Clinical trial NCT05731323: D-Cycloserine+iTBS PK Study
Official title: A Pharmacokinetic Study of Adjunctive D-cycloserine to Intermittent Theta Burst Stimulation in Major Depressive Disorder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Major Depressive Disorder
Lead sponsor: University of Calgary
Sponsor class: OTHER
First posted: 2023-02-16
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background \& Rationale: Major Depressive Disorder (MDD) is a common and debilitating illness that that commonly does not respond to conventional treatments. Transcranial magnetic stimulation (TMS) and intermittent theta-burst stimulation (iTBS) are non-invasive neurostimulation treatments for depression that are Health Canada approved. These work by generating magnetic fields outside of the body to change the activity of brain cells to change how the brain works. They have a very favorable profile, with many patients experiencing improvement with minimal side effects.

The investigators recently completed a study pairing iTBS with an FDA approved medication that was chosen because it might enhance iTBS improvements. This medication is called D-cycloserine, an old antibiotic that is rarely used in modern times. Years after it stopped being useful as an antibiotic, scientists recognized other properties that the molecule has, and it is some of these that make it interesting to pair with iTBS. When the investigators did so, they found that compared to iTBS with a placebo, participants who received iTBS+D-cycloserine were more likely to benefit from treatment.

In this original study, all participants received a fixed dose of 100mg daily. This means that people of very different sizes could have had different drug levels, and the investigators do not know how that impacted outcomes. With this study, there will be no placebo condition because the purpose is to understand whether dosing according to weight matters.

Research Question and Objectives: To describe the pharmacokinetic profile of 100mg oral D-cycloserine and weight-based oral D-cycloserine dosed 25mg/17.5kg among individuals with depression undergoing non-invasive intermittent theta-burst stimulation to the left dorsolateral prefrontal cortex (DLPFC) in Major Depressive Disorder.

Detailed description: Methods: An open-label study of D-cycloserine (DCS) pharmacokinetics will be performed in patients undergoing iTBS to the left DLPFC as a treatment for Major Depressive Disorder. Twelve patients (males and females aged 18-65, with a score ≥18 on the Hamilton Rating Scale for Depression-17 items, and stable pharmacological and psychological regimens) with an acute Major Depressive Episode will be recruited. Bloodwork and an echocardiogram will be obtained prior to the initiation of the study, and enrollment in the study will be contingent on normal lab results.

Prior to initiating iTBS treatment, participants will receive one oral dose of 100mg DCS. A pharmacokinetic curve will be generated from D-Cycloserine levels obtained at 6 timepoints; pre-ingestion, +30 mins, + 60 mins, + 90mins, +120mins and +24 hrs.

Participants will receive iTBS daily for 4 weeks (20 sessions). All participants will be provided with weight-based dosing of DCS to take 120 minutes prior to each iTBS session. Serum levels of weight-based DCS dosing will be measured by blood draws at several time points throughout iTBS treatment. Specifically, a pharmacokinetic curve will be generated on Day 1 of iTBS treatment from D-Cycloserine levels obtained at 6 timepoints; pre-ingestion, +30 mins, + 60 mins, + 90mins, +120mins and +24 hrs. Additional time points will be obtained prior to and 120 minutes after the fifth dose (Day 5 of TMS) and prior to and 120 minutes after the sixth dose (Day 6 of TMS, corresponding to the beginning of the second week of TMS).

Antidepressant effects will be quantified using the Montgomery Asberg Depression Rating Scale, a gold standard clinician rated instrument. Participants will complete a short battery of cognitive tests at the beginning and end of the study. Blood work and echocardiogram will be repeated after 4 weeks to confirm safety of low-dose DCS.

Participants will return to the lab for a follow-up assessment 4 weeks after they have finished the TMS protocol (week 8).

Eligibility criteria: Inclusion Criteria:

1. Males and females aged 18 to 65 years
2. are competent to consent to treatment
3. have a confirmed diagnosis of DSM-5 criteria Major Depressive Disorder with a current episode of at least moderate severity of depression, single or recurrent
4. 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.
5. have current episode of at least moderate severity of depression, as defined by a score ≥ 18 on the HAMD-17 item
6. have had no change in dose, or initiation of any psychotropic medication in the 4 weeks prior to randomization
7. are able to adhere to the treatment schedule
8. pass the TMS adult safety screening (TASS) questionnaire
9. have had blood work (complete blood count, electrolytes, BUN, creatinine, eGFR, AST, ALT and GGT, and ECG) within the reference range. Female participants must have a negative pregnancy test.

