Hippocampal Gray Volumes Increase in Treatment-Resistant ...

ORIGINAL STUDY

Hippocampal Gray Volumes Increase in Treatment-Resistant Depression Responding to Vagus Nerve Stimulation Giulia Ida Perini, MD,*† Tommaso Toffanin, PhD,* Giorgio Pigato, MD,* Giovanni Ferri, PhD,*‡ Halima Follador, PhD,*§ Filippo Zonta, MD, PhD,*§ Carlo Pastorelli, MD,|| Giulia Piazzon, MD,* Luca Denaro, MD,¶ Giuseppe Rolma, MD,# Mario Ermani, MD,** and Domenico D'Avella, MD¶

Background: Changes in hippocampal gray matter volumes are proposed to be involved in pathogenesis, course, and treatment response of major depressive disorder. Converging evidence suggests that reduced neurogenesis may occur in treatment-resistant depression (TRD). Vagus nerve stimulation (VNS) is a well-defined, long-term brain stimulation treatment for TRD. However, its in vivo positive effect on hippocampal modulation as mechanism of action has never been investigated before in clinical studies. In this study, we intended to explore hippocampal volumetric changes and clinical antidepressant responses in patients with TRD after 6 and 12 months of treatment with VNS. Methods: The TRD outpatients were evaluated for VNS implantation. Right and left hippocampal volumes in 6 TRD patients, who met the criteria for VNS treatment, were measured at baseline before the implantation and after 6 and 12 months. The patients were assessed using Beck Depression Inventory and Hamilton Depression Rating Scale at baseline and at follow-up visits. Results: There was a statistically significant and progressive increase in right and left hippocampal volumes during the follow up (P < 0.05). Furthermore, patients showed a significant improvement on Hamilton Depression Rating Scale and Beck Depression Inventory scores (P < 0.05). Conclusions: Our data suggest a VNS modulatory effect on hippocampal plasticity as measured by hippocampal gray volume increase in TRD patients. These preliminary findings indicate the fundamental role of hippocampal remodeling as a marker of response to VNS in TRD. Key Words: treatment-resistant depression, vagus nerve stimulation, hippocampus, magnetic resonance imaging (J ECT 2017;00: 00–00)

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ajor depressive disorder (MDD), one of the most prevalent mental disorders worldwide, has a profound effect on public health. The Global Burden of Disease Study 2010 indicates that major depression is a leading cause of disability-adjusted life years worldwide, accounting for 40% to 50% of disability-adjusted life years caused by mental and substance use disorders.1,2 Despite the widespread availability of effective treatments for depression, many patients do not achieve adequate symptomatic relief.2 In fact, 20% to 40% of patients do not respond to currently available antidepressant treatments; one-third to one-half of patients did not

From the *Department of Neurosciences, Section of Psychiatry, UniversityHospital of Padova, Padova; †Casa di Cura Parco dei Tigli, Teolo, Padova; ‡Department of Psychiatry, ULSS 6, Padova; §Department of Psychiatry, ULSS 2, Treviso; ||Private Practitioner in Psychiatry, Padova; and ¶Neurosurgery Unit, #Neuroradiology Unit, and **Section of Neurology, Department of Neurosciences, University-Hospital of Padova, Padova, Italy. Received for publication July 10, 2016; accepted April 14, 2017. Reprints: Tommaso Toffanin, MD, PhD, Department of Neurosciences, Section of Psychiatry, University-Hospital of Padova, via Nicolò Giustianiani, 2 35121 Padova, Italy (e‐mail: [email protected]). The authors have no conflicts of interest or financial disclosures to report. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/YCT.0000000000000424

