D-Cycloserine+iTBS PK Study

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.

Examine whether differential change in clinical outcomes will be mediated by D-Cycloserine plasma levels following weight-based dosing. Participants will provide 10 blood samples to characterize plasma levels of D-Cycloserine following a weight-based dose. The primary efficacy measures will be examined in relation to drug blood levels.

All participants will be instructed to take the blinded capsule 90 - 120 minutes prior to TMS treatment, ensuring adequate time for drug absorption. Daily logs will be kept by the study staff to confirm time of capsule ingestion and TMS treatment. Any TMS sessions missed, capsule doses missed and/or capsule doses taken at the incorrect time will be tracked. The primary efficacy measures will be examined in relation to adherence to the protocol (20/20 TMS session completed with oral capsule taken between 90 - 120 minutes prior).

The maximum serum concentration of D-cycloserine in blood serum will be measured by taking blood samples at various timepoints following oral D-cycloserine. Maximum serum concentration following 100mg oral D-cycloserine and weight-based oral D-cycloserine (dosed 25mg/17.5kg) will be compared. Blood samples will be drawn at baseline (pre-ingestion), +30 minutes, +60 minutes, +90 minutes and +24hours after a uniform dosing of 100mg of D-cycloserine and after a weight-based dosing of 25mg D-cycloserine per 17.5kg of body weight.

Serum concentrations of weight-based oral D-cycloserine (dosed 25mg/17.5kg body weight) will be described by collecting blood samples 120 minutes after ingestion of the first, fifth and sixth dose.

Clinical remission of depressive symptoms will be measured by the Montgomery-Asberg Depression Rating Scale (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. A score of </= 10 on the MADRS indicates clinical remission.

Clinical depression response will be measured by the Montgomery-Asberg Depression Rating Scale (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. A reduction of >/= 50% in the MADRS score indicates clinical response.

The Quick Inventory of Depressive Symptomatology (QIDS) rates depression symptoms via self-assessment.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

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.

The Scale for Suicide Ideation (SSI) is a brief 19-item scale that assesses the person's current intensity of attitudes, plans, and behaviors to commit suicide. Each question has 3 answer choices. The answer choice suggesting the least suicide intentions is scored as 0, and answer choice suggesting the most suicide intentions are scored as 2.

Total score is determined based on the sum of all individual scores.

Cognitive function will be assessed using the THINC-it brief cognitive assessment tool. THINC-it includes a summation of four objective cognitive tests and a subjective cognitive questionnaire.

The first objective cognitive test is called "spotter" and measures choice reaction time by calculating the total time that elapses between the presentation of a stimulus and the occurrence of a response in a task that requires a participant to make one of two different responses depending on which stimuli is presented. Less time between presentation of stimulus and occurrence of a response can be used as an indicator for better reaction time.

Total results from the THINC-it assessment indicate cognitive performance compared to healthy age-, sex- and education-matched individuals. Change between the two arms will be assessed.

Cognitive function will be assessed using the THINC-it brief cognitive assessment tool. THINC-it includes a summation of four objective cognitive tests and a subjective cognitive questionnaire.

The second objective cognitive test is called "Symbol Check" and is an n-back test. N-back tests measure working memory by presenting the subject with a sequence of stimuli, and the task consists of selecting the stimuli that was presented n steps earlier in the sequence. The greater amount of correct responses can be used as an indicator of better working memory.

Total results from the THINC-it assessment indicate cognitive performance compared to healthy age-, sex- and education-matched individuals. Change between the two arms will be assessed.

Cognitive function will be assessed using the THINC-it brief cognitive assessment tool. THINC-it includes a summation of four objective cognitive tests and a subjective cognitive questionnaire.

The third objective cognitive test is called "CodeBreaker" and is a Digit Symbol Substitution Test (DSST). DSST involves a key consisting of the numbers 1-6, each paired with a unique symbol. Below the key are a series of the numbers 1-6 in random order and repeated several times. Subjects must select the corresponding symbol as fast as possible. The number of correct symbols within the allowed time is measured, with higher number of correct symbols indicating greater cognitive function.

Total results from the THINC-it assessment indicate cognitive performance compared to healthy age-, sex- and education-matched individuals. Change between the two arms will be assessed.

Cognitive function will be assessed using the THINC-it brief cognitive assessment tool. THINC-it includes a summation of four objective cognitive tests and a subjective cognitive questionnaire.

