Adjunctive D-Cycloserine in Major Depressive Disorder

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Placebo-controlled Trial of Adjunctive D-cycloserine in Repetitive Transcranial Magnetic Stimulation for Major Depressive Disorder

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: D-cycloserine
* Device: Transcranial Magnetic Stimulator
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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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 have an exclusion criteria for MRI: Those with a history of cranial, thoracic or abdominal surgery, with pacemakers, artificial joints or other metallic implants will be excluded from the MRI scan. Subjects that have agreed to participate in the MRI portion of the study will be pre-screened for any potential metal fragments in the body (particularly in the orbits) if they have had any history of doing metal work or have been involved in use/deployment of ammunitions/explosives, welding, piping etc).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: D-Cycloserine<br>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<br>* Daily oral D-cycloserine 100mg during the blinded phase (10 days).<br>* Other names: Seromycin;Device: Transcranial Magnetic Stimulator<br>* 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.<br>|
| Placebo Comparator: Placebo<br>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<br>* 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.<br>Drug: Placebo oral capsule<br>* Daily oral placebo during the blinded phase (10 days).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Magnetic Resonance Imaging (fMRI) | Change in task and resting state functional connectivity as determined by an fMRI. | Administered at baseline and week 2. Change in cycloserine group vs change in placebo group | 
| Magnetic Resonance (MR) spectroscopy | Change in brain metabolites in regions of interest. | Administered at baseline and week 2. Change in cycloserine group vs change in placebo group | 
| Clinical Remission | Score of </= 10 on the MADRS | Administered at baseline, at the halfway point (week 2), and after rTMS treatment (week 4) | 
| Clinical Response | >/= 50% reduction in MADRS scores | 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 | The WHOQOL-BREF is a self-reported questionnaire which assesses individual's perception of their quality of life across 4 domains; physical health, psychological, social relationships and environment. 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, week 1, at the halfway point (week 2), week 3, and after rTMS treatment (week 4) | 
| Anxiety Symptoms | Anxiety symptoms will be assessed using the 7 item Generalized Anxiety Disorder (GAD-7) questionnaire. The GAD-7 measures self-reported feelings of anxiety within the last 2 weeks. Scores range from 0-21. Scores of 5, 10, and 15 represent cut points for mild, moderate, and severe anxiety, respectively. | Administered at baseline, week 1, at the halfway point (week 2), week 3, and after rTMS treatment (week 4) | 
| Workplace Productivity | Productivity will be assessed using the Lam Employment Absence and Disability Scale (LEAPS). The LEAPS is a 10-item, self-rated scale and provides information on how participants are functioning at work. Scores range from 0 - 28, with higher scores representing more severe work impairment. | Administered at baseline, week 1, at the halfway point (week 2), week 3, and after rTMS treatment (week 4) | 
| Functional Disability | Functional disability will be assessed using the Sheehan Disability Scale (SDS). The SDS is a self-report scale to assess functional impairment in three domains; work/school, social and family life. Scores range from 0 - 30, with higher scores representing greater impairment. | Administered at baseline, week 1, at the halfway point (week 2), week 3, and after rTMS treatment (week 4) | 
| Clinical Global Impression | Clinical Global Impression will be assessed using the Clinical Global Impression (CGI) Severity and Improvement scales. 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, at the halfway point (week 2), and after rTMS treatment (week 4) | 
| Cognitive Function | Cognitive function will be assessed using the THINC-it brief cognitive assessment tool. THINC-it includes 4 objective cognitive tests (adapted from choice reaction time, 1-back working memory task, symbol digit coding, and Trails-B) and a subjective cognitive questionnaire (PDQ-5). Results indicate cognitive performance compared to healthy age-, sex- and education-matched individuals. | Administered at baseline and at the halfway point (week 2) | 
| Implicit Suicidal Thoughts | Death Implicit Association Test (D-IAT) is a behavioral test that measures the strength of automatic (implicit) associations between concepts in people's minds relying on latency measures in a simple sorting task. The strength of an association between concepts of death and ones self is measured by the standardized mean difference score of the 'hypothesis-inconsistent' pairings and 'hypothesis-consistent' pairings | Administered at baseline and at the halfway point (week 2) | 
| Personality Measures- BFI | The Big Five Inventory (BFI) is a self-report inventory designed to measure the Big Five dimensions of personality: extroversion, agreeableness, openness, conscientiousness, and neuroticism. The test consists of 44 items that you must rate on how true they are about you on a five point scale where 1=Disagree, 3=Neutral and 5=Agree. | Administered at baseline and after rTMS treatment (week 4) | 
| Personality Measures- DEQ | The Depressive Experiences Questionnaire (DEQ) is a 66 item questionnaire where participants rate themselves on life experiences and personality characteristics frequently associated with depression. Participants are asked to rate each item on a seven-point Likert-type scale ranging from strongly disagree (1) to strongly agree (7). Analysis of results produces 3 factors: Dependency, Self-criticism, and Efficacy. | Administered at baseline and after rTMS treatment (week 4) | 
| Anhedonia | The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item self report developed to measure ability to experience pleasure (hedonic tone) and its absence (anhedonia) in the last few days. Each item asks participants to agree or disagree with how pleasurable a certain scenario would be. Disagree responses receive a score of 1 and Agree responses receive a score of 0. The SHAPS is scored as the sum of the 14 items so that total scores ranged from 0 to 14. A higher total SHAPS score indicated higher levels of anhedonia. | Administered at baseline and after rTMS treatment (week 4) | 
| Self-reported Cognition | The Cognitive Failures Questionnaire (CFQ) measures self-reported failures in perception, memory, and motor function in the completion of everyday tasks. Individuals are asked to rate the frequency experiences and behaviors on a 5-point scale: 0-Never, 1-Very rarely, 2-Occasionally, 3-Quite often, 4-Very often. | Administered at baseline, week 1, at the halfway point (week 2), week 3, and after rTMS treatment (week 4) | 
| Depressive Symptoms | The Quick Inventory of Depressive Symptomatology- Self Report (QIDS-SR) is a scale of self-report measure of depression. Questions in the QIDS - SRcorrelate with the nine DSM-IV symptom criterion domains, Including: Sleep disturbance, Sad mood, Decrease/increase in appetite/weight, Concentration, Self-criticism, Suicidal ideation, Interest, Energy/fatigue, Psychomotor agitation/retardation.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, week 1, at the halfway point (week 2), week 3, and after rTMS treatment (week 4) | 
| VAS for General Health | A Visual Analog Scale (VAS) will ask participants how good or bad their health is today. This scale is numbered from 0 to 100. 100 indicates the best health they can imagine. 0 indicates the worst health they can imagine. | Administered at baseline, at the halfway point (week 2), and after rTMS treatment (week 4) | 
| Perception of Illness | The Brief Illness Perception Questionnaire (BIPQ) is a nine-item scale designed to rapidly assess the cognitive and emotional representations of illness. The BIPQ assesses perception on a 0 (minimum) -10 (maximum) response scale. It includes 5 items on cognitive representation of illness perception, 2 items on emotional representation, 1 item on illness comprehensibility, and 1 item on perceived cause of illness. | Administered at baseline and after rTMS treatment (week 4) |