D-Cycloserine Augmentation of Intermittent Theta Burst Stimulation (iTBS) in Depression (COGENT)

Study Overview
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Brief Summary
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The goal of this clinical trial is to investigate if the drug D-Cycloserine (DCS) improves the antidepressant effects of Intermittent Theta Burst Stimulation (iTBS), a non-invasive brain stimulation therapy, in patients with Major Depressive Disorder (MDD). The main questions it aims to answer are: Whether taking DCS prior to iTBS therapy will be more effective in improving depressive symptoms than iTBS therapy alone. Compare the effect of DCS 100mg/day versus 50mg/day on depressive symptoms. Test the safety and tolerability of DCS. Participants will take either 50mg DCS per day, 100mg DCS or placebo prior to each iTBS treatment session. iTBS treatment will be administered daily, 5 days a week for 4 weeks. Clinical measures will be conducted at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment.

Detailed Description
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Major Depressive Disorder (MDD) is a common and debilitating condition with high rates of treatment resistance. Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for treatment-resistant depression with few adverse effects. Intermittent Theta Burst Stimulation (iTBS) is a time-efficient form of rTMS with evidence base in the treatment of treatment-resistant depression (TRD). The most commonly supported understanding of iTBS's mechanism of action appear to be its strengthening of connections between networks of neurons, which is modulated by the N-methyl-D-aspartate (NMDA) receptor. D-cycloserine (DCS) is a partial NMDA receptor agonist that has demonstrable impact on rTMS and TBS's neuromodulatory effects. This study protocol proposes the conduct of a prospective multi-site, parallel-arm design, randomized, double-blinded, placebo-controlled clinical trial to investigate DCS augmentation of iTBS in MDD. We will investigate if adjuvant DCS 50mg or 100mg/day might have superior iTBS antidepressant augmentation effects.

Official Title
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D-Cycloserine Augmentation of Intermittent Theta Burst Stimulation (iTBS) in Depression: A Multi-Site, Randomised, Placebo-Controlled Trial (COGENT)