Exclusion Criteria:

1. Allergy to cycloserine.
2. have failed adequate trials of ≥4 antidepressant treatments in the current episode.
3. have an alcohol or substance use disorder within the last 3 months
4. have suicidal ideation (score of 4 ≥ on item 10 of MADRS)
5. are at a significant risk of harm to themselves or others
6. current symptoms of psychosis
7. history of psychosis
8. are currently pregnant, breast feeding or plan to become pregnant over the duration of the study
9. have a diagnosis of other primary psychiatric diagnoses as assessed by a study investigator to be primary and causing greater impairment than Major Depressive Disorder.
10. have failed a course of ECT in the current episode. Previous ECT treatment outside of the current episode does not influence inclusion.
11. history of non-response to TMS treatment.
12. 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
13. have concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump
14. 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
15. 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
16. are currently (or in the last 4 weeks) taking any benzodiazepine, cyclopyrrolone, gabapentin/pregabalin or anticonvulsant due to the potential to limit TMS efficacy
17. 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).
18. are being currently treated with ethionamide or isoniazid (contraindicated with D-cycloserine)

Primary outcomes:
measure: Montgomery-Asberg Depression Rating Scale (MADRS)
timeFrame: Administered at baseline, at the halfway point (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Individual differences in D-cycloserine serum concentration will be correlated with clinical outcomes
timeFrame: 10 blood samples: PK curve over the first 2 days of TMS treatment (6 draws) and prior to ingestion and after 120 minutes on day 5 and day 6
measure: Individual fidelity to the protocol will be correlated with differential change in primary outcomes
timeFrame: Daily Monday-Friday throughout study (4 weeks)
measure: The variance in D-cycloserine level will be greater in the 100mg dosing condition than in the weight-based dosing condition.
timeFrame: PK curve done at baseline (fixed dose) and Day 1 of TMS (weight-based dose). Samples at pre-ingestion, +30 minutes, +60 minutes, +90 minutes, +120 minutes, and +24hours.
measure: Determine whether blood serum levels of D-cycloserine achieved by weight-based dosing is consistent across time.
timeFrame: Day 1 of TMS, Day 5 of TMS, and Day 6 of TMS.
Secondary outcomes:
measure: Number of participants that achieve clinical remission of depression
timeFrame: Administered at baseline, halfway (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Number of participants that achieve clinical response (>=50% improvement in depression)
timeFrame: Administered at baseline, halfway (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Changes in self-reported depression as measured by the Quick Inventory of Depressive Symptoms (QIDS-SR)
timeFrame: Administered at baseline, halfway (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Changes in self-reported anxiety as measured by the Generalized Anxiety Disorder (GAD-7) questionnaire
timeFrame: Administered at baseline, halfway (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in suicidal intentions
timeFrame: Administered at baseline, halfway (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Cognitive Function - THINC-integrated tool (THINC-it)- Choice Reaction Time
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Cognitive Function - THINC-integrated tool (THINC-it)- Working Memory
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Cognitive Function - THINC-integrated tool (THINC-it)- Digit Symbol Substitution
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Cognitive Function - THINC-integrated tool (THINC-it)- Trail Making Test part B
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Implicit Suicidality
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Clinical Global Impression- Severity
timeFrame: Administered at baseline, halfway (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Clinical Global Impression- Improvement
timeFrame: Administered at baseline, halfway (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Improvements in depressive symptoms will persist until the 8 week timepoint
timeFrame: Administered at baseline, halfway (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Cognitive Function - THINC-integrated tool (THINC-it)- Perceived Deficits Questionnaire - 5 item scale (PDQ-5)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
Other outcomes:
measure: Side Effects
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: Daily Monday-Friday throughout study (4 weeks) and at one month follow up
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; Sodium level
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; Potassium level
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; Chloride level
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; Hemoglobin
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; Hematocrit
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; White Blood Cell count
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; Red Blood Cell count
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; platelets
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; AST
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; ALT
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; GGT
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; BUN
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; Creatinine
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in bloodwork; eGFR
timeFrame: Baseline and after rTMS treatment (week 4)
measure: Safety hypothesis: There will be no clinically significant changes in QTc
timeFrame: Baseline and after rTMS treatment (week 4)
Locations:
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
Study officials:
affiliation: University of Calgary
name: Alexander McGirr, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: