Major Depression
Conditions
Keywords
Transcranial Magnetic Stimulation, NRX101, Depression, Pharmacologic Augmentation
Brief summary
In this pilot study, investigators aim to combine D-cycloserine, lurasidone, and single-day repeated intermittent Theta Burst Stimulation (iTBS) to preliminarily assess clinical improvement in an open-label cohort and monitor for adverse events over a 6-week follow-up period.
Detailed description
Current therapeutic approaches for depression are limited in efficacy and accessibility. For many patients, Transcranial Magnetic Stimulation (TMS) has provided relief from treatment-resistant depression; however, invetigators are still far from maximizing the benefits of TMS. Here, investigators combine state-of-the-art interventions proven in depression (D-cycloserine (DCS), lurasidone (LRD), rapid intermittent Theta Burst Stimulation (iTBS)) with the aim of inducing and capitalizing on brain plasticity to support the alleviation of depressive symptoms. The rationale for pharmacologically augmenting TMS is that 100 mg/day DCS with repetitive TMS, as proposed here, has been demonstrated to enhance remission and response rates in patients with depression in two weeks, with no serious adverse events reported in this trial of 50 patients. Importantly, previous studies examining DCS efficacy as an adjunct to antidepressant regimens also found no adverse events and a trend-level improvement of depression severity, and another evaluating safety for treatment of TB in patients with and without depression found an overall decrease in depression severity over treatment course. Combining DCS with LRD (NRX-101) should enhance these effects because it will modulate activity of both NMDA and 5-HT7 receptors in a manner that should reduce depressive symptoms. Indeed, Phase 2 clinical trial data showed clinical superiority of NRX-101 over LRD only for treating bipolar disorder, with no serious adverse events in 22 completers. For transparency, investigators note here that while depression is listed as a contraindication when DCS is used to treat tuberculosis, the label reflects risks associated with DCS doses approximately 20 times higher than those used for modulation of neuroplasticity. Higher doses of DCS produce opposite (antagonistic) effects of the NMDA receptor relative to lower doses (agonistic), and dose-dependent side effects such as depression present at the highest doses (Lexicomp). investigators plan to use small doses of DCS that, when paired with TMS, have been shown to reduced depressive symptoms with minimal side effects.
Interventions
DEVICETMS
Transcranial Magnetic Stimulation (TMS): TMS involves a procedure where a coil is placed on the scalp and magnetic energy enters the participant's brain in pulses. TMS does not alter consciousness or impose restrictions of any kind on a participant after a session. Single pulses of TMS are delivered to probe cortical excitability, as a surrogate of plasticity, before and after each treatment session. Excitability is measured with neurophysiology including electromyography (EMG). Repetitive TMS (rTMS) administered in the study is delivered in a pattern protocol called intermittent-theta burst stimulation (iTBS) which has been FDA-cleared for-and shown to be effective in-the treatment of depression. We aim to deliver up to 20 sessions per day but can adapt for patient or staff related scheduling challenges or tolerability
DRUGNRX-101
NRX-101 is a combination capsule of fixed dose d-cycloserine (175 mg) and lurasidone (8.25 mg)
Sponsors
Mclean Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is an open-label pilot study of n = 30, where everyone receives a single day of ultra-accelerated TMS (uaTMS) with a single dose of NRX-101.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or Female adults (+18 years old) * from any ethnic or racial background * with moderate to severe depression, as indicated by scores of: ≥ 20 on the MADRS; AND ≥ 10 on PHQ-9.
Exclusion criteria
* History of manic or hypomanic symptoms; * lifetime DSM-5 psychotic spectrum disorder or current clinically significant psychotic symptoms; * active alcohol or substance use disorder that, in the opinion of a study physician/PI, is of sufficient severity to impede engagement in treatment or is associated with significant risk of medical withdrawal; * anorexia nervosa or eating disorder not otherwise specified that, in the opinion of a study physician/PI, is of sufficient severity to be associated with significant medical risks; * current suicide risk sufficient to require immediate hospitalization (C-SSRS 4 or above) * history of traumatic brain injury (TBI) that, in the opinion of a study physician/PI, would significantly increase risk of seizure; * any other significant neurological disorder likely to increase risk of seizure, in the opinion of a study physician/PI; * diagnosed neurodevelopmental disorder (e.g., autism, Down syndrome; Ehlers-Danlos Syndrome); * current diagnosis of delirium or greater than mild dementia; * cognitive disorder secondary to a general medical condition suggesting probable TBI or intellectual impairment; * Pregnant and breastfeeding women are not eligible to participate in this study excluded in line with prior work using DCS and TMS (Rossi et al., 2021). To confirm eligibility, all female participants of childbearing potential will be required to undergo a urine pregnancy test prior to enrollment. Additionally, if at any point during the study the participant or the researcher suspects that the participant may have become pregnant, a urine pregnancy test will be administered to ensure continued eligibility; * Participants with contraindications to TMS (e.g., metal in head or neck area), or at increased risk for adverse events (e.g., seizure history or markedly heightened risk factors for seizures, serious medical problems, implanted devices) will be excluded; * Participants with a known allergy to DCS or LRD will be excluded; * fMRI contraindications follow those of TMS and individuals unable to safely receive either will be excluded; * No healthy volunteers will be recruited; * No patients with involuntary hospitalization status will be recruited.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Montgomery-Åsberg Depression Rating Scale (MADRS) | From day of treatment to six weeks after treatment | Clinician-rated measure of depressive symptom severity. Higher scores indicate worse symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Depression Rating Scale (HAM-D) | From day of treatment to six weeks after treatment | Clinician-rated measure of depressive symptom severity. Higher score indicate worse symptoms. |
| Patient Health Questionnaire 9-item (PHQ-9) | From day of treatment to six weeks after treatment | self-rated measure of depression symptom severity. Higher scores indicate worse symptoms |
Countries
United States
Contacts
CONTACTPrem Ganesh, MS
CONTACTDennis W Guevara
PRINCIPAL_INVESTIGATORKerry Ressler, MD, PhD
Mclean Hospital
Outcome results
None listed