMed, ProQuest Dissertations and Theses Global, Embase, PsycNet, and Scopus. An all-fields search was conducted in all databases except for ProQuest Dissertations and Theses Global and Scopus in where the search was conducted in all fields except for full text to limit the number of search outcomes to relevant hits only. An overview of the search terms can be seen in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eA schematic illustration of the search string used for the systematic search. The full search string is presented in the supplementary materials.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003eAND\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eOR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePsychiatric disorder\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDisease stage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIntervention\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eComparison\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eDepres*\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eMajor depression\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eDepressive disorder\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eTreatment resist*\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eFailed treatment\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eUnresponsive\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eUnmanageable\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eRefractory treat*\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eDrug resist*\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eIntractable\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eDBS\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eDeep brain stimulation\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eSham\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eCompar*\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003ePlacebo\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eSet against\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eRelation\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAdditionally, to maximize the number of potentially eligible articles, a hand search was performed in the following journals: Jama Network, Brain Stimulation, Depression \u0026amp; Anxiety, Biological Psychiatry, Neuropsychopharmacology, and Journal of Psychiatry \u0026amp; Neuroscience with the search term: \u0026ldquo;Treatment-resistant Depression and Deep Brain Stimulation\u0026rdquo;. An additional search for ongoing trials in clinicaltrials.gov and a hand search in related articles such as citations from previously published systematic reviews and included studies were also conducted. The authors of the present manuscript also attempted to contact researchers identified in the literature search to obtain possible unpublished data, although no data was received. All identified articles were independently screened for inclusion by AS, HA and VA, and discrepancies were resolved internally with the senior authors CB and TM.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSelection Criteria\u003c/h3\u003e\n\u003cp\u003eAll potentially eligible articles were subjected to the following inclusion/exclusion criteria.\u003c/p\u003e\u003cp\u003eInclusion:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eArticles include patients with TRUD \u003csup\u003e(\u003c/sup\u003etreatment-resistant unipolar depression as primary diagnosis), as defined by the authors of the included study\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAny form of a controlled trial with at least one comparison group such as sham, lithium treatment, another DBS target etc.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eArticles containing any form of DBS treatment for TRUD\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eOnly studies on humans, no age restriction\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eApplied the proper instruments to measure depression, such as HAMD or any similar measurement tools\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eQuantitative analysis of outcomes in the intervention and comparison group\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eArticles from any country, articles in the English, Danish and Turkish languages were eligible\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eFull text should be available for free online (including institutional access provided by the Aalborg University)\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eExclusion:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eArticles include patients with anxiety, schizophrenia, and other psychiatric disorders except for unipolar depression\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAnimal models of DBS for TRD\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eCase studies, reviews, books, newspaper articles, posters, and letters to editors\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eExclusively qualitative analysis of outcomes\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eArticles that do not include DBS treatment\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\n\u003ch3\u003eData Extraction\u003c/h3\u003e\n\u003cp\u003eAll the included articles assessed depression severity using various versions of the HAMD \u003csup\u003e(\u003c/sup\u003eHamilton Depression Rating Scale) such as HAMD-17, HAMD-24, HAMD-29 or MADRS \u003csup\u003e(\u003c/sup\u003eMontgomery-\u0026Aring;sberg Depression Rating Scale\u003csup\u003e)\u003c/sup\u003e. HAMD or MADRS scores were extracted. Only data from patients with TRUD was extracted when possible. Authors were contacted if data from bipolar patients could not be separated.\u003c/p\u003e\u003cp\u003eFor each study, group means, and standard deviation (HAMD/MADRS score) were extracted, as well as publication year, national setting, sample size (number of patients included in the quantitative analysis), mean age of subjects at study entry, duration of active stimulation in the controlled trial phase, DBS target, and utilized depression scale. These were obtained from tables or calculated from individual data found in the published version of the studies included. For some studies, the tool WebPlotDigitizer was utilized to extract means and standard deviations from the graphs provided.\u003c/p\u003e\n\u003ch3\u003eQuality Assessment\u003c/h3\u003e\n\u003cp\u003eThe methodological quality of each study was assessed using the JADAD scale for RCTs and the NOS (Newcastle-Ottawa scale) for non-RCTs (non-randomized controlled trials). Each scale returns a score, and based on this score, each article was given a ranking of either low, medium, or high quality. For RCTs, a maximum of five points was given in the following domains: randomization, blinding, and an account of outcomes in all patients. Studies were of high, moderate, or low quality if the score was \u0026ge;\u0026thinsp;4, 2\u0026ndash;3, or \u0026lt;\u0026thinsp;2, respectively.