Journal of ECT • Volume 00, Number 00, Month 2017

respond to several weeks of treatment in a randomized clinical trial,3 and approximately one-third of patients did not achieve remission after 4 trials of treatment in the largest pragmatic trial for depression, Sequenced Treatment Alternatives to Relieve Depression study.4 Although failure to an adequate response to antidepressant treatment is very frequent, there is no universally accepted definition for treatment-resistant depression (TRD). Among several proposed definitions of TRD, the most commonly accepted one refers to a situation in which a major depressive episode (both of a unipolar or bipolar disorder) has failed to respond after 2 sequential, adequate-in-dose/duration, antidepressant trials.5 Brain stimulation techniques such as vagus nerve stimulation (VNS) have been successfully applied to a substantial proportion of patients, and VNS has been approved by the Food and Drug Administration in 2005 as “…adjunctive long-term treatment of chronic or recurrent depression for adult patients experiencing a major depressive episode who had failed to respond to 4 or more adequate antidepressant treatments.” Recent guidelines indicate VNS as a third-line acute treatment, with a recommendation for maintenance treatment in chronic patients with poor pharmacological treatment adherence.6 Volumetric changes in mood-relevant distributed limbic/ paralimbic neurocircuitry are important neurobiological correlates of recurrent MDDs.7 Structural changes in hippocampal gray matter volumes are proposed to be involved in the pathogenesis, the course, and the treatment response of MDD.7–10 Converging evidence suggests that patients with depression have a smaller hippocampal volume compared with healthy subjects; this hippocampal reduction has been related to MDD recurrent/chronic clinical course and poor response to antidepressant therapy.9,11–15 Reduced neurogenesis may be a final common pathogenetic pathway in recurrent/resistant MDD, being present both as a vulnerability trait in genetically predisposed patients7 and as result of the “biological scars” (memory) of having multiple severe and recurrent episodes with early and late activation of stress-related systems, likely through an epigenetic mechanism.16,17 On the other hand, neurogenesis has shown to be positively modulated by both plasticity-inducing stimuli (such as environmental enrichment, exercise, and electrical stimulation) and pharmacological and nonpharmacological treatments (eg, antidepressant medication and electroconvulsive therapy [ECT]) in preclinical and clinical models.8–20 Several antidepressant treatment strategies in depressed patients increased hippocampal volumes in clinical studies.15–23 The VNS is considered a well-established, long-term brain stimulation treatment for TRD. Several mechanisms of action (MOA) have been proposed to explain its antidepressant/maintenance effect in MDD. However, its in vivo positive effect on hippocampal modulation as MOA has never been investigated before in clinical studies. In this study, we intended to explore hippocampal volumetric changes and clinical antidepressant responses in patients with TRD after 6 and 12 months of treatment with VNS. www.ectjournal.com

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MATERIALS AND METHODS Patient Selection Male and female outpatients, aged between 18 and 65 years and affected by unipolar TRD, were enrolled in this study at the Affective Disorders Clinic in the Department of Neurosciences of the University-Hospital of Padua. They met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic criteria for chronic (≥2 years) current major depressive episode (MDE) and/or a history of recurrent MDEs (at least 4 lifetime MDEs including the current MDE) with a minimum score of 18 points on the 21-item Hamilton Depression Rating Scale (HDRS).24 The TRD was defined as a depression that is nonresponsive to at least 2 treatments from different drug categories during the current MDE. Exclusion criteria included a concurrent or previous Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition axis I disorder other than TRD, alcohol or substance abuse/dependence or abuse within the previous 12 months, history of suicide attempts, acute suicidal behavior or ideation, significant current unstable medical diseases, and known neurological diseases or a contraindication to VNS or magnetic resonance imaging (MRI) scanning. The study was conducted according to the Declaration of Helsinki25 and Good Clinical Practice. It was approved by institutional review board of University-Hospital of Padua. All participants gave written informed consent to participate after our complete description of the study's procedures.

Clinical Assessment An extensive psychiatric and medical assessment was performed by completing a personal and family medical history, a mental status examination, and a structured mini-international neuropsychiatric interview.26 The 21-item HDRS and the Beck Depression Inventory (BDI)27 were used to assess the severity of depressive symptoms at the following assessment time points: before VNS implantation (T0) and at 6 and 12 months after device activation (T1 and T2, respectively). Treatment resistance was measured by using an antidepressant resistance rating score of 3 or higher, obtained with the modified version of the Antidepressant Treatment History Form (ATHF).28 In each subject, the handedness, years of education, age at onset of illness and of current MDE, length of illness and of current MDE, and the number of previous depressive episodes were recorded. Of 12 screened individuals, 6 patients (4 males and 2 females) were enrolled and implanted with a VNS device. Demographic and clinical characteristics of the participants are listed

