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The investigators will perform a double-blind, randomized, sham-controlled clinical trial of theta-burst stimulation (TBS) in mixed depressive episodes of both bipolar and major depressive disorders. Will be selected 90 patients aged 18-65 years with diagnosis of TB (I or II) or MDD in moderate or severe major depressive episode with mixed features. The primary endpoint of efficacy will be a continuous outcome of change in Montgomery-Asberg Depression Rating Scale (MADRS) from baseline to week 3.
INTRODUCTION: Mixed-specifier mood disorders are probably a different subgroup in terms of response to treatment, socio-demographic parameters, course and family history. The investigators will perform a clinical trial of theta-burst stimulation (TBS) in mixed depressive episodes of both bipolar (I and II) and major depressive disorders. METHODS: The study is designed as a randomized, sham-controlled, double-blinded clinical trial evaluating TBS for the treatment of moderate or severe major depressive episodes with mixed features of patients receiving at least one first or second line pharmacological treatment for depressive episodes without adequate response. Ninety adult (18 to 65 yo) patients will be enrolled and submitted to 6-week (comprising 5 consecutive days a week sessions for the first 3 weeks and then 2 days a week for a further 3 week) of inhibitory followed by excitatory TBS in dorsolateral prefrontal cortex. Participants will be assessed using clinical and neuropsychological tests before and after the intervention. The primary outcome is change in Montgomery-Asberg Depression Scale (MADRS) score over time and across groups. Cognitive parameters will also be assessed with neuropsychological tests.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active TBS Arm | Active Comparator | Patients randomized to this arm will receive active TBS 5 consecutive days of the week (Monday to Friday) in the first 3 weeks and then 2 alternate days of the week (with interval of at least 1 day between sessions) for another 3 weeks. |
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| Sham TBS Arm | Sham Comparator | Patients randomized to this arm will receive sham TBS 5 consecutive days of the week (Monday to Friday) in the first 3 weeks and then 2 alternate days of the week (with interval of at least 1 day between sessions) for another 3 weeks. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Active Theta Burst Stimulation (TBS) | Device | Each session will be comprised of ACTIVE TBS: first, continuous inhibitory stimulation (cTBS) in the right dorsolateral prefrontal cortex followed by intermittent excitatory stimulation (iTBS) in the left dorsolateral prefrontal cortex. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) at week 3. | Change in Montgomery-Asberg Depression Rating Scale (MADRS) in each patient in both interventional groups. The outcome will be assessed by a continuous change using a mixed models statistic. The scale range is: 0 to 6 - normal/symptom absent; 7 to 19 - mild depression; 20 to 34 - moderate depression; 35 - 60 - severe depression. Reduction is a better and increase is a worse outcome. | From baseline until week 3. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) at week 6. | Change in Montgomery-Asberg Depression Rating Scale (MADRS) in each patient in both interventional groups. The outcome will be assessed by a continuous change using a mixed models statistic. The scale range is: 0 to 6 - normal/symptom absent; 7 to 19 - mild depression; 20 to 34 - moderate depression; 35 - 60 - severe depression. Reduction is a better and increase is a worse outcome. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Diego Tavares, MD | Contact | +5511941854053 | diego.tavares@hc.fm.usp.br | |
| Carla Garcia, MD | Contact | +5511982732856 | dracarlagarcia@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Ricardo Moreno, PHD | University of Sao Paulo | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Institute of Psychiatry, University of Sao Paulo | Recruiting | São Paulo | 05403-010 | Brazil |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34193961 | Derived | Tavares DF, Suen P, Rodrigues Dos Santos CG, Moreno DH, Lane Valiengo LDC, Klein I, Borrione L, Marques Forte P, Brunoni AR, Alberto Moreno R. Treatment of mixed depression with theta-burst stimulation (TBS): results from a double-blind, randomized, sham-controlled clinical trial. Neuropsychopharmacology. 2021 Dec;46(13):2257-2265. doi: 10.1038/s41386-021-01080-9. Epub 2021 Jun 30. | |
| 32499730 |
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| Type | Date | Date Unknown |
|---|---|---|
| Release | Sep 11, 2022 | |
| Reset | Jul 27, 2023 |
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| Release Date | Unrelease Date | Unrelease Date Unknown | Reset Date | MCP Release Number |
|---|---|---|---|---|
| Sep 11, 2022 | Jul 27, 2023 |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D001714 | Bipolar Disorder |
| ID | Term |
|---|---|
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| D000068105 | Bipolar and Related Disorders |
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Double-blind, randomized, parallel-group, 6-week, sham-controlled clinical trial.
