Adjunctive D-Cycloserine in Major Depressive Disorder

NCT ID: NCT03937596

Last Updated: 2022-01-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-12-01
• Study Completion Date: 2020-12-24

Brief Summary

Transcranial magnetic stimulation (rTMS) is an approved treatment for depression. The purpose of this study is to test an adjunctive medication, D-cycloserine, in rTMS for depression using a placebo-controlled design. D-Cycloserine is a partial N-Methyl-D-Aspartate receptor (NMDAr) agonist, and therefore may enhance the effects of rTMS, however there is data to support and refute this hypothesis. Using a double-blind design, the investigators will randomize patients with Major Depressive Disorder to receive either daily low dose D-cycloserine or placebo in conjunction with rTMS to the left dorsolateral prefrontal cortex. After 10 treatments (2 weeks), this double-blind period will conclude and all participants will receive an additional 10 treatments (2 weeks) of rTMS without any adjuncts. The primary outcome will be improvement in clinician rated depressive symptoms at the conclusion of the study.

Detailed Description

Major Depressive Disorder (MDD) is a common and debilitating illness. For an unacceptable proportion of patients, depressive symptoms remain impairing despite multiple treatments. Increasingly, non-invasive brain stimulation techniques are being explored as a means of targeting specific brain regions and networks that are implicated in depression. Repetitive transcranial magnetic stimulation (rTMS) is the non-invasive stimulation technique with the largest evidence base in MDD. Targeting the dorsolateral prefrontal cortex (DLPFC) with rTMS has proven an effective treatment for MDD, however as many as 2/3 of patients will not experience substantial improvement. Adjunctive agents are a potential strategy to improve patient outcomes.

The objective of the proposed study is to determine the efficacy of adjunctive D-cycloserine with rTMS directed to the left dorsolateral prefrontal cortex (DLPFC) in acute Major Depressive Episodes. The investigators propose to utilize a stimulation protocol called the intermittent theta-burst protocol to study rTMS in conjunction with D-cyloserine using a randomized double-blind, placebo-controlled design with allocation concealment. Patients with Major Depressive Disorder will be randomized to receive 1) rTMS+cycloserine, or 2) rTMS+placebo in a 1:1 ratio for two weeks (10 sessions).

At the conclusion of the 2-week blinded augmentation phase, patients will continue to receive two weeks of rTMS without an augmentation agent or placebo.

The primary outcome measures will be improvement in depression as measured by change in Montgomery Asberg Depression Rating Scale (MADRS). In addition, the investigators will also be looking at the improvement of other clinical outcome measures, quality of life and changes in brain functional dynamics, as assessed with functional Magnetic Resonance Imaging (MRI), and metabolites, as assessed by Magnetic Resonance (MR) Spectroscopy.

Conditions

Major Depressive Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

D-Cycloserine

Participants will orally ingest a capsule containing 100mg of the antibiotic d-cycloserine daily (Monday-Friday) for the first 2 weeks of rTMS treatment (10 sessions), followed by 2 weeks of rTMS without adjunctive medication.

Group Type: EXPERIMENTAL

D-cycloserine

Intervention Type: DRUG

Daily oral D-cycloserine 100mg during the blinded phase (10 days).

Transcranial Magnetic Stimulator

Intervention Type: DEVICE

Repetitive Transcranial magnetic stimulation (rTMS) will be delivered using a MagPro X100 device with B70 coil and the intermittent theta burst (iTBS) protocol to the left dorsolateral prefrontal cortex. Participants will receive daily treatments (Monday-Friday) over four weeks.

Placebo

Participants will orally ingest a capsule identical to that containing the study medication, however this capsule will contain a placebo. They will ingest this capsule daily (Monday-Friday) for the first 2 weeks of rTMS treatment (10 sessions), followed by 2 weeks of rTMS without adjunctive medication.

Group Type: PLACEBO_COMPARATOR

Transcranial Magnetic Stimulator

Intervention Type: DEVICE

Repetitive Transcranial magnetic stimulation (rTMS) will be delivered using a MagPro X100 device with B70 coil and the intermittent theta burst (iTBS) protocol to the left dorsolateral prefrontal cortex. Participants will receive daily treatments (Monday-Friday) over four weeks.

Placebo oral capsule

Intervention Type: DRUG

Daily oral placebo during the blinded phase (10 days).

Interventions

D-cycloserine

Daily oral D-cycloserine 100mg during the blinded phase (10 days).

Intervention Type: DRUG

Transcranial Magnetic Stimulator

Repetitive Transcranial magnetic stimulation (rTMS) will be delivered using a MagPro X100 device with B70 coil and the intermittent theta burst (iTBS) protocol to the left dorsolateral prefrontal cortex. Participants will receive daily treatments (Monday-Friday) over four weeks.

Intervention Type: DEVICE

Placebo oral capsule

Daily oral placebo during the blinded phase (10 days).

Intervention Type: DRUG

Other Intervention Names

Seromycin

Eligibility Criteria

Inclusion Criteria

• are competent to consent to treatment
• have a Mini-International Neuropsychiatric Interview (MINI) confirmed diagnosis of DSM-5 criteria Major Depressive Disorder with a current episode of at least moderate severity of depression, single or recurrent
• have failed to achieve a clinical response to one adequate trial of antidepressant medication within the current episode, or been unable to tolerate antidepressant medications.
• have a score ≥ 18 on the Hamilton Depression Rating Scale 17-item
• have a Young Mania Rating Scale Score of ≤ 8
• have had no change in dose, or initiation of any psychotropic medication in the 4 weeks prior to randomization
• are able to adhere to the treatment schedule
• pass the TMS adult safety screening (TASS) questionnaire

Exclusion Criteria

• Allergy to Cycloserine
• Have failed adequate trials of ≥4 antidepressant treatments in the current episode.
• have an alcohol or substance use disorder within the last 3 months
• have suicidal ideation (score of 4 ≥ on item 10 of MADRS)
• are at a significant risk of harm to themselves or others
• history of psychosis
• are currently pregnant , breast feeding or plan to become pregnant
• have a lifetime Mini-International Neuropsychiatric Interview (MINI) diagnosis of other primary psychiatric diagnoses as assessed by a study investigator to be primary and causing greater impairment than Major Depressive Disorder.
• have failed a course of electroconvulsive therapy (ECT) in the current episode. Previous ECT treatment outside of the current episode does not influence inclusion.
• history of non-response to rTMS treatment.
• have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, any history of epilepsy, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than or equal to 5 minutes
• have concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump
• have an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed
• If participating in psychotherapy, must have been in stable treatment for at least 3 months prior to entry into the study, with no anticipation of change in the frequency of therapeutic sessions, or the therapeutic focus over the duration of the study
• are currently (or in the last 4 weeks) taking lorazepam or any other benzodiazepine due to the potential to limit rTMS efficacy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Calgary

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alexander McGirr, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University of Calgary

Locations

University of Calgary

Calgary, Alberta, Canada

Countries

Canada

References

Cole J, Sohn MN, Harris AD, Bray SL, Patten SB, McGirr A. Efficacy of Adjunctive D-Cycloserine to Intermittent Theta-Burst Stimulation for Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2022 Dec 1;79(12):1153-1161. doi: 10.1001/jamapsychiatry.2022.3255.

Reference Type: DERIVED

PMID: 36223114 (View on PubMed)

Other Identifiers

REB18-2142

Identifier Type: -

Identifier Source: org_study_id