rTMS combined with CBT as a next step in antidepressant non-responders: a study protocol for a randomized comparison with current antidepressant treatment approaches.

BACKGROUND: Major depressive disorder (MDD) is one of the most common psychiatric disorders, however, current treatment options are insufficiently effective for about 35% of patients, resulting in treatment-resistant depression (TRD). Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive neuromodulation that is effective in treating TRD. Not much is known about the comparative efficacy of rTMS and other treatments and their timing within the treatment algorithm, making it difficult for the treating physician to establish when rTMS is best offered as a treatment option. This study aims to investigate the (cost-)effectiveness of rTMS (in combination with cognitive behavioral therapy (CBT) and continued antidepressant medication), compared to the next step in the treatment algorithm. This will be done in a sample of patients with treatment resistant non-psychotic unipolar depression. METHODS: In this pragmatic multicenter randomized controlled trial 132 patients with MDD are randomized to either rTMS or the next pharmacological step within the current treatment protocol (a switch to a tricyclic antidepressant or augmentation with lithium or a second-generation antipsychotic). Both groups also receive CBT. The trial consists of 8 weeks of unblinded treatment followed by follow-up of the cohort at four and 6 months. A subgroup of patients (n = 92) will have an extended follow-up at nine and 12 months to assess effect decay or retention. We expect that rTMS is more (cost-)effective than medication in reducing depressive symptoms in patients with TRD. We will also explore the effects of both treatments on symptoms associated with depression, e.g. anhedonia and rumination, as well as the effect of expectations regarding the treatments on its effectiveness. DISCUSSION: The present trial aims to inform clinical decision making about whether rTMS should be considered as a treatment option in patients with TRD. The results may improve treatment outcomes in patients with TRD and may facilitate adoption of rTMS in the treatment algorithm for depression and its implementation in clinical practice. TRIAL REGISTRATION: This trial is registered within the Netherlands Trial Register (code: NL7628 , date: March 29th 2019).

Longitudinal effects of rTMS on neuroplasticity in chronic treatment-resistant depression.

Major depressive disorder (MDD) is amongst the most prevalent of psychiatric disorders. Unfortunately, a third of patients will not respond to conventional treatments and suffer from treatment-resistant depression (TRD). Repetitive transcranial magnetic stimulation (rTMS) has been proven effective in treating TRD. The research suggests that rTMS acts via neuroplastic effects on the brain, which can be measured by changes in hippocampal and amygdala volume as well as cortical thickness. This sham-controlled study investigates longitudinal effects of rTMS on the volumes of the hippocampus and amygdala and cortical thickness in patients with chronic TRD. 31 patients received 20 sessions of high-frequency rTMS (N = 15) or sham treatment (N = 16) over the left dorsolateral prefrontal cortex during 4 consecutive weeks. Using structural magnetic resonance imaging, we investigated longitudinal treatment effects on hippocampus and amygdala volume as well as thickness of the paralimbic cortex. We found no clinical differences between the active and sham rTMS group. Longitudinal changes in hippocampal and amygdala volume did not differ significantly, although males showed a significant decrease in left amygdala volume, irrespective of treatment group. Changes in cortical thickness of the paralimbic cortex differed significantly between the active and sham groups. Most notably, the increase in cortical thickness of the isthmus of the left cingulate gyrus was greater in the active as compared to the sham rTMS group. Our data suggest that rTMS can induce neuroplastic changes, particularly in cortical thickness, independent of treatment response. We also found longitudinal changes in amygdala volume in males. For clinical effects to follow these neuroplastic effects, more intensive rTMS treatment might be needed in chronically depressed patients.Trial registration number: ISRCTN 15535800, registered on 29-06-2017.

Studying additive effects of combining rTMS with cognitive control training: a pilot investigation.

