Long-Term Immunomodulatory Impact of VNS on Peripheral Cytokine Profiles and Its Relationship with Clinical Response in Difficult-to-Treat Depression (DTD).

Vagus nerve stimulation (VNS) represents a long-term adjunctive treatment option in patients with difficult-to-treat depression (DTD). Anti-inflammatory effects have been discussed as a key mechanism of action of VNS. However, long-term investigations in real-world patients are sparse. In this naturalistic observational study, we collected data on cytokines in peripheral blood in n = 6 patients (mean age 47.8) with DTD and VNS treatment at baseline and at 6 months follow-up. We have identified clusters of peripheral cytokines with a similar dynamic over the course of these 6 months using hierarchical clustering. We have investigated cytokine changes from baseline to 6 months as well as the relationship between the cytokine profile at 6 months and long-term response at 12 months. After 6 months of VNS, we observed significant correlations between cytokines (p < 0.05) within the identified three cytokine-pairs which were not present at baseline: IL(interleukin)-6 and IL-8; IL-1ß and TNF-α; IFN-α2 and IL-33. At 6 months, the levels of all the cytokines of interest had decreased (increased in non-responders) and were lower (5-534 fold) in responders to VNS than in non-responders: however, these results were not statistically significant. VNS-associated immunomodulation might play a role in long-term clinical response to VNS.

Emotional Blunting in Depression in the PREDDICT Clinical Trial: Inflammation-Stratified Augmentation of Vortioxetine With Celecoxib.

BACKGROUND: Emotional symptoms are recognized as a key feature in individuals with major depressive disorder. Previously, emotional blunting has been described both as a side effect of antidepressant treatment and as a symptom of depression. Little is known about the change of emotional blunting during antidepressant treatment. METHODS: The PREDDICT trial is a randomized, placebo-controlled, 6-week trial on the augmentation of vortioxetine with the anti-inflammatory agent celecoxib or placebo. Presently we report on exploratory secondary outcomes of changes in emotional blunting in depression assessed with the Oxford Depression Questionnaire (ODQ) total score and subscores from baseline to 8-week, 3-month, and 6-month follow-up assessments. RESULTS: In the whole group, there was a significant improvement in the ODQ total score and all subscores after 8 weeks. After stratification of participants into the treatment groups, the ODQ total score as well as subscores related to emotional blunting as a symptom of depression (reduction in positive emotions, not caring) improved between baseline and all follow-up time points in both treatment groups. Changes in subscores considered as a side effect of antidepressants (general reduction in emotions, emotional detachment) were inconclusive in both treatment groups. Overall, the placebo-augmented group showed slightly better results in changes of emotional blunting scores than the celecoxib group as did those with elevated inflammation at screening, regardless of treatment group. CONCLUSIONS: This analysis suggests favorable effects of vortioxetine on emotional blunting in both short- and long-term course. The beneficial impact of vortioxetine on emotional blunting was weaker in celecoxib-augmented patients compared with placebo, possibly due to pharmacokinetic interactions. Clinical Trials Registration: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p.

Impact of Adjunctive VNS on Drug Load, Depression Severity, and Number of Neuromodulatory Maintenance Treatments.

Vagus nerve stimulation (VNS) is a long-term adjunctive treatment option in patients with difficult-to-treat depression (DTD). A total of n = 20 patients (mean age 52.6 years) were included in the multicenter, prospective, observational, naturalistic RESTORE-LIFE study and were treated with adjunctive VNS as an add-on to treatment as usual. Exploratory and secondary outcome parameters from a single center were investigated for this present analysis. The overall mean drug load slightly decreased from 4.5 at baseline to 4.4 at 12 months (Z = -0.534, p = 0.594). The drug load was lower in previous electroconvulsive therapy (ECT) responders than in non-responders. There was a reduction in the mean number of hospitalizations per month after VNS implantation (Z = 1.975, p = 0.048) and a significant decrease in the mean Montgomery Åsberg Depression Rating Scale (MADRS) score from 27.3 at baseline to 15.3 at 12 months (T = 4.230, degree of freedom (df) = 19, p = 0.001). A history of ECT response at baseline was associated with greater improvement in the MADRS score after 12 months of VNS (F = 8.171, p = 0.013). The number of neuromodulatory maintenance treatments decreased during the follow-up period. In summary, there was an alleviation in the burden of illness among DTD patients treated with VNS.

