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      string(254) "NCT02418585 - A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects With Treatment-resistant Depression"
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      string(193) "nct02418585-a-randomized-double-blind-multicenter-active-controlled-study-to-evaluate-the-efficacy-safety-and-tolerability-of-flexible-doses-of-intranasal-esketamine-plus-an-oral-antidepressant"
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  ["project_title"]=>
  string(124) "Comparing effectiveness of rTMS and intranasal esketamine on the reduction of depressive symptoms after 4 weeks of treatment"
  ["project_narrative_summary"]=>
  string(651) "Repetitive transcranial magnetic stimulation (rTMS) and intranasal esketamine are both approved treatments for treatment-resistant depression. However, the effectiveness of these treatments has never been compared with each other.  The current work proposes to use data from recent clinical trials combined with advanced statistical methods to compare these two interventions in terms of their effectiveness at reducing symptoms of depression amongst those with TRD. We hypothesize that esketamine will be more effective than rTMS, which will provide important information for guiding treatment decisions of patients and providers for people with TRD."
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    ["first_name"]=>
    string(4) "Greg"
    ["last_name"]=>
    string(4) "Rhee"
    ["degree"]=>
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    ["primary_affiliation"]=>
    string(23) "Yale School of Medicine"
    ["email"]=>
    string(19) "taeho.rhee@yale.edu"
    ["state_or_province"]=>
    string(2) "CT"
    ["country"]=>
    string(3) "USA"
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      ["p_pers_f_name"]=>
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      ["p_pers_l_name"]=>
      string(6) "Kaster"
      ["p_pers_degree"]=>
      string(7) "MD, PhD"
      ["p_pers_pr_affil"]=>
      string(21) "University of Toronto"
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      ["requires_data_access"]=>
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  ["project_ext_grants"]=>
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    ["label"]=>
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  ["project_date_type"]=>
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  ["property_scientific_abstract"]=>
  string(1042) "Background: Repetitive transcranial magnetic stimulation (rTMS) and intranasal esketamine are both approved treatments for treatment-resistant depression. However, the effectiveness of these treatments has never been compared with each other. 



Objective: To compare the effectiveness of rTMS and intranasal esketamine on the reduction of depressive symptoms after 4 weeks of treatment.



Study Design: A secondary analysis of two randomized clinical trials using propensity-score weighting 



Participants: Adults age 18-64 with non-psychotic treatment-resistant depression of at least moderate severity



Primary and Secondary Outcome Measure(s): Montgomery Asberg Depression Rating Scale (MADRS)



Statistical Analysis: Propensity-score weights will be derived using baseline covariates to account for potential covariate imbalance between trials. Linear regression will be used to compare the MADRS at treatment completion between rTMS (6 weeks) and esketamine (4 weeks). "
  ["project_brief_bg"]=>
  string(1918) "Treatment-resistant depression (TRD) is a leading source of illness burden and disability worldwide. Individuals who have not responded to several trials of pharmacotherapy or psychotherapy have less than a 15% probability of achieving remission with subsequent trials (Rush et al., 2006). Electroconvulsive therapy historically has been the only treatment with clear evidence of superiority in TRD; however, it is associated with significant cognitive effects that limit its widespread use (Kellner et al., 2010). Recently, two treatment modalities have become available for TRD that have superior tolerability profiles. 



The first of these is repetitive transcranial magnetic stimulation (rTMS), which uses magnetic pulses to focally stimulate cortical regions implicated in the pathophysiology of depression (Blumberger et al., 2018). Amongst individuals with TRD, it has been shown to achieve response (≥50% reduction from baseline) and remission (absence of symptoms) in 50% and 30%, respectively (Blumberger et al., 2018). 



The second of these treatments is intranasal esketamine which is an NMDA receptor antagonist that has demonstrated robust effects for reducing depressive symptoms. Amongst individuals with TRD participating in an industry-led study, after 4 weeks of treatment with intransal esketamine combined with a new antidepressant, the response rate was 70% and remission rate was 53% (Popova et al., 2019). 



Though both esketamine and rTMS have been approved for TRD, they have not yet been directly compared. This is an important limitation because individuals with TRD often must make a decision between these treatments, and currently there is limited evidence to guide physicians and patients for deciding between treatments. The objective of this work will be to generate evidence to improve the decision-making process for individuals with TRD."
  ["project_specific_aims"]=>
  string(783) "Specific Aim 1: To determine the comparative effectiveness of intranasal esketamine compared rTMS for treatment-resistant depression. We will compare the reduction in depressive symptoms between individuals who received rTMS or esketamine at treatment completion (4 weeks for esketamine, 6 weeks for rTMS). 



Specific Aim 2: To determine the comparative tolerability of intranasal esketamine compared rTMS for treatment-resistant depression. We will then compare the all-cause dropout rate in the rTMS and esketamine trials.



Specific Aim 3: To determine the comparative reduction in suicidality of intranasal esketamine compared rTMS for treatment-resistant depression. We will the MADRS item related to suicidal thoughts at treatment completion.

