D-Cycloserine Augmentation of Intermittent Theta Burst Stimulation (iTBS) in Depression (COGENT)

Major Depressive Disorder (MDD) is a common and debilitating condition with high rates of treatment resistance. Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for treatment-resistant depression with few adverse effects. Intermittent Theta Burst Stimulation (iTBS) is a time-efficient form of rTMS with evidence base in the treatment of treatment-resistant depression (TRD). The most commonly supported understanding of iTBS's mechanism of action appear to be its strengthening of connections between networks of neurons, which is modulated by the N-methyl-D-aspartate (NMDA) receptor. D-cycloserine (DCS) is a partial NMDA receptor agonist that has demonstrable impact on rTMS and TBS's neuromodulatory effects. This study protocol proposes the conduct of a prospective multi-site, parallel-arm design, randomized, double-blinded, placebo-controlled clinical trial to investigate DCS augmentation of iTBS in MDD. We will investigate if adjuvant DCS 50mg or 100mg/day might have superior iTBS antidepressant augmentation effects.

Inclusion criteria

• Diagnosis of major depressive episode (MDE), in accordance with the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), in the context of unipolar major depressive disorder or bipolar affective disorder.
• 18 years or older in age.
• Treatment resistant depression at Stage II of the Thase and Rush classification.56
• Baseline Montgomery Åsberg Depression Rating Scale score of ≥ 20 (moderate-to-severe depression severity).57,58
• No increase or initiation of new antidepressant therapy in the four weeks prior to screening.
• Demonstrated capacity to give informed consent.

Exclusion criteria

• Inability to provide informed consent.
• Medically unstable patients at the discretion of the investigator.
• Concomitant neurological disorder or a history of a seizure disorder.
• Participants who are pregnant.
• Current substance use meeting DSM-5 criteria for substance use disorder.
• Per DSM-5, had ever met diagnostic criteria for schizophrenia, schizoaffective disorder, schizophreniform disorder or delusional disorder as assessed by the Mini-International Neuropsychiatric Interview (MINI) at the time of screening.
• Diagnosis of any other mental disorder that is the participant's primary diagnosis or main mental health syndrome of concern at the time of screening, which may significantly affect psychiatric status and assessed as likely to impact trial participation, in the clinical judgement of the investigator.