Combination of Acute and Maintenance Esketamine Treatment With Adjunctive Long-Term Vagus Nerve Stimulation in Difficult-to-Treat Depression.

INTRODUCTION: The antidepressant effect of N-methyl-D-aspartate antagonists is often short lasting, raising the question of the best maintenance strategy, which has remained unanswered. Vagus nerve stimulation (VNS) as a treatment option for refractory and chronic major depression was shown to reduce the need for maintenance treatment sessions in patients receiving electroconvulsive therapy. To our knowledge, there are no published data on the combination of VNS and esketamine in the literature. MATERIALS AND METHODS: This is a naturalistic prospective and retrospective observational study in patients treated with long-term VNS owing to difficult-to-treat depression. These patients also have received esketamine maintenance sessions in addition to short-term treatment. We have investigated the need for maintenance esketamine sessions per month after VNS implantation (number of sessions/number of months between visits), the change in depression severity (mean Montgomery-Asberg Depression Rating Scale [MADRS] score), and the number of hospitalizations per month (number of hospitalizations/number of postoperative observation months). Follow-up visits have been scheduled every three months after VNS implantation (follow-up period 12-24 months, mean 17). RESULTS: All patients (n = 8, mean age 53.1 years) had severe difficult-to-treat depression (DTD) (mean MADRS at baseline 30.9). Mean number of hospitalizations per month decreased from 0.17 to 0.11 after VNS implantation (p = 0.041, T = 2.030, df = 7). Mean MADRS at 12 months was 18.3 (40.8% MADRS reduction, p = 0.008, T = 3.146, df = 7). Six of eight patients were offered maintenance esketamine treatment. Mean number of esketamine treatment sessions per month and case decreased from 2.3 at the six-month visit to 0.8 at 12 months (p = 0.076, T = 1,690, df = 5) after VNS implantation. Termination of maintenance esketamine was possible in four cases after a mean of 11.5 months. CONCLUSIONS: Combination of esketamine and VNS was effective in patients with DTD to relieve disease severity and reduce hospitalizations. The need for esketamine treatment sessions decreased after 6 months of VNS. No safety concerns arose in this study regarding the combination treatment. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03320304.

Long-term effects of electroconvulsive therapy on brain structure in major depression.

BACKGROUND: Magnetic resonance imaging (MRI) studies on major depressive disorder (MDD) have predominantly found short-term electroconvulsive therapy (ECT)-related gray matter volume (GMV) increases, but research on the long-term stability of such changes is missing. Our aim was to investigate long-term GMV changes over a 2-year period after ECT administration and their associations with clinical outcome. METHODS: In this nonrandomized longitudinal study, patients with MDD undergoing ECT (n = 17) are assessed three times by structural MRI: Before ECT (t0), after ECT (t1) and 2 years later (t2). A healthy (n = 21) and MDD non-ECT (n = 33) control group are also measured three times within an equivalent time interval. A 3(group) × 3(time) ANOVA on whole-brain level and correlation analyses with clinical outcome variables is performed. RESULTS: Analyses yield a significant group × time interaction (pFWE < 0.001) resulting from significant volume increases from t0 to t1 and decreases from t1 to t2 in the ECT group, e.g., in limbic areas. There are no effects of time in both control groups. Volume increases from t0 to t1 correlate with immediate and delayed symptom increase, while volume decreases from t1 to t2 correlate with long-term depressive outcome (all p ⩽ 0.049). CONCLUSIONS: Volume increases induced by ECT appear to be a transient phenomenon as volume strongly decreased 2 years after ECT. Short-term volume increases are associated with less symptom improvement suggesting that the antidepressant effect of ECT is not due to volume changes. Larger volume decreases are associated with poorer long-term outcome highlighting the interplay between disease progression and structural changes.

[Vagus Nerve Stimulation (VNS) in Depression]. / Vagusnervstimulation (VNS) als Behandlungsoption für Depressionen.