\u003c/p\u003e\u003cp\u003eThe NOS assigns a maximum of nine points, assessing the categories of comparability, selection, and outcome. Studies were judged to be of high, medium, or low methodological quality if the score was \u0026gt;\u0026thinsp;5, 3\u0026ndash;5, or \u0026lt;\u0026thinsp;3 respectively.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eThe SMD (standardized mean difference), Hedge\u0026rsquo;s g of each study was computed manually (accounting for paired and non-paired samples) based on the mean score and standard deviation of the depression scale in the intervention and comparison group post-treatment. Potential differences in sample sizes in the beginning and end of an intervention were accounted for through modified pooled standard deviation, where both sample sizes were included in addition to the sample size from the sham group, and the harmonic mean was used to account for changes in the intervention group. The effect sizes were synthesized by using the DerSimonian and Laird random effects model\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e in the statistics software R\u003csup\u003e21\u003c/sup\u003e. The random effects model was applied\u003csup\u003e,\u003c/sup\u003e since the studies were estimating related but different effect sizes due to variations in study design, surgical procedure, stimulation duration, depression rating scale, etc\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. A two-way p-value of \u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e\u003cp\u003eStatistical heterogeneity was assessed by I\u003csup\u003e2\u003c/sup\u003e, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026lt;\u0026thinsp;50% was considered low.\u003c/p\u003e\u003cp\u003eFor sensitivity analysis\u003csup\u003e,\u003c/sup\u003e different meta-analyses were conducted where:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eOnly the results of RCTs for estimating the pooled effect size were included.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eStudies were excluded when the data from patients with unipolar and bipolar depression could not be separated.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eStudies were used when upfront randomization or blinded discontinuation were used.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eOnly medium and high quality RCTs were included.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eOnly medium and high quality non-RCTs were included.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eMeta-regression analysis was performed in R to identify potential moderator variables that might have influenced the effect sizes\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. The included potential moderators were age, gender, stimulation length in the controlled trial phase, duration of the current depressive episode at the study entry\u003csup\u003e,\u003c/sup\u003e stimulation optimization duration, long-term follow-up duration, upfront randomization or blinded discontinuation. Effect sizes from two different DBS targets vs. sham in the studies by Raymaekers et al. (2017)\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e were considered separately in the meta-analysis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003ePublication Bias\u003c/h2\u003e\u003cp\u003eFunnel plots were used to evaluate bias and plot asymmetry. Additionally, Egger\u0026rsquo;s test was utilized to quantitatively assess the asymmetry in the funnel plot. Finally, the non-parametric trim-and-fill method\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e was applied to detect whether any studies should be imputed in calculating the pooled effect sizes, possibly adjusting these effects.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe initial search returned 1864 results (1082 after removal of duplicates); these were all screened for relevance based on title and abstract. Following this selection, 245 articles remained. Articles were then filtered by full-text screening based on the previously described inclusion/exclusion criteria. A total of 11 articles remained, which were all quantitatively analyzed. A PRISMA flow diagram illustrating the search procedure can be seen in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e189 unique patients were included in the meta-analysis\u003csup\u003e;\u003c/sup\u003e the number of patients with unipolar depression was 187, and the number of patients with bipolar depression was 2. The average stimulation duration (trial phase) was 20.13 weeks. Some studies reported a follow-up extension period, where changes in pharmacotherapy were allowed concurrently with DBS or DBS parameters were adjusted to induce greater clinical efficacy.\u003c/p\u003e\u003cp\u003eThe mean age of subjects across all studies was 49.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.9 years. All studies were blinded, and, among the included studies, 4/11 utilized a crossover design with patients functioning as their own controls. Eight of the studies included were RCTs (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Inclusion criteria and the definition of TRD differed from study to study. HAMD measures for inclusion ranged from \u0026ge;\u0026thinsp;17 to \u0026ge;\u0026thinsp;21 and MADRS from \u0026ge;\u0026thinsp;21 to \u0026ge;\u0026thinsp;26. Most studies defined TRD as a failure of four adequate antidepressant trials and ECT, analogous to stage V resistance described by Thase et al. in their seminal study of TRD\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. All studies utilized a definition of TRD where at least two adequate antidepressant trials had failed to alleviate depressive symptoms. The definition of TRD in each study can be found in Supplementary Table S1.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummary of study characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"14\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAuthor (Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNational setting\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStudy design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSample size (female %)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMean/SD age at disease onset (years)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMean age at study entry (years)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStimulation target(s)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eStimulation duration (Trial phase) (weeks)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eOptimization phase\u003c/p\u003e\u003cp\u003e(weeks)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eFollow-up duration after trial phase (weeks)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003eDepression scale\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c13\"\u003e\u003cp\u003eHedge\u0026rsquo;s g\u003c/p\u003e\u003cp\u003e(g\u0026thinsp;\u0026lt;\u0026thinsp;0\u0026thinsp;=\u0026thinsp;favors active stimulation)\u003c/p\u003e\u003cp\u003e(g\u0026thinsp;\u0026gt;\u0026thinsp;0\u0026thinsp;=\u0026thinsp;favors sham stimulation)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c14\"\u003e\u003cp\u003eQuality Assessment\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBergfeld et al. (2016)\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eThe Netherlands\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRCT (crossover)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16 (NA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e37.8 \u0026plusmn;\u003c/p\u003e\u003cp\u003e(9.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e53.1\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;8.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVentral anterior limb of the IC (internal capsule)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eHAMD-17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-1.55\u003c/p\u003e\u003cp\u003e[-2.35; -0.90]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCoenen et al. (2019)\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGermany\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003cp\u003e(parallel)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16 (38)\u003c/p\u003e\u003cp\u003e[1 BPIID]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e28.5\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;9.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e51.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSuperolateral MFB (medial forebrain bundle)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eMADRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-0.65\u003c/p\u003e\u003cp\u003e[-1.59; 0.32]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDougherty et al., (2015)\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003cp\u003e(parallel)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e29 (45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e47.7\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;12.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVC/VS (Ventral Capsule/Ventral Striatum)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eMADRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.11\u003c/p\u003e\u003cp\u003e[-0.60; 0.82]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFenoy et al.\u003c/p\u003e\u003cp\u003e(2018)\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eControlled trial (single blinded)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6 (60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e15.2\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;6.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e50.2\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;10.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSuperolateral MFB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e52***\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eMADRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-0.30\u003c/p\u003e\u003cp\u003e[-1.39; 0.80]\u003c/p\u003e\u003cp\u003e**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFenoy et al.\u003c/p\u003e\u003cp\u003e(2022)\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eControlled trial (single blinded)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e22\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;4.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e50.8\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSuperolateral MFB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e600 (5 years) ***\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eMADRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.94\u003c/p\u003e\u003cp\u003e[-0.48; 2.28]\u003c/p\u003e\u003cp\u003e**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHoltzheimer et al. (2012)\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eControlled trial (single blinded)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10 (NA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20.3\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;5.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e40.0\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;9.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSCC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e144 (2 years)\u003c/p\u003e\u003cp\u003e+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eHAMD-17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-1.64\u003c/p\u003e\u003cp\u003e[-2.80; -0.83]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eMedium\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHoltzheimer et al. (2017)\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003cp\u003e(parallel)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e85 (NA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e50.5\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;9.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSCC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e144 (2 years)++\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eMADRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-0.17\u003c/p\u003e\u003cp\u003e[-0.63; 0.29]\u003c/p\u003e\u003cp\u003e+++\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMerkl et al.\u003c/p\u003e\u003cp\u003e(2018)\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGermany\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003cp\u003e(parallel)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8 (13)\u003c/p\u003e\u003cp\u003e[1 BPID]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e28.6\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;9.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e48.3\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;12.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSCC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e144 (24 months) ******\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eHAMD-24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.53\u003c/p\u003e\u003cp\u003e[-0.73; 1.75]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePuigdemont et al.\u003c/p\u003e\u003cp\u003e(2015)\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSpain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRCT (crossover)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5 (N/A)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e23.2\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e47.2\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;13.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSCC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eHAMD-17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-0.53\u003c/p\u003e \u003cp\u003e[-1.76; 0.49]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRamasubbu et al.\u003c/p\u003e\u003cp\u003e(2013)\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCanada\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRCT (crossover)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e50.2\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e50.3\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;3.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSCC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eHAMD-17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-0.49\u003c/p\u003e\u003cp\u003e[-1.88; 0.63]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRaymaekers et al.