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

• ClinicalTrials.gov Identifier: NCT05591677
• Recruitment Status: Recruiting
• First Posted: October 24, 2022
• Last Update Posted: January 22, 2024
• Sponsor: The Alfred
• Collaborators: Blue Bell Health, Australia; Gold Coast Hospital and Health Service
• Information provided by (Responsible Party): Leo Chen, The Alfred

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Major Depressive Disorder	Drug: D-Cycloserine; Device: Intermittent Theta Burst Stimulation	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 180 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: D-Cycloserine Augmentation of Intermittent Theta Burst Stimulation (iTBS) in Depression: A Multi-Site, Randomised, Placebo-Controlled Trial (COGENT)
• Actual Study Start Date: April 21, 2023
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Active iTBS + active DCS 50mg/day; 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; 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.; Device: Intermittent Theta Burst Stimulation; 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.
Active Comparator: Active iTBS + active DCS 100mg/day; 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; 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.; Device: Intermittent Theta Burst Stimulation; 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.
Placebo Comparator: Active iTBS + placebo; 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; 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.

Outcome Measures

Primary Outcome Measures :

1. Rate of treatment response as per Montgomery Åsberg Depression Rating Scale (MADRS) [ Time Frame: Determined at Week 4 (primary study endpoint) ]

   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.

Secondary Outcome Measures :

1. Change in Montgomery Åsberg Depression Rating Scale (MADRS) [ Time Frame: Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. ]
   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.
2. Change in Clinical Global Impression (CGI) [ Time Frame: Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. ]
   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'.
3. Change in Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR) [ Time Frame: Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. ]
   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.
4. Beck's Anxiety Inventory (BAI) [ Time Frame: Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. ]
   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.
5. International Trauma Questionnaire (ITQ) [ Time Frame: Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. ]
   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).
6. Beck's Scale for Suicide Ideation (BSS) [ Time Frame: Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. ]
   Self-reported symptom rating scale for suicidal ideation. Scores range from 0 to 38, a higher score indicating a higher level of suicide ideation.
7. Change in World Health Organization Quality of Life (WHOQOL-BREF) [ Time Frame: Administered at baseline and at the ends of weeks 1, 2, 3 and 4 of treatment. ]
   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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Kaila Bianco; +61 3 9076 6564; tms-trials@monash.edu

Contact: Violet Francis; +61 3 9076 6564; tms-trials@monash.edu

Locations

Australia, Victoria

Monash Alfred Psychiatry Research Centre; Recruiting

Melbourne, Victoria, Australia, 3004

Contact: Jacqui Noonan +61 3 9076 6596 jacqui.noonan@monash.edu

Sponsors and Collaborators

The Alfred

Blue Bell Health, Australia

Gold Coast Hospital and Health Service

Investigators

• Principal Investigator: Leo Chen, MBBS PhD FRANZCP; The Alfred

More Information

• Responsible Party: Leo Chen, Head, Clinical TMS and Psychopharmacology Research Units, Monash Alfred Psychiatry Research Centre (MAPrc), The Alfred
• ClinicalTrials.gov Identifier: NCT05591677
• Other Study ID Numbers: 567-22
• First Posted: October 24, 2022
• Last Update Posted: January 22, 2024
• Last Verified: January 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Depressive Disorder; Depressive Disorder, Major; Mood Disorders; Mental Disorders; Cycloserine; Anti-Infective Agents, Urinary; Anti-Infective Agents; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action