Major depressive disorder is a common mental health disease with a chronic and treatment-resistant course in about one-third of patients. Invasive vagus nerve stimulation (VNS) as a long-term adjunctive treatment option has increasingly been used in the last years. VNS was CE-certified in the European Union for use in chronic and treatment-resistant depression in 2001. Method In this narrative literature review we provide an overview on VNS as a treatment option in patients with depression. We particularly focus on aspects with high clinical relevance. Results Indication to conduct VNS is determined after comprehensive evaluation of the patients' symptoms and psychiatric history. After education of patients and caregivers and obtaining informed consent, a pacemaker-like pulse generator is implanted in the left chest in a short surgical procedure. In the first weeks after implantation, the stimulation is turned on stepwise in an outpatient setting. The left vagal nerve is stimulated for 30 sec. every 5 minutes. Hoarseness during stimulation is the most frequent side-effect. There is a delay in the onset of antidepressant action of about 6-12 months. In a large registry, the cumulative response rate after 5 years was significantly higher (67.6%) in patients treated with VNS plus treatment-as-usual (TAU) than TAU alone (40.9%). Long-term benefits of VNS on quality of life, cognition, morbidity and mortality have been described previously. Conclusion VNS is a long-term safe treatment option in severely affected patients with depression with positive impact on depression severity, quality of life and cognitive function. Increase of monoaminergic transmission and anti-inflammatory effects of VNS are possible mechanisms of action.

Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.

Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this causal depression network (CDN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis Principal Component Analysis (PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CDN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CDN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes (t = -2.35, p = 0.019). This evidence further supports that treatment interventions converge on a CDN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.

Inflammation-stratified augmentation of vortioxetine with celecoxib: Results from a double-blind, randomized, placebo-controlled trial in major depressive disorder.

Low-grade inflammation is considered as a pathophysiological mechanism in a subtype of patients with major depressive disorder (MDD). Anti-inflammatory drugs have shown efficacy in treating MDD. However, it remains unclear how to identify suitable patients for anti-inflammatory treatment of depression. This study investigates the predictive value of pre-treatment high-sensitivity C-Reactive Protein (hsCRP) stratification on the outcome of celecoxib augmentation of vortioxetine. The PREDDICT study was conducted as a randomized, double-blind, placebo-controlled 6-week trial on augmentation of vortioxetine with celecoxib between December 2017 and April 2020 at the University of Adelaide (Australia). The present analysis focusses on the question of whether the pre-treatment hsCRP measurement and stratification of patients to depression with inflammation (hsCRP >3 mg/L) or without inflammation (hsCRP ≤3 mg/L) has an impact on the outcome of anti-inflammatory treatment with celecoxib. A total of n = 119 mostly treatment-resistant MDD patients with moderate to severe symptomatology were recruited in the trial. There was no effect of treatment group (celecoxib or placebo), pre-treatment hsCRP strata (with/without inflammation), or interaction between the two terms on treatment outcome. The results of the current analysis do not support the hypothesis that pre-treatment hsCRP level is predictive for response to anti-inflammatory treatment with celecoxib in MDD patients. Further research is needed to identify appropriate biomarkers for the prediction of anti-inflammatory treatment outcome in depression. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p.

Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.

Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this common causal network (CCN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis (Principal Component Analysis, PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CCN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CCN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes. This evidence further supports that treatment interventions converge on a CCN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.

Differences in Cognitive Adverse Effects and Seizure Parameters Between Thiopental and Propofol Anesthesia for Electroconvulsive Therapy.

INTRODUCTION: Electroconvulsive therapy (ECT) is a well-established treatment option in case of severe and treatment-resistant psychiatric conditions. In this retrospective study, we compared the 2 anesthetics propofol and thiopental in terms of seizure quality, cognitive adverse effects, and clinical outcome. METHODS: Data collection was performed retrospectively by a chart review, including patient files and medical records. A total of 64 patients (female = 60.9%) treated with ECT within the period of February 2019 to March 2020 were included. Of these, 35 (54.7%) received thiopental for ECT narcosis and 29 (45.3%) were treated with propofol. RESULTS: Six hundred sixteen ECT treatments (mean number per case, 9.6) were performed in total. The mean electroencephalogram seizure duration (38.3 vs 28.1 seconds, t = 3.534, degrees of freedom [ df ] = 62, P < 0.001) and motor seizure duration (21.5 vs 12.0, t = 4.336, df = 62, P < 0.001) as well as postictal suppression index and heart rate increase were significantly higher in the thiopental group. Mean stimulation energy needed per session was higher in the propofol group (88.6% vs 73.0%, Mann-Whitney U test, P = 0.042). The ECT series was more likely to be interrupted due to cognitive adverse effects in the thiopental group ( P = 0.001, Pearson χ 2 = 10.514, df = 1). Number of patients achieving remission was significantly higher in the thiopental group (31.4% vs 6.9%, P = 0.015, χ 2 = 5.897, df = 1). CONCLUSIONS: Thiopental led to better seizure duration and quality and was associated with a higher rate of remission. As a downside, thiopental was also associated with a greater risk of cognitive adverse effects.