Background: Repetitive transcranial magnetic stimulation (rTMS) on the dorsolateral prefrontal cortex (DLPFC) is an effective treatment for depression that has been proposed to work via the enhancement of cognitive control. Cognitive control training (CCT) can also alleviate depression by relying on DLPFC activation. As the additive effects of rTMS and CCT are unclear, we set out to conduct a within-subject pilot study in healthy controls. Methods: Seventeen participants received two sessions of individualized resting-state connectivity-guided high-frequency rTMS, while randomly performing CCT or a control task. After each session, a negative mood was induced. Results: We found effects on mood and cognitive control after rTMS + CCT as well as rTMS + control, which were indiscriminative between conditions. Based on the statistical evidence for the absence of an additive effect of CCT, we did not perform a full study. Conclusion: Our results demonstrate no differential effects of single sessions combining rTMS and CCT in a healthy population, even with the methodological improvement of individualized neuronavigation. The improvement in cognitive control seen in both conditions could indicate that a simple cognitive task is sufficient when studying additive rTMS effects. Future studies should focus on augmenting the effects of various cognitive tasks and compare the present interventions with rTMS or cognitive tasks alone.

Efficacy and acceptability of next step treatment strategies in adults with treatment-resistant major depressive disorder: protocol for systematic review and network meta-analysis.

INTRODUCTION: For major depression, a one-size-fits-all treatment does not exist. Patients enter a 'trial-and-change' algorithm in which effective therapies are subsequently applied. Unfortunately, an empirically based order of treatments has not yet been determined. There is a magnitude of different treatment strategies while clinical trials only compare a small number of these. Network meta-analyses (NMA) might offer a solution, but so far have been limited in scope and did not account for possible differences in population characteristics that arise with increasing levels of treatment-resistance, potentially violating the transitivity assumption. We; therefore, present a protocol for a systematic review and NMA aiming at summarising and ranking treatments for treatment-resistant depression (TRD) while covering a broad range of therapeutic options and accounting for possible differences in population characteristics at increasing levels of treatment-resistance. METHODS AND ANALYSIS: Randomised controlled trials will be included that compared next-step pharmacological, neuromodulation or psychological treatments for treatment-resistant depression (TRD; ie, failure to respond to ≥1 adequate antidepressant drug trial(s) in the current episode) to each other or to a control condition. Primary outcomes will be the proportion of patients who responded to (efficacy) and dropped out of (acceptability) the allocated treatment. A random effects NMA will be conducted, synthesising the evidence for each outcome and determining the differential efficacy of treatments. Heterogeneity in treatment nodes will be reduced by considering alternative geometries of the network structure and by conducting a meta-regression examining different levels of TRD. Local and global methods will be applied to evaluate consistency. The Cochrane Risk of Bias 2 tool, Confidence in Network Meta-Analysis and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework will be used to assess risk of bias and certainty. ETHICS AND DISSEMINATION: This review does not require ethical approval.

The association between sample and treatment characteristics and the efficacy of repetitive transcranial magnetic stimulation in depression: A meta-analysis and meta-regression of sham-controlled trials.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive neuromodulation that is increasingly used to treat major depressive disorder (MDD). However, treatment with rTMS could be optimized by identifying optimal treatment parameters or characteristics of patients that are most likely to benefit. This meta-analysis and meta-regression aims to identify sample and treatment characteristics that are associated with change in depressive symptom level, treatment response and remission. METHODS: The databases PubMed, Embase, Web of Science and Cochrane library were searched for randomized controlled trials (RCTs) reporting on the therapeutic efficacy of high-frequent, low-frequent, or bilateral rTMS for MDD compared to sham. Study and sample characteristics as well as rTMS parameters and outcome variables were extracted. Effect sizes were calculated for change in depression score and risk ratios for response and remission. RESULTS: Sixty-five RCTs with a total of 2982 subjects were included in this meta-analysis. Active rTMS resulted in a larger depressive symptom reduction than sham protocol (Hedges' g = -0.791 95% CI -0.977; -0.605). Risk ratios for response and remission were 2.378 (95% CI 1.882; 3.005) and 2.450 (95% CI 1.779; 3.375), respectively. We found no significant association between sample and treatment parameters and rTMS efficacy. CONCLUSIONS: rTMS is an efficacious treatment for MDD. No associations between sample or treatment characteristics and efficacy were found, for which we caution that publication bias, heterogeneity and lack of consistency in the definition of remission might bias these latter null findings. Our results are clinically relevant and support the use of rTMS as a non-invasive and effective treatment option for depression.