Adjunctive D-Cycloserine in Major Depressive Disorder

NCT03937596 | Completed Phase 2 FDA Drug FDA Device

• 1 other identifier: REB18-2142
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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.

Conditions

Major Depressive Disorder

Outcome Measures

Primary Outcomes (1)

• Montgomery-Asberg Depression Rating Scale (MADRS)

  Change in severity of depressive symptoms as measured by the MADRS, a clinician-rated instrument. The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes. 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, at the halfway point (week 2), and after rTMS treatment (week 4)

Secondary Outcomes (18)

• Functional Magnetic Resonance Imaging (fMRI)

  Administered at baseline and week 2. Change in cycloserine group vs change in placebo group

• Magnetic Resonance (MR) spectroscopy

  Administered at baseline and week 2. Change in cycloserine group vs change in placebo group

• Clinical Remission

  Administered at baseline, at the halfway point (week 2), and after rTMS treatment (week 4)

• Clinical Response

  Administered at baseline, at the halfway point (week 2), and after rTMS treatment (week 4)

• Quality of Life as measured by the World Health Organization Quality of Life (WHOQOL-BREF) questionnaire

  Administered at baseline, week 1, at the halfway point (week 2), week 3, and after rTMS treatment (week 4)

Other Outcomes (2)

• Incidence of Treatment-Emergent Adverse Events

  Daily Monday-Friday throughout study (4 weeks)

• Side Effects

  Daily Monday-Friday throughout study (4 weeks)

Study Arms (2)

D-Cycloserine

EXPERIMENTAL

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.

Drug: D-cycloserine; Device: Transcranial Magnetic Stimulator

Placebo

PLACEBO COMPARATOR

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.

Device: Transcranial Magnetic Stimulator; Drug: Placebo oral capsule

Interventions

D-cycloserine DRUG

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

Also known as: Seromycin

D-Cycloserine

Transcranial Magnetic Stimulator 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.

D-Cycloserine; Placebo

Placebo oral capsule DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• University of Calgary: lead

Study Sites (1)

University of Calgary

Calgary, Alberta, T2N1N4, Canada

Location

Related Publications (1)

• 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.

  PMID: 36223114 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major

Interventions

Cycloserine

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oxazolidinones; Oxazoles; Serine; Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Alexander McGirr, MD PhD

  University of Calgary

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 29, 2019
• First Posted: May 6, 2019
• Study Start: December 1, 2019
• Primary Completion: December 24, 2020
• Study Completion: December 24, 2020
• Last Updated: January 10, 2022

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)