in Table 1. Of the 5 outpatients who were excluded, 1 presented with atrial fibrillation, 1 had a history of latero-cervical surgery for a previous lymphoma, 1 responded to a medication change, and 2 had not given consent to intervention and follow-up. One patient was still in the optimization phase of the pharmacological treatment. All patients met or exceeded the eligibility criteria by failing at least 2 robust treatment trials in the current MDE according to the ATHF.28 To qualify, each drug had to be used at doses of established efficacy for a period sufficient enough (eg, at least 4 weeks) to verify that the drug was ineffective.29,30 The clinical course of disease was monitored, and the pharmacological therapy was optimized for at least 8 weeks before the VNS intervention. This time was also necessary to educate patients on the VNS procedure and its efficacy and adverse effects. The patients were treated with antidepressants, benzodiazepines, and/or second generation antipsychotics and/or mood stabilizers (Table 2). In the first year after VNS surgery, doses and type of medications were not changed.

VNS Intervention and Follow-up The VNS is delivered by neurocybernetic prosthesis system (Cyberonics, Houston). Surgical intervention for the device application was performed at the Neurosurgery Unit of the Department of Neurosciences at the University-Hospital of Padua. The patients were hospitalized for 48 hours to perform presurgical routine examination, anesthesiology visit, and a baseline MRI acquisition. Intervention took 1 to 2 hours under general anesthesia; no surgical complications were observed, and mean recovery time of the surgical wounds was 2 weeks. After completion of the 2-week, postimplantation, single-blind “recovery period,” the device was turned on with initial stimulation parameters, including current, frequency, and pulse width at 0.25 mA, 20 or 30 Hz, and 500 milliseconds, respectively. All stimulation cycle were set to 30 seconds of stimulation every 5 minutes (30/5). At this visit, the output current was increased gradually (in 0.25-mA increments) to allow accommodation to the stimulation until a comfortable tolerance level was reached. After a comfortably tolerated output current was attained, the patient left the clinic with these parameter settings. Additional increases (in 0.25-mA steps) in output current were made any time during the “stimulation adjustment period” over the next 2 weeks. Stimulation parameter settings were determined based on patient tolerance. Investigators were allowed by protocol a range of frequency (eg, 20–30 Hz), pulse width (eg, 250–500 milliseconds), and on/off cycle (eg, off for 3 or 5 minutes) parameters.

MRI Acquisition TABLE 1. Demographic Features of VNS Sample Patients With VNS Age, y Sex (female/male) Handedness (right/left) Education, y Age at onset of illness, y Age at onset of current MDE, y Length of illness, y Length of current MDE, mo No. depressive episodes No. ADs lifetime (ATHF) ADs indicates antidepressants.

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Number

Mean (SD) 51.3 (9.5)

2/4 6/0 10.0 (2.74) 29 (5.5) 46.2 (8.9) 22.3 (7.2) 22.67 (22.3) 5.17 (1.60) 7.00 (1.26)

Baseline MRI acquisitions have been performed and repeated at 6 and 12 months after VNS activation using a 1.5 Tesla MRI system (Philips Medical Systems). A sequence sagittal T1weighted, magnetization-prepared, rapidly acquired gradient echo was acquired for volumetric measurements (repetition time = 10 milliseconds, echo time = 4 milliseconds, inversion time = 300 milliseconds, matrix size = 256 256, voxel resolution = 1 1 1.25 mm, slice thickness = 1.25 mm, and flip angle = 8degree angle). The sagittal images were aligned approximately parallel to the anterior-posterior commissure line. Axial proton density and T2-weighted images were obtained to enable the exclusion of structural abnormalities on the MRI scan. A boardcertified neuroradiologist reviewed all scans. The procedure was well tolerated by all subjects, and no sedation was used. During the MRI follow-up study, the device was deactivated, and all stimulation parameters were lowered at minimum, whereas off time was set at 180 minutes. The brain MRI protocol for safe procedure © 2017 Wolters Kluwer Health, Inc. All rights reserved.



