[Clinical management of treatment-resistant depression]. / Klinisches Management der therapieresistenten Depression.

Treatment-resistant depression (TRD) is a complex disorder. Although no standardized definition has been established to date, there are promising and well-established treatment options for the condition. Looking at the current pharmacological and neuromodulatory strategies, there is an urgent need for fast-acting and well-tolerated treatment options. The search for new mechanisms of action goes beyond the monoamine hypothesis. For example, esketamine is already an established treatment method that is fast-acting and well tolerated, while psychedelics or esmethadone are currently still undergoing clinical trials. Compounds that can be used off-label, such as dextromethorphan or anti-inflammatory strategies are also presented. Pharmacological approaches that focus on the modulation of the glutamatergic system or belong to the class of psychedelics, appear to be of particular importance for current research and development. These particularly include substances that rapidly exert clinical effects and have a favorable side-effect profile.

Altered reward network responses to social touch in major depression.

BACKGROUND: Social touch is an integral part of social relationships and has been associated with reward. Major depressive disorder (MDD) is characterized by severe impairments in reward processing, but the neural effects of social touch in MDD are still elusive. In this study, we aimed to determine whether the neural processing of social touch is altered in MDD and to assess the impact of antidepressant therapy. METHODS: Before and after antidepressant treatment, 53 MDD patients and 41 healthy controls underwent functional magnetic resonance imaging (fMRI) while receiving social touch. We compared neural responses to social touch in the reward network, behavioral ratings of touch comfort and general aversion to interpersonal touch in patients to controls. Additionally, we examined the effect of treatment response on those measures. RESULTS: Clinical symptoms decreased after treatment and 43.4% of patients were classified as responders. Patients reported higher aversion to interpersonal touch and lower comfort ratings during the fMRI paradigm than controls. Patients showed reduced responses to social touch in the nucleus accumbens, caudate nucleus and putamen than controls, both before and after treatment. Contrary to our hypotheses, these effects were independent of touch velocity. Non-responders exhibited blunted response in the caudate nucleus and the insula compared to responders, again irrespective of time. CONCLUSIONS: These findings suggest altered striatal processing of social touch in MDD. Persistent dysfunctional processing of social touch despite clinical improvements may constitute a latent risk factor for social withdrawal and isolation.

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.

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.

Evidence of Neuroplastic Changes after Transcranial Magnetic, Electric, and Deep Brain Stimulation.

Electric and magnetic stimulation of the human brain can be used to excite or inhibit neurons. Numerous methods have been designed over the years for this purpose with various advantages and disadvantages that are the topic of this review. Deep brain stimulation (DBS) is the most direct and focal application of electric impulses to brain tissue. Electrodes are placed in the brain in order to modulate neural activity and to correct parameters of pathological oscillation in brain circuits such as their amplitude or frequency. Transcranial magnetic stimulation (TMS) is a non-invasive alternative with the stimulator generating a magnetic field in a coil over the scalp that induces an electric field in the brain which, in turn, interacts with ongoing brain activity. Depending upon stimulation parameters, excitation and inhibition can be achieved. Transcranial electric stimulation (tES) applies electric fields to the scalp that spread along the skull in order to reach the brain, thus, limiting current strength to avoid skin sensations and cranial muscle pain. Therefore, tES can only modulate brain activity and is considered subthreshold, i.e., it does not directly elicit neuronal action potentials. In this review, we collect hints for neuroplastic changes such as modulation of behavior, the electric activity of the brain, or the evolution of clinical signs and symptoms in response to stimulation. Possible mechanisms are discussed, and future paradigms are suggested.

Repetitive transcranial magnetic stimulation in non-treatment-resistant depression.

Repetitive transcranial magnetic stimulation (rTMS) has been investigated as treatment for major depressive episodes since the early 1990s. Using data from a recent meta-analysis, we show that most patients included in randomised trials display relatively high degrees of treatment resistance. This might have unfavourably biased the clinical reputation of rTMS.Declaration of interestsM.K. has received a lecture fee from Innomed Medizintechnik in 2017 and 2018.

Cognitive effects of non-surgical brain stimulation for major depressive disorder: protocol for a systematic review and meta-analysis.

INTRODUCTION: Non-surgical brain stimulation techniques may be considered as alternative or add-on treatments for patients with major depressive disorder who failed to respond to pharmacological interventions. Electroconvulsive therapy has been shown to be highly effective in reducing depressive symptoms but stakeholders remain concerned about adverse cognitive effects. Repetitive transcranial magnetic stimulation and transcranial direct current stimulation may be associated with more benign adverse effect profiles and may indeed improve certain cognitive functions such as memory and attention. To guide clinical decision-making, we will carry out a systematic review and meta-analysis of the cognitive effects of eight non-surgical brain stimulation techniques. METHODS AND ANALYSIS: A systematic literature search of the Embase, PubMed/MEDLINE and PsycINFO databases, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and OpenGrey will be performed. We will include both randomised clinical trials which report on at least one cognitive measure post treatment as well as non-randomised trials and pre-post intervention studies. There are no restrictions to the type of cognitive outcome measures, except that the tests are standardised and psychometrically validated. The Revised Cochrane tool for assessing risk of bias in randomised trials (RoB 2.0) will be used to evaluate included trials. Pre-post studies will be evaluated using the quality assessment tool developed by the US National Heart, Lung and Blood Institute. Meta-analysis, meta-regression, subgroup and sensitivity analyses will be conducted where sufficient data are available. ETHICS AND DISSEMINATION: No ethical approval is needed to conduct this work. The findings will be submitted for publication in peer-reviewed journals and presented at scientific meetings. PROSPERO REGISTRATION NUMBER: CRD42018118850.