The fourth objective cognitive test is called "Trails" and is a version of the Trail Making Test part B (TMT-B). The subject is presented with numbers and letters in circles placed in random array on the screen. The subject must draw a line from one circle to the next in ascending order; however, s/he must alternate the circles with numbers in them and circles with letters in them (ie, 1-A-2-B-3-C etc). The TMT is a timed test and the goal is to complete the tests accurately and as quickly as possible. Less time to accurately complete the trial indicates greater cognitive function.

Total results from the THINC-it assessment indicate cognitive performance compared to healthy age-, sex- and education-matched individuals. Change between the two arms will be assessed.

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

The CGI-Severity scale is clinician rated from 1-7 representing 'Not at all ill' to 'Severely ill'.

The CGI-Improvement scale is a clinician rated 1-7, representing the range between 'Very much improved' and 'Very much worse' from the baseline visit.

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.

Cognitive function will be assessed using the THINC-integrated tool (THINC-it) brief cognitive assessment tool. THINC-it includes a summation of four objective cognitive tests and a subjective cognitive questionnaire.

The cognitive questionnaire is called the Perceived Deficits Questionnaire - 5 item scale (PDQ-5). The questionnaire assesses self perceived cognition by asking questions about attention/concentration, retrospective memory, prospective memory, and planning/organization. Each item is rated on a 5-point scale ranging from 0 (never) to 5 (almost always). Higher scores indicate greater perceived deficits in cognition.

Total results from the THINC-it assessment indicate cognitive performance compared to healthy age-, sex- and education-matched individuals. Change between the two arms will be assessed.

Side effects will be tracked through the Toronto Side Effects Scale (TSES). The TSES is a self reported questionnaire that assesses incidence, frequency, and severity of central nervous system, gastrointestinal, and sexual side effects. Individuals will be asked to rate frequency of each symptom within the last week on a 5-point scale, from "Never" (1) to "Everyday" (5). Severity of each symptom is similarly rated on a 5-point scale, from "No trouble" (1) to "Extreme Trouble" (5). Total score from the Toronto Side Effect Scale will be analyzed using paired t-test.

Adverse events will be tracked and recorded. Adverse events will not occur at a higher rate than is expected for iTBS.

An electrolyte panel will be used to measure the amount of sodium present in the blood from a whole blood sample, measured in mmol/L. Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

An electrolyte panel will be used to measure the amount of potassium present in the blood from a whole blood sample, measured in mmol/L. Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

An electrolyte panel will be used to measure the amount of chloride present in the blood from a whole blood sample, measured in mmol/L. Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

A complete blood count (CBC) panel will be used to measure the amount of hemoglobin present in the blood from a whole blood sample, measured in g/L. Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

A complete blood count (CBC) panel will be used to measure the amount of hematocrit present in the blood from a whole blood sample, measured in L/L. Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

A complete blood count (CBC) panel will be used to measure the amount of white blood cells (WBC) present in the blood from a whole blood sample, measured in 10^9/L. Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

A complete blood count (CBC) panel will be used to measure the amount of red blood cells (RBC) present in the blood from a whole blood sample, measured in 10^12/L. Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

A complete blood count (CBC) panel will be used to measure the amount of platelets present in the blood from a whole blood sample, measured in 10^9/L. Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

An AST test measures the level of aspartate aminotransferase (AST) present in the blood from a whole blood sample, measured in U/L. Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

An ALT test measures the level of alanine transaminase (ALT) present in the blood from a whole blood sample, measured in U/L. Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

A GGT test measures the level of gamma-glutamyl transpeptidase (GGT) present in the blood from a whole blood sample, measured in U/L. Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

A BUN test (aka blood urea nitrogen test) measures the level of urea nitrogen present in the blood from a whole blood sample, measured in mmol/L. Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

A creatinine blood test measures the level creatinine present in the blood from a whole blood sample, measured in umol/L. Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

In adults, glomerular filtration rate can be easily estimated using the CKD-EPI GFR equation.

This formula uses the patient's age and gender with the measured blood creatinine value to estimate glomerular filtration rate, or eGFR. eGFR is measured in mL/min/1.73m^2.

Results must be within normal reference range prior to entering the study. Results from baseline and treatment end will be compared with paired t-tests.

Electrical activity of the heart will be measured by an electrocardiogram (ECG). The QT interval is calculated as the time from the start of the Q wave to the end of the T wave. The QT interval is corrected for heartrate (QTc), a process performed automatically by modern ECG recorders. Results must be within normal range prior to entering the study. QTc from baseline to treatment end will be compared with paired t-tests.