\u003c/p\u003e\u003cp\u003e(2017)\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eThe Netherlands \u0026amp; Belgium\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRCT (crossover)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCrossover 1 n\u0026thinsp;=\u0026thinsp;6\u003c/p\u003e\u003cp\u003eCrossover 2 n\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e\u003cp\u003e(NA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e35.3\u003c/p\u003e\u003cp\u003e\u0026plusmn;\u0026thinsp;8.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e50.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2 (at cross over 1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVentral anterior limb of the IC \u0026amp; ITP\u003c/p\u003e\u003cp\u003e(Inferior Thalamic Peduncle)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e22 (5 months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e156 (3 years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eHAMD-17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eIC vs sham:\u003c/p\u003e\u003cp\u003e-1,24\u003c/p\u003e \u003cp\u003e[-2.11; -0.34]\u003c/p\u003e\u003cp\u003eITP vs sham:\u003c/p\u003e\u003cp\u003e-0,58 [-1.81; 0.42]\u003c/p\u003e\u003cp\u003eIC vs ITP (g\u0026thinsp;\u0026lt;\u0026thinsp;0\u0026thinsp;=\u0026thinsp;favors IC DBS\u003c/p\u003e\u003cp\u003e(g\u0026thinsp;\u0026gt;\u0026thinsp;0\u0026thinsp;=\u0026thinsp;favors IT DBS):\u003c/p\u003e\u003cp\u003e-0,21 [-1.42; 0.92]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"14\"\u003eBPID\u0026thinsp;=\u0026thinsp;Bipolar I Disorder, BPIID\u0026thinsp;=\u0026thinsp;Bipolar II Disorder, TRD\u0026thinsp;=\u0026thinsp;treatment-resistant depression, NA\u0026thinsp;=\u0026thinsp;not available, HAMD\u0026thinsp;=\u0026thinsp;Hamilton Depression Rating Scale, RCT: randomized controlled trial, MADRS: Montgomery-\u0026Aring;sberg Depression Rating Scale, SCC: Subcallosal cingulate gyrus, IC: internal capsule, MFB: medial forebrain bundle, * Data from the first year of the study was included, due to high dropout rate, **active outcome based on data from 26 weeks of stimulation. Although stimulation was continued for 52 weeks, patients were required to maintain the same medication for 6 months post-surgery,*** data from 1 year of follow-up included in subgroup meta analysis. ****active outcome\u0026thinsp;=\u0026thinsp;average of all active settings.***** Data from only 24 months was used for long-term follow-up analysis since data from all patients after 36 weeks (about 8 and a half months) were not available, ****** Data from only 24 weeks used for long-term follow-up analysis, data excluded from 28 weeks due to 50% drop out. + only 8 MDD patients remained after 2 years, not possible to separate BP from MDD patients for response rate analysis. ++ data from 2 years not included due to significant dropout rate in follow-up meta-analysis. For follow-up meta-analysis, data from n\u0026thinsp;=\u0026thinsp;82 was included, Data from 26 weeks (n\u0026thinsp;=\u0026thinsp;90) at baseline were included in a primary meta-analysis of controlled results compared to long-term active (n\u0026thinsp;=\u0026thinsp;30) baseline sham.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe meta-analysis of 11 included studies (189 patients) comparing DBS to sham treatment revealed that active DBS led to a greater reduction in depressive symptoms compared to sham, with Hedges\u0026rsquo; g = \u0026minus;\u0026thinsp;0.51, 95% CI [\u0026ndash;0.97; \u0026minus;\u0026thinsp;0.05], \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 64%. The non-parametric trim-and-fill analysis did not adjust the effect size (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e., Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e(a)).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummary of meta-analysis and sensitivity analysis (trial phase)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026minus;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of studies (subjects at baseline)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHedge\u0026rsquo;s g with\u003c/p\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAdjusted Hedge\u0026rsquo;s g with\u003c/p\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSignificant Moderators\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (189)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.51 [-0.97; -0.05]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham (only RCTs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (169)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.52 [-1.01, -0.04]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.19 [-0.76, 0.39]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham (only medium to high quality non-RCTs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-1.64\u003c/p\u003e\u003cp\u003e[-2.80; -0.83]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham (excluding studies with bipolar patients)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (165)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.58 [-1.10; -0.06]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham upfront randomization\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.35 [-1.07, 0.36]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.80 [-1.62, 0.015]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham blinded discontinuation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (140)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.65 [-1.30, 0.01]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.14 [-0.93, 0.66]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS SCC vs sham\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (112)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.47 [-1.13, 0.19]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS SCC vs sham (only RCTs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (102)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.18 [-0.56, 0.21]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS SCC vs sham (excluding studies bipolar patients)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (104)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.65 [-1.33, 0.04]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.24 [-0.99, 0.51]\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS IC vs sham\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.88 [-1.90, 0.14]\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.88 [-1.904, 0.14]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS MFB vs sham\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (26)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.12 [-0.97, 0.73]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.12 [-0.97, 0.73]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS MFB vs sham (RCT)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.65 [-1.60, 0.32]\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS MFB vs sham (excluding bipolar patients)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e0.25 [-0.96, 1.45]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eITP DBS vs. sham\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.58 [-1.70, 0.53]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e*Adjusted Hedge\u0026rsquo;s g values were calculated in STATA following the application of non-parametric trim-and-fill analysis for reducing publication bias by imputing more studies.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAfter excluding non-RCTs, the analysis of eight studies (169 patients) resulted in an effect size of g = \u0026minus;\u0026thinsp;0.52, 95% CI [\u0026ndash;1.01; \u0026minus;\u0026thinsp;0.04] (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003csup\u003e,\u003c/sup\u003e \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 62%. Six studies utilized upfront randomization, and the combined pooled effect size was g = -0.35, 95% CI [-1.07, 0.36], \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 59% (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In a separate comparison of internal capsule (IC) vs. inferior thalamic peduncle (ITP) DBS (5 patients), the effect size was g = \u0026minus;\u0026thinsp;0.21, 95% CI [\u0026ndash;1.38; 0.96] (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Egger\u0026rsquo;s test indicated publication bias in the pooled analysis of all studies, that had a long-term follow-up phase (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e\u003cp\u003eThe overall pooled response rate was r\u0026thinsp;=\u0026thinsp;0.56, 95% CI [0.36; 0.76], \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 92% (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e(a)). When non-RCTs were excluded, the response rate adjusted to r\u0026thinsp;=\u0026thinsp;0.48, 95% CI [0.25; 0.70], \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 91% (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Furthermore, upfront randomization vs. blinded discontinuation as a moderator was also significant in DBS vs sham (excluding studies with bipolar patients, response rate) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Eight studies (166 patients) conducted open-label long-term follow-up, yielding a pooled effect size of g = \u0026minus;\u0026thinsp;1.12, 95% CI [\u0026ndash;1.89; \u0026minus;\u0026thinsp;0.36], \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 74% (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummary of response rate meta-analysis\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of studies (subjects)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHedge\u0026rsquo;s g with\u003c/p\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAdjusted Hedge\u0026rsquo;s g with\u003c/p\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSignificant Moderators\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (166)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.56 [0.36; 0.76]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.29 [0.0184, 0.55]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham (only RCTs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (146)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.48 [0.25, 0.70]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.010.26 [-0.01, 0.53]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham (excluding studies with bipolar patients)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (142)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.54 [0.30, 0.77]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.28 [-0.02, 0.58]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUpfront randomization vs blinded discontinuation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham (only medium to high quality non-RCTs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.92 [0.65, 0.99]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham upfront randomization\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.81 [0.56, 1.06]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham blinded discontinuation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (122)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.37 [0.20, 0.54]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.31 [0.09, 0.52]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS SCC vs sham\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (107)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.50 [0.19, 0.82]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.28 [0.018, 0.55]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS SCC vs sham (only RCTs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (97)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.28 [0.18, 0.38]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.26 [-0.01, 0.53]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS SCC vs sham (excluding studies bipolar patients)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.56 [0.15, 0.96]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.26 [-0.19, 0.70]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS IC vs sham\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.46 [-0.01, 0.93]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS MFB vs sham\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (26)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.79 [0.59, 1.00]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS MFB vs sham (RCT)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.88 [0.64, 0.97]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS MFB vs sham (excluding bipolar patients)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.66 [0.35, 0.88]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e*Adjusted Hedge\u0026rsquo;s g values were calculated in STATA following the application of non-parametric trim-and-fill analysis for reducing publication bias by imputing more studies.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummary of meta-analysis and sensitivity analysis (long term follow-up phase)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026minus;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of studies (subjects)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHedge\u0026rsquo;s g with\u003c/p\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAdjusted Hedge\u0026rsquo;s g with\u003c/p\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSignificant Moderators\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (166)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-1.12 [-1.89; -0.36]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026minus;\u0026thinsp;0.59 [-1.64, 0.46]\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham (only RCTs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (146)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.80 [-1.29, -0.30]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.41 [-0.98, 0.16]\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUpfront Randomization or Blinded discontinuation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham (excluding studies with bipolar patients)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (142)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-1.08 [-2.12; -0.04]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham (only medium to high quality non-RCTs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-1.64 [-2.8; -0.83]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham upfront randomization\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-1.73 [-3.29, -0.18]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS vs sham blinded discontinuation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (122)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.49 [-0.86, -0.13]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.40 [-0.75, -0.05]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS SCC vs sham\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (107)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-1.42 [-3.07, 0.23]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.43 [-2.27, 1.40]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS SCC vs sham (only RCTs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (97)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.47 [-0.92, -0.01]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.37 [-0.78, 0.0371]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS SCC vs sham (excluding studies bipolar patients)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-1.63 [-3.94, 0.69]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-1.63 [-3.95, 0.69]\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS IC vs sham\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.73 [-1.61, 0.16]\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS MFB vs sham\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (26)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-1.09 [-2.52, 0.33]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNne\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS MFB vs sham (RCT)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-1.80 [-2.77, -0.81]\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt; 0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBS MFB vs sham (excluding bipolar patients)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026minus;\" colname=\"c3\"\u003e\u003cp\u003e-0.35 [-0.53, 1.45]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo adjustments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e*Adjusted Hedge\u0026rsquo;s g values were calculated in STATA following the application of non-parametric trim-and-fill analysis for reducing publication bias by imputing more studies.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eNumber of subjects in baseline is included.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003eILLUSTRATIONS\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u0026#129128; Favors ACTIVE Favors SHAM \u0026#129130;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e(b) SCC DBS vs. sham (all studies included)\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e \u0026#129128; Favors ACTIVE Favors SHAM \u0026#129130;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e(c) IC DBS vs. sham (all studies included)\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e \u0026#129128; Favors ACTIVE Favors SHAM \u0026#129130;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e(d) MFB DBS vs. sham (all studies included)\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFor the long-term follow-up, the exclusion of non-RCTs resulted in six studies, yielding g = \u0026minus;\u0026thinsp;0.80, 95% CI [\u0026ndash;1.29; \u0026minus;\u0026thinsp;0.30], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 42% (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The trim-and-fill analysis adjusted the effect size to g = \u0026minus;\u0026thinsp;0.41, 95% CI [\u0026ndash;0.98; 0.16]. When studies involving bipolar patients were excluded, the meta-analysis of DBS vs. sham produced an effect size of g = -1.08, 95% CI [\u0026ndash;2.12; \u0026minus;\u0026thinsp;0.04\u003csup\u003e],\u003c/sup\u003e \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 68% (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Five studies specifically assessed SCC DBS vs. sham, with an effect size of g = \u0026minus;\u0026thinsp;0.47, 95% CI [\u0026ndash;1.13; 0.19], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05, \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 58% (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e(b)). Excluding non-RCTs in the analysis of SCC DBS vs. sham adjusted the result to g = \u0026minus;\u0026thinsp;0.18, 95% CI [\u0026ndash;0.56; 0.21], \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 47% (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). For medial forebrain bundle (MFB) DBS vs. sham (26 patients), the effect size was g = \u0026minus;\u0026thinsp;0.12, 95% CI [\u0026ndash;0.97; 0.73], \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 43% (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e(d)). Since all the RCTs were of high quality, no further sensitivity analysis was required. Accordingly, only high quality RCTs were included in the relevant analyses. Age was found to be a significant moderator in the analysis of DBS vs. sham (all studies included, long-term follow-up), and DBS vs. sham (excluding studies with bipolar patients, long-term follow-up). Upfront randomization vs. blinded discontinuation was a significant moderator in the analysis: DBS vs. sham (only RCTs, long-term follow-up) (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The most relevant funnel plots are presented in (Figs.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis paper analyzed the efficacy of DBS as a treatment for TRD \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Corroborating earlier reports, DBS significantly alleviated depressive symptoms in TRD patients. Meta-analysis yielded a medium-large\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e effect size comparing DBS to sham, with a Hedges\u0026rsquo; g = \u0026minus;\u0026thinsp;0.51, 95% CI [\u0026ndash;0.97; \u0026minus;\u0026thinsp;0.05]. Additionally, meta-analysis of DBS vs. sham (excluding non-RCTs) yielded a SMD of g = \u0026minus;\u0026thinsp;0.52, 95% CI [\u0026ndash;1.01; \u0026minus;\u0026thinsp;0.04], which suggests that DBS represents a possible alternative when conventional treatment strategies fail. Analysis of the different targets showed that SCC as DBS target has greater efficacy than sham g = \u0026minus;\u0026thinsp;0.47, 95% CI [\u0026ndash;1.13; 0.19]. Furthermore, the sensitivity analysis of SCC DBS vs sham (excluding non-RCTs) did not yield significant difference g = \u0026minus;\u0026thinsp;0.18, 95% CI [\u0026ndash;0.56; 0.21]. Consequently, future RCTs with bigger sample sizes are required to assess whether SCC DBS outperforms sham surgery. Most of the RCTs had small sample sizes, resulting in wider confidence intervals and greater uncertainty in interpreting the results. Patient-specific stimulation design in RCTs, originally guided by MRI/CT scans\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e and now by diffusion tractography\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e, vary in both target location and stimulation settings (amplitude, pulse width, frequency)\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. The chosen settings critically influence clinical outcomes, highlighting the need for individualized treatment protocols.