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: D-Cycloserine
* Device: Intermittent Theta Burst Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of major depressive episode (MDE), in accordance with the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), in the context of unipolar major depressive disorder or bipolar affective disorder. 18 years or older in age. Treatment resistant depression at Stage II of the Thase and Rush classification.56 Baseline Montgomery Åsberg Depression Rating Scale score of ≥ 20 (moderate-to-severe depression severity).57,58 No increase or initiation of new antidepressant therapy in the four weeks prior to screening. Demonstrated capacity to give informed consent. Exclusion Criteria: Inability to provide informed consent. Medically unstable patients at the discretion of the investigator. Concomitant neurological disorder or a history of a seizure disorder. Participants who are pregnant. Current substance use meeting DSM-5 criteria for substance use disorder. Per DSM-5, had ever met diagnostic criteria for schizophrenia, schizoaffective disorder, schizophreniform disorder or delusional disorder as assessed by the Mini-International Neuropsychiatric Interview (MINI) at the time of screening. Diagnosis of any other mental disorder that is the participant's primary diagnosis or main mental health syndrome of concern at the time of screening, which may significantly affect psychiatric status and assessed as likely to impact trial participation, in the clinical judgement of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active iTBS + active DCS 50mg/day<br>Active iTBS (600 pulses), 5 days/week x 4 weeks + active DCS 50mg/day x 2 weeks, taken 2-hours prior to scheduled iTBS treatment. | Drug: D-Cycloserine<br>* D-cycloserine (DCS) is a partial NMDA receptor agonist that has demonstrable impact on rTMS and TBS's neuromodulatory effects. Participants will be asked to orally ingest one capsule 2-hours prior to their scheduled iTBS treatment time.<br>Device: Intermittent Theta Burst Stimulation<br>* Intermittent Theta Burst Stimulation (iTBS) will be administered with a magnetic stimulator using a figure-of-8 coil or equivalent FDA-approved device. Initial treatment coil localisation and individual calibration of stimulation intensity will be conducted by TMS-trained investigators/staff using standard approaches.67,68 Stimulation intensity will be at 90% of the individual's calibrated resting motor threshold. iTBS treatment session delivers 600 pulses and is approximately 3½ minutes in duration. The total pulse number applied over a course of 20 treatments will be 12,000. This regimen is analogous with the iTBS protocol approved by the US FDA to treat TRD.<br>|
| Active Comparator: Active iTBS + active DCS 100mg/day<br>Active iTBS (600 pulses), 5 days/week x 4 weeks + active DCS 100mg/day x 2 weeks, taken 2-hours prior to scheduled iTBS treatment. | Drug: D-Cycloserine<br>* D-cycloserine (DCS) is a partial NMDA receptor agonist that has demonstrable impact on rTMS and TBS's neuromodulatory effects. Participants will be asked to orally ingest one capsule 2-hours prior to their scheduled iTBS treatment time.<br>Device: Intermittent Theta Burst Stimulation<br>* Intermittent Theta Burst Stimulation (iTBS) will be administered with a magnetic stimulator using a figure-of-8 coil or equivalent FDA-approved device. Initial treatment coil localisation and individual calibration of stimulation intensity will be conducted by TMS-trained investigators/staff using standard approaches.67,68 Stimulation intensity will be at 90% of the individual's calibrated resting motor threshold. iTBS treatment session delivers 600 pulses and is approximately 3½ minutes in duration. The total pulse number applied over a course of 20 treatments will be 12,000. This regimen is analogous with the iTBS protocol approved by the US FDA to treat TRD.<br>|
| Placebo Comparator: Active iTBS + placebo<br>Active iTBS (600 pulses), 5 days/week x 4 weeks + placebo x 2 weeks, taken 2-hours prior to scheduled iTBS treatment. | Device: Intermittent Theta Burst Stimulation<br>* Intermittent Theta Burst Stimulation (iTBS) will be administered with a magnetic stimulator using a figure-of-8 coil or equivalent FDA-approved device. Initial treatment coil localisation and individual calibration of stimulation intensity will be conducted by TMS-trained investigators/staff using standard approaches.67,68 Stimulation intensity will be at 90% of the individual's calibrated resting motor threshold. iTBS treatment session delivers 600 pulses and is approximately 3½ minutes in duration. The total pulse number applied over a course of 20 treatments will be 12,000. This regimen is analogous with the iTBS protocol approved by the US FDA to treat TRD.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of treatment response as per Montgomery Åsberg Depression Rating Scale (MADRS) | Clinical treatment response defined as >/= 50% reduction in MADRS scores from baseline to primary study endpoint. Clinician-administered depression rating scale. The overall score ranges from 0 - 60. Cutoff points are 0-6 = normal, 7-9 = mild depression, 20-34 = moderate depression, >34 = severe depression. | Determined at Week 4 (primary study endpoint) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Montgomery Åsberg Depression Rating Scale (MADRS) | Clinician-administered depression rating scale. The overall score ranges from 0 - 60. Cutoff points are 0-6 = normal, 7-9 = mild depression, 20-34 = moderate depression, >34 = severe depression. | Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. | 
| Change in Clinical Global Impression (CGI) | Clinician assessment of overall illness severity and global functioning. The CGI-Severity scale is clinician rated from 1-7 representing 'Not at all ill' to 'Severely ill'. The CGI-Improvement scale is also rated 1-7, representing the range between 'Very much improved' and 'Very much worse'. | Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. | 
| Change in Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR) | Self-reported symptom rating scale for depression severity. Severity of depression can be judged based on the total score. 1-5 = No depression 6-10 = Mild depression 11-15 = Moderate depression 16-20 = Severe depression 21-27 = Very severe depression. | Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. | 
| Beck's Anxiety Inventory (BAI) | Self-reported symptom rating scale for anxiety severity. The score range is 0-63. A total score of 0-7 is considered minimal range, 8-15 is mild, 16-25 is moderate, and 26-63 is severe. | Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. | 
| International Trauma Questionnaire (ITQ) | Self-reported symptom rating of trauma-related symptoms and their severity. All ITQ items are answered on a 5-point Likert scale ranging from 0 (Not at all) to 4 (Extremely). | Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. | 
| Beck's Scale for Suicide Ideation (BSS) | Self-reported symptom rating scale for suicidal ideation. Scores range from 0 to 38, a higher score indicating a higher level of suicide ideation. | Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. | 
| Change in World Health Organization Quality of Life (WHOQOL-BREF) | Self-reported rating scale of quality of life. Domains scores are calculated to range from 0-20 and scaled in a positive direction (ie. higher scores denote higher quality of life). | Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. |