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Background Nearly 1 billion people globally are estimated to live with a mental disorder, and among this 1 billion, 5% of adults have major depression.1 The symptoms of major depressive disorder (MDD) can be categorized into emotional, neurovegetative, and neurocognitive domains.1 These symptoms can profoundly impar quality of life, psychosocial functioning, and the economic productivity of the individuals. In 2008, WHO ranked MDD as the third leading cause of burden of disease worldwide and estimated that it will be ranked first by 2030.2 The development of effective treatment modality for psychiatric disorders is an enduring goal of translational research and evidence-based medicine. Psychopharmacological treatment focuses on the link between specific neurotransmitters and a proposed pathophysiology, while treatment response to this approach may be suboptimal in several major psychiatric disorder, including MDD.3 In recent decades, progress in neuroscience has identified the disordered brain circuits and networks that may underpin the pathogenesis of psychiatric disorders.4 Non-invasive brain stimulation (NIBS) is a set of technologies and techniques that modulate excitability of a specific region or large-scale networks in the brain.5 Studies have showed promising results in circuit-based psychiatric treatments in either diagnosis- or symptom-based clinical conditions.6-8 Transcranial magnetic stimulation (TMS) is one of the most widespread NIBS techniques in research and clinical practice. The application of TMS involves a strong, pulsed magnetic field to a targeted brain region.5 A coil generating an electromagnetic field is placed on the scalp, such that strong magnetic pulses are delivered to a relatively focal area of cerebral cortex, resulting in regional neuronal depolarization and generation of action potentials. In treatment protocol, TMS is typically delivered in bundles or “trains” of pulses, separated by periods of rest. Such protocol is the relevance for application of TMS in treating psychiatric disorders and now is referred as repetitive TMS (rTMS).5 In 2008, the Food and Drug Administration agency of the United States approved rTMS as a treatment for medication-resistant patients with MDD (also known as treatment-resistant depression [TRD]).9 The suggested protocol of rTMS was the delivery of 3,000 pulses per session of excitatory rTMS (10 hertz (Hz)) at 120% resting motor threshold in left dorsolateral prefrontal cortex (DLPFC), and a series of 20–30 once-daily sessions are given over the course of four to six weeks. Of note, a large variability existed in the published protocols of rTMS studies, such as the stimulation intensity, the number of sessions proposed (10–30), the number of stimuli per session (120–3000), the targeted brain regions (e.g., left DLPFC, right DLPFC, bilateral DLPFC), and the included population (MDD or TRD). The number of sessions and stimuli are usually lower when applying low frequency rTMS of the right DLPFC as compared to high frequency rTMS of the left DLPFC. One recent meta-analysis showed that increasing the number of sessions and the total number of pulses per session (with an optimal value of 1200–1500 pulses/session) was associated with an increased antidepressant efficacy of high frequency rTMS of the left DLPFC.10 A few studies compared the both types of stimulation (low frequency rTMS on the right vs. high frequency rTMS on the left) and rather showed a similar antidepressant efficacy, even when rTMS was used in augmentation or as an add-on treatment to antidepressants in pharmacological refractory MDD.11 Aims The aim of the current study is to examine the dose-response relationship between different rTMS parameters and clinical effectiveness of depression improvement in patients with TRD. The parameters of rTMS included intensity, frequency, pulse per session, treatment duration, total session, and total pulses. Total pulses is a product of total sessions and stimuli per session. For example, the dose of a protocol of 20 sessions with 3000 stimuli per session will be calculated as 60000 pulses, and the dose of a protocol of 5 sessions with 3000 stimuli per session will be calculated as 15000 pulses. Methods The protocol of the current systematic review and meta-analysis will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 statement. Ethical approval is waived in this meta-analytic study. Search strategy The MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, PsycINFO, Clinical trials.gov, and World Health Organization (ICTRP) will be systematically searched to identify RCTs testing different antimanic agents without language restriction. The specific search terms are to be determined and will be adapted to each database. We will manually search the bibliographies of selected studies and reference lists of review articles meeting the inclusion criteria to locate additional relevant studies. At least two authors will independently screen and select the potentially eligible studies. Any discrepancies will be resolved by consensus. PICO The PICO (population, intervention, comparison, outcome) settings of the current meta-analysis are: P: Adults patients with treatment-resistant depression I: rTMS over left DLPFC C: Sham control or another protocol of rTMS over left DLPFC O: Improvement of depressive symptoms Inclusion and exclusion criteria We will only include blinded randomized controlled trials (RCTs) that reported the necessary information (e.g., standard deviations, means, and sample sizes). We will exclude: (1). Nonblind RCT. (2). Non-RCT. (3). RCT that enrolled participants without TRD (4). Relapse prevention studies (i.e., RCT addressing on maintenance treatment). (5). RCT of other brain regions (6). RCT only including participants <18 years old Outcome definition and data extraction The primary outcome will be improvement of depressive symptoms. The secondary outcomes will be acceptability and serious adverse events. For each study, we will extract the following data: (1). Trial characteristics (e.g., sample size, authors, publication years). (2). Treatment protocols (e.g., Hz, total session, pulses per session) (3). Standard deviation (or variance, standard error) and means of changes in depressive symptoms over the study period for both active and control groups, as measured with standard rating scale for depression (e.g., Hamilton Depression Rating Scale; Montgomery Asberg Depression Rating Scale, Beck Depression Scale). Where multiple publications of the same study existed, maximal data will be extracted from these subsequent publications and included as part of the initial publication. In some studies, after a defined period of blinded treatment, continuation treatment was offered only to the responders (resulting in different patient retention rate between conditions) that became unblinded or open-label conditions. As for these studies, we will use only the data from the blinded acute treatment period, which will include the original randomized sample. At least two authors will double-check the data-transfer accuracy and calculations. The quality of the included studies will be rated using the Cochrane Risk of Bias Assessment Tool. 12 Any discrepancies will be resolved by consensus. Data analysis Data management and analysis will be carried out using Stata (version 16) and R-Project (V.4.0.3, R Foundation). A p value of <0.05 is considered significant (two-tailed). The standardized mean difference in improvement of depression scores will be used as the effect size with a 95% confidence interval. A dose-response meta-analysis with a random-effects model will be conducted. An intention-to-treat approach will be used. PCA will be performed for dimension reduction. The I² statistic will be used to evaluate heterogeneity. Subgroup analysis, meta-regression, and assessment of possible publication bias (Egger’s test and visual inspection of funnel plots) analyses will be conducted if feasible. Sensitivity analyses will include: (1). Excluding studies with a high risk of bias. (2). Excluding studies that enrolled specific populations (e.g., all participants > 65 years old). References 1. The L. Ensuring care for people with depression. Lancet. Mar 5 2022;399(10328):885. doi:10.1016/S0140-6736(21)01149-1 2. Malhi GS, Mann JJ. Depression. The Lancet. 2018;392(10161):2299-2312. doi:10.1016/S0140-6736(18)31948-2 3. Chang JP, Su KP. Nutrition and immunology in mental health: Precision medicine and integrative approaches to address unmet clinical needs in psychiatric treatments. Brain Behav Immun. Mar 2020;85:1-3. doi:10.1016/j.bbi.2019.09.022 4. Haber SN, Tang W, Choi EY, et al. Circuits, Networks, and Neuropsychiatric Disease: Transitioning From Anatomy to Imaging. Biological Psychiatry. 2020/02/15/ 2020;87(4):318-327. doi:https://doi.org/10.1016/j.biopsych.2019.10.024 5. Aaron D. Boes, M.D., Ph.D. ,, Michael S. Kelly, B.A. ,, Nicholas T. Trapp, M.D. ,, Adam P. Stern, M.D. ,, Daniel Z. Press, M.D. ,, Alvaro Pascual-Leone, M.D., Ph.D. Noninvasive Brain Stimulation: Challenges and Opportunities for a New Clinical Specialty. The Journal of Neuropsychiatry and Clinical Neurosciences. 2018;30(3):173-179. doi:10.1176/appi.neuropsych.17110262 6. Chu C-S, Li C-T, Brunoni AR, et al. Cognitive effects and acceptability of non-invasive brain stimulation on Alzheimer’s disease and mild cognitive impairment: a component network meta-analysis. Journal of Neurology, Neurosurgery & Psychiatry. 2021;92(2):195-203. 7. Shan H. Siddiqi, M.D. ,, Stephan F. Taylor, M.D. ,, Danielle Cooke, B.S. ,, Alvaro Pascual-Leone, M.D. , Ph.D. ,, Mark S. George, M.D. ,, Michael D. Fox, M.D. , Ph.D. Distinct Symptom-Specific Treatment Targets for Circuit-Based Neuromodulation. American Journal of Psychiatry. 2020;177(5):435-446. doi:10.1176/appi.ajp.2019.19090915 8. Lisa M. McTeague, Ph.D. ,, Benjamin M. Rosenberg, M.A. ,, James W. Lopez, B.S. ,, et al. Identification of Common Neural Circuit Disruptions in Emotional Processing Across Psychiatric Disorders. American Journal of Psychiatry. 2020;177(5):411-421. doi:10.1176/appi.ajp.2019.18111271 9. Harika-Germaneau G, Wassouf I, Le Tutour T, et al. Baseline Clinical and Neuroimaging Biomarkers of Treatment Response to High-Frequency rTMS Over the Left DLPFC for Resistant Depression. Original Research. Frontiers in Psychiatry. 2022-May-20 2022;13doi:10.3389/fpsyt.2022.894473 10. Teng S, Guo Z, Peng H, et al. High-frequency repetitive transcranial magnetic stimulation over the left DLPFC for major depression: Session-dependent efficacy: A meta-analysis. Eur Psychiatry. Mar 2017;41:75-84. doi:10.1016/j.eurpsy.2016.11.002 11. Dell’Osso B, Oldani L, Camuri G, et al. Augmentative Repetitive Transcranial Magnetic Stimulation (rTMS) in the Acute Treatment of Poor Responder Depressed Patients: A Comparison Study Between High and Low Frequency Stimulation. European Psychiatry. 2015;30(2):271-276. doi:10.1016/j.eurpsy.2014.12.001 12. Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. doi:10.1136/bmj.d5928