\u003c/p\u003e\u003cp\u003eAge was found to be a significant moderator in the analysis of DBS vs. sham (all studies included, long-term follow-up), and upfront randomization vs. blinded discontinuation as a moderator variable was also significant in DBS vs. sham (only RCTs, long-term follow-up). These findings suggest that age and stimulation strategy could play a role in how well patients respond to DBS over time. However, these findings are based on a few studies, and no moderator was consistently significant across all sensitivity analyses; consequently, current evidence remains too limited for firm conclusions.\u003c/p\u003e\u003cp\u003ePrior meta-analyses have also assessed the efficacy of DBS in TRD. All have demonstrated significantly better results with active stimulation compared to sham\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. A meta-analysis of Hitti and colleagues\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e yielded similar results to the current study. The authors found DBS to be better than sham overall in the trial phase. The differences can be attributed to the inclusion of the study by Fenoy et al. and accounting for changes in sample sizes during the time course of some of the trials\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Furthermore, in studies where patients underwent sham stimulation before active stimulation, we used the difference between sham and corresponding active stimulation endpoints to account for possible insertional effects.\u003c/p\u003e\u003cp\u003eAdditionally, when calculating the effect sizes for individual studies, no considerations regarding paired or unpaired samples were made. The differing efficacies reported by literature may be attributed to multiple factors\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Firstly, the neurophysiological properties of depression vary from individual to individual, making it difficult to pinpoint which target(s) is ideal for DBS\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Current studies do not fully account for these neurobiological differences. Secondly, it is yet to be explored whether non-responders to DBS of one brain target region may benefit from stimulation of an alternative target\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. However, the neurosurgical nature of DBS treatment limits these possibilities. Thirdly, differing efficacy may relate to the accuracy of measurement of treatment outcomes. As noted by Rabin et al.\u003csup\u003e34\u003c/sup\u003e, suboptimal measures of outcomes stand in the way of truly recognizing signs of effective treatment. While depression rating scales are generally acknowledged for assessing depression, they do present some inadequacies, especially when synthesizing data in meta-analyses\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eFor instance, multiple versions of the HAMD scale were used in the literature, despite all versions being tailored to different uses and including different domains of assessment. This may lead to overestimation of the importance of certain factors, depending on which scale is used. This, of course, extends to differences between HAMD and other rating scales, such as MADRS.\u003c/p\u003e\u003cp\u003eA great advantage of DBS is that active/sham stimulation can be compared within the same patient. This reduces inter\u003csup\u003e\u0026minus;\u003c/sup\u003esubject variability and allows for greater statistical power with fewer participants. This advantage was reflected in the included trials that utilized crossover design. However, the two largest of the included trials both used a parallel design analysis\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Both studies reported substantially lower efficacy of active stimulation compared to sham. A possible explanation for this discrepancy, as noted in the study by Raymaekers et al.\u003csup\u003e23\u003c/sup\u003e, is that subjects were able to correctly \u0026ldquo;guess\u0026rdquo; whether stimulation was on or off, which suggests that adequate blinding was not achieved.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eLimitations and direction for future research\u003c/h2\u003e\u003cp\u003eMost studies utilized various versions of HAMD, which have been criticized for being flawed and incapable of depicting depression severity, as well as some of the main aspects of depression\u003csup\u003e,\u003c/sup\u003e e.g. feelings of worthlessness and anhedonia\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. Furthermore, some evidence suggests that the total score of HAMD, which was utilized in the present study, does not adequately reflect depression severity\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. However, a more recent critical review of various forms of HAMD validated the scale and reported it as being sensitive\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. MADRS was utilized as well in some studies\u003csup\u003e;\u003c/sup\u003e however\u003csup\u003e,\u003c/sup\u003e this scale has been criticized for being less sensitive in detecting treatment effects compared to HAMD\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAnother limitation may be the lack of a coherent definition for TRD in scientific literature. Some studies resorted to defining TRD as the failure of response to multiple adequate trials of various antidepressants, while others utilized a staging approach such as the Thase-Rush five-stage classification. Nevertheless\u003csup\u003e,\u003c/sup\u003e further evidence is required to assess the efficacy of such staging models\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. A consensus that seems to emerge is to define TRD as a failure of response to at least two adequate trials of antidepressants\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eFuture studies should consider utilizing large-scale double\u003csup\u003e\u0026minus;\u003c/sup\u003eblinded RCT designs and utilize a better definition of TRD, where consensus is emerging. Additionally, researchers should consider the most appropriate depression scale based on their approach for assessing treatment efficacy; for instance, if the goal is to assess the different severity levels of depression, then HAMD-17 can be utilized. Conversely, if treatment efficacy of DBS is compared to sham, then HAMD-6 may be better suited\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. An optimal study design for future trials should consider methods of blinding patients, where patients are not able to \u0026ldquo;guess\u0026rdquo; whether DBS is on or off, as reported in the study by Raymaekers et al \u003csup\u003e23\u003c/sup\u003e. Future studies should compare DBS to a specific type of conventional treatment for TRD such as lithium or ECT.