ONE-P TMS Military Veterans

In this feasibility and tolerability trail, 50 patients with PTSD will be recruited at UBC. Patients will be randomised to receive either aiTBS plus DCS or aiTBS plus placebo DCS. The primary outcome is to evaluate the feasibility and tolerability of active aiTBS plus D-Cycloserine (DCS) versus active aiTBS plus placebo-DCS, using a one-day regimen of 15 treatment sessions, in active military personnel or veterans who suffer PTSD. A secondary aim is to explore preliminary signal of clinical efficacy of active aiTBS plus D-Cycloserine (DCS) on the primary outcome to inform sample size calculation for a definitive trial.

• D-Cycloserine (DCS) (Drug): Participants randomized to the active treatment arm will receive DCS 125 mg orally, administered as one capsule around one hour before active aiTBS treatment.
• Placebo (Drug): Participants randomized to the placebo arm will receive one matched placebo capsule administered orally at the same time point and according to the same procedures as the active investigational product.
• Intermittent Theta Burst Stimulation (iTBS) (Device): rTMS will employ the MagPro X100/R30 stimulator (MagVenture, Farum, Denmark) equipped with the B70 coil. A scalp heuristic will be used to localize the treatment site over the right DLPFC by modifying the BeamF3 method to the contralateral side. We have previously reported good congruency between the BeamF3 heuristic method and MRI-guided neuronavigation. Prior to the first treatment, each subject's resting motor threshold (RMT) will first be determined according to published methods. Patients will receive 3 minutes of iTBS every 30 minutes for a total of 15 session over two separate days three weeks apart day of treatment using the following parameters: 50 Hz triplet bursts, 5 bursts per second, 2 s on and 8 s off for 20 trains of 600 pulses, preceded by an introductory 3-train acclimatization titration, at an intensity of 80% of the RMT. The treatment protocol will be repeated 3 weeks after the initial treatment day.

Primary outcomes

• Feasibility of one-day iTBS+DCS: Enrolment [1.5 years]: Enrollment rate: participants enrolled ÷ enrolment target by the end of 1.5 years will be ≥ 70% of the enrollment target.
• Feasibility: Adherence [1.5 years]: Proportion of randomized participants receiving ≥80% of scheduled iTBS sessions, defined as ≥24 sessions
• Feasibility: dropout rates [1.5 years]: Percentage of dropout rates attributable to the intervention will be ≤ 10%

Other outcomes

• Treatment group differences in change from baseline to 3-weeks post-first one-day treatment on the Clinician-Administered Posttraumatic Stress Disorder Scale for DSM 5 (CAPS-5) Total Severity Score [3 weeks]: Exploratory efficacy outcome: change in Clinician-Administered PTSD Scale for DSM 5 (CAPS-5). Total Severity Score (20 item sum, range 0-80, higher score=greater severity) in change from baseline to 3-weeks after the intervention. Weathers, FW, Blake, DD, Schnurr, PP, Kaloupek, DG, Marx, BP, \& Keane, TM. The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). www.ptsd.va.gov: National Center for PTSD, 2013.
• Treatment group differences in change from baseline to 6-weeks post-first one-day treatment on the Clinician-Administered Posttraumatic Stress Disorder Scale for DSM 5 (CAPS-5) Total Severity Score [6 weeks]: Exploratory efficacy outcome: change in Clinician-Administered PTSD Scale for DSM 5 (CAPS-5). Total Severity Score (20-item sum, range 0-80, higher score=greater severity) in change from baseline to 6-weeks after the intervention. Weathers, FW, Blake, DD, Schnurr, PP, Kaloupek, DG, Marx, BP, \& Keane, TM. The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). www.ptsd.va.gov: National Center for PTSD, 2013. Time Frame: 6 weeks

Sex: All, ages: 19 Years to 60 Years

Inclusion Criteria:

* are outpatients between the ages of 19-60;
* are voluntary and competent to consent;
* are military personnel or veterans;
* have DSM-5 diagnosis of PTSD with a CAPS for DSM-5 (CAPS-5) score ≥ 25;
* 17-item Hamilton Depression Rating Scale score ≤ 23;
* have had no increase or initiation of any psychotropic medication in the 4 weeks prior to screening;
* if participating in psychotherapy, must have been in stable treatment for at least 1 month 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;
* able to adhere to the treatment schedule;
* Pass the TMS adult safety screening (TASS) questionnaire, and the MRI safety screening.

Exclusion Criteria:

* have a Severe Substance Use Disorder (except tobacco) within the last three (3) months;
* have a concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump;
* have active suicidal intent;
* are pregnant;
* have a lifetime MINI diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms;
* have a MINI diagnosis of OCD, or mood disorder that is assessed by a study investigator to be primary and causing greater impairment than PTSD;
* have a diagnosis of any personality disorder, assessed by a study investigator to be primary and causing greater impairment than MDD;
* have failed a course of ECT in the current episode or previous episode;
* have received rTMS for any previous indication;
* have any significant neurological disorder, history of seizure disorder (except those therapeutically induced by ECT), or any significant head trauma with clear radiological evidence of cerebrovascular injury on imaging;
* 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;
* clinically significant laboratory abnormality, in the opinion of the one of the principal investigators or study physicians (including but not limited to abnormal blood urea nitrogen (BUN), creatinine, estimated glomerular filtration rate (eGFR));
* currently take more than lorazepam 2 mg daily (or equivalent) or any dose of an anticonvulsant due to the potential to limit rTMS efficacy;
* currently take dicumarol, gingko biloba, isoniazid, ethionamide, fluphenazine, metrizamide, tramadol, warfarin due to potential interactions with D-Cycloserine;
* planned vaccination with Bacille Calmette-Guérin, cholera or typhoid or planned imaging procedure with an injectable die, within one week following the treatment days, due to potential interactions with DCS.
* allergy to DCS

• Fidel Vila-Rodriguez, M.D., PhD, FRCPC, DFAPA, Principal investigator, University of British Columbia