"
  ["project_study_design"]=>
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    ["label"]=>
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  ["project_purposes"]=>
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      ["value"]=>
      string(56) "new_research_question_to_examine_treatment_effectiveness"
      ["label"]=>
      string(114) "New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations"
    }
    [1]=>
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      ["label"]=>
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    }
    [2]=>
    array(2) {
      ["value"]=>
      string(76) "confirm_or_validate previously_conducted_research_on_treatment_effectiveness"
      ["label"]=>
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    }
    [3]=>
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      ["value"]=>
      string(69) "confirm_or_validate previously_conducted_research_on_treatment_safety"
      ["label"]=>
      string(69) "Confirm or validate previously conducted research on treatment safety"
    }
    [4]=>
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      ["value"]=>
      string(22) "participant_level_data"
      ["label"]=>
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    [5]=>
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      ["value"]=>
      string(56) "participant_level_data_meta_analysis_from_yoda_and_other"
      ["label"]=>
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    }
    [6]=>
    array(2) {
      ["value"]=>
      string(28) "research_on_comparison_group"
      ["label"]=>
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    }
    [7]=>
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      ["label"]=>
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  ["project_research_methods"]=>
  string(884) "Inclusion Criteria:

1.	Age 18-64

2.	Diagnosis of non-psychotic major depressive disorder as determined by the MINI

3.	Between 1-5 adequate medication trials

4.	Moderate severity of depression (IDS-C ≥34 or HAMD-17 ≥18)

5.	Medically suitable to receive rTMS or esketamine

6.	No failure of electroconvulsive therapy (ECT)

7.	No active suicidal intent

8.	No active substance use disorder (excluding nicotine or caffeine)

9.	No history of seizures

10.	Benzodiazepine is ≤6mg (esketamine) or ≤2mg (rTMS)



** The requested data will be combined with another trial data [NCT01887782; https://doi.org/10.1016/S0140-6736(18)30295-2]; The PI has/owns full data from this clinical trial [NCT01887782].  We will include all the study participants from both trials.



Exclusion criteria: None"
  ["project_main_outcome_measure"]=>
  string(697) "The primary outcome is the MADRS, a validated psychometric scale for depression severity (Montgomery and \AAsberg, 1979). This will be measured at the end of the treatment course, which is 4 weeks for esketamine and 6 weeks for rTMS. The primary measure of this will be as a continuous measure. Secondary analyses will consider response (≥50% reduction from baseline) and remission (≤12) considered as binary outcomes. Secondary outcomes will include all-cause drop-out rate measured as a proportion to assess tolerability. We will also examine item 10 of the MADRS as a measure of suicidality and this will be measured as a continuous variable as well as a binary outcome (present or absent)."
  ["project_main_predictor_indep"]=>
  string(195) "The main predictor in the current study is the intervention received at baseline, which is either rTMS or esketamine, one from each trial. This will be defined as a 2-level categorical variable. "
  ["project_other_variables_interest"]=>
  string(533) "We will consider the following variables to characterize the study sample: age (continuous), sex (categorical), baseline MADRS score (continuous), number of failed medication trials (ordinal), Clinical Global Impression Severity (ordinal), depressive episode duration (continuous; log transformed), age of depression onset (continuous), baseline Sheehan disability scale (continuous), baseline GAD-7 scale (continuous), psychiatric comorbidities (binary), concomitant medication (binary). These will be included as a propensity score"
  ["project_stat_analysis_plan"]=>
  string(824) "We will combine two individual-level trial data from THREE-D and TRANSFORM-2 studies. First, we will make the comparison groups similar at baseline using propensity score methods (or inverse probability weighting methods). We will then conduct descriptive analyses (e.g., simple t-tests or chi-squared tests) to describe the study samples at baseline. In our multivariate analyses, we will examine comparative effectiveness of rTMS versus esketamine for 1) remission rates measured by HAM-D and/or MADRS measures at the end of week 4; and 2) response rates measured by HAM-D and/or MADRS measures at the end of week 4.  We will also conduct analyses examining trajectories of depressive symptoms over the 4-week period between the comparison groups (i.e., rTMS versus esketamine) using linear mixed-effect models.   

"
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    ["label"]=>
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  ["project_timeline"]=>
  string(374) "When we have access to the data (i.e., beginning of June 2024), all analyses will be completed by the end of summer or beginning of fall 2024.  The manuscript will be drafted within a month after analyses are completed; The manuscript (with full findings will be reported to the YODA project accordingly).  All aspects of the project are to be completed by January 2025.    "
  ["project_dissemination_plan"]=>
  string(191) "The primary dissemination plan is to publish our work in a peer-reviewed journal.  We expect to submit our work in the high-quality journals (e.g., JAMA Psychiatry) for possible publication. "
  ["project_bibliography"]=>
  string(1802) "
Y., Kennedy, S.H., Lam, R.W., Daskalakis, Z.J., Downar, J., 2018. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. The Lancet 391, 1683–1692. https://doi.org/10.1016/S0140-6736(18)30295-2
Kellner, C.H., Knapp, R., Husain, M.M., Rasmussen, K., Sampson, S., Cullum, M., McClintock, S.M., Tobias, K.G., Martino, C., Mueller, M., Bailine, S.H., Fink, M., Petrides, G., 2010. Bifrontal, bitemporal and right unilateral electrode placement in ECT: randomised trial. Br J Psychiatry 196, 226–234. https://doi.org/10.1192/bjp.bp.109.066183
Montgomery, S.A., \AAsberg, M., 1979. A New Depression Scale Designed to be Sensitive to Change. British Journal of Psychiatry 134, 382–389. https://doi.org/10.1192/bjp.134.4.382
Popova, V., Daly, E.J., Trivedi, M., Cooper, K., Lane, R., Lim, P., Mazzucco, C., Hough, D., Thase, M.E., Shelton, R.C., Molero, P., Vieta, E., Bajbouj, M., Manji, H., Drevets, W.C., Singh, J.B., 2019. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry 176, 428–438. https://doi.org/10.1176/appi.ajp.2019.19020172
Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W., Warden, D., Niederehe, G., Thase, M.E., Lavori, P.W., Lebowitz, B.D., McGrath, P.J., Rosenbaum, J.F., Sackeim, H.A., Kupfer, D.J., Luther, J., Fava, M., 2006. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. The American journal of psychiatry 163, 1905–17. https://doi.org/10.1176/appi.ajp.163.11.1905
"
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