\u003c/p\u003e\u003cp\u003eAdvances in target-localization methodologies, from conventional anatomical MRI to individualized tractography, indicate that DBS efficacy in TRD is contingent upon both the selected anatomical target and the fiber bundle. Consequently, a singular \u0026ldquo;one-target-fits-all\u0026rdquo; is unlikely to optimize therapeutic outcomes across the heterogeneous TRD population. Future clinical trials should therefore consider personalized targets, rather than restricting DBS to a single region such as SCC, to enhance the efficacy and reproducibility of DBS interventions in TRD.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe results obtained indicate that DBS, when performed correctly at the correct target in the correctly identified patient\u003csup\u003e,\u003c/sup\u003e is potentially superior to sham. DBS indicated greater efficacy compared to sham in clinical trial phase and long-term follow-up phase. The pooled response rate after long-term follow-up was found to be 56%.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\u003cp\u003eNot applicable\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eNot applicable\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eData sharing\u003c/h2\u003e\u003cp\u003eUpon request additional data is available\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eSupplementary materials\u003c/h2\u003e\u003cp\u003eThe following search string was used for pubmed: (\"depres*\"[All Fields] OR \"Depressive disorder\"[All Fields] OR \"Major depression\"[All Fields]) AND (\"refractory treat*\"[All Fields] OR \"Failed treatment\"[All Fields] OR \"treatment resist*\"[All Fields] OR \"drug resist*\"[All Fields] OR \"Intractable\"[All Fields] OR \"Unmanageable\"[All Fields] OR \"Unresponsive\"[All Fields]) AND (\"DBS\"[All Fields] OR \"Deep Brain Stimulation\"[All Fields]) AND (\"Placebo\"[All Fields] OR \"compar*\"[All Fields] OR \"sham*\"[All Fields] OR (\"set\"[All Fields] AND \"against\"[All Fields]) OR \"Relation\"[All Fields])\u003c/p\u003e\u003cp\u003eSimilar search terms were utilized for the other databases.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eNo funding has been provided\u003c/p\u003e\u003ch2\u003eAuthor contributions\u003c/h2\u003e\u003cp\u003eStudy design: All authors. Screening of literature: AS, HA and VA. Data extraction and statistical analysis: AS and HA. Manuscript first draft: AS and HA. Manuscript editing and reviewing: AS, HA, CB, and TM. All authors have read and approved the final revised version of this manuscript\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eThe authors wish to thank Professor Helen S. Mayberg\u003csup\u003e,\u003c/sup\u003e Icahn School of Medicine at Mount Sinai, New York, for providing unpublished data regarding patients with treatment-resistant unipolar depression. Dr. Mohtadin Hashemi is acknowledged for giving feedback on the final draft of the paper.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJames SL et al (2018) Global, regional, and national incidence, prevalence, and years lived with disability for 354 Diseases and Injuries for 195 countries and territories, 1990\u0026ndash;2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 392:1789\u0026ndash;1858\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSander J, Moessner M, Bauer S (2021) Depression, anxiety and eating disorder-related impairment: Moderators in female adolescents and young adults. Int J Environ Res Public Health 18:1\u0026ndash;12\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNutt DJ, Wilson S, Paterson L (2008) Sleep disorders as core symptoms of depression. 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Arch Gen Psychiatry 69:150\u0026ndash;158\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Aalborg University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7736553/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7736553/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eMost conventional treatments for MDD (major depressive disorder\u003csup\u003e)\u003c/sup\u003e fail to demonstrate significant results, which highlights an urgent need for novel treatments. DBS (deep brain stimulation\u003csup\u003e)\u003c/sup\u003e has shown great promise in several clinical trials. However, the efficacy of DBS, compared to conventional treatments for patients with TRD \u003csup\u003e(\u003c/sup\u003etreatment\u003csup\u003e\u0026minus;\u003c/sup\u003eresistant depression\u003csup\u003e)\u003c/sup\u003e, and the targets with highest efficiency for treatment of TRD remain understudied objectives.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA systematic search in PubMed, ProQuest Dissertations and Theses Global, Embase, PsycINFO, and Scopus accompanied by a hand search in journals and grey literature was conducted in (January 10th, 2025\u003csup\u003e)\u003c/sup\u003e. Any controlled trial with at least one group for comparison such as sham group was included. A random-effects meta-analysis was performed, quantitatively probing the efficacy of DBS vs sham/placebo for patients with TRD. A meta-analysis of response rate after long\u003csup\u003e\u0026minus;\u003c/sup\u003eterm follow-up was also conducted. In addition, a meta-regression analysis was implemented to detect potentially moderating variables. Quality assessment was performed by utilizing the NOS (Newcastle Ottawa Scale\u003csup\u003e)\u003c/sup\u003e and Jadad scale.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003e1744 records were identified and screened for relevance, among which 14 were included in the quantitative analysis. Meta-analysis of the included studies revealed a medium-large effect size (SMD (standardized mean difference) Hedge\u0026rsquo;s g = -0.51) in favor of active stimulation compared to sham. In the sensitivity analysis the effect size was statistically insignificant only when randomized controlled trials were included. The effect size and pooled response rate after long-term follow-up was = -1.12 and 56.14%, respectively.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThe results indicate that DBS is potentially favorable for TRD compared to sham, as DBS exhibited greater efficacy compared to sham in both clinical trial and long-term follow-up phases. Further large-scale evidence-based studies, however, are required to substantially support these findings.\u003c/p\u003e","manuscriptTitle":"Deep brain stimulation is beneficial for treatment-resistant depression: A systematic review and meta–analysis of clinical trials and long-term follow-ups","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-30 16:38:12","doi":"10.21203/rs.3.rs-7736553/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"572f6fa1-2d35-44d7-8040-231ca5126754","owner":[],"postedDate":"September 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":55463764,"name":"Neurology"}],"tags":[],"updatedAt":"2025-09-30T16:38:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-30 16:38:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7736553","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7736553","identity":"rs-7736553","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}