Hippocampal Gray Volumes in TRD Responding to VNS

TABLE 2. Detail Pharmacological Treatment of VNS Sample Case 1 2 3 4 5 6

ADs

Benzodiazepines

Venlafaxine, 225 mg/d Duloxetine, 120 mg/d Mirtazapine, 30 mg/d Bupropion, 150 mg/d Mirtazapine, 15 mg/d Duloxetine, 60 mg/d Duloxetine, 120 mg/d Duloxetine, 120 mg/d Bupropion, 150 mg/d

Delorazepam, 6 mg/d Flurazepam, 30 mg/d

Valproic acid, 1500 mg/d

Lorazepam, 3 mg/d

Lamotrigine, 50 mg/d

Quetiapine ER, 300 mg/d

Valproic acid, 500 mg/d Carbamazepine, 800 mg/d Carbolithium, 600 mg/d Lamotrigine, 200 mg/d

Aripiprazole, 15 mg/d Olanzapine, 10 mg/d

Flurazepam, 30 mg/d

Mood Stabilizer

Atypical Antipsychotics Quetiapine, 400 mg/d

ADs indicates antidepressants; ER, extended release.

of VNS implanted in patient from Cyberonics was applied. The imaging data were transferred from the MRI unit to a PC workstation and analyzed using Analyze software (version 10.0, Biomedical Imaging Resource, Mayo Foundation, Rochester, MN).

Volumetric Analysis The volumes of brain regions of interest (ROIs) were based on stereologic estimation methods, which have been used with precision in magnetic resonance volumetry and are considered as the gold standard for volume estimation of subcortical structures.31,32 Sampling parameters and grid size were set to yield at least 150 “hits” per measurement, a number that has previously been determined to yield reliable measurements in brain volume determination.33,34 From 3-dimensional MRI images composed of 1.0 1.0 1.0–mm voxels, coronal slices were sampled every 1.0 mm for the hippocampus and every 20 mm for the whole brain. A 3 3–mm2 rigid grid of points for the hippocampus and a 20 20–mm2 grid for the whole brain with a random starting position and angle of deviation from the horizontal were then superimposed onto the images. These parameters were optimized to achieve a coefficient of error of less than 5%.32–35 Measurements were made in the coronal orientation, but all 3 orthogonal views were simultaneously displayed on the screen. Hippocampi were traced, referencing an anatomical atlas36 and a segmentation protocol for the hippocampus37 as previously described.7 In addition, the whole-brain volume was calculated, including both the grey and white matter above the superior border of the pons and excluding the cerebellum and cerebral spinal fluid. A ratio of the absolute right and left hippocampal volumes to whole-brain volume was used for comparison purposes. These ratio scores will be referred here in after to corrected volumes.

Statistics All data were statistically analyzed using Statistical Package for the Social Sciences version 16.0 for Windows (SPSS, Chicago, Illinois). Given the small sample size, the clinical outcome measures (HDRS and BDI) and the hippocampal volumes have been analyzed with nonparametric models. Friedman test was performed for comparison in test-retest analysis at T0, T1, and T2 followed by post hoc Wilcoxon test at T0 and T2. The statistical significance was set at P of less than 0.05.

RESULTS Outcome Measures The HDRS and BDI scores at baseline, 6, and 12 months are shown in Table 3. Although lack of adequate response to © 2017 Wolters Kluwer Health, Inc. All rights reserved.

antidepressant treatment is very frequent, post hoc analyses revealed that both the HDRS (Wilcoxon test: Z = −2201, P = 0.028) and BDI (Wilcoxon test: Z = −2201, P = 0.028) were significantly lower at 12 months relative to baseline. The data of clinical outcomes are presented in Figures 1A and 1B referring respectively to HDRS and BDI.

Hippocampal Volumes The right and left hippocampal volumes at baseline, 6, and 12 months are presented in Table 4. There was a statistically significant increase in the corrected volumes of the right and left hippocampus during the follow-up (Friedman test: χ2 = 6333, df = 2, P = 0.042; and χ2 = 7, df = 2, P = 0.03, respectively) and in post hoc analyses from baseline to 12 months (Wilcoxon test: Z = −1997, P = 0.046; and Z = −2201, P = 0.028, respectively) as can be seen in Figure 1C and 1D.