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Allocation masking will be done through sequentially numbered cards that will determine which group each patient will belong to. The card determines whether the coil to be used will produce actual or simulated stimulation. A secretary who does not participate directly in the research will be responsible for handling the numbered cards to the patient prior to each session. Participants and staff will not fully know the status of allocation groups.
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| Sham Theta Burst Stimulation (TBS) | Device | The sham-TBS sessions will be performed using an identical coil that produces SHAM Stimulation: first, sham continuous inhibitory stimulation (cTBS) in the right dorsolateral prefrontal cortex followed by sham intermittent excitatory stimulation (iTBS) in the left dorsolateral prefrontal cortex. |
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| From baseline until week 6. |
| Change in Young Mania Rating Scale (YMRS) at week 3. | Change in Young Mania Rating Scale (YMRS) in each patient in both interventional groups. The outcome will be assessed by a continuous change using a mixed models statistic. The scale range is: 13-19 - hypomania; 20-25 - mild mania; 26-37 - moderate mania ; 38-60 - severe mania. Reduction is a better and increase is a worse outcome. | From baseline until week 3. |
| Change in Young Mania Rating Scale (YMRS) at week 6. | Change in Young Mania Rating Scale (YMRS) in each patient in both interventional groups. The outcome will be assessed by a continuous change using a mixed models statistic. The scale range is: 13-19 - hypomania; 20-25 - mild mania; 26-37 - moderate mania ; 38-60 - severe mania. Reduction is a better and increase is a worse outcome. | From baseline until week 6. |
| Response rate using Montgomery-Asberg Depression Rating Scale (MADRS) at week 3 | Reduction of 50% or more of the Montgomery-Asberg Depression Rating Scale (MADRS) in each patient in both interventional groups. The scale range is: 0 to 6 - normal/symptom absent; 7 to 19 - mild depression; 20 to 34 - moderate depression; 35 - 60 - severe depression. Reduction is a better and increase is a worse outcome. | From baseline until week 3. |
| Response rate using Montgomery-Asberg Depression Rating Scale (MADRS) at week 6. | Reduction of 50% or more of the Montgomery-Asberg Depression Rating Scale (MADRS) in each patient in both interventional groups. The scale range is: 0 to 6 - normal/symptom absent; 7 to 19 - mild depression; 20 to 34 - moderate depression; 35 - 60 - severe depression. Reduction is a better and increase is a worse outcome. | From baseline until week 6. |
| Remission rate using Montgomery-Asberg Depression Rating Scale (MADRS) at week 3 | Montgomery-Asberg Depression Rating Scale (MADRS) < 11 points in each patient in both interventional groups. The scale range is: 0 to 6 - normal/symptom absent; 7 to 19 - mild depression; 20 to 34 - moderate depression; 35 - 60 - severe depression. Reduction is a better and increase is a worse outcome. | From baseline until week 3. |
| Remission rate using Montgomery-Asberg Depression Rating Scale (MADRS) at week 6. | Montgomery-Asberg Depression Rating Scale (MADRS) < 11 points in each patient in both interventional groups. The scale range is: 0 to 6 - normal/symptom absent; 7 to 19 - mild depression; 20 to 34 - moderate depression; 35 - 60 - severe depression. Reduction is a better and increase is a worse outcome. | From baseline until week 6. |
| Change in Hamilton Anxiety Scale (HAM-A scale) at week 3. | Change in Hamilton Anxiety Scale (HAM-A scale) in each patient in both interventional groups. The outcome will be assessed by a continuous change using a mixed models statistic. The scale range is: 0-17 - mild anxiety; 18-24 moderate anxiety; 25-30 - severe anxiety. Reduction is a better and increase is a worse outcome. | From baseline until week 3. |
| Change in Hamilton Anxiety Scale (HAM-A scale) at week 6. | Change in Hamilton Anxiety Scale (HAM-A scale) in each patient in both interventional groups. The outcome will be assessed by a continuous change using a mixed models statistic. The scale range is: 0-17 - mild anxiety; 18-24 moderate anxiety; 25-30 - severe anxiety. Reduction is a better and increase is a worse outcome. | From baseline until week 6. |