Immunological changes following electroconvulsive therapy in multiple sclerosis.

INTRODUCTION: Electroconvulsive therapy (ECT) is a well-established treatment option in case of treatment-resistant depression (TRD). Only a few cases of ECT in depressed patients with multiple sclerosis (MS) were reported so far suggesting efficacy for the treatment of severe depression in MS, while data on possible neurological deterioration remained unclear. METHODS: In this case study we report on a case of a middle-aged man with MS. He was on dimethyl fumarate for relapse prevention since 2019 and without signs of active disease in a recent cerebral MRI. He suffered from treatment-resistant severe bipolar depression and thus received a total of 14 ECT sessions. We changed from right-unilateral to bilateral stimulation technique after the 7th session. We rated depression severity and measured biomarkers of neurodegeneration and inflammation before and after the ECT series to determine the impact of ECT on tolerance, response and neurobiology. RESULTS: The ECT series was tolerated well without neurological deterioration and any new neurological symptoms. The seizure quality was sufficient on average. We saw partial response corresponding to an improvement of about 35% in BDI-II and MADRS. The concentration of inflammation and neurodegeneration biomarkers was low both pre-treatment and post-treatment with increases from pre- to post ECT mainly in the CCL-2 pathway. CONCLUSION: In our patient with TRD and MS ECT was safe and feasible. We did not see any neurobiological signs of disease activation of MS or neurodegeneration during the course of ECT, which may even be beneficial as it led to increase in the neuroprotective CCL-2 pathway in the presented patient.

Setting Up a Successful Vagus Nerve Stimulation Service for Patients With Difficult-to-Treat Depression.

BACKGROUND: A substantial number of patients with major depressive disorder (MDD) do not sufficiently remit after the first lines of antidepressant treatments, making them vulnerable to poor clinical outcomes. Patients who have not had adequate resolution of their depressive symptoms after four antidepressant treatments and/or have been experiencing their current episode of MDD for two years or more (with insufficient responses to adequate antidepressant treatments) should be evaluated for antidepressant vagus nerve stimulation (VNS Therapy). Adjunctive VNS Therapy is a promising long-term treatment option for patients with difficult-to-treat depression (DTD), offering significantly improved remission rates in comparison with usual treatments. However, VNS Therapy requires specialized treatment centers to support patients. MATERIALS AND METHODS: In this narrative review, we aim to outline the necessary steps for setting up an antidepressant VNS Therapy service in an efficient manner. RESULTS: Establishing a VNS Therapy service requires several high-level considerations: initiation of a collaborative multidisciplinary team of health care professionals; developing a surgical pathway for implantation; consideration of reimbursement and health care coverage; setting up a specialist clinic to identify optimal candidates for VNS Therapy; educating patients and their families about VNS Therapy; and training health care providers on patient-specific VNS Therapy treatment and long-term treatment management. CONCLUSIONS: Antidepressant VNS Therapy is a promising treatment option for the long-term treatment of patients with DTD. We have successfully initiated four VNS Therapy service centers for DTD in the United States, Austria, and Germany. Based on our experiences and lessons learned, herein, we have provided advice to psychiatric centers planning to set up a VNS Therapy service for their patients with DTD.

Combination of Tranylcypromine and Mirtazapine in Difficult-to-Treat Depression.

BACKGROUND: About one third of depression patients do not respond to the first antidepressant trial. Difficult-to-treat depression was suggested to characterize the often chronic and severe course of disease. Previous data indicate that tranylcypromine is effective in case of treatment-refractory depression. Many antidepressants are contraindicated in combination with tranylcypromine and other monoamine-oxidase inhibitors because of the risk of serotonin syndrome. The combination of tranylcypromine and amitriptyline was reported to be efficacious and safe in patients with electroconvulsive therapy-resistant major depression. METHODS: In this retrospective chart review, we report a series of 3 cases, in which patients with electroconvulsive therapy-resistant depression were treated with the combination of tranylcypromine and mirtazapine. There are no published clinical data on this combination yet. Disease severity and treatment response were retrospectively assessed with the Clinical Global Impression-Severity and Improvement Scales. RESULTS: All 3 patients had severe difficult-to-treat depression with chronic course of disease and several times of inpatient treatment without achieving remission. The combination treatment was tolerated well, although the patients had somatic comorbidities. One patient developed mild and self-limiting neuroleptic malignant syndrome in the long-term course after dose increase of concomitant aripiprazole. All 3 patients showed either much or very much improvement. CONCLUSIONS: Under tight clinical controls in inpatient setting and after exhausting of alternatives, the combination of tranylcypromine and mirtazapine could be considered in patients, who do not achieve adequate improvement through common treatment options recommended in the guidelines. The combination has to be ceased, if symptoms of possible serotonin syndrome occur.

Acute effect of vagus nerve stimulation (VNS) on brain function.

INTRODUCTION: VNS is a non-pharmalogical neuromodulatory treatment option for difficult-to-treat depression. A pulse generator implanted in the left chest area is connected to an electrode that is wrapped around the left vagal nerve. It is presumed, that the vagal afferent network modulates neuronal activity in key monoaminergic structures. METHODS: We performed MEG recording during active stimulation of the left vagal nerve. Our patient was a 60 years old female treated with VNS since December 2019 due to unipolar major depression. RESULTS: MEG recording and analysis were possible despite stimulation signals and the metal stimulation systems. We saw a reproducible reduction of the 10-Hz-alpha amplitude after the end of the 30 s stimulation period in wide-spread areas including parieto-occipital cortex where alpha oscillations are prominently generated. During stimulation, however, alpha oscillations remained unaffected. These findings could be reproduced in a second measurement. CONCLUSION: Increased alpha power was linked to depressive states and alterations of cortical activity. A reduction may indicate cortical activation by stimulation of the vagal nerve as a possible mechanism of action of VNS in depression.

Elevated body weight modulates subcortical volume change and associated clinical response following electroconvulsive therapy.

Background: Obesity is a frequent somatic comorbidity of major depression, and it has been associated with worse clinical outcomes and brain structural abnormalities. Converging evidence suggests that electroconvulsive therapy (ECT) induces both clinical improvements and increased subcortical grey matter volume in patients with depression. However, it remains unknown whether increased body weight modulates the clinical response and structural neuroplasticity that occur with ECT. Methods: To address this question, we conducted a longitudinal investigation of structural MRI data from the Global ECT-MRI Research Collaboration (GEMRIC) in 223 patients who were experiencing a major depressive episode (10 scanning sites). Structural MRI data were acquired before and after ECT, and we assessed change in subcortical grey matter volume using FreeSurfer and Quarc. Results: Higher body mass index (BMI) was associated with a significantly lower increase in subcortical grey matter volume following ECT. We observed significant negative associations between BMI and change in subcortical grey matter volume, with pronounced effects in the thalamus and putamen, where obese participants showed increases in grey matter volume that were 43.3% and 49.6%, respectively, of the increases found in participants with normal weight. As well, BMI significantly moderated the association between subcortical grey matter volume change and clinical response to ECT. We observed no significant association between BMI and clinical response to ECT. Limitations: Because only baseline BMI values were available, we were unable to study BMI changes during ECT and their potential association with clinical and grey matter volume change. Conclusion: Future studies should take into account the relevance of body weight as a modulator of structural neuroplasticity during ECT treatment and aim to further explore the functional relevance of this novel finding.

The relationship between social cognition and executive function in Major Depressive Disorder in high-functioning adolescents and young adults.

To understand how cognitive dysfunction contributes to social cognitive deficits in depression, we investigated the relationship between executive function and social cognitive performance in adolescents and young adults during current and remitted depression, compared to healthy controls. Social cognition and executive function were measured in 179 students (61 healthy controls and 118 patients with depression; Mage = 20.60 years; SDage = 3.82 years). Hierarchical regression models were employed within each group (healthy controls, remitted depression, current depression) to examine the nature of associations between cognitive measures. Social cognitive and executive function did not significantly differ overall between depressed patients and healthy controls. There was no association between executive function and social cognitive function in healthy controls or in remitted patients. However, in patients with a current state of depression, lower cognitive flexibility was associated with lower performance in facial-affect recognition, theory-of-mind tasks and overall affect recognition. In this group, better planning abilities were associated with decreased performance in facial affect recognition and overall social cognitive performance. While we infer that less cognitive flexibility might lead to a more rigid interpretation of ambiguous social stimuli, we interpret the counterintuitive negative correlation of planning ability and social cognition as a compensatory mechanism.