DISCUSSION In our study, we found significant bilateral volumetric MRI increases in the hippocampal gray matter of TRD patients who responded to VNS after 6 and 12 months of treatment. Our TRD patients with chronic or recurrent depression demonstrated a progressively increasing and significant clinical response to VNS after 6 and 12 months of active stimulation therapy as measured by both HDRS and BDI. These results are in line with those of the pivotal studies of VNS in resistant depression.30 Open-label studies, in fact, showed a reduction of HDRS depressive score from baseline after 10 weeks of acute phase stimulation with a response rate between 30% and 40% and remission rate between 15.3% and 17%.5–29 Moreover, an increase in VNS response rate over time has been reported from 3 months to 1 and 2 years, suggesting that VNS is effective in the acute treatment of TRD, but it may also prove more useful in the long-term maintenance treatment, because approximately 65% of the VNS responsive patients at 1 year maintained their response at 2 years.38,39 Furthermore, recent systematic reviews and meta-analyses of open-label studies have confirmed that the antidepressant effects of VNS may accrue over time. A patient-level meta-analysis (6 trials, N = 1460) of all randomized and open-label data with VNS TABLE 3. Psychometric Test Data Mean (SD) Comparison at 3 Times Measures HDRS, score BDI, score

Baseline

6 Mo

12 Mo

26.8 (7.85) 33.4 (18.55)

10.6 (2.30) 19.4 (13.45)

9.6 (4.01) 16.8 (12.46)

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FIGURE 1. Significant change in HDRS (A), BDI (B), and right (C) and left (D) hippocampal volumes.

found significantly higher odds ratios (ORs) for response (OR, 3.19) and remission (OR, 4.99) for VNS plus treatment as usual (TAU) compared with TAU alone. For patients who had responded to VNS plus TAU at 24 weeks, sustained response was more likely at 48 weeks (OR = 1.98) and 96 weeks (OR = 3.42).39–46 The Milev et al6 suggested that the longer term results with VNS seemed encouraging and that VNS can be considered for patients with chronic depression, particularly in situations where treatment adherence may be an issue. Our study has been designed to investigate a MOA of VNS that was never examined before in previous clinical studies: its modulatory effect on hippocampal plasticity as measured by hippocampal gray volumes in TRD patients. Our results confirm our hypothesis; in fact, we found a sustained bilateral increase of hippocampal gray volumes at 6 and 12 months in all 6 TRD patients. The increase of left and right hippocampal volumes paralleled the clinical response as measured by HDRS and BDI significantly decreased scores. To the best of our knowledge, this study is the first report on MRI volumetric increase in limbic structures with VNS, which suggests a possible modulatory role of VNS on hippocampal neurogenesis of TRD patients with good clinical response.

Several mechanisms underlying the therapeutic efficacy of VNS treatment in depression have been postulated by previous preclinical and clinical studies. Preclinical neurobiological studies suggested the idea that VNS acts directly by stimulating brainstem structures and indirectly by regulating the activity of neurons in limbic and cortical regions involved in mood modulation.41 The possible antidepressant mechanisms tested in preclinical studies of the action of VNS on hippocampal plasticity are: 1. increased monoaminergic neurotransmission mediated through VNS stimulation of the nucleus tractus solitarii–locus coeruleus stimulation, which has an antidepressant-like effect in animal model (forced swim test)42–44; 2. VNS-induced increase in noradrenaline in hippocampus,45,46 which has neuroplasticity effects41–48; 3. VNS-induced upregulation of brain-derived neurotrophic factor expression in hippocampus41; 4. decreased neuroinflammation markers such as central levels of proinflammatory cytokines and percentage of microglia and macrophages and reduction in activated microglia in hippocampus in neuroinflammation models of VNS treatment49,50; and

TABLE 4. Volumetric Data Mean (SD) Comparison at 3 Times Measures Right hippocampus Corrected right*, 10−2 Left Hippocampus Corrected left*, 10−2 Whole brain

Baseline

6 Mo

12 Mo

2149 (345) 0.198 (0.25) 2061 (387) 0.191 (0.04) 1,087,003 (160,428)

2189 (360) 0.216 (0.28) 2246 (475) 0.221 (0.04) 1,017,618 (144,149)

2476 (494) 0.228 (0.03) 2542 (424) 0.235 (0.02) 1,091,218 (207,820)

*Tissue volumes are in cubic millimeter.