| Change in Global Clinical Impression Scale of Severity (GCI-S) at week 3. | Change in Global Clinical Impression Scale of Severity (GCI-S) in each patient in both interventional groups. The outcome will be assessed by a continuous change using a mixed models statistic. The scale range is: 1- not sick; 2- very mild disease; 3- mild disease; 4- moderate disease; 5- intense disease; 6- severe disease; 7- extremely severe disease. Reduction is a better and increase is a worse outcome. | From baseline until week 3. |
| Change in Global Clinical Impression Scale of Severity (GCI-S) at week 6. | Change in Global Clinical Impression Scale of Severity (GCI-S) in each patient in both interventional groups. The outcome will be assessed by a continuous change using a mixed models statistic. The scale range is: 1- not sick; 2- very mild disease; 3- mild disease; 4- moderate disease; 5- intense disease; 6- severe disease; 7- extremely severe disease. Reduction is a better and increase is a worse outcome. | From baseline until week 6. |
| Change in the brief version of the World Health Organization Quality of Life Questionnaire (WHOQOL-brief scale) at week 3. | Change in the brief version of the World Health Organization Quality of Life Questionnaire (WHOQOL-brief scale) in both interventional groups.The scale range is: 26 to 130 points. Increase is a better and reduction is a worse outcome. | From baseline until week 3. |
| Change in the brief version of the World Health Organization Quality of Life Questionnaire (WHOQOL-brief scale) at week 6. | Change in the brief version of the World Health Organization Quality of Life Questionnaire (WHOQOL-brief scale) in both interventional groups.The scale range is: 26 to 130 points. Increase is a better and reduction is a worse outcome. | From baseline until week 6. |
| Change in Global Assessment of Functioning (GAF) Scale at week 3. | Change in Global Assessment of Functioning (GAF) Scale in both interventional groups. The scale range is: 1 to 100 points. Increase is a better and reduction is a worse outcome. | From baseline until week 3. |
| Change in Global Assessment of Functioning (GAF) Scale at week 6. | Change in Global Assessment of Functioning (GAF) Scale in both interventional groups. The scale range is: 1 to 100 points. Increase is a better and reduction is a worse outcome. | From baseline until week 6. |
| Change in Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN) at week 3. | Change in Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN) in both interventional groups. The scale range is: 18 to 72 points. Reduction is a better and increase is a worse outcome. | From baseline until week 3. |
| Change in Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN) at week 6. | Change in Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN) in both interventional groups. The scale range is: 18 to 72 points. Reduction is a better and increase is a worse outcome. | From baseline until week 6. |
| Change in Barratt Impulsivity Scale of 11 items (BIS-11) at week 3. | Change in Barratt Impulsivity Scale of 11 items (BIS-11) in both interventional groups. The scale range is: 30 to 120 points. Reduction is a better and increase is a worse outcome. | From baseline until week 3. |
| Change in Barratt Impulsivity Scale of 11 items (BIS-11) at week 6. | Change in Barratt Impulsivity Scale of 11 items (BIS-11) in both interventional groups. The scale range is: 30 to 120 points. Reduction is a better and increase is a worse outcome. | From baseline until week 6. |
| Frequency of adverse events in UKU-SERS Scale at week 6. | Frequency of adverse events in UKU-SERS Scale in both interventional groups.The scale range is: 0 to 57 points. Reduction is a better and increase is a worse outcome. | From baseline until week 6. |
| Derived |
| Tavares DF, Dos Santos CGR, Valiengo LDCL, Klein I, Borrione L, Forte PM, Brunoni AR, Moreno RA. Efficacy, Safety, and Tolerability of Theta-Burst Stimulation in Mixed Depression: Design, Rationale, and Objectives of a Randomized, Double-Blinded, Sham-Controlled Trial. Front Psychiatry. 2020 May 15;11:435. doi: 10.3389/fpsyt.2020.00435. eCollection 2020. |