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5. changing sensitivity of hypothalamic-pituitary-adrenal axis to early and repeated stressor/episodes may be through epigenetic mechanism.16,17

In clinical studies, 5 processes have been posited for VNS efficacy in depression: anticonvulsant effect, change in regional anatomy and blood flow in mood-related fronto-limbic regions,51 stress desensitization, modulation of neurotransmission, and finally, increased hippocampal neurogenesis.7 The increased hippocampal plasticity in antidepressant responders has been reported in clinical studies on the effect of pharmacological and nonpharmacological treatments on hippocampal volume in depressed patients. Sheline et al14 found that in unipolar depression the longer a patient is treated with antidepressants, the better maintained the hippocampal volume, in contrast to the typical decrease in hippocampal volume seen in patients who are on antidepressants for shorter periods of time during their illness. In 2004, Frodl et al21 reported that the left and right hippocampal volumes were reduced at baseline and after 1 year of follow-up in patients who were unresponsive to antidepressant treatment compared with remitters. In another study on 30 MDD patients compared with 30 controls after 3 years of follow-up, neither hippocampal nor amygdala volumes changed significantly among patients or controls. However, in the subgroup of patients who took antidepressants over the full 3 years, the left hippocampal volumes increased significantly.52 Schermuly et al15 found a selective increase in posterior hippocampal volume during antidepressant treatment in 15 MDD patients compared with controls that is not correlated to the degree of functional restitution, and they considered this as a potential surrogate for neuroplasticity during antidepressant therapy. Regarding nonpharmacological treatments, Tendolkar et al22 found a significant volumetric increase of the hippocampus after ECT in antidepressant-free patients. In a study by Nordanskog et al,53 an immediate but transient increase in volumes was found in both left and right hippocampi among patients with depression treated with ECT, but this increase returned to baseline after 6 months. In a functional MRI study on hippocampal structural and functional changes associated with ECT, Abbott et al54 reported an increase (normalization) in right hippocampal functional connectivity and a volume increase as well as correlation with reduction in depressive symptoms. The authors concluded that increased connectivity and volumes of right hippocampus may be biomarkers for ECT response. Although the clinical improvement of resistant depression could not be directly correlated with hippocampal gray volumes in our study because of the small number of patients, there was a significant improvement in HDRS and BDI scores, and the clinical stabilization paralleled the hippocampal bilateral increases. The data from this first study on effects of VNS on hippocampal gray matter volumes increase is in line with the hypothesis that increasing hippocampal neurogenesis is a possible target of antidepressant and stabilization treatment in recurrent unipolar severe resistant depression.15,16 Moreover, an increase in the hippocampal volumes after 6 months of VNS treatment could be a biomarker for VNS maintenance of remission at longer time points. In this sample, VNS demonstrated to have a clinical and neurobiological positive effect in a group of patients with a previous poor response and a history of frequent and severe episodes, when added to a standard antidepressant therapy. Further studies are needed with a more extended clinical sample to better explore if these changes correlate with clinical and functional outcome and to examine the effects of VNS on the well-known cognitive impairment related to the course of recurrent depression. © 2017 Wolters Kluwer Health, Inc. All rights reserved.


This study has not been designed to compare the effectiveness of VNS with other neurostimulation treatments such as ECT, which is well known for its efficacy in TRD. The ECT indeed is a well-established treatment for depression with level I evidence on acute efficacy and relapse prevention and level II for safety and tolerability55; it is more effective than antidepressants, particularly in highly severe and/or treatment-resistant depressed patients, but its relapse rates are high, without ECT maintenance treatment.3,56 The VNS could be a better strategy than ECT for patients with chronic recurrent treatment-resistant depression, particularly in situations where treatment adherence may be an issue.6 This study demonstrated improvement of the depressive symptoms (as measured by HDRS and BDI) that increased over time (from baseline to 6 and 12 months). Such a time course of clinical improvement is unlikely to be due to placebo effect, which is usually greater in acute treatment and tends to decrease over time, particularly among patients with chronic, severe, or treatmentresistant depressive episodes.3,57 In conclusion, the results of this study confirm previous positive clinical effectiveness studies of VNS therapy across TRD patients and suggest possible neurotrophic effects of such stimulation treatment on hippocampal plasticity, which may be putatively interpreted as a biomarker of response in the long-term treatment of TRD. Further studies across a larger sample of patients suffering from TRD are warranted to verify the preliminary data of this study. Moreover, future studies are needed to confirm effectiveness of TRD treatment through neurotrophic MOA not only among previous VNS therapy but also among other neurostimulation treatments.

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